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

Summary
EudraCT number	2015-002866-21
Trial protocol	DE ES GB PL FR IT
Global end of trial date	01 Dec 2020

Results information
Results version number	v2(current)
This version publication date	12 Jun 2021
First version publication date	04 Nov 2017
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BH29884

ISRCTN number

US NCT number

NCT02622321

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001839-PIP01-15

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

01 Dec 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Dec 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Costa Rica: 5

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Japan: 12

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

Poland: 9

Country: Number of subjects enrolled

South Africa: 6

Country: Number of subjects enrolled

Korea, Republic of: 1

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Taiwan: 4

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

113

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: 1.5 mg/kg Emicizumab QW

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.

Arm B (Control): No Prophylaxis

Arm description

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.

Arm type

Active comparator

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Arm C: 1.5 mg/kg Emicizumab QW

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Arm D: 1.5 mg/kg Emicizumab QW

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 1	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW
Started	35	18	49	11
Received at Least One Dose of Treatment	34	18	49	11
Completed 24 Weeks in the Study	31 ^[1]	18	49	11
Dose Up-Titrated to 3 mg/kg QW	2 ^[2]	0 ^[3]	3 ^[4]	2 ^[5]
Completed	32	18	48	11
Not completed	3	0	1	0
Adverse event, serious fatal	-	-	1	-
Consent withdrawn by subject	2	-	-	-
Physician decision	1	-	-	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly.

Baseline characteristics

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Reporting group title

Arm A: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm B (Control): No Prophylaxis

Reporting group description

Reporting group title

Arm C: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm D: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Total
Number of subjects	35	18	49	11	113
Age Categorical
Units: Subjects
Adolescents (12-17 years)	4	2	26	0	32
Adults (18-64 years)	30	15	21	10	76
Elderly (From 65-84 years)	1	1	2	1	5
Age Continuous
Units: years
arithmetic mean (standard deviation)	35.8 ( 13.9 )	37.2 ( 13.7 )	25.6 ( 16.8 )	39.0 ( 16.1 )	-
Gender Categorical
Units: Subjects
Female	0	0	0	0	0
Male	35	18	49	11	113
Number of Participants by the Number of Bleeds (<9 or ≥9) in the Last 24 Weeks Prior to Study Entry
Units: Subjects
<9 Bleeds	11	5	23	6	45
≥9 Bleeds	24	13	26	5	68

End points

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Reporting group title

Arm A: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm B (Control): No Prophylaxis

Reporting group description

Reporting group title

Arm C: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm D: 1.5 mg/kg Emicizumab QW

Reporting group description

Subject analysis set title

Arm A (NIS): Previous Episodic Bypassing Agents

Subject analysis set type

Sub-group analysis

Subject analysis set description

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.

Subject analysis set title

Arm C (NIS): Previous Prophylactic Bypassing Agents

Subject analysis set type

Sub-group analysis

Subject analysis set description

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.

Subject analysis set title

Arm B (Emi): 1.5 mg/kg Emicizumab QW

Subject analysis set type

Sub-group analysis

Subject analysis set description

This arm includes Arm B participants who switched to emicizumab prophylaxis after having first completed at least 24 weeks on study of 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.

Subject analysis set title

All Participants: 1.5 mg/kg Emicizumab QW

Subject analysis set type

Intention-to-treat

Subject analysis set description

This analysis set includes all enrolled participants on the study. For Arm B, it only includes participants starting after study Week 24 when they crossed over to first receive prophylactic treatment with emicizumab (i.e., Arm B (Emi): 1.5 mg/kg Emicizumab QW). 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.

Primary: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[1]

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

End point type

Primary

End point timeframe

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)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: treated bleeds per year
number (confidence interval 95%)	2.9 (1.69 to 5.02)	23.3 (12.33 to 43.89)

Statistical Analysis 1

Statistical analysis description

Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (less than [<] 9 or greater than or equal to [>/=] 9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.057

upper limit

0.277

Notes
[2] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[3]

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

End point type

Secondary

End point timeframe

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)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: all bleeds per year
number (confidence interval 95%)	5.5 (3.58 to 8.60)	28.3 (16.79 to 47.76)

Statistical Analysis 1

Statistical analysis description

Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.102

upper limit

0.375

Notes
[4] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

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End point title

Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents ^[5]

End point 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.

End point type

Secondary

End point timeframe

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

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm A (NIS): Previous Episodic Bypassing Agents
Number of subjects analysed	24	24
Units: all bleeds per year
number (confidence interval 95%)	4.1 (2.10 to 8.02)	37.7 (28.40 to 50.04)

Statistical Analysis 1

Statistical analysis description

This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm A NIS) and on study (Arm A).

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm A (NIS): Previous Episodic Bypassing Agents

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Non-Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.055

upper limit

0.218

Notes
[6] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

Top of page

End point title

Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents ^[7]

End point 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.

End point type

Secondary

End point timeframe

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

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm A (NIS): Previous Episodic Bypassing Agents
Number of subjects analysed	24	24
Units: treated bleeds per year
number (confidence interval 95%)	1.7 (0.71 to 4.06)	21.6 (15.40 to 30.22)

Statistical Analysis 1

Statistical analysis description

This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm A NIS) and on study (Arm A).

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm A (NIS): Previous Episodic Bypassing Agents

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

Non-Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.031

upper limit

0.198

Notes
[8] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[9]

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

End point type

Secondary

End point timeframe

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)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: treated joint bleeds per year
number (confidence interval 95%)	0.8 (0.26 to 2.20)	6.7 (1.99 to 22.42)

Statistical Analysis 1

Statistical analysis description

Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[10]

Method

Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.52

Notes
[10] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

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End point title

Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents ^[11]

End point 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.

End point type

Secondary

End point timeframe

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

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm C: 1.5 mg/kg Emicizumab QW	Arm C (NIS): Previous Prophylactic Bypassing Agents
Number of subjects analysed	24	24
Units: all bleeds per year
number (confidence interval 95%)	5.5 (2.98 to 10.26)	24.3 (18.11 to 32.67)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Arm C: 1.5 mg/kg Emicizumab QW v Arm C (NIS): Previous Prophylactic Bypassing Agents

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[12]

Method

Non-Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.119

upper limit

0.435

Notes
[12] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

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End point title

Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents ^[13]

End point 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.

End point type

Secondary

End point timeframe

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

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm C: 1.5 mg/kg Emicizumab QW	Arm C (NIS): Previous Prophylactic Bypassing Agents
Number of subjects analysed	24	24
Units: treated bleeds per year
number (confidence interval 95%)	3.3 (1.33 to 8.08)	15.7 (11.08 to 22.29)

Statistical Analysis 1

Statistical analysis description

This intra-participant comparison of ABR for treated bleeds between arms was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm C NIS) and on study (Arm C).

Comparison groups

Arm C: 1.5 mg/kg Emicizumab QW v Arm C (NIS): Previous Prophylactic Bypassing Agents

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003 ^[14]

Method

Non-Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.089

upper limit

0.486

Notes
[14] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[15]

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

End point type

Secondary

End point timeframe

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)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: treated spontaneous bleeds per year
number (confidence interval 95%)	1.3 (0.73 to 2.19)	16.8 (9.94 to 28.30)

Statistical Analysis 1

Statistical analysis description

Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[16]

Method

Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.154

Notes
[16] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[17]

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

End point type

Secondary

End point timeframe

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)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: treated target joint bleeds per year
number (confidence interval 95%)	0.1 (0.03 to 0.58)	3.0 (0.96 to 9.13)

Statistical Analysis 1

Statistical analysis description

Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[18]

Method

Stratified Wald Test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.227

Notes
[18] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

Secondary: 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

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End point 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 ^[19]

End point 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. ITT population.

End point type

Secondary

End point timeframe

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)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: bleeds per year
arithmetic mean (confidence interval 95%)
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)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[20]

End point description

End point type

Secondary

End point timeframe

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)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: bleeds per year
median (inter-quartile range (Q1-Q3))
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)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[21]

End point 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. ITT population.

End point type

Secondary

End point timeframe

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)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	35	18
Units: Percentage of participants
number (confidence interval 95%)
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)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[22]

End point description

Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). ITT population. Number of subjects analyzed=adult participants with available data for this endpoint.

End point type

Secondary

End point timeframe

Week 25

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	26 ^[23]	14 ^[24]
Units: score on a scale
arithmetic mean (standard deviation)	30.19 ( 26.59 )	57.14 ( 23.35 )

Notes
[23] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25
[24] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25

Statistical Analysis 1

Statistical analysis description

Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term. Analysis was performed using Analysis of Covariance (ANCOVA).

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029 ^[25]

Method

ANCOVA

Parameter type

Adjusted Mean Difference

Point estimate

21.55

Confidence interval

level

95%

sides

2-sided

lower limit

7.89

upper limit

35.22

Notes
[25] - Statistical significance was controlled at a two-sided alpha level of 0.05.

Secondary: Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[26]

End point description

Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life. ITT population. Number of subjects analyzed=adult participants with available data for this endpoint.

End point type

Secondary

End point timeframe

Week 25

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	26 ^[27]	14 ^[28]
Units: score on a scale
arithmetic mean (standard deviation)	26.465 ( 18.666 )	47.504 ( 17.435 )

Notes
[27] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25
[28] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25

Statistical Analysis 1

Statistical analysis description

Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0019 ^[29]

Method

ANCOVA

Parameter type

Adjusted Mean Difference

Point estimate

14.01

Confidence interval

level

95%

sides

2-sided

lower limit

5.56

upper limit

22.45

Notes
[29] - Statistical significance was controlled at a two-sided alpha level of 0.05.

Secondary: 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

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End point 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 ^[30]

End point description

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. ITT population. Number of subjects analyzed=participants with available data for this endpoint.

End point type

Secondary

End point timeframe

Week 25

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	30 ^[31]	16 ^[32]
Units: score on a scale
arithmetic mean (standard deviation)	83.8 ( 12.9 )	76.4 ( 15.7 )

Notes
[31] - Participants who responded to the questionnaire at Week 25
[32] - Participants who responded to the questionnaire at Week 25

Statistical Analysis 1

Statistical analysis description

Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0171 ^[33]

Method

ANCOVA

Parameter type

Adjusted Mean Difference

Point estimate

-9.72

Confidence interval

level

95%

sides

2-sided

lower limit

-17.62

upper limit

-1.82

Notes
[33] - Statistical significance was controlled at a two-sided alpha level of 0.05.

Secondary: EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis

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End point title

EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis ^[34]

End point description

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed). ITT population. Number of subjects analyzed=participants with available data for this endpoint.

End point type

Secondary

End point timeframe

Week 25

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis
Number of subjects analysed	30 ^[35]	16 ^[36]
Units: score on a scale
arithmetic mean (standard deviation)	0.83 ( 0.22 )	0.60 ( 0.35 )

Notes
[35] - Participants who responded to the questionnaire at Week 25
[36] - Participants who responded to the questionnaire at Week 25

Statistical Analysis 1

Statistical analysis description

Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.

Comparison groups

Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0014 ^[37]

Method

ANCOVA

Parameter type

Adjusted Mean Difference

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

-0.07

Notes
[37] - Statistical significance was controlled at a two-sided alpha level of 0.05.

Secondary: 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)

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End point 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)

End point description

The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. 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.

End point type

Secondary

End point timeframe

Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW
Number of subjects analysed	4 ^[38]	2 ^[39]	26 ^[40]	0 ^[41]	2 ^[42]
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n=2,2,25,2)	34.643 ( 22.728 )	37.143 ( 12.122 )	30.714 ( 15.625 )	( )	30.000 ( 14.142 )
Week 25 (n=3,2,22,2)	33.095 ( 17.559 )	30.000 ( 14.142 )	19.286 ( 14.507 )	( )	12.143 ( 7.071 )

Notes
[38] - Adolescent participants (12-17 years old)
[39] - Adolescent participants (12-17 years old)
[40] - Adolescent participants (12-17 years old)
[41] - None of the participants in Arm D were adolescents (12-17 years old).
[42] - Adolescent participants (12-17 years old)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[43]

End point 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.

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	35	49	11	18	113
Units: bleeds per year
number (confidence interval 95%)
Treated Bleeds	1.9 (1.02 to 3.53)	3.2 (1.51 to 6.65)	1.5 (0.20 to 11.72)	0.6 (0.22 to 1.36)	2.4 (1.50 to 3.82)
All Bleeds	3.5 (2.11 to 5.74)	4.3 (2.43 to 7.77)	2.3 (0.79 to 6.77)	1.3 (0.66 to 2.39)	3.6 (2.55 to 5.13)
Treated Spontaneous Bleeds	0.6 (0.33 to 1.26)	2.1 (0.89 to 4.80)	0.8 (0.07 to 9.16)	0.1 (0.06 to 0.29)	1.3 (0.76 to 2.18)
Treated Joint Bleeds	0.5 (0.16 to 1.69)	0.4 (0.14 to 0.96)	0.4 (0.05 to 3.41)	0.1 (0.04 to 0.31)	0.4 (0.21 to 0.82)
Treated Target Joint Bleeds	0.1 (0.01 to 0.31)	0.3 (0.09 to 0.84)	0.3 (0.04 to 2.36)	0.01 (0.01 to 0.18)	0.2 (0.10 to 0.57)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[44]

End point description

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	35	49	11	18	113
Units: bleeds per year
arithmetic mean (confidence interval 95%)
Treated Bleeds	2.9 (0.58 to 8.63)	3.3 (0.77 to 9.28)	1.6 (0.14 to 6.61)	0.6 (0.00 to 4.85)	2.6 (0.46 to 8.16)
All Bleeds	4.8 (1.49 to 11.33)	4.6 (1.40 to 11.09)	2.5 (0.42 to 8.02)	1.3 (0.07 to 6.11)	3.9 (1.05 to 10.13)
Treated Spontaneous Bleeds	1.2 (0.06 to 5.99)	2.2 (0.32 to 7.59)	0.9 (0.01 to 5.33)	0.2 (0.00 to 4.01)	1.5 (0.10 to 6.35)
Treated Joint Bleeds	0.9 (0.02 to 5.42)	0.4 (0.00 to 4.53)	0.4 (0.00 to 4.56)	0.1 (0.00 to 3.95)	0.5 (0.00 to 4.73)
Treated Target Joint Bleeds	0.4 (0.00 to 4.44)	0.3 (0.00 to 4.35)	0.4 (0.00 to 4.40)	0.1 (0.00 to 3.79)	0.3 (0.00 to 4.30)

No statistical analyses for this end point

Secondary: 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

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End point 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 ^[45]

End point description

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	35	49	11	18	113
Units: bleeds per year
median (inter-quartile range (Q1-Q3))
Treated Bleeds	0.3 (0.00 to 2.05)	0.0 (0.00 to 1.13)	0.0 (0.00 to 0.67)	0.0 (0.00 to 0.48)	0.0 (0.00 to 1.09)
All Bleeds	1.9 (0.22 to 5.13)	0.6 (0.00 to 2.25)	0.5 (0.00 to 4.41)	0.5 (0.00 to 2.18)	0.6 (0.00 to 3.34)
Treated Spontaneous Bleeds	0.0 (0.00 to 0.87)	0.0 (0.00 to 0.47)	0.0 (0.00 to 0.00)	0.0 (0.00 to 0.24)	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)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point title

Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

End point 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.

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: treated bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 110)	3.9 (1.05 to 10.12)
13 to 24 Weeks (n = 109)	2.2 (0.31 to 7.53)
25 to 36 Weeks (n = 102)	0.9 (0.01 to 5.31)
37 to 48 Weeks (n = 101)	0.3 (0.00 to 4.38)
49 to 60 Weeks (n = 99)	0.4 (0.00 to 4.56)
61 to 72 Weeks (n = 98)	0.5 (0.00 to 4.73)
73 to 84 Weeks (n = 92)	0.6 (0.00 to 4.80)
85 to 96 Weeks (n = 79)	0.4 (0.00 to 4.46)
97 to 108 Weeks (n = 67)	0.5 (0.00 to 4.71)
109 to 120 Weeks (n = 50)	0.0 (0.0 to 3.69)
121 to 132 Weeks (n = 44)	0.4 (0.00 to 4.48)
133 to 144 Weeks (n = 37)	0.5 (0.00 to 4.62)
145 to 156 Weeks (n = 31)	0.4 (0.00 to 4.53)
157 to 168 Weeks (n = 28)	0.2 (0.00 to 4.01)
169 to 180 Weeks (n = 23)	0.2 (0.00 to 4.08)
181 to 192 Weeks (n = 19)	0.0 (0.0 to 3.69)
193 to 204 Weeks (n = 13)	0.0 (0.0 to 3.69)
205 to 216 Weeks (n = 9)	0.0 (0.0 to 3.69)
217 to 228 Weeks (n = 4)	0.0 (0.0 to 3.69)
229 to 240 Weeks (n = 2)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point title

Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

End point description

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: treated bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 110)	0.0 (0.00 to 4.35)
13 to 24 Weeks (n = 109)	0.0 (0.00 to 0.00)
25 to 36 Weeks (n = 102)	0.0 (0.00 to 0.00)
37 to 48 Weeks (n = 101)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 99)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 98)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 92)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 79)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 67)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 50)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 44)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 37)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 31)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 28)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 23)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 19)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 13)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 9)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 4)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 2)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point title

Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

End point 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.

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: all bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 110)	6.2 (2.35 to 13.40)
13 to 24 Weeks (n = 109)	3.4 (0.78 to 9.29)
25 to 36 Weeks (n = 102)	1.5 (0.11 to 6.40)
37 to 48 Weeks (n = 101)	1.4 (0.09 to 6.29)
49 to 60 Weeks (n = 99)	1.1 (0.04 to 5.74)
61 to 72 Weeks (n = 98)	1.0 (0.02 to 5.53)
73 to 84 Weeks (n = 92)	1.3 (0.07 to 6.12)
85 to 96 Weeks (n = 79)	1.0 (0.02 to 5.56)
97 to 108 Weeks (n = 67)	1.2 (0.05 to 5.86)
109 to 120 Weeks (n = 50)	0.9 (0.01 to 5.34)
121 to 132 Weeks (n = 44)	0.8 (0.01 to 5.20)
133 to 144 Weeks (n = 37)	0.5 (0.00 to 4.62)
145 to 156 Weeks (n = 31)	0.8 (0.01 to 5.20)
157 to 168 Weeks (n = 28)	0.3 (0.00 to 4.31)
169 to 180 Weeks (n = 23)	0.8 (0.01 to 5.14)
181 to 192 Weeks (n = 19)	0.2 (0.00 to 4.15)
193 to 204 Weeks (n = 13)	0.0 (0.0 to 3.69)
205 to 216 Weeks (n = 9)	0.0 (0.0 to 3.69)
217 to 228 Weeks (n = 4)	0.0 (0.0 to 3.69)
229 to 240 Weeks (n = 2)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point title

Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

End point description

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: all bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 110)	0.0 (0.00 to 8.70)
13 to 24 Weeks (n = 109)	0.0 (0.00 to 4.35)
25 to 36 Weeks (n = 102)	0.0 (0.00 to 0.00)
37 to 48 Weeks (n = 101)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 99)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 98)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 92)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 79)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 67)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 50)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 44)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 37)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 31)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 28)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 23)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 19)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 13)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 9)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 4)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 2)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point 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

End point 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.

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: treated spontaneous bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 110)	2.2 (0.31 to 7.56)
13 to 24 Weeks (n = 109)	1.3 (0.06 to 6.04)
25 to 36 Weeks (n = 102)	0.4 (0.00 to 4.45)
37 to 48 Weeks (n = 101)	0.2 (0.00 to 4.04)
49 to 60 Weeks (n = 99)	0.1 (0.00 to 3.96)
61 to 72 Weeks (n = 98)	0.2 (0.00 to 4.05)
73 to 84 Weeks (n = 92)	0.2 (0.00 to 4.08)
85 to 96 Weeks (n = 79)	0.1 (0.00 to 3.92)
97 to 108 Weeks (n = 67)	0.3 (0.00 to 4.34)
109 to 120 Weeks (n = 50)	0.0 (0.0 to 3.69)
121 to 132 Weeks (n = 44)	0.1 (0.00 to 3.89)
133 to 144 Weeks (n = 37)	0.0 (0.0 to 3.69)
145 to 156 Weeks (n = 31)	0.4 (0.00 to 4.53)
157 to 168 Weeks (n = 28)	0.2 (0.00 to 4.01)
169 to 180 Weeks (n = 23)	0.2 (0.00 to 4.08)
181 to 192 Weeks (n = 19)	0.0 (0.0 to 3.69)
193 to 204 Weeks (n = 13)	0.0 (0.0 to 3.69)
205 to 216 Weeks (n = 9)	0.0 (0.0 to 3.69)
217 to 228 Weeks (n = 4)	0.0 (0.0 to 3.69)
229 to 240 Weeks (n = 2)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

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End point 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

End point description

End point type

Secondary

End point timeframe

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

End point values	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	113
Units: treated spontaneous bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 110)	0.0 (0.00 to 0.00)
13 to 24 Weeks (n = 109)	0.0 (0.00 to 0.00)
25 to 36 Weeks (n = 102)	0.0 (0.00 to 0.00)
37 to 48 Weeks (n = 101)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 99)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 98)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 92)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 79)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 67)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 50)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 44)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 37)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 31)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 28)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 23)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 19)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 13)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 9)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 4)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 2)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

Secondary: Safety Summary of the Overall Percentage of Participants with at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale

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End point title

Safety Summary of the Overall Percentage of Participants with at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale

End point 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

End point type

Secondary

End point timeframe

From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm B (Control): No Prophylaxis	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW
Number of subjects analysed	34	18	49	11	18
Units: Percentage of participants
number (not applicable)
Any Adverse Event (AE)	100.0	50.0	93.9	81.8	83.3
AE with Fatal Outcome	0	0	2.0	0	0
Serious AE	29.4	22.2	18.4	18.2	22.2
AE Leading to Withdrawal from Treatment	5.9	0	2.0	0	0
AE Leading to Dose Mod./Interruption	2.9	0	10.2	0	0
Grade ≥3 AE	29.4	22.2	14.3	27.3	16.7
Related AE	44.1	0	26.5	36.4	22.2
Local Injection Site Reaction	26.5	0	14.3	36.4	16.7
Systemic Hypersens./Anaphylac(tic/toid) Reaction	0	0	0	0	0
Thrombotic Microangiopathy (TMA)	2.9	0	4.1	0	0
TMA Event Related to aPCC and Emicizumab	2.9	0	4.1	0	0
Thromboembolic Event (TE)	2.9	5.6	2.0	0	5.6
TE Event Related to aPCC and Emicizumab	2.9	0	2.0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study

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End point title

Percentage of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study ^[46]

End point 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.

End point type

Secondary

End point timeframe

From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW
Number of subjects analysed	33	49	11	18
Units: Percentage of participants
number (not applicable)
Total ADA Negative (Neg+Neg Unaffected)	100	95.9	100	100
ADA Negative, Negative	100	93.9	100	94.4
ADA Negative, Negative (Treatment Unaffected)	0	2.0	0	5.6
Total ADA Positive (Boosted + Induced)	0	4.1	0	0
ADA Positive, Positive (Treatment Boosted)	0	0	0	0
ADA Positive, Positive (Treatment Induced)	0	4.1	0	0
ADA Positive with Neutralizing ADAs	0	4.1	0	0

No statistical analyses for this end point

Secondary: Plasma Trough Concentrations of Emicizumab at Specified Timepoints

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End point title

Plasma Trough Concentrations of Emicizumab at Specified Timepoints ^[47]

End point description

Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. Here, n=participants with available data for this endpoint at specified timepoints for each arm (Arms A, C, D, B (Emi), and All Participants, respectively). Because Arm B (Emi) participants switched to emicizumab prophylaxis after Week 24, Study Weeks for Arm B (Emi) are expressed relative to first emicizumab dose in the results table. Here, '99999' represents no data available because the measurements were all below the LLOQ; '999999' represents data not available because standard deviation not calculable for a single participant; '9999999' represents data not available because no samples were collected.

End point type

Secondary

End point timeframe

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)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks).

End point values	Arm A: 1.5 mg/kg Emicizumab QW	Arm C: 1.5 mg/kg Emicizumab QW	Arm D: 1.5 mg/kg Emicizumab QW	Arm B (Emi): 1.5 mg/kg Emicizumab QW	All Participants: 1.5 mg/kg Emicizumab QW
Number of subjects analysed	34	49	11	18	112
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Week 1 (n=33,48,11,18,110)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Week 2 (n=34,46,10,17,107)	16.2 ( 4.4 )	15.8 ( 5.5 )	18.3 ( 6.5 )	21.7 ( 10.6 )	17.1 ( 6.6 )
Week 3 (n=34,47,11,18,110)	31.6 ( 7.3 )	31.7 ( 8.3 )	32.7 ( 13.0 )	32.3 ( 10.4 )	31.9 ( 8.8 )
Week 4 (n=32,46,11,18,107)	43.8 ( 12.2 )	44.7 ( 11.5 )	49.0 ( 13.5 )	44.6 ( 18.6 )	44.9 ( 13.2 )
Week 5 (n=33,46,11,18,108)	53.5 ( 15.1 )	54.0 ( 13.2 )	59.1 ( 14.6 )	52.2 ( 14.2 )	54.1 ( 14.0 )
Week 7 (n=33,46,11,17,107)	52.8 ( 16.2 )	53.6 ( 14.3 )	54.9 ( 9.2 )	53.3 ( 18.0 )	53.4 ( 14.9 )
Week 9 (n=32,46,11,17,106)	50.4 ( 12.4 )	52.6 ( 15.7 )	53.7 ( 13.8 )	48.9 ( 16.7 )	51.5 ( 14.7 )
Week 13 (n=32,46,11,17,106)	49.3 ( 13.4 )	52.6 ( 15.0 )	53.4 ( 14.0 )	45.2 ( 16.2 )	50.5 ( 14.7 )
Week 17 (n=32,46,11,17,106)	50.7 ( 15.0 )	51.2 ( 14.9 )	57.5 ( 16.9 )	46.5 ( 17.4 )	51.0 ( 15.6 )
Week 21 (n=32,44,11,17,104)	52.6 ( 17.4 )	51.6 ( 17.1 )	55.0 ( 13.7 )	44.5 ( 15.4 )	51.1 ( 16.6 )
Week 25 (n=31,45,11,17,104)	54.6 ( 19.1 )	50.4 ( 16.8 )	52.8 ( 14.1 )	45.8 ( 18.6 )	51.2 ( 17.6 )
Week 33 (n=27,41,10,17,95)	50.7 ( 17.2 )	54.8 ( 16.7 )	57.1 ( 15.2 )	48.1 ( 21.1 )	52.7 ( 17.5 )
Week 41 (n=27,40,10,17,94)	45.3 ( 13.7 )	54.8 ( 23.4 )	63.3 ( 19.4 )	49.3 ( 25.9 )	52.0 ( 21.6 )
Week 49 (n=27,40,9,15,91)	48.0 ( 12.3 )	56.1 ( 22.2 )	55.1 ( 18.7 )	54.6 ( 27.6 )	53.3 ( 20.5 )
Week 61 (n=27,40,10,15,92)	52.2 ( 16.3 )	60.9 ( 27.7 )	53.2 ( 13.8 )	51.8 ( 33.4 )	56.0 ( 24.8 )
Week 73 (n=27,39,9,12,87)	55.5 ( 14.9 )	62.9 ( 24.9 )	51.9 ( 13.0 )	45.6 ( 26.2 )	57.1 ( 22.0 )
Week 85 (n=27,36,5,10,78)	56.9 ( 18.3 )	56.6 ( 22.7 )	50.9 ( 12.5 )	42.5 ( 34.4 )	54.5 ( 22.7 )
Week 97 (n=25,27,5,9,66)	53.2 ( 15.2 )	54.6 ( 20.0 )	53.8 ( 16.9 )	34.4 ( 26.4 )	51.3 ( 19.9 )
Week 109 (n=23,15,3,6,47)	49.6 ( 15.9 )	47.4 ( 12.4 )	49.3 ( 12.8 )	32.8 ( 31.4 )	46.7 ( 17.6 )
Week 121 (n=19,11,2,7,39)	53.8 ( 16.3 )	46.3 ( 12.5 )	53.1 ( 5.0 )	36.1 ( 33.6 )	48.5 ( 19.7 )
Week 133 (n=15,7,1,6,29)	50.5 ( 15.9 )	49.0 ( 18.5 )	52.0 ( 999999 )	48.7 ( 29.4 )	49.8 ( 18.8 )
Week 145 (n=13,5,2,4,24)	51.3 ( 16.6 )	44.0 ( 21.7 )	49.5 ( 10.3 )	38.2 ( 19.0 )	47.4 ( 17.4 )
Week 157 (n=15,4,2,0,21)	58.0 ( 16.5 )	45.5 ( 17.0 )	55.4 ( 19.2 )	9999999 ( 9999999 )	55.3 ( 16.7 )
Week 169 (n=12,3,1,0,16)	55.0 ( 19.3 )	43.2 ( 20.2 )	50.8 ( 999999 )	9999999 ( 9999999 )	52.5 ( 18.7 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)

Adverse event reporting additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Arm A: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm B (Control): No Prophylaxis

Reporting group description

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.

Reporting group title

Arm B (Emi): 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm C: 1.5 mg/kg Emicizumab QW

Reporting group description

Reporting group title

Arm D: 1.5 mg/kg Emicizumab QW

Reporting group description

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
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 34 (32.35%)	5 / 18 (27.78%)	4 / 18 (22.22%)	9 / 49 (18.37%)	2 / 11 (18.18%)
number of deaths (all causes)	0	0	0	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	2 / 49 (4.08%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intentional self-injury
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device loosening
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombotic microangiopathy
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Tooth development disorder
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin necrosis
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcapsular renal haematoma
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	2 / 34 (5.88%)	2 / 18 (11.11%)	1 / 18 (5.56%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cavernous sinus thrombosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm A: 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
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 34 (97.06%)	9 / 18 (50.00%)	15 / 18 (83.33%)	42 / 49 (85.71%)	9 / 11 (81.82%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Skin papilloma
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	5 / 34 (14.71%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	2 / 11 (18.18%)
occurrences all number	5	0	0	3	2
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	1	1	0	1	0
Catheter site pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0
Device related thrombosis
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Fatigue
subjects affected / exposed	3 / 34 (8.82%)	0 / 18 (0.00%)	2 / 18 (11.11%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	4	0	2	2	0
Influenza like illness
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	1
Injection site reaction
subjects affected / exposed	9 / 34 (26.47%)	0 / 18 (0.00%)	3 / 18 (16.67%)	8 / 49 (16.33%)	4 / 11 (36.36%)
occurrences all number	18	0	3	21	5
Pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0
Peripheral swelling
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	1
Pyrexia
subjects affected / exposed	2 / 34 (5.88%)	1 / 18 (5.56%)	2 / 18 (11.11%)	8 / 49 (16.33%)	1 / 11 (9.09%)
occurrences all number	2	1	2	10	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 34 (14.71%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	0 / 11 (0.00%)
occurrences all number	5	0	0	3	0
Nasal congestion
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	0	2
Rhinitis allergic
subjects affected / exposed	4 / 34 (11.76%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	4	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	0	1	0	3	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	2 / 49 (4.08%)	1 / 11 (9.09%)
occurrences all number	1	0	0	2	1
Product issues
Device occlusion
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	1 / 11 (9.09%)
occurrences all number	2	0	0	4	1
Blood glucose increased
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Body temperature increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
C-reactive protein increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Indeterminable ABO blood type
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	0 / 11 (0.00%)
occurrences all number	0	0	0	3	0
Prothrombin fragment 1.2 increased
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	3	0	1	1	0
Fall
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	2
Fibula fracture
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Incision site swelling
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Ligament sprain
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	1
Limb injury
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	3	0	0	1	1
Post procedural constipation
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Procedural nausea
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Procedural pain
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	2 / 18 (11.11%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	1	1	2	2	0
Rib fracture
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	0
Skin abrasion
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	2 / 11 (18.18%)
occurrences all number	1	0	0	0	2
Skin laceration
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	2	0	1	1	0
Thermal burn
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Tibia fracture
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Tooth fracture
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	1	0	1
Procedural hypotension
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 34 (11.76%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	4	1	0	0	1
Headache
subjects affected / exposed	6 / 34 (17.65%)	1 / 18 (5.56%)	4 / 18 (22.22%)	13 / 49 (26.53%)	3 / 11 (27.27%)
occurrences all number	9	1	4	22	3
Neuropathy peripheral
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Migraine
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	0	0	2	1	0
Iron deficiency anaemia
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	0 / 11 (0.00%)
occurrences all number	1	0	0	3	0
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	1
Vision blurred
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	2	0	0	2	0
Abdominal pain upper
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	1	1	0	2	0
Dental caries
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	3 / 18 (16.67%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	3	0	4	1	1
Diarrhoea
subjects affected / exposed	4 / 34 (11.76%)	0 / 18 (0.00%)	1 / 18 (5.56%)	5 / 49 (10.20%)	0 / 11 (0.00%)
occurrences all number	4	0	1	8	0
Enteritis
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0
Large intestine polyp
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0
Food poisoning
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Gastritis
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	0
Nausea
subjects affected / exposed	4 / 34 (11.76%)	0 / 18 (0.00%)	0 / 18 (0.00%)	3 / 49 (6.12%)	0 / 11 (0.00%)
occurrences all number	5	0	0	3	0
Toothache
subjects affected / exposed	4 / 34 (11.76%)	0 / 18 (0.00%)	2 / 18 (11.11%)	2 / 49 (4.08%)	2 / 11 (18.18%)
occurrences all number	4	0	2	3	2
Vomiting
subjects affected / exposed	3 / 34 (8.82%)	0 / 18 (0.00%)	0 / 18 (0.00%)	4 / 49 (8.16%)	0 / 11 (0.00%)
occurrences all number	3	0	0	4	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0
Ecchymosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Eczema
subjects affected / exposed	3 / 34 (8.82%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	3	0	0	0	1
Erythema
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Hair growth abnormal
subjects affected / exposed	3 / 34 (8.82%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	0	0	0
Hand dermatitis
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	0	0	0
Neurodermatitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	0
Rash
subjects affected / exposed	2 / 34 (5.88%)	1 / 18 (5.56%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	2	1	1	1	0
Urticaria
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	9 / 34 (26.47%)	0 / 18 (0.00%)	6 / 18 (33.33%)	12 / 49 (24.49%)	3 / 11 (27.27%)
occurrences all number	17	0	9	33	5
Arthropathy
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	1
Back pain
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	2	0	0	2	0
Groin pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1
Joint swelling
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	0	0	2	1	0
Muscle spasms
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	2 / 49 (4.08%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0
Myalgia
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	2	0	1	1	0
Pain in extremity
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	4 / 49 (8.16%)	0 / 11 (0.00%)
occurrences all number	3	0	0	4	0
Plantar fasciitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Synovitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	2 / 49 (4.08%)	1 / 11 (9.09%)
occurrences all number	2	0	0	2	1
Cellulitis
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	1
Folliculitis
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	0	0	0
Device related infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	3 / 34 (8.82%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	3	0	0	1	0
Herpes virus infection
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Influenza
subjects affected / exposed	1 / 34 (2.94%)	0 / 18 (0.00%)	2 / 18 (11.11%)	10 / 49 (20.41%)	0 / 11 (0.00%)
occurrences all number	2	0	2	10	0
Lower respiratory tract infection
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	11 / 34 (32.35%)	2 / 18 (11.11%)	7 / 18 (38.89%)	16 / 49 (32.65%)	2 / 11 (18.18%)
occurrences all number	29	2	14	27	2
Rhinitis
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0
Sinusitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 18 (0.00%)	3 / 18 (16.67%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	0
Upper respiratory tract infection
subjects affected / exposed	8 / 34 (23.53%)	2 / 18 (11.11%)	2 / 18 (11.11%)	7 / 49 (14.29%)	2 / 11 (18.18%)
occurrences all number	21	2	2	8	2
Urinary tract infection
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)	1 / 49 (2.04%)	0 / 11 (0.00%)
occurrences all number	0	1	1	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0
Dehydration
subjects affected / exposed	1 / 34 (2.94%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0
Electrolyte imbalance
subjects affected / exposed	0 / 34 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0
Hypercholesterolaemia
subjects affected / exposed	2 / 34 (5.88%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 49 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

21 Apr 2016

The main changes were as follows: - The planned number of participants to be enrolled in Arm C was increased from approximately 10-20 to 30-50, to enable the collection of additional safety and efficacy data from participants previously treated with prophylactic bypassing agents; - An additional emicizumab treatment arm (Arm D) was added, to enroll participants on episodic bypassing agents who had participated in NIS BH29768 but were unable to enroll in time to either Arm A or Arm B. This arm enabled the collection of additional efficacy, safety, pharmacokinetic, and pharmacodynamic data and plasma samples for the development and validation of in vitro diagnostic assay(s) suitable for participants receiving emicizumab treatment; - A secondary endpoint was added to compare all bleeds (i.e., treated with coagulation factors or not treated) as an additional assessment of efficacy given that some participants might have reported bleeds they did not treat; A planned interim analysis by the independent Data Monitoring Committee (iDMC), scheduled to occur during the execution of the primary efficacy period, was removed. This was due to the anticipated rapid completion of enrollment (i.e., approximately 7 months) and the very short time interval between the interim and primary analyses; - An option was provided for participants who were approved to up-titrate their dose to potentially combine emicizumab volumes from more than 1 vial into 1 syringe to reduce the number of subcutaneous injections they required.

30 Nov 2016

The main changes were as follows: - The permitted treatment for breakthrough bleeds was specified with guidance regarding the use of concomitant bypassing agents in participants being treated with emicizumab, as well as additional local and central laboratory assessments, in order to minimize the risk and monitor for thromboembolic and thrombotic microangiopathy events; - The use of short-term prophylaxis with aPCC concomitantly with emicizumab was prohibited, in order to minimize the risk of thromboembolic and thrombotic microangiopathy events; Microangiopathic hemolytic anemia/ thrombotic microangiopathy was newly classified as an adverse event of special interest (AESI), and an exclusion criterion to exclude participants at high risk to experience thrombotic microangiopathy was added; - A new efficacy objective to evaluate the clinical effect of emicizumab prophylaxis on the number of spontaneous bleeds over time (spontaneous bleed rate) was added, because this is a bleed category that is impacted by an effective treatment.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
07 Oct 2016	4 participants experienced serious adverse events (2 participants experienced thromboembolic events and 2 participants experienced thrombotic microangiopathy) that resulted in temporary enrollment halt until further evaluation of these safety events, implementation of adequate mitigation measures and discussion with iDMC.	28 Nov 2016

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Primary: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

Secondary: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: 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

Secondary: 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

Secondary: EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis

Secondary: 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)

Secondary: 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)

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants

Secondary: Safety Summary of the Overall Percentage of Participants with at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale

Secondary: Safety Summary of the Overall Percentage of Participants with at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale

Secondary: Percentage of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study

Secondary: Percentage of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study

Secondary: Plasma Trough Concentrations of Emicizumab at Specified Timepoints

Secondary: Plasma Trough Concentrations of Emicizumab at Specified Timepoints

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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