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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 Without Inhibitors

Summary
EudraCT number	2016-000072-17
Trial protocol	GB IE ES DE PL FR IT
Global end of trial date	12 May 2022

Results information
Results version number	v2(current)
This version publication date	05 Nov 2022
First version publication date	30 Sep 2018
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

BH30071

ISRCTN number

US NCT number

NCT02847637

WHO universal trial number (UTN)

Other trial identifiers

Study Acronym: HAVEN 3

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

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

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

12 May 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 May 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to evaluate the efficacy of prophylactic emicizumab (1.5 mg/kg/week or 3 mg/kg/2weeks) compared with no prophylaxis in patients with haemophilia A without Factor VIII (FVIII) inhibitors on the basis of the number of bleeds over time.

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Sep 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 12

Country: Number of subjects enrolled

Costa Rica: 9

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Ireland: 4

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

Japan: 19

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

South Africa: 10

Country: Number of subjects enrolled

Korea, Republic of: 4

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

United States: 26

Worldwide total number of subjects

152

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)

139

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 161 participants were screened; 9 failed screening, and 152 participants, who had previously received either episodic or prophylactic treatment with FVIII agents, were enrolled in this study. Participants in Arms C, A, and B were randomized in a 1:2:2 ratio, respectively; participants in Arm D were enrolled without randomization.

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 C (Control): No Prophylaxis

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Arm type

Active comparator

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

After having completed 24 weeks of episodic factor VIII (FVIII) treatment (no prophylaxis), participants were given the opportunity to switch to emicizumab prophylaxis. Emicizumab was administered subcutaneously (SC) at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks, followed by a maintenance dose of 3 mg/kg/2 weeks.

Arm A: Emicizumab 1.5 mg/kg QW

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered subcutaneously (SC) at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/week.

Arm B: Emicizumab 3 mg/kg Q2W

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered subcutaneously (SC) at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks, followed by a maintenance dose of 3 mg/kg/2 weeks.

Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Arm description

Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered subcutaneously (SC) at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg/week.

Number of subjects in period 1	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Started	18	36	35	63
Completed First 24 Weeks of Treatment	16 ^[1]	35	34	63
Emicizumab Dose Was Up-Titrated	0 ^[2]	1 ^[3]	1 ^[4]	7 ^[5]
Changed Emicizumab Dosing Regimen	1 ^[6]	3 ^[7]	1 ^[8]	1 ^[9]
Completed	17	34	34	63
Not completed	1	2	1	0
Consent withdrawn by subject	-	1	1	-
Lost to follow-up	1	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: A total of 17 participants switched from No Prophylaxis to emicizumab prophylaxis after 24 weeks and completed the study, but 1 of those participants did so after having completed just 23.5 weeks on No Prophylaxis.
[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: Emicizumab dose up-titration was not a study milestone that applied to all participants, but rather only to those who met the criteria for such a change to their dosing.
[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: Emicizumab dose up-titration was not a study milestone that applied to all participants, but rather only to those who met the criteria for such a change to their dosing.
[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: Emicizumab dose up-titration was not a study milestone that applied to all participants, but rather only to those who met the criteria for such a change to their dosing.
[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: Emicizumab dose up-titration was not a study milestone that applied to all participants, but rather only to those who met the criteria for such a change to their dosing.
[6] - 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: Change to a preferred emicizumab dosing regimen was not a study milestone that applied to all participants, but rather only to those who opted for such a change to their dosing after the implementation of protocol version 4.
[7] - 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: Change to a preferred emicizumab dosing regimen was not a study milestone that applied to all participants, but rather only to those who opted for such a change to their dosing after the implementation of protocol version 4.
[8] - 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: Change to a preferred emicizumab dosing regimen was not a study milestone that applied to all participants, but rather only to those who opted for such a change to their dosing after the implementation of protocol version 4.
[9] - 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: Change to a preferred emicizumab dosing regimen was not a study milestone that applied to all participants, but rather only to those who opted for such a change to their dosing after the implementation of protocol version 4.

Baseline characteristics

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Reporting group title

Arm C (Control): No Prophylaxis

Reporting group description

Reporting group title

Arm A: Emicizumab 1.5 mg/kg QW

Reporting group description

Reporting group title

Arm B: Emicizumab 3 mg/kg Q2W

Reporting group description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Reporting group title

Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Reporting group description

Reporting group values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Total
Number of subjects	18	36	35	63	152
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	1	0	0	7	8
Adults (18-64 years)	17	34	34	54	139
From 65-84 years	0	2	1	2	5
85 years and over	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	37.8 ( 12.9 )	39.8 ( 14.0 )	40.4 ( 11.4 )	36.4 ( 14.4 )	-
Sex: Female, Male
Units: participants
Female	0	0	0	0	0
Male	18	36	35	63	152
Number of Participants with <9 or ≥9 Bleeds in the Last 24 Weeks Prior to Study Entry
Units: Subjects
Less Than (<) 9 Bleeds	4	9	5	53	71
Greater Than or Equal To (≥) 9 Bleeds	14	27	30	10	81
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	4	6	10	12	32
Native Hawaiian or Other Pacific Islander	0	1	0	0	1
Black or African American	3	3	1	1	8
White	11	24	20	47	102
More than one race	0	0	0	0	0
Unknown or Not Reported	0	2	4	3	9
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	4	5	7	16
Not Hispanic or Latino	17	32	30	53	132
Unknown or Not Reported	1	0	0	3	4
Number of Target Joints in the Last 24 Weeks Prior to Study Entry
A target joint was defined as at least 3 bleeds into the same joint over the last 24 weeks prior to study entry.
Units: target joints
arithmetic mean (standard deviation)	2.2 ( 1.4 )	2.1 ( 1.4 )	2.2 ( 1.7 )	1.0 ( 1.6 )	-

End points

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Reporting group title

Arm C (Control): No Prophylaxis

Reporting group description

Reporting group title

Arm A: Emicizumab 1.5 mg/kg QW

Reporting group description

Reporting group title

Arm B: Emicizumab 3 mg/kg Q2W

Reporting group description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Reporting group title

Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Reporting group description

Subject analysis set title

Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768

Subject analysis set type

Sub-group analysis

Subject analysis set description

This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received FVIII prophylaxis and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Arm D of this study.

Subject analysis set title

Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This arm includes data from the same participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry and then enrolled in Arm D of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg once per week (QW) subcutaneously (SC) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW until the end of study. The data reported was collected only during emicizumab prophylaxis treatment.

Subject analysis set title

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768

Subject analysis set type

Sub-group analysis

Subject analysis set description

This arm includes historical data from participants in the non-interventional study (NIS) BH29768 who had received episodic FVIII treatment and were followed for a minimum of 24 weeks on the NIS prior to randomization to Arms A or B of this study. A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B.

Subject analysis set title

A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This arm includes data from the same participants who had received episodic FVIII treatment in NIS BH29768 prior to study entry and then were randomized to Arms A or B of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of either 1.5 mg/kg emicizumab SC QW (Arm A) or 3 mg/kg emicizumab SC Q2W (Arm B). A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B. The data reported was collected only during emicizumab prophylaxis treatment.

Subject analysis set title

Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)

Subject analysis set type

Safety analysis

Subject analysis set description

This arm includes all participants from Arm C who had switched to emicizumab prophylaxis up to the primary completion date (PCD; i.e., analysis cutoff) after having completed 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment up to the PCD. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emcizumab SC Q2W.

Subject analysis set title

Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)

Subject analysis set type

Safety analysis

Subject analysis set description

This arm includes all participants from Arm C who switched to emicizumab prophylaxis during the entire study after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. Emicizumab was administered at a loading dose of 3 mg/kg SC once per week (QW) for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC Q2W. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Subject analysis set title

All Emicizumab Participants

Subject analysis set type

Safety analysis

Subject analysis set description

This analysis set included all participants who received emicizumab on the study. For Arm C, it only includes participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab.

Subject analysis set title

Arms A and D: Emicizumab 1.5 mg/kg QW

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set is a combination of all emicizumab-treated participants from Arms A and D who received the same emicizumab prophylaxis dosing regimen at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW.

Subject analysis set title

Arms B and C (Emi): Emicizumab 3 mg/kg Q2W

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set is a combination of all emicizumab-treated participants from Arms B and C (Emi) who received the same emicizumab prophylaxis dosing regimen at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W).

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Bleeds

End point description

The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a negative binomial (NB) regression model, which accounts for different follow-up times, with the number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated bleed rate per year
number (confidence interval 95%)	38.2 (22.86 to 63.76)	1.5 (0.89 to 2.47)	1.3 (0.75 to 2.25)	1.6 (1.07 to 2.44)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.075

Notes
[1] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

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

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.066

Notes
[2] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

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End point title

Annualized Bleeding Rate (ABR) for All Bleeds

End point description

The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient’s number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: all bleed rate per year
number (confidence interval 95%)	47.6 (28.45 to 79.59)	2.5 (1.63 to 3.90)	2.6 (1.63 to 4.29)	3.3 (2.22 to 4.83)

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.103

Notes
[3] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

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

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

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.028

upper limit

0.099

Notes
[4] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

End point description

The number of treated joint bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the patient’s number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "joint bleed" is defined as a bleed reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint; and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. It is considered a “treated joint bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated joint bleed rate per year
number (confidence interval 95%)	26.5 (14.67 to 47.79)	1.1 (0.59 to 1.89)	0.9 (0.44 to 1.67)	1.2 (0.70 to 2.01)

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.07

Notes
[5] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.085

Notes
[6] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

End point description

The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient’s number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated spontaneous bleed rate per year
number (confidence interval 95%)	15.6 (7.60 to 31.91)	1.0 (0.48 to 1.91)	0.3 (0.11 to 0.75)	0.5 (0.23 to 0.94)

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[7]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.056

Notes
[7] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.151

Notes
[8] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

End point description

The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the patient’s number of bleeds as a function of randomization and the time that each patient stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "target joint bleed" is defined as a bleed reported as a joint bleed into a target joint, defined as at least 3 bleeds into the same joint during the last 24 weeks prior to study entry. It is considered a “treated target joint bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated target joint bleed rate per year
number (confidence interval 95%)	13.0 (5.22 to 32.33)	0.6 (0.28 to 1.42)	0.7 (0.27 to 1.64)	0.6 (0.26 to 1.53)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.143

Notes
[9] - Not controlled for type I error

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.147

Notes
[10] - Not controlled for type I error

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

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End point title

Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus pre-study in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks)

End point values	Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768	Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Number of subjects analysed	48	48
Units: treated bleed rate per year
number (confidence interval 95%)	4.8 (3.22 to 7.09)	1.5 (0.98 to 2.33)

ABR Ratio - Dnisp: Emicizumab vs FVIII Prophylaxis

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1. This is an intra-participant analysis of the ABR Ratio for a total of 48 participants (not 96) over two different periods: on study while receiving emicizumab prophylaxis (Dnisp: Emicizumab Prophylaxis) versus before study entry while receiving FVIII prophylaxis in NIS BH29768 (Dnisp: Pre-Study FVIII Prophylaxis).

Comparison groups

Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768 v Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.195

upper limit

0.514

Notes
[11] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

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End point title

Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus pre-study in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768	Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Number of subjects analysed	48	48
Units: all bleed rate per year
number (confidence interval 95%)	8.9 (5.72 to 13.87)	3.3 (2.17 to 5.06)

ABR Ratio - Dnisp: Emicizumab vs FVIII Prophylaxis

Statistical analysis description

Comparison groups

Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768 v Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[12]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

0.626

Notes
[12] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

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End point title

Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus pre-study in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for A+Bnise-FVIII Episodic: 25.71 [15.4-40.9] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for A+Bnise-Emicizumab: 34.71 [24.1-50.6] weeks)

End point values	A+Bnise: Pre-Study Episodic FVIII in NIS BH29768	A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Number of subjects analysed	20	20
Units: treated bleed rate per year
number (confidence interval 95%)	34.4 (27.45 to 43.14)	1.0 (0.43 to 2.54)

ABR Ratio Emicizumab Prophylaxis vs Episodic FVIII

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1. This is an intra-participant analysis of the ABR Ratio for a total of 20 participants (not 40) over two different periods: on study while receiving emicizumab prophylaxis (A+Bnise: Emicizumab Prophylaxis) versus before study entry while receiving episodic FVIII in NIS BH29768 (A+Bnise: Pre-Study Episodic FVIII).

Comparison groups

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 v A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[13]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.067

Notes
[13] - Not controlled for type I error

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Top of page

End point title

Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus pre-study in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	A+Bnise: Pre-Study Episodic FVIII in NIS BH29768	A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Number of subjects analysed	20	20
Units: all bleed rate per year
number (confidence interval 95%)	39.6 (31.94 to 49.04)	1.6 (0.85 to 2.92)

ABR Ratio Emicizumab Prophylaxis vs Episodic FVIII

Statistical analysis description

Comparison groups

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 v A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[14]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.068

Notes
[14] - Not controlled for type I error

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

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End point title

Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25 ^[15]

End point description

The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain ranges from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applies to adults in the randomized population, and only participants in Arms A, B, and C were randomized in this study.

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W
Number of subjects analysed	13	34	29
Units: units on a scale
arithmetic mean (standard deviation)	44.32 ( 17.15 )	31.81 ( 27.86 )	28.35 ( 25.57 )

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0349 ^[16]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

15.97

Confidence interval

level

95%

sides

2-sided

lower limit

1.16

upper limit

30.78

Notes
[16] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0891 ^[17]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

12.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.96

upper limit

26.98

Notes
[17] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

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End point title

Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25 ^[18]

End point description

The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain ranges from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores and it ranges from 0 to 100, with lower scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applies to adults in the randomized population, and only participants in Arms A, B, and C were randomized in this study.

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W
Number of subjects analysed	13	34	29
Units: units on a scale
arithmetic mean (standard deviation)	29.95 ( 13.56 )	24.04 ( 15.26 )	21.39 ( 12.64 )

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1269 ^[19]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

5.91

Confidence interval

level

95%

sides

2-sided

lower limit

-1.72

upper limit

13.55

Notes
[19] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0317 ^[20]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

8.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

16.35

Notes
[20] - Not controlled for type I error

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

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End point title

European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25 ^[21]

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 VAS. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applies to the randomized population, and only participants in Arms A, B, and C were randomized in this study.

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W
Number of subjects analysed	14	34	29
Units: units on a scale
arithmetic mean (standard deviation)	72.57 ( 8.20 )	76.61 ( 20.99 )	81.72 ( 15.55 )

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3402 ^[22]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-4.04

Confidence interval

level

95%

sides

2-sided

lower limit

-12.43

upper limit

4.35

Notes
[22] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0373 ^[23]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-9.15

Confidence interval

level

95%

sides

2-sided

lower limit

-17.74

upper limit

-0.55

Notes
[23] - Not controlled for type I error

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

Top of page

End point title

EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25 ^[24]

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 VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applies to the randomized population, and only participants in Arms A, B, and C were randomized in this study.

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W
Number of subjects analysed	14	34	29
Units: units on a scale
arithmetic mean (standard deviation)	0.63 ( 0.20 )	0.76 ( 0.24 )	0.76 ( 0.18 )

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[25]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

-0.04

Notes
[25] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

Arm C (Control): No Prophylaxis v Arm B: Emicizumab 3 mg/kg Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0059 ^[26]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

-0.04

Notes
[26] - Not controlled for type I error

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25

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End point title

Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25 ^[27]

End point description

The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. The analysis was not performed due to the small number of adolescents randomized or enrolled in this study.

End point type

Secondary

End point timeframe

Week 25

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint applies to adolescents in the randomized population, and only participants in Arms A, B, and C were randomized in this study.

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W
Number of subjects analysed	0 ^[28]	0 ^[29]	0 ^[30]
Units: units on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[28] - Analysis was not performed due to small number of adolescents randomized to this study.
[29] - Analysis was not performed due to small number of adolescents randomized to this study.
[30] - Analysis was not performed due to small number of adolescents randomized to this study.

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis

End point description

The percentage of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks)

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	33.3	94.4	85.7	87.3	50.0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis

End point description

The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	5.6	8.3	11.4	9.3	0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	2.9	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis

End point description

The percentage of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants with at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants with at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis

End point description

The percentage of participants with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries. It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	5.6	17.1	4.8	6.3

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis

End point description

Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis

End point description

Local adverse events that occurred within 24 hours after study drug administration and, in the investigator’s opinion, were judged to be related to study drug injection, were captured as an “injection-site reaction” on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a “local injection-site reaction.” At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	25.0	20.0	33.3	12.5

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis

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End point title

Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of at least 24 weeks.

End point type

Secondary

End point timeframe

End point values	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W (Switch up to PCD)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study

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End point title

Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study ^[31]

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 and those who opted for a change in dosing regimen (after implementation of protocol v4), only AEs that occurred before either one of those events are included. Hypersens.= hypersensitivity; Mod. = modification

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)

Notes
[31] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: percentage of participants
number (not applicable)
Any Adverse Event (AE)	100.0	97.1	100.0	88.2	98.0
AE with Fatal Outcome	0.0	0.0	0.0	0.0	0.0
Serious AE	27.8	22.9	25.4	5.9	23.2
AE Leading to Withdrawal from Treatment	0.0	2.9	0.0	0.0	0.7
AE Leading to Dose Mod./Interruption	2.8	0.0	1.6	0.0	1.3
Grade ≥3 AE	36.1	28.6	20.6	5.9	24.5
Related AE	30.6	34.3	47.6	23.5	37.7
Local Injection Site Reaction	27.8	22.9	39.7	23.5	31.1
Systemic Hypersens./Anaphylac(tic/toid) Reaction	0.0	0.0	0.0	0.0	0.0
Thromboembolic Event (TE)	0.0	2.9	1.6	0.0	1.3
Thrombotic Microangiopathy (TMA)	0.0	0.0	0.0	0.0	0.0

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

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End point title

Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants ^[32]

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 or change of dosing regimen were excluded.

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)

Notes
[32] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: bleeds per year
number (confidence interval 95%)
Treated Bleeds	0.8 (0.48 to 1.29)	0.7 (0.40 to 1.08)	1.5 (1.02 to 2.34)	1.2 (0.47 to 3.19)	1.2 (0.92 to 1.56)
All Bleeds	1.1 (0.72 to 1.66)	1.1 (0.73 to 1.73)	2.4 (1.68 to 3.43)	2.2 (1.16 to 4.15)	1.8 (1.46 to 2.29)
Treated Spontaneous Bleeds	0.5 (0.23 to 1.03)	0.2 (0.10 to 0.45)	0.5 (0.30 to 0.78)	0.4 (0.12 to 1.35)	0.4 (0.29 to 0.58)
Treated Joint Bleeds	0.4 (0.24 to 0.73)	0.4 (0.21 to 0.68)	1.0 (0.60 to 1.76)	0.7 (0.25 to 1.66)	0.7 (0.53 to 1.00)
Treated Target Joint Bleeds	0.2 (0.11 to 0.43)	0.2 (0.08 to 0.39)	0.6 (0.26 to 1.42)	0.4 (0.13 to 1.31)	0.4 (0.29 to 0.66)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

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End point title

Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants ^[33]

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 or change of dosing regimen were excluded.

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)

Notes
[33] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: bleeds per year
arithmetic mean (confidence interval 95%)
Treated Bleeds	1.2 (0.04 to 5.83)	0.8 (0.01 to 5.23)	1.7 (0.15 to 6.69)	1.2 (0.05 to 5.95)	1.3 (0.07 to 6.07)
All Bleeds	1.4 (0.09 to 6.29)	1.3 (0.07 to 6.10)	2.6 (0.45 to 8.15)	2.2 (0.32 to 7.58)	2.0 (0.23 to 7.19)
Treated Spontaneous Bleeds	0.7 (0.00 to 4.97)	0.3 (0.00 to 4.22)	0.6 (0.00 to 4.81)	0.4 (0.00 to 4.48)	0.5 (0.00 to 4.68)
Treated Joint Bleeds	0.6 (0.00 to 4.94)	0.5 (0.00 to 4.64)	1.1 (0.04 to 5.78)	0.6 (0.00 to 4.95)	0.8 (0.01 to 5.23)
Treated Target Joint Bleeds	0.4 (0.00 to 4.54)	0.3 (0.00 to 4.28)	0.6 (0.00 to 4.92)	0.4 (0.00 to 4.50)	0.5 (0.00 to 4.64)

No statistical analyses for this end point

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

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End point title

Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants ^[34]

End point description

End point type

Secondary

End point timeframe

From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks)

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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: bleeds per year
median (inter-quartile range (Q1-Q3))
Treated Bleeds	0.4 (0.00 to 1.28)	0.4 (0.00 to 1.06)	0.5 (0.00 to 1.07)	0.0 (0.00 to 2.48)	0.4 (0.00 to 1.15)
All Bleeds	0.5 (0.09 to 1.77)	0.8 (0.23 to 1.92)	1.0 (0.38 to 2.70)	1.6 (0.20 to 3.8)	1.0 (0.19 to 2.37)
Treated Spontaneous Bleeds	0.0 (0.00 to 0.51)	0.0 (0.00 to 0.23)	0.0 (0.00 to 0.48)	0.0 (0.00 to 0.65)	0.0 (0.00 to 0.40)
Treated Joint Bleeds	0.2 (0.00 to 0.89)	0.2 (0.00 to 0.49)	0.0 (0.00 to 0.59)	0.0 (0.00 to 1.09)	0.2 (0.00 to 0.72)
Treated Target Joint Bleeds	0.1 (0.00 to 0.55)	0.0 (0.00 to 0.37)	0.0 (0.00 to 0.00)	0.0 (0.00 to 0.81)	0.0 (0.00 to 0.38)

No statistical analyses for this end point

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

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End point title

Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Emicizumab 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: Treated bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 150)	1.9 (0.21 to 7.04)
13 to 24 Weeks (n = 148)	1.9 (0.20 to 6.99)
25 to 36 Weeks (n = 144)	1.0 (0.02 to 5.57)
37 to 48 Weeks (n = 144)	0.9 (0.01 to 5.35)
49 to 60 Weeks (n = 142)	1.0 (0.02 to 5.54)
61 to 72 Weeks (n = 140)	1.1 (0.04 to 5.72)
73 to 84 Weeks (n = 140)	0.7 (0.01 to 5.12)
85 to 96 Weeks (n = 131)	1.1 (0.03 to 5.68)
97 to 108 Weeks (n = 117)	0.9 (0.01 to 5.32)
109 to 120 Weeks (n = 104)	0.6 (0.00 to 4.83)
121 to 132 Weeks (n = 99)	0.5 (0.00 to 4.72)
133 to 144 Weeks (n = 94)	1.1 (0.03 to 5.68)
145 to 156 Weeks (n = 93)	1.1 (0.03 to 5.70)
157 to 168 Weeks (n = 89)	1.1 (0.04 to 5.78)
169 to 180 Weeks (n = 85)	1.3 (0.06 to 6.05)
181 to 192 Weeks (n = 83)	1.0 (0.02 to 5.56)
193 to 204 Weeks (n = 82)	1.6 (0.13 to 6.57)
205 to 216 Weeks (n = 80)	0.8 (0.01 to 5.15)
217 to 228 Weeks (n = 76)	0.5 (0.00 to 4.59)
229 to 240 Weeks (n = 72)	0.8 (0.01 to 5.30)
241 to 252 Weeks (n = 67)	0.3 (0.00 to 4.21)
253 to 264 Weeks (n = 58)	0.5 (0.00 to 4.72)
265 to 276 Weeks (n = 22)	0.2 (0.00 to 4.09)
277 to 288 Weeks (n = 5)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

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

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End point title

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

End point description

End point type

Secondary

End point timeframe

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: Treated bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 150)	0.0 (0.00 to 4.35)
13 to 24 Weeks (n = 148)	0.0 (0.00 to 2.17)
25 to 36 Weeks (n = 144)	0.0 (0.00 to 0.00)
37 to 48 Weeks (n = 144)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 142)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 140)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 140)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 131)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 117)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 104)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 99)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 94)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 93)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 89)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 85)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 83)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 82)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 80)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 76)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 72)	0.0 (0.00 to 0.00)
241 to 252 Weeks (n = 67)	0.0 (0.00 to 0.00)
253 to 264 Weeks (n = 58)	0.0 (0.00 to 0.00)
265 to 276 Weeks (n = 22)	0.0 (0.00 to 0.00)
277 to 288 Weeks (n = 5)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

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

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End point title

Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Emicizumab 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

End point type

Secondary

End point timeframe

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: All bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 150)	3.8 (0.97 to 9.91)
13 to 24 Weeks (n = 148)	2.8 (0.53 to 8.45)
25 to 36 Weeks (n = 144)	1.8 (0.17 to 6.83)
37 to 48 Weeks (n = 144)	1.4 (0.10 to 6.33)
49 to 60 Weeks (n = 142)	1.5 (0.10 to 6.37)
61 to 72 Weeks (n = 140)	1.6 (0.14 to 6.66)
73 to 84 Weeks (n = 140)	1.2 (0.05 to 5.88)
85 to 96 Weeks (n = 131)	1.4 (0.09 to 6.30)
97 to 108 Weeks (n = 117)	1.3 (0.06 to 6.02)
109 to 120 Weeks (n = 104)	0.8 (0.01 to 5.21)
121 to 132 Weeks (n = 99)	0.8 (0.01 to 5.20)
133 to 144 Weeks (n = 94)	1.2 (0.04 to 5.84)
145 to 156 Weeks (n = 93)	1.3 (0.06 to 6.02)
157 to 168 Weeks (n = 89)	1.4 (0.09 to 6.28)
169 to 180 Weeks (n = 85)	1.7 (0.15 to 6.72)
181 to 192 Weeks (n = 83)	1.4 (0.08 to 6.19)
193 to 204 Weeks (n = 82)	1.7 (0.16 to 6.74)
205 to 216 Weeks (n = 80)	1.1 (0.04 to 5.72)
217 to 228 Weeks (n = 76)	0.6 (0.00 to 4.91)
229 to 240 Weeks (n = 72)	0.9 (0.02 to 5.41)
241 to 252 Weeks (n = 67)	0.4 (0.00 to 4.47)
253 to 264 Weeks (n = 58)	0.6 (0.00 to 4.86)
265 to 276 Weeks (n = 22)	0.2 (0.00 to 4.09)
277 to 288 Weeks (n = 5)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

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

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End point title

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

End point description

End point type

Secondary

End point timeframe

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: All bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 150)	0.0 (0.00 to 4.35)
13 to 24 Weeks (n = 148)	0.0 (0.00 to 4.35)
25 to 36 Weeks (n = 144)	0.0 (0.00 to 4.35)
37 to 48 Weeks (n = 144)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 142)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 140)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 140)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 131)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 117)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 104)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 99)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 94)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 93)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 89)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 85)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 83)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 82)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 80)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 76)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 72)	0.0 (0.00 to 0.00)
241 to 252 Weeks (n = 67)	0.0 (0.00 to 0.00)
253 to 264 Weeks (n = 58)	0.0 (0.00 to 0.00)
265 to 276 Weeks (n = 22)	0.0 (0.00 to 0.00)
277 to 288 Weeks (n = 5)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

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

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End point title

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

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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

End point type

Secondary

End point timeframe

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: Treated spontaneous bleeds per year
arithmetic mean (confidence interval 95%)
1 to 12 Weeks (n = 150)	0.7 (0.00 to 4.98)
13 to 24 Weeks (n = 148)	0.7 (0.00 to 5.00)
25 to 36 Weeks (n = 144)	0.3 (0.00 to 4.30)
37 to 48 Weeks (n = 144)	0.4 (0.00 to 4.53)
49 to 60 Weeks (n = 142)	0.5 (0.00 to 4.60)
61 to 72 Weeks (n = 140)	0.3 (0.00 to 4.25)
73 to 84 Weeks (n = 140)	0.1 (0.00 to 3.95)
85 to 96 Weeks (n = 131)	0.4 (0.00 to 4.48)
97 to 108 Weeks (n = 117)	0.2 (0.00 to 4.14)
109 to 120 Weeks (n = 104)	0.2 (0.00 to 4.03)
121 to 132 Weeks (n = 99)	0.1 (0.00 to 3.96)
133 to 144 Weeks (n = 94)	0.6 (0.00 to 4.78)
145 to 156 Weeks (n = 93)	0.6 (0.00 to 4.87)
157 to 168 Weeks (n = 89)	0.2 (0.00 to 4.09)
169 to 180 Weeks (n = 85)	0.4 (0.00 to 4.50)
181 to 192 Weeks (n = 83)	0.2 (0.00 to 4.01)
193 to 204 Weeks (n = 82)	0.1 (0.00 to 3.80)
205 to 216 Weeks (n = 80)	0.3 (0.00 to 4.24)
217 to 228 Weeks (n = 76)	0.1 (0.00 to 3.81)
229 to 240 Weeks (n = 72)	0.1 (0.00 to 3.94)
241 to 252 Weeks (n = 67)	0.1 (0.00 to 3.82)
253 to 264 Weeks (n = 58)	0.3 (0.00 to 4.29)
265 to 276 Weeks (n = 22)	0.2 (0.00 to 4.09)
277 to 288 Weeks (n = 5)	0.0 (0.0 to 3.69)

No statistical analyses for this end point

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

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End point title

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

End point description

End point type

Secondary

End point timeframe

End point values	All Emicizumab Participants
Number of subjects analysed	151
Units: Treated spontaneous bleeds per year
median (inter-quartile range (Q1-Q3))
1 to 12 Weeks (n = 150)	0.0 (0.00 to 0.00)
13 to 24 Weeks (n = 148)	0.0 (0.00 to 0.00)
25 to 36 Weeks (n = 144)	0.0 (0.00 to 0.00)
37 to 48 Weeks (n = 144)	0.0 (0.00 to 0.00)
49 to 60 Weeks (n = 142)	0.0 (0.00 to 0.00)
61 to 72 Weeks (n = 140)	0.0 (0.00 to 0.00)
73 to 84 Weeks (n = 140)	0.0 (0.00 to 0.00)
85 to 96 Weeks (n = 131)	0.0 (0.00 to 0.00)
97 to 108 Weeks (n = 117)	0.0 (0.00 to 0.00)
109 to 120 Weeks (n = 104)	0.0 (0.00 to 0.00)
121 to 132 Weeks (n = 99)	0.0 (0.00 to 0.00)
133 to 144 Weeks (n = 94)	0.0 (0.00 to 0.00)
145 to 156 Weeks (n = 93)	0.0 (0.00 to 0.00)
157 to 168 Weeks (n = 89)	0.0 (0.00 to 0.00)
169 to 180 Weeks (n = 85)	0.0 (0.00 to 0.00)
181 to 192 Weeks (n = 83)	0.0 (0.00 to 0.00)
193 to 204 Weeks (n = 82)	0.0 (0.00 to 0.00)
205 to 216 Weeks (n = 80)	0.0 (0.00 to 0.00)
217 to 228 Weeks (n = 76)	0.0 (0.00 to 0.00)
229 to 240 Weeks (n = 72)	0.0 (0.00 to 0.00)
241 to 252 Weeks (n = 67)	0.0 (0.00 to 0.00)
253 to 264 Weeks (n = 58)	0.0 (0.00 to 0.00)
265 to 276 Weeks (n = 22)	0.0 (0.00 to 0.00)
277 to 288 Weeks (n = 5)	0.0 (0.00 to 0.00)

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study

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End point title

Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study ^[35]

End point description

A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies (ADAs) against emicizumab in plasma. A sample was considered positive for anti-emicizumab antibodies if the test result reached or exceeded a pre-determined threshold. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample.

End point type

Secondary

End point timeframe

From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks)

Notes
[35] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: percentage of participants
number (not applicable)
Total ADA Positive (Boosted+Induced)	8.3	5.7	1.6	0.0	4.0
ADA Positive (Treatment Boosted)	0.0	2.9	0.0	0.0	0.7
ADA Positive (Treatment Induced)	8.3	2.9	1.6	0.0	3.3

No statistical analyses for this end point

Secondary: Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors

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End point title

Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors ^[36]

End point description

Levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold.

End point type

Secondary

End point timeframe

From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks)

Notes
[36] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	All Emicizumab Participants
Number of subjects analysed	36	35	63	17	151
Units: percentage of participants
number (not applicable)	0.0	0.0	0.0	0.0	0.0

No statistical analyses for this end point

Secondary: Trough Plasma Concentration (Ctrough) of Emicizumab

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End point title

Trough Plasma Concentration (Ctrough) of Emicizumab ^[37]

End point description

Trough plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm C (Control) switched from no prophylaxis to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm C (Emi) are expressed relative to first emicizumab dose. The 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 in each arm (A, B, D, Cemi), respectively. Here, '999999' represents no data available because no patient samples were taken at that timepoint.

End point type

Secondary

End point timeframe

Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, 253, 265, and 277

Notes
[37] - 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: This endpoint only applies to participants in Arms A, B, C (Emi), and D who were treated with emicizumab.

End point values	Arm A: Emicizumab 1.5 mg/kg QW	Arm B: Emicizumab 3 mg/kg Q2W	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	Arms A and D: Emicizumab 1.5 mg/kg QW	Arms B and C (Emi): Emicizumab 3 mg/kg Q2W
Number of subjects analysed	36	35	63	17	99	52
Units: micrograms per milliliter (μg/mL)
arithmetic mean (standard deviation)
Week 1 (n=35,35,61,17,96,52)	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Week 2 (n=36,35,62,17,98,52)	16.3 ( 6.1 )	16.8 ( 5.9 )	17.3 ( 5.4 )	19.6 ( 8.2 )	16.9 ( 5.7 )	17.7 ( 6.8 )
Week 3 (n=36,35,62,17,98,52)	29.1 ( 9.3 )	29.2 ( 6.5 )	30.5 ( 8.7 )	33.0 ( 12.6 )	30.0 ( 8.9 )	30.5 ( 9.0 )
Week 4 (n=36,35,62,17,98,52)	41.9 ( 11.8 )	41.4 ( 9.7 )	42.4 ( 9.4 )	47.9 ( 15.0 )	42.2 ( 10.3 )	43.6 ( 11.9 )
Week 5 (n=34,35,62,17,96,52)	48.0 ( 13.7 )	48.8 ( 12.3 )	54.5 ( 12.5 )	59.6 ( 20.7 )	52.2 ( 13.2 )	52.4 ( 16.2 )
Week 7 (n=32,33,61,17,93,50)	47.9 ( 16.1 )	48.4 ( 11.4 )	52.4 ( 13.3 )	55.2 ( 16.2 )	50.9 ( 14.4 )	50.7 ( 13.5 )
Week 9 (n=33,34,63,17,96,51)	49.0 ( 16.4 )	46.4 ( 14.1 )	55.1 ( 16.1 )	53.1 ( 15.7 )	53.0 ( 16.4 )	48.7 ( 14.9 )
Week 13 (n=33,34,63,17,96,51)	48.7 ( 18.3 )	47.6 ( 16.0 )	55.0 ( 15.9 )	47.9 ( 18.1 )	52.8 ( 16.9 )	47.7 ( 16.5 )
Week 17 (n=33,34,62,17,95,51)	54.3 ( 24.0 )	48.9 ( 17.7 )	55.0 ( 16.5 )	43.4 ( 16.2 )	54.7 ( 19.3 )	47.0 ( 17.2 )
Week 21 (n=32,34,61,16,93,50)	50.7 ( 20.2 )	47.3 ( 15.5 )	55.1 ( 16.2 )	45.6 ( 18.8 )	53.6 ( 17.7 )	46.7 ( 16.4 )
Week 25 (n=31,34,58,17,89,51)	50.5 ( 21.7 )	47.6 ( 18.9 )	54.8 ( 16.8 )	51.8 ( 23.4 )	53.3 ( 18.7 )	49.0 ( 20.4 )
Week 33 (n=30,34,58,16,88,50)	56.3 ( 25.3 )	52.9 ( 22.4 )	59.1 ( 18.5 )	52.0 ( 21.3 )	58.1 ( 20.9 )	52.6 ( 21.9 )
Week 41 (n=31,34,58,17,89,51)	54.8 ( 24.2 )	48.4 ( 18.8 )	59.6 ( 21.4 )	50.7 ( 24.4 )	57.9 ( 22.4 )	49.2 ( 20.6 )
Week 49 (n=31,32,58,17,89,49)	55.4 ( 22.9 )	52.2 ( 20.2 )	60.2 ( 19.9 )	54.3 ( 21.3 )	58.5 ( 21.0 )	52.9 ( 20.4 )
Week 61 (n=31,33,57,17,88,50)	55.3 ( 21.4 )	52.0 ( 21.1 )	61.1 ( 22.5 )	52.5 ( 19.8 )	59.1 ( 22.1 )	52.2 ( 20.5 )
Week 73 (n=31,32,57,15,88,47)	54.4 ( 21.5 )	51.6 ( 21.3 )	58.5 ( 19.2 )	47.8 ( 18.4 )	57.1 ( 20.0 )	50.4 ( 20.3 )
Week 85 (n=31,32,55,13,86,45)	48.8 ( 17.4 )	46.4 ( 20.4 )	56.7 ( 18.5 )	47.7 ( 17.9 )	53.8 ( 18.5 )	46.8 ( 19.5 )
Week 97 (n=28,29,48,11,76,40)	52.6 ( 20.0 )	50.9 ( 21.0 )	58.5 ( 18.7 )	51.7 ( 28.3 )	56.3 ( 19.3 )	51.1 ( 22.9 )
Week 109 (n=26,26,39,11,65,37)	53.9 ( 19.2 )	52.3 ( 19.5 )	59.0 ( 19.1 )	46.4 ( 27.0 )	57.0 ( 19.1 )	50.5 ( 21.7 )
Week 121 (n=23,24,37,10,60,34)	58.8 ( 21.1 )	55.0 ( 22.0 )	57.1 ( 18.2 )	50.0 ( 25.2 )	57.7 ( 19.2 )	53.5 ( 22.7 )
Week 133 (n=23,23,34,10,57,33)	55.3 ( 26.0 )	54.7 ( 18.5 )	59.3 ( 19.2 )	54.6 ( 26.9 )	57.7 ( 22.1 )	54.7 ( 20.9 )
Week 145 (n=23,22,33,6,56,28)	54.1 ( 23.7 )	51.3 ( 17.7 )	55.7 ( 20.4 )	44.8 ( 11.6 )	55.0 ( 21.6 )	49.9 ( 16.6 )
Week 157 (n=19,21,30,9,49,30)	57.6 ( 27.8 )	52.2 ( 21.4 )	55.9 ( 23.7 )	46.8 ( 24.0 )	56.6 ( 25.1 )	50.6 ( 21.9 )
Week 169 (n=16,16,22,8,38,24)	53.9 ( 21.8 )	50.3 ( 19.6 )	56.4 ( 18.0 )	45.8 ( 20.6 )	55.3 ( 19.4 )	48.8 ( 19.6 )
Week 181 (n=15,11,17,8,32,19)	59.8 ( 24.8 )	48.8 ( 22.1 )	57.5 ( 21.3 )	43.5 ( 26.2 )	58.6 ( 22.7 )	46.5 ( 23.4 )
Week 193 (n=17,18,21,7,38,25)	53.9 ( 21.0 )	52.4 ( 24.6 )	60.5 ( 19.6 )	42.1 ( 19.1 )	57.5 ( 20.2 )	49.5 ( 23.3 )
Week 205 (n=18,20,23,8,41,28)	53.5 ( 20.8 )	51.9 ( 22.4 )	58.6 ( 24.1 )	54.2 ( 31.1 )	56.4 ( 22.6 )	52.6 ( 24.6 )
Week 217 (n=16,19,26,9,42,28)	54.4 ( 20.8 )	55.0 ( 20.6 )	60.8 ( 23.2 )	50.8 ( 26.1 )	58.3 ( 22.2 )	53.6 ( 22.1 )
Week 229 (n=17,17,26,9,43,26)	54.9 ( 20.9 )	47.9 ( 18.9 )	54.4 ( 19.3 )	53.5 ( 30.4 )	54.6 ( 19.7 )	49.8 ( 23.1 )
Week 241 (n=16,18,24,6,40,24)	51.9 ( 19.3 )	50.2 ( 16.8 )	60.1 ( 23.3 )	52.0 ( 36.1 )	56.8 ( 21.9 )	50.6 ( 22.2 )
Week 253 (n=15,15,22,4,37,19)	58.6 ( 28.7 )	46.5 ( 17.8 )	58.4 ( 24.7 )	40.3 ( 43.9 )	58.5 ( 26.0 )	45.2 ( 23.9 )
Week 265 (n=10,13,17,0,27,13)	58.7 ( 25.8 )	47.3 ( 14.5 )	60.0 ( 23.9 )	999999 ( 999999 )	59.5 ( 24.2 )	47.3 ( 14.5 )
Week 277 (n=6,5,2,0,8,5)	71.9 ( 34.2 )	49.0 ( 16.2 )	61.3 ( 17.2 )	999999 ( 999999 )	69.2 ( 30.1 )	49.0 ( 16.2 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Total observation time for all participants: From enrollment until study completion (median [min-max] 262.3 [14.4-288.3] weeks); Arm C (Control): From enrollment to 24 weeks on no prophylaxis (median [min-max]: 24.00 [14.4-25.0] weeks)

Adverse event reporting additional description

Adverse events (AEs) in emicizumab-treated subjects are reported from first dose until study completion, including after dose up-titration or change of dosing regimen. AEs in Arm C are reported in 2 groups: Arm C (Control) for the first 24 weeks on no prophylaxis; Arm C (Emi) for those who switched after 24 weeks to receive emicizumab prophylaxis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Arm C (Control): No Prophylaxis

Reporting group description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks of no prophylaxis. The results for this control arm represent data collected during the first 24 weeks on study while receiving their usual care of episodic treatment with FVIII.

Reporting group title

Arm A: Emicizumab 1.5 mg/kg QW

Reporting group description

Reporting group title

Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Reporting group description

Reporting group title

Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)

Reporting group description

This arm includes all participants from Arm C who switched to emicizumab prophylaxis after completing 24 weeks on No Prophylaxis. The data reported was collected only during emicizumab prophylaxis treatment. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) SC QW for the first 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC Q2W. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Reporting group title

Arm B: Emicizumab 3 mg/kg Q2W

Reporting group description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Serious adverse events	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	Arm B: Emicizumab 3 mg/kg Q2W
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 18 (5.56%)	10 / 36 (27.78%)	16 / 63 (25.40%)	1 / 17 (5.88%)	8 / 35 (22.86%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
PARATHYROID TUMOUR BENIGN
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
BONE GIANT CELL TUMOUR BENIGN
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
PAPILLARY THYROID CANCER
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
SALIVARY GLAND NEOPLASM
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
HAEMATOMA
subjects affected / exposed	1 / 18 (5.56%)	1 / 36 (2.78%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
Respiratory, thoracic and mediastinal disorders
EPISTAXIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
SUICIDAL IDEATION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
Product issues
DEVICE LOOSENING
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
Injury, poisoning and procedural complications
POST PROCEDURAL HAEMATOMA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
MUSCLE STRAIN
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
MUSCLE RUPTURE
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
FEMORAL NECK FRACTURE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
DURAL TEAR
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
FEMUR FRACTURE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
POISONING
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
ROAD TRAFFIC ACCIDENT
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
TENDON RUPTURE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
Cardiac disorders
ATRIAL FLUTTER
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
ACUTE CORONARY SYNDROME
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
ARRHYTHMIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
Nervous system disorders
CEREBROSPINAL FLUID LEAKAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
HEADACHE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
PUTAMEN HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
SEIZURE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
CEREBRAL HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
FISTULA OF SMALL INTESTINE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
MELAENA
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
SPLENIC ARTERY ANEURYSM
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
HAEMATEMESIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
HAEMATOCHEZIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
ANAL HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
PANCREATITIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
RETROPERITONEAL HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
MALLORY-WEISS SYNDROME
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
Renal and urinary disorders
NEPHROLITHIASIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMATURIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
URETEROLITHIASIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
RENAL HAEMATOMA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
Endocrine disorders
HYPERPARATHYROIDISM
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	1 / 35 (2.86%)
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
Musculoskeletal and connective tissue disorders
GROIN PAIN
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
BACK PAIN
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
OSTEOARTHRITIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
RHABDOMYOLYSIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
SYNOVITIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
Infections and infestations
PYELONEPHRITIS ACUTE
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
ABSCESS LIMB
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
APPENDICITIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (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
ARTHRITIS BACTERIAL
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
GINGIVAL ABSCESS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (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
SUBPERIOSTEAL ABSCESS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
TONSILLITIS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (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
Metabolism and nutrition disorders
DIABETES MELLITUS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm C (Control): No Prophylaxis	Arm A: Emicizumab 1.5 mg/kg QW	Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)	Arm C(Emi): Emicizumab 3 mg/kg Q2W(Switch From No Prophylaxis)	Arm B: Emicizumab 3 mg/kg Q2W
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 18 (27.78%)	35 / 36 (97.22%)	61 / 63 (96.83%)	15 / 17 (88.24%)	33 / 35 (94.29%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
PAPILLOMA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
Vascular disorders
HAEMATOMA
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	2	1	0	1
HYPERTENSION
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	4 / 63 (6.35%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	4	0	0
General disorders and administration site conditions
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	2 / 63 (3.17%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	2	1	0
PAIN
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	2 / 63 (3.17%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	1	2	1	1
PYREXIA
subjects affected / exposed	0 / 18 (0.00%)	4 / 36 (11.11%)	6 / 63 (9.52%)	1 / 17 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	4	7	1	2
ASTHENIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	0	0	1	2
INJECTION SITE REACTION
subjects affected / exposed	0 / 18 (0.00%)	10 / 36 (27.78%)	24 / 63 (38.10%)	4 / 17 (23.53%)	8 / 35 (22.86%)
occurrences all number	0	37	42	4	25
Immune system disorders
SEASONAL ALLERGY
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	2 / 63 (3.17%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	1	2	1	0
DRUG HYPERSENSITIVITY
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
HYPERSENSITIVITY
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Reproductive system and breast disorders
ERECTILE DYSFUNCTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0
Respiratory, thoracic and mediastinal disorders
NASAL CONGESTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	2 / 63 (3.17%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	2	1	0
OROPHARYNGEAL PAIN
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	6 / 63 (9.52%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	12	0	1
COUGH
subjects affected / exposed	0 / 18 (0.00%)	4 / 36 (11.11%)	7 / 63 (11.11%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	7	9	0	0
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	4 / 63 (6.35%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	4	0	2
SLEEP DISORDER
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
INSOMNIA
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	2 / 63 (3.17%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	2	0	2
ANXIETY
subjects affected / exposed	0 / 18 (0.00%)	4 / 36 (11.11%)	4 / 63 (6.35%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	4	7	0	2
Investigations
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	5 / 63 (7.94%)	1 / 17 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	2	5	1	4
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	3 / 63 (4.76%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	3	0	3
BLOOD PRESSURE DIASTOLIC INCREASED
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	4 / 63 (6.35%)	1 / 17 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	2	4	1	3
Injury, poisoning and procedural complications
BITE
subjects affected / exposed	1 / 18 (5.56%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	2	0	0
LIMB INJURY
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	3 / 63 (4.76%)	1 / 17 (5.88%)	3 / 35 (8.57%)
occurrences all number	0	2	5	1	5
TOOTH FRACTURE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	2 / 63 (3.17%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	2	1	0
LIGAMENT SPRAIN
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	10 / 63 (15.87%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	2	17	1	1
ARTHROPOD BITE
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	5	0	0
LIGAMENT INJURY
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
CONTUSION
subjects affected / exposed	0 / 18 (0.00%)	3 / 36 (8.33%)	6 / 63 (9.52%)	2 / 17 (11.76%)	2 / 35 (5.71%)
occurrences all number	0	15	13	3	3
JOINT INJURY
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	5 / 63 (7.94%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	9	0	5
MUSCLE STRAIN
subjects affected / exposed	0 / 18 (0.00%)	3 / 36 (8.33%)	2 / 63 (3.17%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	3	2	0	0
SKIN ABRASION
subjects affected / exposed	1 / 18 (5.56%)	0 / 36 (0.00%)	3 / 63 (4.76%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	3	0	1
BACK INJURY
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	1	0	1	0
FALL
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	8 / 63 (12.70%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	2	9	1	1
SKIN LACERATION
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	3 / 63 (4.76%)	2 / 17 (11.76%)	1 / 35 (2.86%)
occurrences all number	0	1	3	2	1
TONGUE INJURY
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
ROAD TRAFFIC ACCIDENT
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	1	0	1	1
Congenital, familial and genetic disorders
HYDROCELE
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
Nervous system disorders
HEADACHE
subjects affected / exposed	1 / 18 (5.56%)	7 / 36 (19.44%)	14 / 63 (22.22%)	2 / 17 (11.76%)	7 / 35 (20.00%)
occurrences all number	1	13	33	2	30
PARAESTHESIA
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	3 / 63 (4.76%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	1	3	1	1
DIZZINESS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	2	1	1	2
SCIATICA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	0	0	3	1
Ear and labyrinth disorders
TINNITUS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0
Eye disorders
CATARACT
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
Gastrointestinal disorders
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	2	2	0	1
CONSTIPATION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	5 / 63 (7.94%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	6	0	1
GASTRITIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	1 / 63 (1.59%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	1	0	3
DIARRHOEA
subjects affected / exposed	1 / 18 (5.56%)	4 / 36 (11.11%)	6 / 63 (9.52%)	2 / 17 (11.76%)	5 / 35 (14.29%)
occurrences all number	2	4	6	3	6
VOMITING
subjects affected / exposed	1 / 18 (5.56%)	1 / 36 (2.78%)	3 / 63 (4.76%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	2	1	5	1	1
DENTAL CARIES
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	3 / 63 (4.76%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	7	3	0	1
ABDOMINAL PAIN
subjects affected / exposed	0 / 18 (0.00%)	3 / 36 (8.33%)	2 / 63 (3.17%)	3 / 17 (17.65%)	0 / 35 (0.00%)
occurrences all number	0	5	3	4	0
NAUSEA
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	7 / 63 (11.11%)	0 / 17 (0.00%)	4 / 35 (11.43%)
occurrences all number	0	1	9	0	4
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	4 / 63 (6.35%)	0 / 17 (0.00%)	3 / 35 (8.57%)
occurrences all number	0	0	4	0	3
DYSPEPSIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	1	0	2
LARGE INTESTINE POLYP
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	1 / 63 (1.59%)	1 / 17 (5.88%)	1 / 35 (2.86%)
occurrences all number	0	1	1	1	1
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	0 / 18 (0.00%)	5 / 36 (13.89%)	9 / 63 (14.29%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	7	9	0	1
ECZEMA
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	3 / 63 (4.76%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	3	0	0
PRURITUS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	4 / 63 (6.35%)	1 / 17 (5.88%)	2 / 35 (5.71%)
occurrences all number	0	1	5	1	2
RASH MACULO-PAPULAR
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
ALOPECIA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Renal and urinary disorders
NEPHROLITHIASIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	0	0	3
Endocrine disorders
HYPOTHYROIDISM
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Musculoskeletal and connective tissue disorders
GROIN PAIN
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	4 / 63 (6.35%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	5	0	0
ARTHRITIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	1	0	1	0
JOINT SWELLING
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	8 / 63 (12.70%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	10	0	1
PAIN IN EXTREMITY
subjects affected / exposed	1 / 18 (5.56%)	5 / 36 (13.89%)	6 / 63 (9.52%)	0 / 17 (0.00%)	4 / 35 (11.43%)
occurrences all number	1	6	7	0	4
SYNOVITIS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	7 / 63 (11.11%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	3	9	0	0
MUSCLE SPASMS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	2 / 63 (3.17%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	3	2	0	0
MUSCLE CONTRACTURE
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	2 / 63 (3.17%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	2	0	2
MUSCULOSKELETAL STIFFNESS
subjects affected / exposed	1 / 18 (5.56%)	0 / 36 (0.00%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	1	0	0
TENOSYNOVITIS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
TENDONITIS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	2 / 63 (3.17%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	3	0	0
BACK PAIN
subjects affected / exposed	1 / 18 (5.56%)	6 / 36 (16.67%)	8 / 63 (12.70%)	2 / 17 (11.76%)	3 / 35 (8.57%)
occurrences all number	1	11	10	3	4
HAEMOPHILIC ARTHROPATHY
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	1 / 63 (1.59%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	1	0	2
MYALGIA
subjects affected / exposed	0 / 18 (0.00%)	4 / 36 (11.11%)	6 / 63 (9.52%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	4	7	0	1
ARTHRALGIA
subjects affected / exposed	1 / 18 (5.56%)	16 / 36 (44.44%)	25 / 63 (39.68%)	3 / 17 (17.65%)	11 / 35 (31.43%)
occurrences all number	1	41	78	5	26
Infections and infestations
SINUSITIS
subjects affected / exposed	1 / 18 (5.56%)	0 / 36 (0.00%)	4 / 63 (6.35%)	2 / 17 (11.76%)	0 / 35 (0.00%)
occurrences all number	3	0	4	2	0
BRONCHITIS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	3 / 63 (4.76%)	2 / 17 (11.76%)	1 / 35 (2.86%)
occurrences all number	0	4	4	2	1
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0
BACTERIAL INFECTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
GASTRIC INFECTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	1 / 63 (1.59%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0
INFLUENZA
subjects affected / exposed	0 / 18 (0.00%)	7 / 36 (19.44%)	9 / 63 (14.29%)	2 / 17 (11.76%)	4 / 35 (11.43%)
occurrences all number	0	8	10	2	4
NASOPHARYNGITIS
subjects affected / exposed	1 / 18 (5.56%)	9 / 36 (25.00%)	20 / 63 (31.75%)	3 / 17 (17.65%)	8 / 35 (22.86%)
occurrences all number	1	16	35	4	19
EAR INFECTION
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0
CONJUNCTIVITIS
subjects affected / exposed	1 / 18 (5.56%)	1 / 36 (2.78%)	0 / 63 (0.00%)	1 / 17 (5.88%)	2 / 35 (5.71%)
occurrences all number	1	1	0	1	2
LOCALISED INFECTION
subjects affected / exposed	1 / 18 (5.56%)	0 / 36 (0.00%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	0	0	2
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 18 (5.56%)	8 / 36 (22.22%)	14 / 63 (22.22%)	3 / 17 (17.65%)	6 / 35 (17.14%)
occurrences all number	2	11	19	4	9
GASTROENTERITIS
subjects affected / exposed	0 / 18 (0.00%)	3 / 36 (8.33%)	1 / 63 (1.59%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	3	1	0	2
PHARYNGITIS
subjects affected / exposed	0 / 18 (0.00%)	4 / 36 (11.11%)	3 / 63 (4.76%)	0 / 17 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	4	10	0	1
RHINITIS
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	2	0	0	2
DIARRHOEA INFECTIOUS
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
COVID-19
subjects affected / exposed	0 / 18 (0.00%)	3 / 36 (8.33%)	7 / 63 (11.11%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	3	7	1	0
BODY TINEA
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
PERIODONTITIS
subjects affected / exposed	0 / 18 (0.00%)	1 / 36 (2.78%)	0 / 63 (0.00%)	2 / 17 (11.76%)	1 / 35 (2.86%)
occurrences all number	0	1	0	2	1
ABSCESS LIMB
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
CORONAVIRUS INFECTION
subjects affected / exposed	0 / 18 (0.00%)	0 / 36 (0.00%)	0 / 63 (0.00%)	1 / 17 (5.88%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	0
Metabolism and nutrition disorders
HYPERURICAEMIA
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	0 / 63 (0.00%)	0 / 17 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	2	0	0	2
HYPERCHOLESTEROLAEMIA
subjects affected / exposed	0 / 18 (0.00%)	2 / 36 (5.56%)	1 / 63 (1.59%)	0 / 17 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

12 Sep 2016

The main changes to the protocol are as follows: - The specific factor VIII (FVIII) prophylactic dose and frequency was removed from the definition for FVIII prophylaxis regimen for the inclusion criterion for patients previously treated with FVIII prophylaxis to be enrolled in Arm D.; - Modified dose escalation criteria to more precisely define the subpopulation who may benefit from an increased dose of emicizumab; - Added clarification regarding the efficacy analyses that will be performed for treated bleeds (i.e., treated with coagulation factors) and all bleeds (i.e., both treated and not treated with coagulation factors) given that some patients may report bleeds that they did not treat. In addition, rate of spontaneous bleeds was added as a secondary endpoint.; - Added safety updates regarding a case of atypical hemolytic uremic syndrome (aHUS) and a patient who developed cavernous sinus thrombosis. Both occurred in patients with hemophilia A with FVIII inhibitors receiving bypassing agents.; - The optional interim analysis section was removed based on the anticipated study timelines, as no interim analyses are expected for this study.; - Provided the option for patients to potentially combine emicizumab volumes (if necessary) from up to two vials into 1 syringe to reduce the number of subcutaneous injections they may require.

30 Nov 2016

The main changes to the protocol are as follows: - The safety sections were updated with the most recent safety information regarding 2 cases of thrombotic microangiopathy (TMA) and 2 patients who developed thromboembolic events in Study BH29884. Both occurred in patients with hemophilia A with FVIII inhibitors receiving bypassing agents. The section for risks associated with emicizumab was updated accordingly, and microangiopathic hemolytic anemia/TMA is newly classified as an adverse event of special interest.; - Although factor VIII (FVIII) and activated prothrombin complex concentrate (aPCC) are fundamentally different in their potential interaction with emicizumab, the amended protocol points investigators to the fact that circulating emicizumab increases patients’ coagulation potential and provides suggestions about the use of FVIII in conjunction with emicizumab.; - The van Elteren test will be used as back-up statistical method for the primary analysis instead of the Wilcoxon rank sum test to allow a stratified analysis to be performed.; - Although the use of bypassing agents is unlikely in patients without inhibitors, for completeness and clarity, the amended protocol includes guidelines for their use in patients receiving emicizumab, including dosage and requirements for laboratory monitoring.

20 Dec 2019

Protocol v4 (dated 20 December 2019): Upon implementation of this amendment, treatment duration was extended until 5 years after the last patient was enrolled to enable the collection of additional long-term safety and efficacy data. During this study prolongation, each patient chose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg every 4 weeks [Q4W]) and continued on that dosing regimen until discontinuation from the study.

Were there any global interruptions to the trial? No

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 Without Inhibitors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25

Secondary: Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants with at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants with at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Adverse Event of Changes from Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis

Secondary: Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis

Secondary: Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study

Secondary: Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study

Secondary: Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

Secondary: Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

Secondary: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

Secondary: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study

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 Without Inhibitors