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A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors (HAVEN 3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02847637
Recruitment Status : Completed
First Posted : July 28, 2016
Results First Posted : November 14, 2018
Last Update Posted : November 16, 2022
Sponsor:
Collaborator:
Chugai Pharmaceutical
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia A
Interventions Drug: Emicizumab
Drug: Factor VIII (FVIII)
Enrollment 152
Recruitment Details  
Pre-assignment Details A total of 161 participants were screened; 9 failed screening, and 152 participants, who had previously received either episodic or prophylactic treatment with FVIII agents, were enrolled in this study. Participants in Arms C, A, and B were randomized in a 1:2:2 ratio, respectively; participants in Arm D were enrolled without randomization.
Arm/Group Title Arm C (Control): No Prophylaxis, Then Emicizumab Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Period Title: Overall Study
Started 18 36 35 63
Completed First 24 Weeks of Treatment 16 [1] 35 34 63
Emicizumab Dose Was Up-Titrated 0 1 1 7
Opted to Change Emicizumab Dosing Regimen [2] 1 3 1 1
Completed 17 34 34 63
Not Completed 1 2 1 0
Reason Not Completed
Withdrawal by Subject             0             1             1             0
Lost to Follow-up             1             1             0             0
[1]
A total of 17 participants in Arm C switched from no prophylaxis to receive emicizumab prophylaxis; however, 1 switched to emicizumab prior to completing 24 weeks on no prophylaxis (at 23.5 weeks).
[2]
Upon Implementation of Protocol Version 4
Arm/Group Title Arm C (Control): No Prophylaxis, Then Emicizumab Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) Total
Hide Arm/Group Description Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Total of all reporting groups
Overall Number of Baseline Participants 18 36 35 63 152
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
37.8  (12.9) 39.8  (14.0) 40.4  (11.4) 36.4  (14.4) 38.3  (13.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Male
18
 100.0%
36
 100.0%
35
 100.0%
63
 100.0%
152
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
Hispanic or Latino
0
   0.0%
4
  11.1%
5
  14.3%
7
  11.1%
16
  10.5%
Not Hispanic or Latino
17
  94.4%
32
  88.9%
30
  85.7%
53
  84.1%
132
  86.8%
Unknown or Not Reported
1
   5.6%
0
   0.0%
0
   0.0%
3
   4.8%
4
   2.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
4
  22.2%
6
  16.7%
10
  28.6%
12
  19.0%
32
  21.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   2.8%
0
   0.0%
0
   0.0%
1
   0.7%
Black or African American
3
  16.7%
3
   8.3%
1
   2.9%
1
   1.6%
8
   5.3%
White
11
  61.1%
24
  66.7%
20
  57.1%
47
  74.6%
102
  67.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
2
   5.6%
4
  11.4%
3
   4.8%
9
   5.9%
Number of Participants with <9 or ≥9 Bleeds in the Last 24 Weeks Prior to Study Entry  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
Less Than (<) 9 Bleeds
4
  22.2%
9
  25.0%
5
  14.3%
53
  84.1%
71
  46.7%
Greater Than or Equal To (≥) 9 Bleeds
14
  77.8%
27
  75.0%
30
  85.7%
10
  15.9%
81
  53.3%
Number of Target Joints in the Last 24 Weeks Prior to Study Entry   [1] 
Mean (Standard Deviation)
Unit of measure:  Target joints
Number Analyzed 18 participants 36 participants 35 participants 63 participants 152 participants
2.2  (1.4) 2.1  (1.4) 2.2  (1.7) 1.0  (1.6) 1.7  (1.6)
[1]
Measure Description: A target joint was defined as at least 3 bleeds into the same joint over the last 24 weeks prior to study entry.
1.Primary Outcome
Title Annualized Bleeding Rate (ABR) for Treated Bleeds
Hide Description The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a negative binomial (NB) regression model, which accounts for different follow-up times, with the number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. 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 the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.
Time Frame From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated bleed rate per year
38.2
(22.86 to 63.76)
1.5
(0.89 to 2.47)
1.3
(0.75 to 2.25)
1.6
(1.07 to 2.44)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
0.020 to 0.075
Estimation Comments Arm A is the numerator and Arm C is the denominator for this ABR Ratio.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
0.017 to 0.066
Estimation Comments Arm B is the numerator and Arm C is the denominator for this ABR Ratio.
2.Secondary Outcome
Title Annualized Bleeding Rate (ABR) for All Bleeds
Hide Description The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient's number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. "All bleeds" comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.
Time Frame From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: all bleed rate per year
47.6
(28.45 to 79.59)
2.5
(1.63 to 3.90)
2.6
(1.63 to 4.29)
3.3
(2.22 to 4.83)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.05
Confidence Interval (2-Sided) 95%
0.028 to 0.099
Estimation Comments Arm A is the numerator and Arm C is the denominator for this ABR Ratio.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
0.030 to 0.103
Estimation Comments Arm B is the numerator and Arm C is the denominator for this ABR Ratio.
3.Secondary Outcome
Title Annualized Bleeding Rate (ABR) for Treated Joint Bleeds
Hide Description The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient's number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "joint bleed" is defined as a bleed 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. It is considered a "treated joint bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed". Bleeds due to surgery/procedure are excluded.
Time Frame From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated joint bleed rate per year
26.5
(14.67 to 47.79)
1.1
(0.59 to 1.89)
0.9
(0.44 to 1.67)
1.2
(0.70 to 2.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
0.019 to 0.085
Estimation Comments Arm A is the numerator and Arm C is the denominator for this ABR Ratio.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
0.015 to 0.070
Estimation Comments Arm B is the numerator and Arm C is the denominator for this ABR Ratio.
4.Secondary Outcome
Title Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds
Hide Description The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient's number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. 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 is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed". Bleeds due to surgery/procedure are excluded.
Time Frame From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated spontaneous bleed rate per year
15.6
(7.60 to 31.91)
1.0
(0.48 to 1.91)
0.3
(0.11 to 0.75)
0.5
(0.23 to 0.94)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
0.025 to 0.151
Estimation Comments Arm A is the numerator and Arm C is the denominator for this ABR Ratio.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
0.006 to 0.056
Estimation Comments Arm B is the numerator and Arm C is the denominator for this ABR Ratio.
5.Secondary Outcome
Title Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds
Hide Description The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient's number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "target joint bleed" is defined as a bleed reported as a joint bleed into a target joint, defined as at least 3 bleeds into the same joint during the last 24 weeks prior to study entry. It is considered a "treated target joint bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed". Bleeds due to surgery/procedure are excluded.
Time Frame From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 63
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated target joint bleed rate per year
13.0
(5.22 to 32.33)
0.6
(0.28 to 1.42)
0.7
(0.27 to 1.64)
0.6
(0.26 to 1.53)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Not controlled for type I error
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.05
Confidence Interval (2-Sided) 95%
0.016 to 0.143
Estimation Comments Arm A is the numerator and Arm C is the denominator for this ABR Ratio.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Not controlled for type I error
Method Stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.05
Confidence Interval (2-Sided) 95%
0.018 to 0.147
Estimation Comments Arm B is the numerator and Arm C is the denominator for this ABR Ratio.
6.Secondary Outcome
Title Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants From the Non-Interventional Study Population Previously Treated With Factor VIII (FVIII) Prophylaxis (NISP)
Hide Description This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus pre-study in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. 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 the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.
Time Frame Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intra-participant comparison in the NIS population previously treated with FVIII prophylaxis (NISP), which includes all participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry in Arm D.
Arm/Group Title Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768 Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Hide Arm/Group Description:
This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received FVIII prophylaxis and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Arm D of this study.
This arm includes data from the same participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry and then enrolled in Arm D of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg once per week (QW) subcutaneously (SC) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW until the end of study. The data reported was collected only during emicizumab prophylaxis treatment.
Overall Number of Participants Analyzed 48 48
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated bleed rate per year
4.8
(3.22 to 7.09)
1.5
(0.98 to 2.33)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768, Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Comments H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level.
Method Non-stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.32
Confidence Interval (2-Sided) 95%
0.195 to 0.514
Estimation Comments Dnisp: Emicizumab Prophylaxis is the numerator and Dnisp: Pre-Study FVIII Prophylaxis is the denominator for this ABR ratio.
7.Secondary Outcome
Title Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants From the Non-Interventional Study Population Previously Treated With FVIII Prophylaxis (NISP)
Hide Description This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus pre-study in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant's number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. "All bleeds" comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.
Time Frame Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intra-participant comparison in the NIS population previously treated with FVIII prophylaxis (NISP), which includes all participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry in Arm D.
Arm/Group Title Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768 Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Hide Arm/Group Description:
This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received FVIII prophylaxis and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Arm D of this study.
This arm includes data from the same participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry and then enrolled in Arm D of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg once per week (QW) subcutaneously (SC) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW until the end of study. The data reported was collected only during emicizumab prophylaxis treatment.
Overall Number of Participants Analyzed 48 48
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: all bleed rate per year
8.9
(5.72 to 13.87)
3.3
(2.17 to 5.06)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768, Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Comments H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level.
Method Non-stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
0.220 to 0.626
Estimation Comments Dnisp: Emicizumab Prophylaxis is the numerator and Dnisp: Pre-Study FVIII Prophylaxis is the denominator for this ABR ratio.
8.Secondary Outcome
Title Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants From the NIS Population Previously Treated With Episodic FVIII (NISE)
Hide Description This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus pre-study in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. 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 the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.
Time Frame Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for A+Bnise-FVIII Episodic: 25.71 [15.4-40.9] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for A+Bnise-Emicizumab: 34.71 [24.1-50.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intra-participant comparison in the NIS population previously treated with episodic FVIII (NISE), which includes all participants who had received episodic FVIII in NIS BH29768 prior to study entry in Arms A and B (pooled data).
Arm/Group Title A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Hide Arm/Group Description:
This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received episodic FVIII treatment and were followed for a minimum of 24 weeks on the NIS prior to randomization to Arms A or B of this study. A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B.
This arm includes data from the same participants who had received episodic FVIII treatment in NIS BH29768 prior to study entry and then were randomized to Arms A or B of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of either 1.5 mg/kg emicizumab SC QW (Arm A) or 3 mg/kg emicizumab SC Q2W (Arm B). A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B. The data reported was collected only during emicizumab prophylaxis treatment.
Overall Number of Participants Analyzed 20 20
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: treated bleed rate per year
34.4
(27.45 to 43.14)
1.0
(0.43 to 2.54)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A+Bnise: Pre-Study Episodic FVIII in NIS BH29768, A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Comments H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Not controlled for type I error
Method Non-stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
0.014 to 0.067
Estimation Comments Arm A+Bnise: Emicizumab Prophylaxis is the numerator and Arm A+Bnise: Pre-Study Episodic FVIII is the denominator for this ABR Ratio.
9.Secondary Outcome
Title Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants From the NIS Population Previously Treated With Episodic FVIII (NISE)
Hide Description This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus pre-study in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant's number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. "All bleeds" comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.
Time Frame Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for A+Bnise-FVIII Episodic: 25.71 [15.4-40.9] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for A+Bnise-Emicizumab: 34.71 [24.1-50.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intra-participant comparison in the NIS population previously treated with episodic FVIII (NISE), which includes all participants who had received episodic FVIII in NIS BH29768 prior to study entry in Arms A and B (pooled data).
Arm/Group Title A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Hide Arm/Group Description:
This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received episodic FVIII treatment and were followed for a minimum of 24 weeks on the NIS prior to randomization to Arms A or B of this study. A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B.
This arm includes data from the same participants who had received episodic FVIII treatment in NIS BH29768 prior to study entry and then were randomized to Arms A or B of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of either 1.5 mg/kg emicizumab SC QW (Arm A) or 3 mg/kg emicizumab SC Q2W (Arm B). A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B. The data reported was collected only during emicizumab prophylaxis treatment.
Overall Number of Participants Analyzed 20 20
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: all bleed rate per year
39.6
(31.94 to 49.04)
1.6
(0.85 to 2.92)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A+Bnise: Pre-Study Episodic FVIII in NIS BH29768, A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Comments H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Not controlled for type I error
Method Non-stratified Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR Ratio
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
0.023 to 0.068
Estimation Comments Arm A+Bnise: Emicizumab Prophylaxis is the numerator and Arm A+Bnise: Pre-Study Episodic FVIII is the denominator for this ABR Ratio.
10.Secondary Outcome
Title Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25
Hide Description The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.
Time Frame Baseline, Week 25
Hide Outcome Measure Data
Hide Analysis Population Description
Adult participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 13 34 29
Mean (Standard Deviation)
Unit of Measure: units on a scale
44.32  (17.15) 31.81  (27.86) 28.35  (25.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0891
Comments Statistical significance is controlled at the 2-sided, 0.05 alpha level.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 12.51
Confidence Interval (2-Sided) 95%
-1.96 to 26.98
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm A.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0349
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 15.97
Confidence Interval (2-Sided) 95%
1.16 to 30.78
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm B.
11.Secondary Outcome
Title Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25
Hide Description The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores and it ranges from 0 to 100, with lower scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.
Time Frame Baseline, Week 25
Hide Outcome Measure Data
Hide Analysis Population Description
Adult participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 13 34 29
Mean (Standard Deviation)
Unit of Measure: units on a scale
29.95  (13.56) 24.04  (15.26) 21.39  (12.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1269
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 5.91
Confidence Interval (2-Sided) 95%
-1.72 to 13.55
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm A.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0317
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 8.56
Confidence Interval (2-Sided) 95%
0.77 to 16.35
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm B.
12.Secondary Outcome
Title European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25
Hide 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 VAS. The VAS 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. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.
Time Frame Baseline, Week 25
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 14 34 29
Mean (Standard Deviation)
Unit of Measure: units on a scale
72.57  (8.20) 76.61  (20.99) 81.72  (15.55)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3402
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.04
Confidence Interval (2-Sided) 95%
-12.43 to 4.35
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm A.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0373
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.15
Confidence Interval (2-Sided) 95%
-17.74 to -0.55
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm B.
13.Secondary Outcome
Title EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25
Hide 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 VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.
Time Frame Baseline, Week 25
Hide Outcome Measure Data
Hide Analysis Population Description
Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 14 34 29
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.63  (0.20) 0.76  (0.24) 0.76  (0.18)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm A: Emicizumab 1.5 mg/kg QW
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0060
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-0.22 to -0.04
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm A.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm C (Control): No Prophylaxis, Arm B: Emicizumab 3 mg/kg Q2W
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0059
Comments Not controlled for type I error
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-0.23 to -0.04
Estimation Comments The difference in adjusted means was analyzed as Arm C minus Arm B.
14.Secondary Outcome
Title Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25
Hide 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.
Time Frame Week 25
Hide Outcome Measure Data
Hide Analysis Population Description
The pre-specified efficacy objective was the comparison of Haemo-QoL-SF scores at Week 25 in adolescents who were previously on episodic treatment (i.e., randomized to Arms A, B, or C). Because there was a total of just one adolescent randomized to this study (in Arm C), statistical analyses could not be performed and no data is reported.
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
15.Secondary Outcome
Title Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis
Hide Description The percentage of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
33.3 94.4 85.7 50.0 87.3
16.Secondary Outcome
Title Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis
Hide 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. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
5.6 8.3 11.4 0 9.3
17.Secondary Outcome
Title Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis
Hide Description At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 2.9 0 0
18.Secondary Outcome
Title Percentage of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis
Hide Description The percentage of participants 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. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0
19.Secondary Outcome
Title Percentage of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis
Hide Description Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0
20.Secondary Outcome
Title Percentage of Participants With at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis
Hide Description The percentage of participants 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. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
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Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 5.6 17.1 6.3 4.8
21.Secondary Outcome
Title Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis
Hide 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." At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
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Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 25.0 20.0 12.5 33.3
22.Secondary Outcome
Title Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis
Hide Description At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
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Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0
23.Secondary Outcome
Title Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis
Hide Description At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
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Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0
24.Secondary Outcome
Title Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis
Hide Description At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.
Time Frame From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)
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Hide Analysis Population Description
All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis up to PCD) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Overall Number of Participants Analyzed 18 36 35 16 63
Measure Type: Number
Unit of Measure: percentage of participants
0 0 0 0 0
25.Secondary Outcome
Title Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study
Hide Description Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated and those who opted for a change in dosing regimen (after implementation of protocol v4), only AEs that occurred before either one of those events are included. Hypersens.= hypersensitivity; Mod. = modification
Time Frame From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)
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Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C (Emi), it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study (1 participant was excluded because they were lost to follow-up before Week 24 and did not receive emicizumab).
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Measure Type: Number
Unit of Measure: percentage of participants
Any Adverse Event (AE) 100.0 97.1 88.2 100.0 98.0
AE with Fatal Outcome 0.0 0.0 0.0 0.0 0.0
Serious AE 27.8 22.9 5.9 25.4 23.2
AE Leading to Withdrawal from Treatment 0.0 2.9 0.0 0.0 0.7
AE Leading to Dose Mod./Interruption 2.8 0.0 0.0 1.6 1.3
Grade ≥3 AE 36.1 28.6 5.9 20.6 24.5
Related AE 30.6 34.3 23.5 47.6 37.7
Local Injection Site Reaction 27.8 22.9 23.5 39.7 31.1
Systemic Hypersens./Anaphylac(tic/toid) Reaction 0.0 0.0 0.0 0.0 0.0
Thromboembolic Event (TE) 0.0 2.9 0.0 1.6 1.3
Thrombotic Microangiopathy (TMA) 0.0 0.0 0.0 0.0 0.0
26.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants
Hide Description The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated 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. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
Time Frame From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: bleeds per year
Treated Bleeds
0.8
(0.48 to 1.29)
0.7
(0.40 to 1.08)
1.2
(0.47 to 3.19)
1.5
(1.02 to 2.34)
1.2
(0.92 to 1.56)
All Bleeds
1.1
(0.72 to 1.66)
1.1
(0.73 to 1.73)
2.2
(1.16 to 4.15)
2.4
(1.68 to 3.43)
1.8
(1.46 to 2.29)
Treated Spontaneous Bleeds
0.5
(0.23 to 1.03)
0.2
(0.10 to 0.45)
0.4
(0.12 to 1.35)
0.5
(0.30 to 0.78)
0.4
(0.29 to 0.58)
Treated Joint Bleeds
0.4
(0.24 to 0.73)
0.4
(0.21 to 0.68)
0.7
(0.25 to 1.66)
1.0
(0.60 to 1.76)
0.7
(0.53 to 1.00)
Treated Target Joint Bleeds
0.2
(0.11 to 0.43)
0.2
(0.08 to 0.39)
0.4
(0.13 to 1.31)
0.6
(0.26 to 1.42)
0.4
(0.29 to 0.66)
27.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants
Hide Description The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated 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. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
Time Frame From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Mean (95% Confidence Interval)
Unit of Measure: bleeds per year
Treated Bleeds
1.2
(0.04 to 5.83)
0.8
(0.01 to 5.23)
1.2
(0.05 to 5.95)
1.7
(0.15 to 6.69)
1.3
(0.07 to 6.07)
All Bleeds
1.4
(0.09 to 6.29)
1.3
(0.07 to 6.10)
2.2
(0.32 to 7.58)
2.6
(0.45 to 8.15)
2.0
(0.23 to 7.19)
Treated Spontaneous Bleeds
0.7
(0.00 to 4.97)
0.3
(0.00 to 4.22)
0.4
(0.00 to 4.48)
0.6
(0.00 to 4.81)
0.5
(0.00 to 4.68)
Treated Joint Bleeds
0.6
(0.00 to 4.94)
0.5
(0.00 to 4.64)
0.6
(0.00 to 4.95)
1.1
(0.04 to 5.78)
0.8
(0.01 to 5.23)
Treated Target Joint Bleeds
0.4
(0.00 to 4.54)
0.3
(0.00 to 4.28)
0.4
(0.00 to 4.50)
0.6
(0.00 to 4.92)
0.5
(0.00 to 4.64)
28.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants
Hide Description The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated 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. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
Time Frame From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Median (Inter-Quartile Range)
Unit of Measure: bleeds per year
Treated Bleeds
0.4
(0.00 to 1.28)
0.4
(0.00 to 1.06)
0.0
(0.00 to 2.48)
0.5
(0.00 to 1.07)
0.4
(0.00 to 1.15)
All Bleeds
0.5
(0.09 to 1.77)
0.8
(0.23 to 1.92)
1.6
(0.20 to 3.8)
1.0
(0.38 to 2.70)
1.0
(0.19 to 2.37)
Treated Spontaneous Bleeds
0.0
(0.00 to 0.51)
0.0
(0.00 to 0.23)
0.0
(0.00 to 0.65)
0.0
(0.00 to 0.48)
0.0
(0.00 to 0.40)
Treated Joint Bleeds
0.2
(0.00 to 0.89)
0.2
(0.00 to 0.49)
0.0
(0.00 to 1.09)
0.0
(0.00 to 0.59)
0.2
(0.00 to 0.72)
Treated Target Joint Bleeds
0.1
(0.00 to 0.55)
0.0
(0.00 to 0.37)
0.0
(0.00 to 0.81)
0.0
(0.00 to 0.00)
0.0
(0.00 to 0.38)
29.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Mean (95% Confidence Interval)
Unit of Measure: Treated bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
1.9
(0.21 to 7.04)
13 to 24 Weeks Number Analyzed 148 participants
1.9
(0.20 to 6.99)
25 to 36 Weeks Number Analyzed 144 participants
1.0
(0.02 to 5.57)
37 to 48 Weeks Number Analyzed 144 participants
0.9
(0.01 to 5.35)
49 to 60 Weeks Number Analyzed 142 participants
1.0
(0.02 to 5.54)
61 to 72 Weeks Number Analyzed 140 participants
1.1
(0.04 to 5.72)
73 to 84 Weeks Number Analyzed 140 participants
0.7
(0.01 to 5.12)
85 to 96 Weeks Number Analyzed 131 participants
1.1
(0.03 to 5.68)
97 to 108 Weeks Number Analyzed 117 participants
0.9
(0.01 to 5.32)
109 to 120 Weeks Number Analyzed 104 participants
0.6
(0.00 to 4.83)
121 to 132 Weeks Number Analyzed 99 participants
0.5
(0.00 to 4.72)
133 to 144 Weeks Number Analyzed 94 participants
1.1
(0.03 to 5.68)
145 to 156 Weeks Number Analyzed 93 participants
1.1
(0.03 to 5.70)
157 to 168 Weeks Number Analyzed 89 participants
1.1
(0.04 to 5.78)
169 to 180 Weeks Number Analyzed 85 participants
1.3
(0.06 to 6.05)
181 to 192 Weeks Number Analyzed 83 participants
1.0
(0.02 to 5.56)
193 to 204 Weeks Number Analyzed 82 participants
1.6
(0.13 to 6.57)
205 to 216 Weeks Number Analyzed 80 participants
0.8
(0.01 to 5.15)
217 to 228 Weeks Number Analyzed 76 participants
0.5
(0.00 to 4.59)
229 to 240 Weeks Number Analyzed 72 participants
0.8
(0.01 to 5.30)
241 to 252 Weeks Number Analyzed 67 participants
0.3
(0.00 to 4.21)
253 to 264 Weeks Number Analyzed 58 participants
0.5
(0.00 to 4.72)
265 to 276 Weeks Number Analyzed 22 participants
0.2
(0.00 to 4.09)
277 to 288 Weeks Number Analyzed 5 participants
0.0 [1] 
(NA to 3.69)
[1]
The lower limit of the 95% confidence interval could not be calculated because too few events had occurred.
30.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Median (Inter-Quartile Range)
Unit of Measure: Treated bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
0.0
(0.00 to 4.35)
13 to 24 Weeks Number Analyzed 148 participants
0.0
(0.00 to 2.17)
25 to 36 Weeks Number Analyzed 144 participants
0.0
(0.00 to 0.00)
37 to 48 Weeks Number Analyzed 144 participants
0.0
(0.00 to 0.00)
49 to 60 Weeks Number Analyzed 142 participants
0.0
(0.00 to 0.00)
61 to 72 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
73 to 84 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
85 to 96 Weeks Number Analyzed 131 participants
0.0
(0.00 to 0.00)
97 to 108 Weeks Number Analyzed 117 participants
0.0
(0.00 to 0.00)
109 to 120 Weeks Number Analyzed 104 participants
0.0
(0.00 to 0.00)
121 to 132 Weeks Number Analyzed 99 participants
0.0
(0.00 to 0.00)
133 to 144 Weeks Number Analyzed 94 participants
0.0
(0.00 to 0.00)
145 to 156 Weeks Number Analyzed 93 participants
0.0
(0.00 to 0.00)
157 to 168 Weeks Number Analyzed 89 participants
0.0
(0.00 to 0.00)
169 to 180 Weeks Number Analyzed 85 participants
0.0
(0.00 to 0.00)
181 to 192 Weeks Number Analyzed 83 participants
0.0
(0.00 to 0.00)
193 to 204 Weeks Number Analyzed 82 participants
0.0
(0.00 to 0.00)
205 to 216 Weeks Number Analyzed 80 participants
0.0
(0.00 to 0.00)
217 to 228 Weeks Number Analyzed 76 participants
0.0
(0.00 to 0.00)
229 to 240 Weeks Number Analyzed 72 participants
0.0
(0.00 to 0.00)
241 to 252 Weeks Number Analyzed 67 participants
0.0
(0.00 to 0.00)
253 to 264 Weeks Number Analyzed 58 participants
0.0
(0.00 to 0.00)
265 to 276 Weeks Number Analyzed 22 participants
0.0
(0.00 to 0.00)
277 to 288 Weeks Number Analyzed 5 participants
0.0
(0.00 to 0.00)
31.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Mean (95% Confidence Interval)
Unit of Measure: All bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
3.8
(0.97 to 9.91)
13 to 24 Weeks Number Analyzed 148 participants
2.8
(0.53 to 8.45)
25 to 36 Weeks Number Analyzed 144 participants
1.8
(0.17 to 6.83)
37 to 48 Weeks Number Analyzed 144 participants
1.4
(0.10 to 6.33)
49 to 60 Weeks Number Analyzed 142 participants
1.5
(0.10 to 6.37)
61 to 72 Weeks Number Analyzed 140 participants
1.6
(0.14 to 6.66)
73 to 84 Weeks Number Analyzed 140 participants
1.2
(0.05 to 5.88)
85 to 96 Weeks Number Analyzed 131 participants
1.4
(0.09 to 6.30)
97 to 108 Weeks Number Analyzed 117 participants
1.3
(0.06 to 6.02)
109 to 120 Weeks Number Analyzed 104 participants
0.8
(0.01 to 5.21)
121 to 132 Weeks Number Analyzed 99 participants
0.8
(0.01 to 5.20)
133 to 144 Weeks Number Analyzed 94 participants
1.2
(0.04 to 5.84)
145 to 156 Weeks Number Analyzed 93 participants
1.3
(0.06 to 6.02)
157 to 168 Weeks Number Analyzed 89 participants
1.4
(0.09 to 6.28)
169 to 180 Weeks Number Analyzed 85 participants
1.7
(0.15 to 6.72)
181 to 192 Weeks Number Analyzed 83 participants
1.4
(0.08 to 6.19)
193 to 204 Weeks Number Analyzed 82 participants
1.7
(0.16 to 6.74)
205 to 216 Weeks Number Analyzed 80 participants
1.1
(0.04 to 5.72)
217 to 228 Weeks Number Analyzed 76 participants
0.6
(0.00 to 4.91)
229 to 240 Weeks Number Analyzed 72 participants
0.9
(0.02 to 5.41)
241 to 252 Weeks Number Analyzed 67 participants
0.4
(0.00 to 4.47)
253 to 264 Weeks Number Analyzed 58 participants
0.6
(0.00 to 4.86)
265 to 276 Weeks Number Analyzed 22 participants
0.2
(0.00 to 4.09)
277 to 288 Weeks Number Analyzed 5 participants
0.0 [1] 
(NA to 3.69)
[1]
The lower limit of the 95% confidence interval could not be calculated because too few events had occurred.
32.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Median (Inter-Quartile Range)
Unit of Measure: All bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
0.0
(0.00 to 4.35)
13 to 24 Weeks Number Analyzed 148 participants
0.0
(0.00 to 4.35)
25 to 36 Weeks Number Analyzed 144 participants
0.0
(0.00 to 4.35)
37 to 48 Weeks Number Analyzed 144 participants
0.0
(0.00 to 0.00)
49 to 60 Weeks Number Analyzed 142 participants
0.0
(0.00 to 0.00)
61 to 72 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
73 to 84 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
85 to 96 Weeks Number Analyzed 131 participants
0.0
(0.00 to 0.00)
97 to 108 Weeks Number Analyzed 117 participants
0.0
(0.00 to 0.00)
109 to 120 Weeks Number Analyzed 104 participants
0.0
(0.00 to 0.00)
121 to 132 Weeks Number Analyzed 99 participants
0.0
(0.00 to 0.00)
133 to 144 Weeks Number Analyzed 94 participants
0.0
(0.00 to 0.00)
145 to 156 Weeks Number Analyzed 93 participants
0.0
(0.00 to 0.00)
157 to 168 Weeks Number Analyzed 89 participants
0.0
(0.00 to 0.00)
169 to 180 Weeks Number Analyzed 85 participants
0.0
(0.00 to 0.00)
181 to 192 Weeks Number Analyzed 83 participants
0.0
(0.00 to 0.00)
193 to 204 Weeks Number Analyzed 82 participants
0.0
(0.00 to 0.00)
205 to 216 Weeks Number Analyzed 80 participants
0.0
(0.00 to 0.00)
217 to 228 Weeks Number Analyzed 76 participants
0.0
(0.00 to 0.00)
229 to 240 Weeks Number Analyzed 72 participants
0.0
(0.00 to 0.00)
241 to 252 Weeks Number Analyzed 67 participants
0.0
(0.00 to 0.00)
253 to 264 Weeks Number Analyzed 58 participants
0.0
(0.00 to 0.00)
265 to 276 Weeks Number Analyzed 22 participants
0.0
(0.00 to 0.00)
277 to 288 Weeks Number Analyzed 5 participants
0.0
(0.00 to 0.00)
33.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Mean (95% Confidence Interval)
Unit of Measure: Treated spontaneous bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
0.7
(0.00 to 4.98)
13 to 24 Weeks Number Analyzed 148 participants
0.7
(0.00 to 5.00)
25 to 36 Weeks Number Analyzed 144 participants
0.3
(0.00 to 4.30)
37 to 48 Weeks Number Analyzed 144 participants
0.4
(0.00 to 4.53)
49 to 60 Weeks Number Analyzed 142 participants
0.5
(0.00 to 4.60)
61 to 72 Weeks Number Analyzed 140 participants
0.3
(0.00 to 4.25)
73 to 84 Weeks Number Analyzed 140 participants
0.1
(0.00 to 3.95)
85 to 96 Weeks Number Analyzed 131 participants
0.4
(0.00 to 4.48)
97 to 108 Weeks Number Analyzed 117 participants
0.2
(0.00 to 4.14)
109 to 120 Weeks Number Analyzed 104 participants
0.2
(0.00 to 4.03)
121 to 132 Weeks Number Analyzed 99 participants
0.1
(0.00 to 3.96)
133 to 144 Weeks Number Analyzed 94 participants
0.6
(0.00 to 4.78)
145 to 156 Weeks Number Analyzed 93 participants
0.6
(0.00 to 4.87)
157 to 168 Weeks Number Analyzed 89 participants
0.2
(0.00 to 4.09)
169 to 180 Weeks Number Analyzed 85 participants
0.4
(0.00 to 4.50)
181 to 192 Weeks Number Analyzed 83 participants
0.2
(0.00 to 4.01)
193 to 204 Weeks Number Analyzed 82 participants
0.1
(0.00 to 3.80)
205 to 216 Weeks Number Analyzed 80 participants
0.3
(0.00 to 4.24)
217 to 228 Weeks Number Analyzed 76 participants
0.1
(0.00 to 3.81)
229 to 240 Weeks Number Analyzed 72 participants
0.1
(0.00 to 3.94)
241 to 252 Weeks Number Analyzed 67 participants
0.1
(0.00 to 3.82)
253 to 264 Weeks Number Analyzed 58 participants
0.3
(0.00 to 4.29)
265 to 276 Weeks Number Analyzed 22 participants
0.2
(0.00 to 4.09)
277 to 288 Weeks Number Analyzed 5 participants
0.0 [1] 
(NA to 3.69)
[1]
The lower limit of the 95% confidence interval could not be calculated because too few events had occurred.
34.Secondary Outcome
Title Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants
Hide Description The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
Time Frame 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
Arm/Group Title All Emicizumab Participants
Hide Arm/Group Description:
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 151
Median (Inter-Quartile Range)
Unit of Measure: Treated spontaneous bleeds per year
1 to 12 Weeks Number Analyzed 150 participants
0.0
(0.00 to 0.00)
13 to 24 Weeks Number Analyzed 148 participants
0.0
(0.00 to 0.00)
25 to 36 Weeks Number Analyzed 144 participants
0.0
(0.00 to 0.00)
37 to 48 Weeks Number Analyzed 144 participants
0.0
(0.00 to 0.00)
49 to 60 Weeks Number Analyzed 142 participants
0.0
(0.00 to 0.00)
61 to 72 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
73 to 84 Weeks Number Analyzed 140 participants
0.0
(0.00 to 0.00)
85 to 96 Weeks Number Analyzed 131 participants
0.0
(0.00 to 0.00)
97 to 108 Weeks Number Analyzed 117 participants
0.0
(0.00 to 0.00)
109 to 120 Weeks Number Analyzed 104 participants
0.0
(0.00 to 0.00)
121 to 132 Weeks Number Analyzed 99 participants
0.0
(0.00 to 0.00)
133 to 144 Weeks Number Analyzed 94 participants
0.0
(0.00 to 0.00)
145 to 156 Weeks Number Analyzed 93 participants
0.0
(0.00 to 0.00)
157 to 168 Weeks Number Analyzed 89 participants
0.0
(0.00 to 0.00)
169 to 180 Weeks Number Analyzed 85 participants
0.0
(0.00 to 0.00)
181 to 192 Weeks Number Analyzed 83 participants
0.0
(0.00 to 0.00)
193 to 204 Weeks Number Analyzed 82 participants
0.0
(0.00 to 0.00)
205 to 216 Weeks Number Analyzed 80 participants
0.0
(0.00 to 0.00)
217 to 228 Weeks Number Analyzed 76 participants
0.0
(0.00 to 0.00)
229 to 240 Weeks Number Analyzed 72 participants
0.0
(0.00 to 0.00)
241 to 252 Weeks Number Analyzed 67 participants
0.0
(0.00 to 0.00)
253 to 264 Weeks Number Analyzed 58 participants
0.0
(0.00 to 0.00)
265 to 276 Weeks Number Analyzed 22 participants
0.0
(0.00 to 0.00)
277 to 288 Weeks Number Analyzed 5 participants
0.0
(0.00 to 0.00)
35.Secondary Outcome
Title Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study
Hide Description A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies (ADAs) against emicizumab in plasma. A sample was considered positive for anti-emicizumab antibodies if the test result reached or exceeded a pre-determined threshold. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample.
Time Frame From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
The All Emicizumab Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab).
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Measure Type: Number
Unit of Measure: percentage of participants
Total ADA Positive (Boosted+Induced) 8.3 5.7 0.0 1.6 4.0
ADA Positive (Treatment Boosted) 0.0 2.9 0.0 0.0 0.7
ADA Positive (Treatment Induced) 8.3 2.9 0.0 1.6 3.3
36.Secondary Outcome
Title Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors
Hide Description Levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant 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.
Time Frame From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
The All Emicizumab Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab).
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) All Emicizumab Participants
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.
Overall Number of Participants Analyzed 36 35 17 63 151
Measure Type: Number
Unit of Measure: percentage of participants
0.0 0.0 0.0 0.0 0.0
37.Secondary Outcome
Title Trough Plasma Concentration (Ctrough) of Emicizumab
Hide Description Trough 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). Because participants in Arm C (Control) switched from no prophylaxis to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm C (Emi) are expressed relative to first emicizumab dose.
Time Frame Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, 253, 265, and 277
Hide Outcome Measure Data
Hide Analysis Population Description
The Pharmacokinetics (PK) Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab who had at least one post-dose emicizumab concentration result; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab). Number analyzed represents participants per study arm with available samples at each specified timepoint.
Arm/Group Title Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis) Arms A and D: Emicizumab 1.5 mg/kg QW Arms B and C (Emi): Emicizumab 3 mg/kg Q2W
Hide Arm/Group Description:
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. 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 3 mg/kg once every 2 weeks SC. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
This analysis set is a combination of all emicizumab-treated participants from Arms A and D who received the same emicizumab prophylaxis dosing regimen at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by 1.5 mg/kg emicizumab SC QW until discontinuation from the study.
This analysis set is a combination of all emicizumab-treated participants from Arms B and C (Emi) who received the same emicizumab prophylaxis dosing regimen at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by 3 mg/kg emicizumab SC once every 2 weeks (Q2W) until discontinuation from the study.
Overall Number of Participants Analyzed 36 35 17 63 99 52
Mean (Standard Deviation)
Unit of Measure: micrograms per milliliter (μg/mL)
Week 1 Number Analyzed 35 participants 35 participants 17 participants 61 participants 96 participants 52 participants
NA [1]   (NA) NA [1]   (NA) NA [1]   (NA) NA [1]   (NA) NA [1]   (NA) NA [1]   (NA)
Week 2 Number Analyzed 36 participants 35 participants 17 participants 62 participants 98 participants 52 participants
16.3  (6.1) 16.8  (5.9) 19.6  (8.2) 17.3  (5.4) 16.9  (5.7) 17.7  (6.8)
Week 3 Number Analyzed 36 participants 35 participants 17 participants 62 participants 98 participants 52 participants
29.1  (9.3) 29.2  (6.5) 33.0  (12.6) 30.5  (8.7) 30.0  (8.9) 30.5  (9.0)
Week 4 Number Analyzed 36 participants 35 participants 17 participants 62 participants 98 participants 52 participants
41.9  (11.8) 41.4  (9.7) 47.9  (15.0) 42.4  (9.4) 42.2  (10.3) 43.6  (11.9)
Week 5 Number Analyzed 34 participants 35 participants 17 participants 62 participants 96 participants 52 participants
48.0  (13.7) 48.8  (12.3) 59.6  (20.7) 54.5  (12.5) 52.2  (13.2) 52.4  (16.2)
Week 7 Number Analyzed 32 participants 33 participants 17 participants 61 participants 93 participants 50 participants
47.9  (16.1) 48.4  (11.4) 55.2  (16.2) 52.4  (13.3) 50.9  (14.4) 50.7  (13.5)
Week 9 Number Analyzed 33 participants 34 participants 17 participants 63 participants 96 participants 51 participants
49.0  (16.4) 46.4  (14.1) 53.1  (15.7) 55.1  (16.1) 53.0  (16.4) 48.7  (14.9)
Week 13 Number Analyzed 33 participants 34 participants 17 participants 63 participants 96 participants 51 participants
48.7  (18.3) 47.6  (16.0) 47.9  (18.1) 55.0  (15.9) 52.8  (16.9) 47.7  (16.5)
Week 17 Number Analyzed 33 participants 34 participants 17 participants 62 participants 95 participants 51 participants
54.3  (24.0) 48.9  (17.7) 43.4  (16.2) 55.0  (16.5) 54.7  (19.3) 47.0  (17.2)
Week 21 Number Analyzed 32 participants 34 participants 16 participants 61 participants 93 participants 50 participants
50.7  (20.2) 47.3  (15.5) 45.6  (18.8) 55.1  (16.2) 53.6  (17.7) 46.7  (16.4)
Week 25 Number Analyzed 31 participants 34 participants 17 participants 58 participants 89 participants 51 participants
50.5  (21.7) 47.6  (18.9) 51.8  (23.4) 54.8  (16.8) 53.3  (18.7) 49.0  (20.4)
Week 33 Number Analyzed 30 participants 34 participants 16 participants 58 participants 88 participants 50 participants
56.3  (25.3) 52.9  (22.4) 52.0  (21.3) 59.1  (18.5) 58.1  (20.9) 52.6  (21.9)
Week 41 Number Analyzed 31 participants 34 participants 17 participants 58 participants 89 participants 51 participants
54.8  (24.2) 48.4  (18.8) 50.7  (24.4) 59.6  (21.4) 57.9  (22.4) 49.2  (20.6)
Week 49 Number Analyzed 31 participants 32 participants 17 participants 58 participants 89 participants 49 participants
55.4  (22.9) 52.2  (20.2) 54.3  (21.3) 60.2  (19.9) 58.5  (21.0) 52.9  (20.4)
Week 61 Number Analyzed 31 participants 33 participants 17 participants 57 participants 88 participants 50 participants
55.3  (21.4) 52.0  (21.1) 52.5  (19.8) 61.1  (22.5) 59.1  (22.1) 52.2  (20.5)
Week 73 Number Analyzed 31 participants 32 participants 15 participants 57 participants 88 participants 47 participants
54.4  (21.5) 51.6  (21.3) 47.8  (18.4) 58.5  (19.2) 57.1  (20.0) 50.4  (20.3)
Week 85 Number Analyzed 31 participants 32 participants 13 participants 55 participants 86 participants 45 participants
48.8  (17.4) 46.4  (20.4) 47.7  (17.9) 56.7  (18.5) 53.8  (18.5) 46.8  (19.5)
Week 97 Number Analyzed 28 participants 29 participants 11 participants 48 participants 76 participants 40 participants
52.6  (20.0) 50.9  (21.0) 51.7  (28.3) 58.5  (18.7) 56.3  (19.3) 51.1  (22.9)
Week 109 Number Analyzed 26 participants 26 participants 11 participants 39 participants 65 participants 37 participants
53.9  (19.2) 52.3  (19.5) 46.4  (27.0) 59.0  (19.1) 57.0  (19.1) 50.5  (21.7)
Week 121 Number Analyzed 23 participants 24 participants 10 participants 37 participants 60 participants 34 participants
58.8  (21.1) 55.0  (22.0) 50.0  (25.2) 57.1  (18.2) 57.7  (19.2) 53.5  (22.7)
Week 133 Number Analyzed 23 participants 23 participants 10 participants 34 participants 57 participants 33 participants
55.3  (26.0) 54.7  (18.5) 54.6  (26.9) 59.3  (19.2) 57.7  (22.1) 54.7  (20.9)
Week 145 Number Analyzed 23 participants 22 participants 6 participants 33 participants 56 participants 28 participants
54.1  (23.7) 51.3  (17.7) 44.8  (11.6) 55.7  (20.4) 55.0  (21.6) 49.9  (16.6)
Week 157 Number Analyzed 19 participants 21 participants 9 participants 30 participants 49 participants 30 participants
57.6  (27.8) 52.2  (21.4) 46.8  (24.0) 55.9  (23.7) 56.6  (25.1) 50.6  (21.9)
Week 169 Number Analyzed 16 participants 16 participants 8 participants 22 participants 38 participants 24 participants
53.9  (21.8) 50.3  (19.6) 45.8  (20.6) 56.4  (18.0) 55.3  (19.4) 48.8  (19.6)
Week 181 Number Analyzed 15 participants 11 participants 8 participants 17 participants 32 participants 19 participants
59.8  (24.8) 48.8  (22.1) 43.5  (26.2) 57.5  (21.3) 58.6  (22.7) 46.5  (23.4)
Week 193 Number Analyzed 17 participants 18 participants 7 participants 21 participants 38 participants 25 participants
53.9  (21.0) 52.4  (24.6) 42.1  (19.1) 60.5  (19.6) 57.5  (20.2) 49.5  (23.3)
Week 205 Number Analyzed 18 participants 20 participants 8 participants 23 participants 41 participants 28 participants
53.5  (20.8) 51.9  (22.4) 54.2  (31.1) 58.6  (24.1) 56.4  (22.6) 52.6  (24.6)
Week 217 Number Analyzed 16 participants 19 participants 9 participants 26 participants 42 participants 28 participants
54.4  (20.8) 55.0  (20.6) 50.8  (26.1) 60.8  (23.2) 58.3  (22.2) 53.6  (22.1)
Week 229 Number Analyzed 17 participants 17 participants 9 participants 26 participants 43 participants 26 participants
54.9  (20.9) 47.9  (18.9) 53.5  (30.4) 54.4  (19.3) 54.6  (19.7) 49.8  (23.1)
Week 241 Number Analyzed 16 participants 18 participants 6 participants 24 participants 40 participants 24 participants
51.9  (19.3) 50.2  (16.8) 52.0  (36.1) 60.1  (23.3) 56.8  (21.9) 50.6  (22.2)
Week 253 Number Analyzed 15 participants 15 participants 4 participants 22 participants 37 participants 19 participants
58.6  (28.7) 46.5  (17.8) 40.3  (43.9) 58.4  (24.7) 58.5  (26.0) 45.2  (23.9)
Week 265 Number Analyzed 10 participants 13 participants 0 participants 17 participants 27 participants 13 participants
58.7  (25.8) 47.3  (14.5) 60.0  (23.9) 59.5  (24.2) 47.3  (14.5)
Week 277 Number Analyzed 6 participants 5 participants 0 participants 2 participants 8 participants 5 participants
71.9  (34.2) 49.0  (16.2) 61.3  (17.2) 69.2  (30.1) 49.0  (16.2)
[1]
No results available because the samples were below the limit of quantification (BLQ).
Time Frame Total observation time for all participants: From enrollment until study completion (median [min-max] 262.3 [14.4-288.3] weeks); Arm C (Control): From enrollment to 24 weeks on no prophylaxis (median [min-max]: 24.00 [14.4-25.0] weeks)
Adverse Event Reporting Description All adverse events (AEs) in emicizumab-treated subjects are reported, including after dose up-titration or change of dosing regimen. AEs in Arm C are reported in 2 groups: Arm C (Control) for the first 24 weeks on no prophylaxis; Arm C (Emi) for those who switched after 24 weeks to receive emicizumab prophylaxis.
 
Arm/Group Title Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Hide Arm/Group Description Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. This arm includes all participants from Arm C who had switched to emicizumab prophylaxis during the entire study after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC Q2W. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
All-Cause Mortality
Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)      0/36 (0.00%)      0/35 (0.00%)      0/17 (0.00%)      0/63 (0.00%)    
Hide Serious Adverse Events
Arm C (Control): No Prophylaxis Arm A: Emicizumab 1.5 mg/kg QW Arm B: Emicizumab 3 mg/kg Q2W Arm C (Emi): Emicizumab 3 mg/kg Q2W (Switch From No Prophylaxis) Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/18 (5.56%)      10/36 (27.78%)      8/35 (22.86%)      1/17 (5.88%)      16/63 (25.40%)    
Cardiac disorders           
ACUTE CORONARY SYNDROME † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
ACUTE MYOCARDIAL INFARCTION † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
ARRHYTHMIA † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
ATRIAL FLUTTER † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
Endocrine disorders           
HYPERPARATHYROIDISM † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
Gastrointestinal disorders           
ANAL HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
FISTULA OF SMALL INTESTINE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
GASTRIC HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
HAEMATEMESIS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
HAEMATOCHEZIA † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
MALLORY-WEISS SYNDROME † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
MELAENA † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
PANCREATITIS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
RECTAL HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
RETROPERITONEAL HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
SPLENIC ARTERY ANEURYSM † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
UPPER GASTROINTESTINAL HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
General disorders           
ASTHENIA † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
Infections and infestations           
ABSCESS LIMB † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
APPENDICITIS † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
ARTHRITIS BACTERIAL † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
GINGIVAL ABSCESS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 1/17 (5.88%)  1 0/63 (0.00%)  0
INFECTION † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
PYELONEPHRITIS ACUTE † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
SUBPERIOSTEAL ABSCESS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
TONSILLITIS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  3
WOUND INFECTION † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  3
Injury, poisoning and procedural complications           
DURAL TEAR † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
FEMORAL NECK FRACTURE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
FEMUR FRACTURE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
MUSCLE RUPTURE † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
MUSCLE STRAIN † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
POISONING † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
POST PROCEDURAL HAEMATOMA † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
ROAD TRAFFIC ACCIDENT † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
TENDON RUPTURE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
Metabolism and nutrition disorders           
DIABETES MELLITUS † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
Musculoskeletal and connective tissue disorders           
BACK PAIN † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
GROIN PAIN † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
OSTEOARTHRITIS † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
RHABDOMYOLYSIS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
SYNOVITIS † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
BONE GIANT CELL TUMOUR BENIGN † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
PAPILLARY THYROID CANCER † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
PARATHYROID TUMOUR BENIGN † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
SALIVARY GLAND NEOPLASM † 1  0/18 (0.00%)  0 1/36 (2.78%)  1 0/35 (0.00%)  0 0/17 (0.00%)  0 0/63 (0.00%)  0
Nervous system disorders           
CEREBRAL HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
CEREBROSPINAL FLUID LEAKAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
HEADACHE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 0/35 (0.00%)  0 0/17 (0.00%)  0 1/63 (1.59%)  1
PUTAMEN HAEMORRHAGE † 1  0/18 (0.00%)  0 0/36 (0.00%)  0 1/35 (2.86%)  1 0/17 (0.00%)  0 0/63 (0.00%)  0
SEIZURE † 1  0/18 (0.00%)  0