A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN 1)

• ClinicalTrials.gov Identifier: NCT02622321
• Recruitment Status: Completed
• First Posted: December 4, 2015
• Results First Posted: November 24, 2017
• Last Update Posted: June 24, 2021
• Sponsor: Hoffmann-La Roche
• 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: rFVIIa; Drug: aPCC
• Enrollment: 113

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 113 participants were enrolled in this study: 109 participants prior to the primary completion date plus a further 4 participants to Arm D of the study after the primary completion date. Participants in Arm A and Arm B were randomized in a 2:1 ratio; participants in Arm C and Arm D were enrolled without randomization.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis, Then Emicizumab	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW
Arm/Group Description	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Period Title: Overall Study
Started	35	18	49	11
Received at Least One Dose of Treatment [1]	34 [2]	18	49	11
Completed 24 Weeks in the Study	31	18 [3]	49	11
Dose Up-Titrated to 3 mg/kg QW	2	0	3	2
Completed	32	18	48	11
Not Completed	3	0	1	0
Reason Not Completed
Withdrawal by Subject	2	0	0	0
Death	0	0	1	0
Physician Decision	1	0	0	0
[1] Safety Population; [2] 1 participant withdrew prior to study Day 1.; [3] After 24 weeks, all 18 participants in Arm B switched to receive emicizumab prophylaxis.

Baseline Characteristics

Arm/Group Title		Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis, Then Emicizumab	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Total
Arm/Group Description		Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Total of all reporting groups
Overall Number of Baseline Participants		35	18	49	11	113
Baseline Analysis Population Description		All enrolled participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
		35.8 (13.9)	37.2 (13.7)	25.6 (16.8)	39.0 (16.1)	31.9 (16.2)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
	Adolescents (12-17 years)	4 11.4%	2 11.1%	26 53.1%	0 0.0%	32 28.3%
	Adults (18-64 years)	30 85.7%	15 83.3%	21 42.9%	10 90.9%	76 67.3%
	Elderly (65-84 years)	1 2.9%	1 5.6%	2 4.1%	1 9.1%	5 4.4%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
	Female	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Male	35 100.0%	18 100.0%	49 100.0%	11 100.0%	113 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
	Hispanic or Latino	4 11.4%	1 5.6%	12 24.5%	1 9.1%	18 15.9%
	Not Hispanic or Latino	31 88.6%	17 94.4%	37 75.5%	10 90.9%	95 84.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	1 2.0%	0 0.0%	1 0.9%
	Asian	10 28.6%	3 16.7%	8 16.3%	0 0.0%	21 18.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 5.6%	0 0.0%	0 0.0%	1 0.9%
	Black or African American	4 11.4%	4 22.2%	3 6.1%	0 0.0%	11 9.7%
	White	21 60.0%	10 55.6%	33 67.3%	11 100.0%	75 66.4%
	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%	0 0.0%	4 8.2%	0 0.0%	4 3.5%
Number of Participants by the Number of Bleeds (<9 or ≥9) in the Last 24 Weeks Prior to Study Entry; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants	18 participants	49 participants	11 participants	113 participants
	<9 Bleeds	11 31.4%	5 27.8%	23 46.9%	6 54.5%	45 39.8%
	≥9 Bleeds	24 68.6%	13 72.2%	26 53.1%	5 45.5%	68 60.2%

Outcome Measures

1. Primary Outcome

Title	Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population defined as all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated bleeds per year
	2.9; (1.69 to 5.02)	23.3; (12.33 to 43.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (less than [<] 9 or greater than or equal to [>/=] 9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.057 to 0.277
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	The number of all bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: all bleeds per year
	5.5; (3.58 to 8.60)	28.3; (16.79 to 47.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; 0.102 to 0.375
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
Description	This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks

Outcome Measure Data

Analysis Population Description

Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm A (NIS): Previous Episodic Bypassing Agents
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm A participants who previously participated in NIS BH29768 (NCT02476942) and had received episodic bypassing agents during the NIS.
Overall Number of Participants Analyzed	24	24
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: all bleeds per year
	4.1; (2.10 to 8.02)	37.7; (28.40 to 50.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm A (NIS): Previous Episodic Bypassing Agents
	Comments	This intra-participant comparison of ABR for all bleeds was performed using an NB regression model.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Non-Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.055 to 0.218
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
Description	This was an intra-participant comparison of the ABRs for treated bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of treated 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 were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". 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 whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks

Outcome Measure Data

Analysis Population Description

Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm A (NIS): Previous Episodic Bypassing Agents
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm A participants who previously participated in NIS BH29768 (NCT02476942) and had received episodic bypassing agents during the NIS.
Overall Number of Participants Analyzed	24	24
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated bleeds per year
	1.7; (0.71 to 4.06)	21.6; (15.40 to 30.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm A (NIS): Previous Episodic Bypassing Agents
	Comments	This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Non-Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; 0.031 to 0.198
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	The number of treated joint 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 joint bleeds were defined as 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. Bleeds due to surgery/procedure were excluded.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated joint bleeds per year
	0.8; (0.26 to 2.20)	6.7; (1.99 to 22.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0050
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.520
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
Description	This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm C participants who had previously received prophylactic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks

Outcome Measure Data

Analysis Population Description

Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768.

Arm/Group Title	Arm C: 1.5 mg/kg Emicizumab QW	Arm C (NIS): Previous Prophylactic Bypassing Agents
Arm/Group Description:	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm C participants who previously participated in NIS BH29768 (NCT02476942) and had received prophylactic bypassing agents during the NIS.
Overall Number of Participants Analyzed	24	24
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: all bleeds per year
	5.5; (2.98 to 10.26)	24.3; (18.11 to 32.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm C: 1.5 mg/kg Emicizumab QW, Arm C (NIS): Previous Prophylactic Bypassing Agents
	Comments	This intra-participant comparison of ABR for all bleeds was performed using an NB regression model.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Non-Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; 0.119 to 0.435
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
Description	This was an intra-participant comparison of the ABRs for treated bleeds in Arm C participants who had previously received bypassing agent prophylaxis during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of treated 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 were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". 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 whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks

Outcome Measure Data

Analysis Population Description

Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768.

Arm/Group Title	Arm C: 1.5 mg/kg Emicizumab QW	Arm Cnis: Previous Prophylactic Bypassing Agents
Arm/Group Description:	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm C participants who previously participated in NIS BH29768 (NCT02476942) and had received prophylactic bypassing agents (rFVIIa or/and aPCC) during the NIS BH29768.
Overall Number of Participants Analyzed	24	24
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated bleeds per year
	3.3; (1.33 to 8.08)	15.7; (11.08 to 22.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm C: 1.5 mg/kg Emicizumab QW, Arm Cnis: Previous Prophylactic Bypassing Agents
	Comments	This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Non-Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.089 to 0.486
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	The number of treated spontaneous bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated spontaneous bleeds per year
	1.3; (0.73 to 2.19)	16.8; (9.94 to 28.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; 0.037 to 0.154
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	The number of treated target joint bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. 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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: treated target joint bleeds per year
	0.1; (0.03 to 0.58)	3.0; (0.96 to 9.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.
	Method	Stratified Wald Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ABR Ratio
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.227
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
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 were excluded.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Mean (95% Confidence Interval); Unit of Measure: bleeds per year
Treated Bleeds	3.5; (0.83 to 9.46)	26.2; (17.17 to 38.37)
All Bleeds	6.3; (2.37 to 13.45)	30.8; (20.89 to 43.76)
Treated Spontaneous Bleeds	1.5; (0.11 to 6.42)	18.1; (10.74 to 28.57)
Treated Joint Bleeds	1.0; (0.03 to 5.57)	8.1; (3.55 to 15.95)
Treated Target Joint Bleeds	0.4; (0.00 to 4.48)	6.2; (2.32 to 13.34)

11. Secondary Outcome

Title	Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
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 were excluded.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Median (Inter-Quartile Range); Unit of Measure: bleeds per year
Treated Bleeds	0.0; (0.00 to 3.73)	18.8; (12.97 to 35.08)
All Bleeds	2.0; (0.00 to 9.87)	30.2; (18.26 to 39.37)
Treated Spontaneous Bleeds	0.0; (0.00 to 3.28)	15.2; (6.64 to 30.44)
Treated Joint Bleeds	0.0; (0.00 to 0.00)	1.0; (0.00 to 14.44)
Treated Target Joint Bleeds	0.0; (0.00 to 0.00)	1.0; (0.00 to 6.52)

12. Secondary Outcome

Title	Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	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 were excluded.
Time Frame	From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	35	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Treated Bleeds	62.9; (44.9 to 78.5)	5.6; (0.1 to 27.3)
All Bleeds	37.1; (21.5 to 55.1)	5.6; (0.1 to 27.3)
Treated Spontaneous Bleeds	68.6; (50.7 to 83.1)	11.1; (1.4 to 34.7)
Treated Joint Bleeds	85.7; (69.7 to 95.2)	50.0; (26.0 to 74.0)
Treated Target Joint Bleeds	94.3; (80.8 to 99.3)	50.0; (26.0 to 74.0)

13. Secondary Outcome

Title	Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health).
Time Frame	Week 25

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of adult participants (≥18 years old) in Arms A and B who responded to the questionnaire at Week 25.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	26	14
Mean (Standard Deviation); Unit of Measure: score on a scale
	30.19 (26.59)	57.14 (23.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm. Analysis was performed using Analysis of Covariance (ANCOVA).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0029
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	21.55
	Confidence Interval	(2-Sided) 95%; 7.89 to 35.22
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life.
Time Frame	Week 25

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of adult participants (≥18 years old) in Arms A and B who responded to the questionnaire at Week 25.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	26	14
Mean (Standard Deviation); Unit of Measure: score on a scale
	26.465 (18.666)	47.504 (17.435)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0019
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	14.01
	Confidence Interval	(2-Sided) 95%; 5.56 to 22.45
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Time Frame	Week 25

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of participants in Arms A and B who responded to the questionnaire at Week 25.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	30	16
Mean (Standard Deviation); Unit of Measure: score on a scale
	83.8 (12.9)	76.4 (15.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0171
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-9.72
	Confidence Interval	(2-Sided) 95%; -17.62 to -1.82
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Description	EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed).
Time Frame	Week 25

Outcome Measure Data

Analysis Population Description

ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of participants in Arms A and B who responded to the questionnaire at Week 25.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	30	16
Mean (Standard Deviation); Unit of Measure: score on a scale
	0.83 (0.22)	0.60 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis
	Comments	Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0014
	Comments	Statistical significance was controlled at a two-sided alpha level of 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.25 to -0.07
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old)
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. Baseline was defined as the last assessment prior to treatment. Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose; baseline for Arm B (Emi) is the same as Week 25 for Arm B (Control).
Time Frame	Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)

Outcome Measure Data

Analysis Population Description

The number analyzed is the number of adolescent participants (12-17 years old) who responded to the questionnaire at baseline and Week 25. Arm D is excluded because no adolescents were enrolled in that arm.

Arm/Group Title		Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed		4	2	2	26
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline	Number Analyzed	2 participants	2 participants	2 participants	25 participants
		34.643 (22.728)	37.143 (12.122)	30.000 (14.142)	30.714 (15.625)
Week 25	Number Analyzed	3 participants	2 participants	2 participants	22 participants
		33.095 (17.559)	30.000 (14.142)	12.143 (7.071)	19.286 (14.507)

18. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
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 were excluded.
Time Frame	From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This analysis set included all enrolled participants on the study. For Arm B, it only all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed	35	18	49	11	113
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: bleeds per year
Treated Bleeds	1.9; (1.02 to 3.53)	0.6; (0.22 to 1.36)	3.2; (1.51 to 6.65)	1.5; (0.20 to 11.72)	2.4; (1.50 to 3.82)
All Bleeds	3.5; (2.11 to 5.74)	1.3; (0.66 to 2.39)	4.3; (2.43 to 7.77)	2.3; (0.79 to 6.77)	3.6; (2.55 to 5.13)
Treated Spontaneous Bleeds	0.6; (0.33 to 1.26)	0.1; (0.06 to 0.29)	2.1; (0.89 to 4.80)	0.8; (0.07 to 9.16)	1.3; (0.76 to 2.18)
Treated Joint Bleeds	0.5; (0.16 to 1.69)	0.1; (0.04 to 0.31)	0.4; (0.14 to 0.96)	0.4; (0.05 to 3.41)	0.4; (0.21 to 0.82)
Treated Target Joint Bleeds	0.1; (0.01 to 0.31)	0.01; (0.01 to 0.18)	0.3; (0.09 to 0.84)	0.3; (0.04 to 2.36)	0.2; (0.10 to 0.57)

19. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
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 were excluded.
Time Frame	From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed	35	18	49	11	113
Mean (95% Confidence Interval); Unit of Measure: bleeds per year
Treated Bleeds	2.9; (0.58 to 8.63)	0.6; (0.00 to 4.85)	3.3; (0.77 to 9.28)	1.6; (0.14 to 6.61)	2.6; (0.46 to 8.16)
All Bleeds	4.8; (1.49 to 11.33)	1.3; (0.07 to 6.11)	4.6; (1.40 to 11.09)	2.5; (0.42 to 8.02)	3.9; (1.05 to 10.13)
Treated Spontaneous Bleeds	1.2; (0.06 to 5.99)	0.2; (0.00 to 4.01)	2.2; (0.32 to 7.59)	0.9; (0.01 to 5.33)	1.5; (0.10 to 6.35)
Treated Joint Bleeds	0.9; (0.02 to 5.42)	0.1; (0.00 to 3.95)	0.4; (0.00 to 4.53)	0.4; (0.00 to 4.56)	0.5; (0.00 to 4.73)
Treated Target Joint Bleeds	0.4; (0.00 to 4.44)	0.1; (0.00 to 3.79)	0.3; (0.00 to 4.35)	0.4; (0.00 to 4.40)	0.3; (0.00 to 4.30)

20. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
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 were excluded.
Time Frame	From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed	35	18	49	11	113
Median (Inter-Quartile Range); Unit of Measure: bleeds per year
Treated Bleeds	0.3; (0.00 to 2.05)	0.0; (0.00 to 0.48)	0.0; (0.00 to 1.13)	0.0; (0.00 to 0.67)	0.0; (0.00 to 1.09)
All Bleeds	1.9; (0.22 to 5.13)	0.5; (0.00 to 2.18)	0.6; (0.00 to 2.25)	0.5; (0.00 to 4.41)	0.6; (0.00 to 3.34)
Treated Spontaneous Bleeds	0.0; (0.00 to 0.87)	0.0; (0.00 to 0.24)	0.0; (0.00 to 0.47)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.51)
Treated Joint Bleeds	0.0; (0.00 to 0.24)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)
Treated Target Joint Bleeds	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)	0.0; (0.00 to 0.00)

21. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Mean (95% Confidence Interval); Unit of Measure: treated bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		3.9; (1.05 to 10.12)
13 to 24 Weeks	Number Analyzed	109 participants
		2.2; (0.31 to 7.53)
25 to 36 Weeks	Number Analyzed	102 participants
		0.9; (0.01 to 5.31)
37 to 48 Weeks	Number Analyzed	101 participants
		0.3; (0.00 to 4.38)
49 to 60 Weeks	Number Analyzed	99 participants
		0.4; (0.00 to 4.56)
61 to 72 Weeks	Number Analyzed	98 participants
		0.5; (0.00 to 4.73)
73 to 84 Weeks	Number Analyzed	92 participants
		0.6; (0.00 to 4.80)
85 to 96 Weeks	Number Analyzed	79 participants
		0.4; (0.00 to 4.46)
97 to 108 Weeks	Number Analyzed	67 participants
		0.5; (0.00 to 4.71)
109 to 120 Weeks	Number Analyzed	50 participants
		0.0 [1]; (NA to 3.69)
121 to 132 Weeks	Number Analyzed	44 participants
		0.4; (0.00 to 4.48)
133 to 144 Weeks	Number Analyzed	37 participants
		0.5; (0.00 to 4.62)
145 to 156 Weeks	Number Analyzed	31 participants
		0.4; (0.00 to 4.53)
157 to 168 Weeks	Number Analyzed	28 participants
		0.2; (0.00 to 4.01)
169 to 180 Weeks	Number Analyzed	23 participants
		0.2; (0.00 to 4.08)
181 to 192 Weeks	Number Analyzed	19 participants
		0.0 [1]; (NA to 3.69)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0 [1]; (NA to 3.69)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0 [1]; (NA to 3.69)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0 [1]; (NA to 3.69)
229 to 240 Weeks	Number Analyzed	2 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.

22. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Median (Inter-Quartile Range); Unit of Measure: treated bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		0.0; (0.00 to 4.35)
13 to 24 Weeks	Number Analyzed	109 participants
		0.0; (0.00 to 0.00)
25 to 36 Weeks	Number Analyzed	102 participants
		0.0; (0.00 to 0.00)
37 to 48 Weeks	Number Analyzed	101 participants
		0.0; (0.00 to 0.00)
49 to 60 Weeks	Number Analyzed	99 participants
		0.0; (0.00 to 0.00)
61 to 72 Weeks	Number Analyzed	98 participants
		0.0; (0.00 to 0.00)
73 to 84 Weeks	Number Analyzed	92 participants
		0.0; (0.00 to 0.00)
85 to 96 Weeks	Number Analyzed	79 participants
		0.0; (0.00 to 0.00)
97 to 108 Weeks	Number Analyzed	67 participants
		0.0; (0.00 to 0.00)
109 to 120 Weeks	Number Analyzed	50 participants
		0.0; (0.00 to 0.00)
121 to 132 Weeks	Number Analyzed	44 participants
		0.0; (0.00 to 0.00)
133 to 144 Weeks	Number Analyzed	37 participants
		0.0; (0.00 to 0.00)
145 to 156 Weeks	Number Analyzed	31 participants
		0.0; (0.00 to 0.00)
157 to 168 Weeks	Number Analyzed	28 participants
		0.0; (0.00 to 0.00)
169 to 180 Weeks	Number Analyzed	23 participants
		0.0; (0.00 to 0.00)
181 to 192 Weeks	Number Analyzed	19 participants
		0.0; (0.00 to 0.00)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0; (0.00 to 0.00)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0; (0.00 to 0.00)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0; (0.00 to 0.00)
229 to 240 Weeks	Number Analyzed	2 participants
		0.0; (0.00 to 0.00)

23. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Mean (95% Confidence Interval); Unit of Measure: all bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		6.2; (2.35 to 13.40)
13 to 24 Weeks	Number Analyzed	109 participants
		3.4; (0.78 to 9.29)
25 to 36 Weeks	Number Analyzed	102 participants
		1.5; (0.11 to 6.40)
37 to 48 Weeks	Number Analyzed	101 participants
		1.4; (0.09 to 6.29)
49 to 60 Weeks	Number Analyzed	99 participants
		1.1; (0.04 to 5.74)
61 to 72 Weeks	Number Analyzed	98 participants
		1.0; (0.02 to 5.53)
73 to 84 Weeks	Number Analyzed	92 participants
		1.3; (0.07 to 6.12)
85 to 96 Weeks	Number Analyzed	79 participants
		1.0; (0.02 to 5.56)
97 to 108 Weeks	Number Analyzed	67 participants
		1.2; (0.05 to 5.86)
109 to 120 Weeks	Number Analyzed	50 participants
		0.9; (0.01 to 5.34)
121 to 132 Weeks	Number Analyzed	44 participants
		0.8; (0.01 to 5.20)
133 to 144 Weeks	Number Analyzed	37 participants
		0.5; (0.00 to 4.62)
145 to 156 Weeks	Number Analyzed	31 participants
		0.8; (0.01 to 5.29)
157 to 168 Weeks	Number Analyzed	28 participants
		0.3; (0.00 to 4.31)
169 to 180 Weeks	Number Analyzed	23 participants
		0.8; (0.01 to 5.14)
181 to 192 Weeks	Number Analyzed	19 participants
		0.2; (0.00 to 4.15)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0 [1]; (NA to 3.69)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0 [1]; (NA to 3.69)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0 [1]; (NA to 3.69)
229 to 240 Weeks	Number Analyzed	2 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.

24. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Median (Inter-Quartile Range); Unit of Measure: all bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		0.0; (0.00 to 8.70)
13 to 24 Weeks	Number Analyzed	109 participants
		0.0; (0.00 to 4.35)
25 to 36 Weeks	Number Analyzed	102 participants
		0.0; (0.00 to 0.00)
37 to 48 Weeks	Number Analyzed	101 participants
		0.0; (0.00 to 0.00)
49 to 60 Weeks	Number Analyzed	99 participants
		0.0; (0.00 to 0.00)
61 to 72 Weeks	Number Analyzed	98 participants
		0.0; (0.00 to 0.00)
73 to 84 Weeks	Number Analyzed	92 participants
		0.0; (0.00 to 0.00)
85 to 96 Weeks	Number Analyzed	79 participants
		0.0; (0.00 to 0.00)
97 to 108 Weeks	Number Analyzed	67 participants
		0.0; (0.00 to 0.00)
109 to 120 Weeks	Number Analyzed	50 participants
		0.0; (0.00 to 0.00)
121 to 132 Weeks	Number Analyzed	44 participants
		0.0; (0.00 to 0.00)
133 to 144 Weeks	Number Analyzed	37 participants
		0.0; (0.00 to 0.00)
145 to 156 Weeks	Number Analyzed	31 participants
		0.0; (0.00 to 0.00)
157 to 168 Weeks	Number Analyzed	28 participants
		0.0; (0.00 to 0.00)
169 to 180 Weeks	Number Analyzed	23 participants
		0.0; (0.00 to 0.00)
181 to 192 Weeks	Number Analyzed	19 participants
		0.0; (0.00 to 0.00)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0; (0.00 to 0.00)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0; (0.00 to 0.00)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0; (0.00 to 0.00)
229 to 240 Weeks	Number Analyzed	2 participants
		0.0; (0.00 to 0.00)

25. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Mean (95% Confidence Interval); Unit of Measure: treated spontaneous bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		2.2; (0.31 to 7.56)
13 to 24 Weeks	Number Analyzed	109 participants
		1.3; (0.06 to 6.04)
25 to 36 Weeks	Number Analyzed	102 participants
		0.4; (0.00 to 4.45)
37 to 48 Weeks	Number Analyzed	101 participants
		0.2; (0.00 to 4.04)
49 to 60 Weeks	Number Analyzed	99 participants
		0.1; (0.00 to 3.96)
61 to 72 Weeks	Number Analyzed	98 participants
		0.2; (0.00 to 4.05)
73 to 84 Weeks	Number Analyzed	92 participants
		0.2; (0.00 to 4.08)
85 to 96 Weeks	Number Analyzed	79 participants
		0.1; (0.00 to 3.92)
97 to 108 Weeks	Number Analyzed	67 participants
		0.3; (0.00 to 4.34)
109 to 120 Weeks	Number Analyzed	50 participants
		0.0 [1]; (NA to 3.69)
121 to 132 Weeks	Number Analyzed	44 participants
		0.1; (0.00 to 3.89)
133 to 144 Weeks	Number Analyzed	37 participants
		0.0 [1]; (NA to 3.69)
145 to 156 Weeks	Number Analyzed	31 participants
		0.4; (0.00 to 4.53)
157 to 168 Weeks	Number Analyzed	28 participants
		0.2; (0.00 to 4.01)
169 to 180 Weeks	Number Analyzed	23 participants
		0.2; (0.00 to 4.08)
181 to 192 Weeks	Number Analyzed	19 participants
		0.0 [1]; (NA to 3.69)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0 [1]; (NA to 3.69)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0 [1]; (NA to 3.69)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0 [1]; (NA to 3.69)
229 to 240 Weeks	Number Analyzed	2 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.

26. Secondary Outcome

Title	Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
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, and 229-240 weeks

Outcome Measure Data

Analysis Population Description

All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval.

Arm/Group Title		All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		113
Median (Inter-Quartile Range); Unit of Measure: treated spontaneous bleeds per year
1 to 12 Weeks	Number Analyzed	110 participants
		0.0; (0.00 to 0.00)
13 to 24 Weeks	Number Analyzed	109 participants
		0.0; (0.00 to 0.00)
25 to 36 Weeks	Number Analyzed	102 participants
		0.0; (0.00 to 0.00)
37 to 48 Weeks	Number Analyzed	101 participants
		0.0; (0.00 to 0.00)
49 to 60 Weeks	Number Analyzed	99 participants
		0.0; (0.00 to 0.00)
61 to 72 Weeks	Number Analyzed	98 participants
		0.0; (0.00 to 0.00)
73 to 84 Weeks	Number Analyzed	92 participants
		0.0; (0.00 to 0.00)
85 to 96 Weeks	Number Analyzed	79 participants
		0.0; (0.00 to 0.00)
97 to 108 Weeks	Number Analyzed	67 participants
		0.0; (0.00 to 0.00)
109 to 120 Weeks	Number Analyzed	50 participants
		0.0; (0.00 to 0.00)
121 to 132 Weeks	Number Analyzed	44 participants
		0.0; (0.00 to 0.00)
133 to 144 Weeks	Number Analyzed	37 participants
		0.0; (0.00 to 0.00)
145 to 156 Weeks	Number Analyzed	31 participants
		0.0; (0.00 to 0.00)
157 to 168 Weeks	Number Analyzed	28 participants
		0.0; (0.00 to 0.00)
169 to 180 Weeks	Number Analyzed	23 participants
		0.0; (0.00 to 0.00)
181 to 192 Weeks	Number Analyzed	19 participants
		0.0; (0.00 to 0.00)
193 to 204 Weeks	Number Analyzed	13 participants
		0.0; (0.00 to 0.00)
205 to 216 Weeks	Number Analyzed	9 participants
		0.0; (0.00 to 0.00)
217 to 228 Weeks	Number Analyzed	4 participants
		0.0; (0.00 to 0.00)
229 to 240 Weeks	Number Analyzed	2 participants
		0.0; (0.00 to 0.00)

27. Secondary Outcome

Title	Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale
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, only data before up-titration is included. aPCC = activated prothrombin complex concentrate; Hypersens.= hypersensitivity
Time Frame	From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)

Outcome Measure Data

Analysis Population Description

Safety Population: All treated participants grouped by their assigned treatment. For Arm B, data collected while receiving episodic bypassing agents (no prophyalxis) for the first 24 weeks and 1.5 mg/kg emicizumab QW after Week 24 are reported separately under 'Arm B (Control): No Prophylaxis' and 'Arm B (Emi): 1.5 mg/kg Emicizumab QW', respectively.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Data reported represents data collected during emicizumab treatment only.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	34	18	18	49	11
Measure Type: Count of Participants; Unit of Measure: Participants
Any Adverse Event (AE)	34 100.0%	9 50.0%	15 83.3%	46 93.9%	9 81.8%
AE with Fatal Outcome	0 0.0%	0 0.0%	0 0.0%	1 2.0%	0 0.0%
Serious AE	10 29.4%	4 22.2%	4 22.2%	9 18.4%	2 18.2%
AE Leading to Withdrawal from Treatment	2 5.9%	0 0.0%	0 0.0%	1 2.0%	0 0.0%
AE Leading to Dose Mod./Interruption	1 2.9%	0 0.0%	0 0.0%	5 10.2%	0 0.0%
Grade ≥3 AE	10 29.4%	4 22.2%	3 16.7%	7 14.3%	3 27.3%
Related AE	15 44.1%	0 0.0%	4 22.2%	13 26.5%	4 36.4%
Local Injection Site Reaction	9 26.5%	0 0.0%	3 16.7%	7 14.3%	4 36.4%
Systemic Hypersens./Anaphylac(tic/toid) Reaction	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Thrombotic Microangiopathy (TMA)	1 2.9%	0 0.0%	0 0.0%	2 4.1%	0 0.0%
TMA Event Related to aPCC and Emicizumab	1 2.9%	0 0.0%	0 0.0%	2 4.1%	0 0.0%
Thromboembolic Event (TE)	1 2.9%	1 5.6%	1 5.6%	1 2.0%	0 0.0%
TE Event Related to aPCC and Emicizumab	1 2.9%	0 0.0%	0 0.0%	1 2.0%	0 0.0%

28. Secondary Outcome

Title	Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study
Description	'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. '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. ADA-positive samples were further analyzed for neutralizing capacity using a modified FVIII chromogenic assay; if also positive, they were considered neutralizing ADAs.
Time Frame	From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)

Outcome Measure Data

Analysis Population Description

All emicizumab-treated participants included Arms A, C, and D and Arm B participants who switched to receive emicizumab (Arm B Emi). The overall number of participants analyzed is the number of participants with at least one post-baseline anti-drug antibody assessment.

Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW
Arm/Group Description:	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
Overall Number of Participants Analyzed	33	18	49	11
Measure Type: Count of Participants; Unit of Measure: Participants
Total ADA Negative (Neg+Neg Unaffected)	33 100.0%	18 100.0%	47 95.9%	11 100.0%
ADA Negative, Negative	33 100.0%	17 94.4%	46 93.9%	11 100.0%
ADA Negative, Negative (Treatment Unaffected)	0 0.0%	1 5.6%	1 2.0%	0 0.0%
Total ADA Positive (Boosted + Induced)	0 0.0%	0 0.0%	2 4.1%	0 0.0%
ADA Positive, Positive (Treatment Boosted)	0 0.0%	0 0.0%	0 0.0%	0 0.0%
ADA Positive, Positive (Treatment Induced)	0 0.0%	0 0.0%	2 4.1%	0 0.0%
ADA Positive with Neutralizing ADAs	0 0.0%	0 0.0%	2 4.1%	0 0.0%

29. Secondary Outcome

Title	Plasma Trough Concentrations of Emicizumab at Specified Timepoints
Description	Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose.
Time Frame	Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. The number analyzed includes participants with PK samples at each timepoint.

Arm/Group Title		Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Arm/Group Description:		Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.	Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.	This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Overall Number of Participants Analyzed		34	18	49	11	112
Mean (Standard Deviation); Unit of Measure: micrograms per milliliter (mcg/mL)
Week 1	Number Analyzed	33 participants	18 participants	48 participants	11 participants	110 participants
		NA [1] (NA)	NA [1] (NA)	NA [1] (NA)	NA [1] (NA)	NA [1] (NA)
Week 2	Number Analyzed	34 participants	17 participants	46 participants	10 participants	107 participants
		16.2 (4.4)	21.7 (10.6)	15.8 (5.5)	18.3 (6.5)	17.1 (6.6)
Week 3	Number Analyzed	34 participants	18 participants	47 participants	11 participants	110 participants
		31.6 (7.3)	32.3 (10.4)	31.7 (8.3)	32.7 (13.0)	31.9 (8.8)
Week 4	Number Analyzed	32 participants	18 participants	46 participants	11 participants	107 participants
		43.8 (12.2)	44.6 (18.6)	44.7 (11.5)	49.0 (13.5)	44.9 (13.2)
Week 5	Number Analyzed	33 participants	18 participants	46 participants	11 participants	108 participants
		53.5 (15.1)	52.2 (14.2)	54.0 (13.2)	59.1 (14.6)	54.1 (14.0)
Week 7	Number Analyzed	33 participants	17 participants	46 participants	11 participants	107 participants
		52.8 (16.2)	53.3 (18.0)	53.6 (14.3)	54.9 (9.2)	53.4 (14.9)
Week 9	Number Analyzed	32 participants	17 participants	46 participants	11 participants	106 participants
		50.4 (12.4)	48.9 (16.7)	52.6 (15.7)	53.7 (13.8)	51.5 (14.7)
Week 13	Number Analyzed	32 participants	17 participants	46 participants	11 participants	106 participants
		49.3 (13.4)	45.2 (16.2)	52.6 (15.0)	53.4 (14.0)	50.5 (14.7)
Week 17	Number Analyzed	32 participants	17 participants	46 participants	11 participants	106 participants
		50.7 (15.0)	46.5 (17.4)	51.2 (14.9)	57.5 (16.9)	51.0 (15.6)
Week 21	Number Analyzed	32 participants	17 participants	44 participants	11 participants	104 participants
		52.6 (17.4)	44.5 (15.4)	51.6 (17.1)	55.0 (13.7)	51.1 (16.6)
Week 25	Number Analyzed	31 participants	17 participants	45 participants	11 participants	104 participants
		54.6 (19.1)	45.8 (18.6)	50.4 (16.8)	52.8 (14.1)	51.2 (17.6)
Week 33	Number Analyzed	27 participants	17 participants	41 participants	10 participants	95 participants
		50.7 (17.2)	48.1 (21.1)	54.8 (16.7)	57.1 (15.2)	52.7 (17.5)
Week 41	Number Analyzed	27 participants	17 participants	40 participants	10 participants	94 participants
		45.3 (13.7)	49.3 (25.9)	54.8 (23.4)	63.3 (19.4)	52.0 (21.6)
Week 49	Number Analyzed	27 participants	15 participants	40 participants	9 participants	91 participants
		48.0 (12.3)	54.6 (27.6)	56.1 (22.2)	55.1 (18.7)	53.3 (20.5)
Week 61	Number Analyzed	27 participants	15 participants	40 participants	10 participants	92 participants
		52.2 (16.3)	51.8 (33.4)	60.9 (27.7)	53.2 (13.8)	56.0 (24.8)
Week 73	Number Analyzed	27 participants	12 participants	39 participants	9 participants	87 participants
		55.5 (14.9)	45.6 (26.2)	62.9 (24.9)	51.9 (13.0)	57.1 (22.0)
Week 85	Number Analyzed	27 participants	10 participants	36 participants	5 participants	78 participants
		56.9 (18.3)	42.5 (34.4)	56.6 (22.7)	50.9 (12.5)	54.5 (22.7)
Week 97	Number Analyzed	25 participants	9 participants	27 participants	5 participants	66 participants
		53.2 (15.2)	34.4 (26.4)	54.6 (20.0)	53.8 (16.9)	51.3 (19.9)
Week 109	Number Analyzed	23 participants	6 participants	15 participants	3 participants	47 participants
		49.6 (15.9)	32.8 (31.4)	47.4 (12.4)	49.3 (12.8)	46.7 (17.6)
Week 121	Number Analyzed	19 participants	7 participants	11 participants	2 participants	39 participants
		53.8 (16.3)	36.1 (33.6)	46.3 (12.5)	53.1 (5.0)	48.5 (19.7)
Week 133	Number Analyzed	15 participants	6 participants	7 participants	1 participants	29 participants
		50.5 (15.9)	48.7 (29.4)	49.0 (18.5)	52.0 [2] (NA)	49.8 (18.8)
Week 145	Number Analyzed	13 participants	4 participants	5 participants	2 participants	24 participants
		51.3 (16.6)	38.2 (19.0)	44.0 (21.7)	49.5 (10.3)	47.4 (17.4)
Week 157	Number Analyzed	15 participants	0 participants	4 participants	2 participants	21 participants
		58.0 (16.5)		45.5 (17.0)	55.4 (19.2)	55.3 (16.7)
Week 169	Number Analyzed	12 participants	0 participants	3 participants	1 participants	16 participants
		55.0 (19.3)		43.2 (20.2)	50.8 [2] (NA)	52.5 (18.7)

[1]

No data available because all of the measurements were below the LLOQ.

[2]

Standard deviation (SD) could not be calculated for single participant data.

Adverse Events

Time Frame	From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
Adverse Event Reporting Description	Safety Population: All treated subjects grouped by treatment (including after up-titration). For Arm B, data collected with episodic bypassing agents (no prophyalxis) for first 24 weeks and with 1.5 mg/kg emicizumab QW after Week 24 are reported separately under Arm B (Control): No Prophylaxis and Arm B (Emi): 1.5 mg/kg Emicizumab QW, respectively.
Arm/Group Title	Arm A: 1.5 mg/kg Emicizumab QW		Arm B (Control): No Prophylaxis		Arm B (Emi): 1.5 mg/kg Emicizumab QW		Arm C: 1.5 mg/kg Emicizumab QW		Arm D: 1.5 mg/kg Emicizumab QW
Arm/Group Description	Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.		Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. The safety data reported here represents data collected from all Arm B participants during the first 24 weeks of 'no prophylaxis'; safety data from Arm B participants who switched to emicizumab after Week 24 are reported separately under Arm B (Emi): 1.5 mg/kg Emicizumab QW.		This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Data reported represents data collected during emicizumab treatment only.		Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.		Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
All-Cause Mortality
	Arm A: 1.5 mg/kg Emicizumab QW		Arm B (Control): No Prophylaxis		Arm B (Emi): 1.5 mg/kg Emicizumab QW		Arm C: 1.5 mg/kg Emicizumab QW		Arm D: 1.5 mg/kg Emicizumab QW
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/34 (0.00%)		0/18 (0.00%)		0/18 (0.00%)		1/49 (2.04%)		0/11 (0.00%)
Serious Adverse Events
	Arm A: 1.5 mg/kg Emicizumab QW		Arm B (Control): No Prophylaxis		Arm B (Emi): 1.5 mg/kg Emicizumab QW		Arm C: 1.5 mg/kg Emicizumab QW		Arm D: 1.5 mg/kg Emicizumab QW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/34 (32.35%)		5/18 (27.78%)		4/18 (22.22%)		9/49 (18.37%)		2/11 (18.18%)
Blood and lymphatic system disorders
Iron deficiency anaemia † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Thrombotic microangiopathy † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	2/49 (4.08%)	2	0/11 (0.00%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Gastric ulcer haemorrhage † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Large intestine polyp † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Rectal haemorrhage † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Tooth development disorder † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Upper gastrointestinal haemorrhage † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
General disorders
Chest pain † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Infections and infestations
Device related infection † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Urinary tract infection † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Cavernous sinus thrombosis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Sepsis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Gastroenteritis viral † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Meningitis bacterial † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Vascular device infection † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Device related sepsis † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Gastroenteritis † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Injury, poisoning and procedural complications
Subdural haemorrhage † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Road traffic accident † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Musculoskeletal and connective tissue disorders
Muscle haemorrhage † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Haemarthrosis † 1	2/34 (5.88%)	2	2/18 (11.11%)	2	1/18 (5.56%)	1	2/49 (4.08%)	3	0/11 (0.00%)	0
Arthralgia † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Myalgia † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Osteonecrosis † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Soft tissue haemorrhage † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Nervous system disorders
Headache † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Product Issues
Device loosening † 1	1/34 (2.94%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Psychiatric disorders
Intentional self-injury † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Delirium † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Renal and urinary disorders
Haematuria † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Subcapsular renal haematoma † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Skin and subcutaneous tissue disorders
Skin necrosis † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Vascular disorders
Thrombophlebitis superficial † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Haematoma † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Haemorrhage † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	2/49 (4.08%)	2	0/11 (0.00%)	0
1 Term from vocabulary, MedDRA v23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm A: 1.5 mg/kg Emicizumab QW		Arm B (Control): No Prophylaxis		Arm B (Emi): 1.5 mg/kg Emicizumab QW		Arm C: 1.5 mg/kg Emicizumab QW		Arm D: 1.5 mg/kg Emicizumab QW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/34 (97.06%)		9/18 (50.00%)		15/18 (83.33%)		42/49 (85.71%)		9/11 (81.82%)
Blood and lymphatic system disorders
Anaemia † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	2	1/49 (2.04%)	1	0/11 (0.00%)	0
Iron deficiency anaemia † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	3	0/11 (0.00%)	0
Cardiac disorders
Arrhythmia † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Ear and labyrinth disorders
Ear discomfort † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Eye disorders
Vision blurred † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Cataract † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Gastrointestinal disorders
Abdominal pain upper † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	2/49 (4.08%)	2	0/11 (0.00%)	0
Enteritis † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Large intestine polyp † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Toothache † 1	4/34 (11.76%)	4	0/18 (0.00%)	0	2/18 (11.11%)	2	2/49 (4.08%)	3	2/11 (18.18%)	2
Abdominal pain † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	2	0/11 (0.00%)	0
Dental caries † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	3/18 (16.67%)	4	1/49 (2.04%)	1	1/11 (9.09%)	1
Diarrhoea † 1	4/34 (11.76%)	4	0/18 (0.00%)	0	1/18 (5.56%)	1	5/49 (10.20%)	8	0/11 (0.00%)	0
Nausea † 1	4/34 (11.76%)	5	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	3	0/11 (0.00%)	0
Vomiting † 1	3/34 (8.82%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	4/49 (8.16%)	4	0/11 (0.00%)	0
Gastrooesophageal reflux disease † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Food poisoning † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Gastritis † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
General disorders
Chest pain † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Fatigue † 1	3/34 (8.82%)	4	0/18 (0.00%)	0	2/18 (11.11%)	2	2/49 (4.08%)	2	0/11 (0.00%)	0
Injection site reaction † 1	9/34 (26.47%)	18	0/18 (0.00%)	0	3/18 (16.67%)	3	8/49 (16.33%)	21	4/11 (36.36%)	5
Pyrexia † 1	2/34 (5.88%)	2	1/18 (5.56%)	1	2/18 (11.11%)	2	8/49 (16.33%)	10	1/11 (9.09%)	1
Device related thrombosis † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Catheter site pain † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	2/49 (4.08%)	2	0/11 (0.00%)	0
Influenza like illness † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Pain † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	2/49 (4.08%)	2	0/11 (0.00%)	0
Peripheral swelling † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Hepatobiliary disorders
Drug-induced liver injury † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Immune system disorders
Seasonal allergy † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	2/49 (4.08%)	2	0/11 (0.00%)	0
Infections and infestations
Folliculitis † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Nasopharyngitis † 1	11/34 (32.35%)	29	2/18 (11.11%)	2	7/18 (38.89%)	14	16/49 (32.65%)	27	2/11 (18.18%)	2
Upper respiratory tract infection † 1	8/34 (23.53%)	21	2/18 (11.11%)	2	2/18 (11.11%)	2	7/49 (14.29%)	8	2/11 (18.18%)	2
Bronchitis † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	2/49 (4.08%)	2	1/11 (9.09%)	1
Influenza † 1	1/34 (2.94%)	2	0/18 (0.00%)	0	2/18 (11.11%)	2	10/49 (20.41%)	10	0/11 (0.00%)	0
Gastroenteritis † 1	3/34 (8.82%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	0/11 (0.00%)	0
Herpes virus infection † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Rhinitis † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Urinary tract infection † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Cellulitis † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Device related infection † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Lower respiratory tract infection † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Sinusitis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	3/18 (16.67%)	3	0/49 (0.00%)	0	0/11 (0.00%)	0
Injury, poisoning and procedural complications
Post procedural constipation † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Procedural hypotension † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Procedural nausea † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Procedural pain † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	2/18 (11.11%)	2	2/49 (4.08%)	2	0/11 (0.00%)	0
Contusion † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Fall † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	2
Fibula fracture † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Incision site swelling † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Ligament sprain † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Limb injury † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	1/49 (2.04%)	1	1/11 (9.09%)	1
Rib fracture † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Skin abrasion † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	2/11 (18.18%)	2
Skin laceration † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Thermal burn † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Tibia fracture † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Tooth fracture † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	1/11 (9.09%)	1
Investigations
Blood glucose increased † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Blood creatine phosphokinase increased † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	4	1/11 (9.09%)	1
Body temperature increased † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
C-reactive protein increased † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Indeterminable ABO blood type † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	3	0/11 (0.00%)	0
Prothrombin fragment 1.2 increased † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	2
Metabolism and nutrition disorders
Dehydration † 1	1/34 (2.94%)	1	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Electrolyte imbalance † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Decreased appetite † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Hypercholesterolaemia † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	9/34 (26.47%)	17	0/18 (0.00%)	0	6/18 (33.33%)	9	12/49 (24.49%)	33	3/11 (27.27%)	5
Myalgia † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Arthropathy † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Back pain † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	2/49 (4.08%)	2	0/11 (0.00%)	0
Groin pain † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Joint swelling † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	2	1/49 (2.04%)	1	0/11 (0.00%)	0
Muscle spasms † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	2/49 (4.08%)	2	0/11 (0.00%)	0
Musculoskeletal stiffness † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Pain in extremity † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	4/49 (8.16%)	4	0/11 (0.00%)	0
Plantar fasciitis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Synovitis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Tumour haemorrhage † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Nervous system disorders
Headache † 1	6/34 (17.65%)	9	1/18 (5.56%)	1	4/18 (22.22%)	4	13/49 (26.53%)	22	3/11 (27.27%)	3
Dizziness † 1	4/34 (11.76%)	4	1/18 (5.56%)	1	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Migraine † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Neuropathy peripheral † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Product Issues
Device occlusion † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Psychiatric disorders
Insomnia † 1	1/34 (2.94%)	1	0/18 (0.00%)	0	0/18 (0.00%)	0	2/49 (4.08%)	2	1/11 (9.09%)	1
Renal and urinary disorders
Pollakiuria † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	1	0/49 (0.00%)	0	0/11 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	5/34 (14.71%)	5	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	3	0/11 (0.00%)	0
Oropharyngeal pain † 1	0/34 (0.00%)	0	1/18 (5.56%)	1	0/18 (0.00%)	0	2/49 (4.08%)	3	0/11 (0.00%)	0
Nasal congestion † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	2/11 (18.18%)	2
Rhinitis allergic † 1	4/34 (11.76%)	4	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Skin and subcutaneous tissue disorders
Hair growth abnormal † 1	3/34 (8.82%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Rash † 1	2/34 (5.88%)	2	1/18 (5.56%)	1	1/18 (5.56%)	1	1/49 (2.04%)	1	0/11 (0.00%)	0
Dry skin † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	2	0/49 (0.00%)	0	0/11 (0.00%)	0
Ecchymosis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Eczema † 1	3/34 (8.82%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Erythema † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	1/11 (9.09%)	1
Hand dermatitis † 1	2/34 (5.88%)	3	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Neurodermatitis † 1	0/34 (0.00%)	0	0/18 (0.00%)	0	1/18 (5.56%)	2	0/49 (0.00%)	0	0/11 (0.00%)	0
Urticaria † 1	2/34 (5.88%)	2	0/18 (0.00%)	0	0/18 (0.00%)	0	0/49 (0.00%)	0	0/11 (0.00%)	0
Vascular disorders
Hypertension † 1	5/34 (14.71%)	5	0/18 (0.00%)	0	0/18 (0.00%)	0	3/49 (6.12%)	3	2/11 (18.18%)	2
1 Term from vocabulary, MedDRA v23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, Croteau SE, Lambert T, Kempton CL, Pipe SW, Ko RH, Trzaskoma B, Dhalluin C, Bienz NS, Niggli M, Lehle M, Paz-Priel I, Young G, Jimenez-Yuste V. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Adv. 2022 Dec 27;6(24):6140-6150. doi: 10.1182/bloodadvances.2022007458.

Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02622321
• Other Study ID Numbers: BH29884; 2015-002866-21 ( EudraCT Number )
• First Submitted: December 2, 2015
• First Posted: December 4, 2015
• Results First Submitted: October 19, 2017
• Results First Posted: November 24, 2017
• Last Update Posted: June 24, 2021