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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

Summary
EudraCT number	2026-000042-29
Trial protocol	Outside EU/EEA
Global end of trial date	29 Aug 2025

Results information
Results version number	v1(current)
This version publication date	15 Mar 2026
First version publication date	15 Mar 2026
Other versions

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

YO39309

ISRCTN number

US NCT number

NCT03315455

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche Ltd

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, 4058

Public contact

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

Scientific contact

F. Hoffmann-La Roche Ltd, F. Hoffmann-La Roche Ltd, 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

29 Aug 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Aug 2022

Global end of trial reached?

Yes

Global end of trial date

29 Aug 2025

Was the trial ended prematurely?

Main objective of the trial

- To evaluate the efficacy of prophylactic emicizumab (i.e., administered on a scheduled basis with the intent to prevent bleeds) compared with no prophylaxis in patients with hemophilia A - To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds in pediatric patients

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 applicable 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

The control group for the primary efficacy endpoint will be a concurrent, no prophylaxis “usual care” arm, in which patients who were on episodic therapy prior to study entry will be randomized (2:2:1 prophylactic emicizumab 1.5 mg/kg QW:prophylactic emicizumab 6 mg/kg Q4W:no prophylaxis), which will enable an inter-patient comparison of the treatment and control groups. A second comparison will be a comparison to an individual patient’s bleed rate calculated over the 24 weeks prior to study entry, from the medical record. This will enable intrapatient analyses of bleed rates to be performed. All patients, whether assigned to receive prophylactic emicizumab or no prophylaxis, will continue to receive FVIII or rFVIIa on an episodic basis for the treatment of breakthrough bleeds during the study. Specific doses of FVIII or rFVIIa will not be mandated in the study but investigators should review with patients and approve the appropriate dose to be used to treat breakthrough bleeds. For patients receiving emicizumab, breakthrough bleeds should be treated with the lowest FVIII or rFVIIa dose expected to achieve hemostasis, which may be lower than the patients’ prior FVIII or rFVIIa dose.

Actual start date of recruitment

26 Apr 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hong Kong: 5

Country: Number of subjects enrolled

Malaysia: 5

Country: Number of subjects enrolled

Thailand: 5

Country: Number of subjects enrolled

China: 70

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 76 patients were screened for eligibility, 6 of whom were deemed ineligible, and 70 participants were randomized to this study to Arms A, B, and C. Arm D was added later in a protocol amendment (Version 4) after the study had already started. For Arm D, a total of 16 were screened and 15 eligible pediatric patients were enrolled.

Screening details

Patients with hemophilia A who previously received episodic treatment with FVIII or bypassing agents were recruited for the study at 13 sites across 4 countries/regions. The majority of patients were enrolled from mainland China.

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: No Prophylaxis (Control), Then Emicizumab

Arm description

Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm C did not receive any prophylactic treatment for at least 24 weeks (Control). After 24 weeks, participants had the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

After 24 weeks of no prophylaxis (i.e., episodic standard-of-care treatment for bleeds), participants randomized to Arm C had the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until the end of the study.

Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW

Arm description

Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm A received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants randomized to Arm A received emicizumab prophylaxis at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW until the end of the study.

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W

Arm description

Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm B received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 6 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants randomized to Arm B received emicizumab prophylaxis at a dose of 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until the end of the study.

Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW

Arm description

Participants <12 years old with hemophilia A and FVIII inhibitors who were enrolled to Arm D received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Pediatric participants <12 years old who enrolled in Arm D received emicizumab prophylaxis at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW until the end of the study.

Number of subjects in period 1	Arm C: No Prophylaxis (Control), Then Emicizumab	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW
Started	14	29	27	15
Completed 24 Weeks in the Study	14	29	27	15
Completed Treatment with Emicizumab	14	27	27	15
Completed	14	27	27	15
Not completed	0	2	0	0
Adverse event, serious fatal	-	1	-	-
Consent withdrawn by subject	-	1	-	-

Baseline characteristics

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Reporting group title

Arm C: No Prophylaxis (Control), Then Emicizumab

Reporting group description

Reporting group title

Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Reporting group title

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W

Reporting group description

Reporting group title

Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Reporting group values	Arm C: No Prophylaxis (Control), Then Emicizumab	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Total
Number of subjects	14	29	27	15	85
Age Categorical
Units: Participants
<18 Years Old	2	3	6	15	26
≥18 to <65 Years Old	12	26	20	0	58
≥65 Years Old	0	0	1	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	27.5 ( 10.9 )	32.2 ( 12.0 )	28.6 ( 13.5 )	7.5 ( 2.2 )	-
Sex: Female, Male
Units: Participants
Female	0	0	0	0	0
Male	14	29	27	15	85
Race/Ethnicity, Customized
Units: Subjects
Asian	14	29	27	15	85
Race/Ethnicity, Customized
Units: Subjects
Not Hispanic or Latino	14	29	27	15	85
Factor VIII (FVIII) Inhibitor Status at Study Entry
Units: Subjects
FVIII Inhibitor Positive	3	5	7	15	30
FVIII Inhibitor Negative (Non-Inhibitor)	11	24	20	0	55
Categorical Number of Bleeds (<9 or ≥9) in the Past 24 Weeks Prior to Study Entry
Units: Subjects
<9 Bleeds	3	7	6	5	21
≥9 Bleeds	11	22	21	10	64

End points

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Reporting group title

Arm C: No Prophylaxis (Control), Then Emicizumab

Reporting group description

Reporting group title

Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Reporting group title

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W

Reporting group description

Reporting group title

Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Subject analysis set title

Arm C (Control): No Prophylaxis

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm C did not receive any prophylactic treatment for the first 24 weeks of the study (Control). Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of bleeds during the study.

Subject analysis set title

A+B NIS: Previous Episodic Therapy Pre-Study

Subject analysis set type

Per protocol

Subject analysis set description

The NIS population includes all patients who participated in NIS BH29768 prior to enrollment in Study YO39309 (pooled from Arms A and B). It consists of patients previously treated with episodic FVIII or bypassing agents. This previous episodic therapy analysis group includes historical bleed data during participation in NIS BH29768 prior to enrollment in this study from 2 patients enrolled in Arm A who had FVIII inhibitors and had received episodic therapy with bypassing agents and 2 patients enrolled in Arm B who did not have FVIII inhibitors and had received episodic therapy with FVIII.

Subject analysis set title

A+B NIS: Emicizumab Prophylaxis On-Study

Subject analysis set type

Per protocol

Subject analysis set description

The NIS population includes all patients who participated in NIS BH29768 prior to enrollment in Study YO39309 (pooled from Arms A and B). It consists of patients previously treated with episodic FVIII or bypassing agents. On this study, the participants received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by either 1.5 mg/kg (in Arm A) or 6 mg/kg (in Arm B) via SC injection Q4W for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Subject analysis set title

Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

This Arm C (Emi) is part of Safety Population 2, which includes all patients who switched to receive emicizumab and received at least one dose of emicizumab. After 24 weeks in Arm C (Control) on no prophylaxis, participants were given the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Subject analysis set title

Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W

Subject analysis set type

Per protocol

Subject analysis set description

This Arm C (Emi) is part of the PK-Evaluable Population which includes all patients who received at least one dose of emicizumab and had at least one post-baseline emicizumab concentration result. After 24 weeks in Arm C (Control) on no prophylaxis, participants were given the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Primary: Model-Based Annualized Bleeding Rate for Treated Bleeds

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End point title

Model-Based Annualized Bleeding Rate for Treated Bleeds ^[1]

End point description

The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Primary

End point timeframe

From Baseline to at least 24 weeks

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated bleeds per year
number (confidence interval 95%)	1.0 (0.53 to 1.85)	1.0 (0.50 to 1.84)	1.2 (0.48 to 3.13)	27.0 (13.29 to 54.91)

Arm A vs. Arm C for Treated Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.084

Notes
[2] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Arm B vs. Arm C for Treated Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

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

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.082

Notes
[3] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Primary: Mean Calculated Annualized Bleeding Rate for Treated Bleeds

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End point title

Mean Calculated Annualized Bleeding Rate for Treated Bleeds ^[4] ^[5]

End point description

The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Primary

End point timeframe

From Baseline to at least 24 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis of the primary endpoint was conducted only on the results of the model-based ABR for treated bleeds; the calculated ABR is only a supportive analysis.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated bleeds per year
arithmetic mean (confidence interval 95%)	1.4 (0.09 to 6.29)	1.5 (0.10 to 6.38)	1.2 (0.05 to 5.94)	43.7 (31.71 to 58.71)

No statistical analyses for this end point

Primary: Median Calculated Annualized Bleeding Rate for Treated Bleeds

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End point title

Median Calculated Annualized Bleeding Rate for Treated Bleeds ^[6] ^[7]

End point description

End point type

Primary

End point timeframe

From Baseline to at least 24 weeks

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis of the primary endpoint was conducted only on the results of the model-based ABR for treated bleeds; the calculated ABR is only a supportive analysis.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated bleeds per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 1.23)	0.0 (0.00 to 2.26)	0.0 (0.00 to 2.08)	45.3 (21.74 to 70.49)

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate for All Bleeds

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End point title

Model-Based Annualized Bleeding Rate for All Bleeds ^[8]

End point description

The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As “all bleeds” comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[8] - 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: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: All bleeds per year
number (confidence interval 95%)	1.9 (1.23 to 2.97)	2.1 (1.33 to 3.26)	3.8 (2.21 to 6.69)	41.1 (26.37 to 64.19)

Arm A vs. Arm C for All Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

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

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

0.026

upper limit

0.084

Notes
[9] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Arm B vs. Arm C for All Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

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

0.028

upper limit

0.092

Notes
[10] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Secondary: Mean Calculated Annualized Bleeding Rate for All Bleeds

Top of page

End point title

Mean Calculated Annualized Bleeding Rate for All Bleeds ^[11]

End point description

The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As “all bleeds” comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: All bleeds per year
arithmetic mean (confidence interval 95%)	2.7 (0.51 to 8.37)	3.1 (0.67 to 8.94)	3.8 (1.01 to 10.01)	53.0 (39.71 to 69.33)

No statistical analyses for this end point

Secondary: Median Calculated Annualized Bleeding Rate for All Bleeds

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End point title

Median Calculated Annualized Bleeding Rate for All Bleeds ^[12]

End point description

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[12] - 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: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: All bleeds per year
median (inter-quartile range (Q1-Q3))	1.5 (0.00 to 4.21)	1.9 (0.00 to 5.62)	2.1 (0.00 to 5.77)	56.7 (26.09 to 70.81)

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

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End point title

Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds ^[13]

End point description

The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/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.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated spontaneous bleeds per year
number (confidence interval 95%)	0.4 (0.18 to 0.96)	0.5 (0.20 to 1.12)	0.6 (0.18 to 2.16)	23.6 (9.28 to 60.03)

Arm A vs. Arm C for Treated Spontaneous Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[14]

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

0.053

Notes
[14] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Arm B vs. Arm C for Treated Spontaneous Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[15]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.007

upper limit

0.059

Notes
[15] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

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End point title

Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds ^[16]

End point description

The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/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.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[16] - 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: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated spontaneous bleeds per year
arithmetic mean (confidence interval 95%)	0.5 (0.00 to 4.66)	0.6 (0.00 to 4.88)	0.6 (0.00 to 4.92)	30.9 (20.95 to 43.85)

No statistical analyses for this end point

Secondary: Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

Top of page

End point title

Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds ^[17]

End point description

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated spontaneous bleeds per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 0.96)	0.0 (0.00 to 0.00)	21.8 (6.48 to 52.18)

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

Top of page

End point title

Model-Based Annualized Bleeding Rate for Treated Joint Bleeds ^[18]

End point description

The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as “joint” based on 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, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

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: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated joint bleeds per year
number (confidence interval 95%)	0.7 (0.36 to 1.46)	0.6 (0.28 to 1.22)	0.1 (0.02 to 0.88)	17.7 (8.33 to 37.57)

Arm A vs. Arm C for Treated Joint Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[19]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.102

Notes
[19] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Arm B vs. Arm C for Treated Joint Bleeds

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.084

Notes
[20] - Statistical significance was controlled at a 2-sided alpha level of 0.05. Hierarchical testing was used to account for multiple comparisons.

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Top of page

End point title

Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds ^[21]

End point description

The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as “joint” based on 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, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated joint bleeds per year
arithmetic mean (confidence interval 95%)	1.0 (0.02 to 5.57)	0.8 (0.01 to 5.20)	0.1 (0.00 to 3.93)	25.5 (16.62 to 37.56)

No statistical analyses for this end point

Secondary: Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Top of page

End point title

Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds ^[22]

End point description

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated joint bleeds per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 1.40)	0.0 (0.00 to 0.00)	10.9 (8.70 to 50.00)

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds

Top of page

End point title

Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds ^[23]

End point description

The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated target joint bleeds per year
number (confidence interval 95%)	0.4 (0.18 to 1.09)	0.3 (0.12 to 0.85)	0 (0 to 0)	8.6 (3.15 to 23.42)

Arm B vs. Arm C for Treated Target Joint Bleeds

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[24]

Method

ABR Ratio

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.011

upper limit

0.122

Notes
[24] - Not controlled for Type I error

Arm A vs. Arm C for Treated Target Joint Bleeds

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[25]

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

0.163

Notes
[25] - Not controlled for Type I error

Secondary: Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Top of page

End point title

Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds ^[26]

End point description

The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated target joint bleeds per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 1.13)	0.0 (0.00 to 0.00)	6.5 (0.00 to 19.68)

No statistical analyses for this end point

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Top of page

End point title

Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds ^[27]

End point description

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

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: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	15	14
Units: Treated target joint bleeds per year
arithmetic mean (confidence interval 95%)	0.7 (0.00 to 5.06)	0.5 (0.00 to 4.76)	0.0 (0.0 to 3.69)	15.6 (8.83 to 25.47)

No statistical analyses for this end point

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Top of page

End point title

Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

End point type

Secondary

End point timeframe

Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)

End point values	A+B NIS: Previous Episodic Therapy Pre-Study	A+B NIS: Emicizumab Prophylaxis On-Study
Number of subjects analysed	4	4
Units: Treated bleeds per year
arithmetic mean (full range (min-max))	13.02 (4.96 to 21.61)	0.24 (0.00 to 0.97)

No statistical analyses for this end point

Secondary: Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age

Top of page

End point title

Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age ^[28]

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 and Week 25

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the participants were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	25	21	8
Units: score on a scale
arithmetic mean (standard deviation)	27.85 ( 19.82 )	24.20 ( 16.09 )	42.53 ( 14.00 )

Arm B vs. Arm C for Haem-A-QoL PH Score

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0204 ^[29]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

18.33

Confidence interval

level

95%

sides

2-sided

lower limit

2.97

upper limit

33.68

Notes
[29] - Type I error controlled

Arm A vs. Arm C for Haem-A-QoL PH Score

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0515 ^[30]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

14.68

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

29.46

Notes
[30] - Type I error controlled

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Top of page

End point title

Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The ABR was calculated for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. “All bleeds” comprises both treated and non-treated bleeds, and the 72-hour rule was implemented separately for each type. For treated bleeds, the 72-hour rule meant that 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. For non-treated bleeds, the 72-hour rule was calculated as a treatment-free period of 72 hours from the bleed itself.

End point type

Secondary

End point timeframe

End point values	A+B NIS: Previous Episodic Therapy Pre-Study	A+B NIS: Emicizumab Prophylaxis On-Study
Number of subjects analysed	4	4
Units: All bleeds per year
arithmetic mean (full range (min-max))	39.67 (15.13 to 92.55)	2.04 (1.10 to 3.38)

No statistical analyses for this end point

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age

Top of page

End point title

Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age ^[31]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 25

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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	25	21	8
Units: score on a scale
arithmetic mean (standard deviation)
Value at Baseline (BL)	50.60 ( 20.38 )	42.14 ( 14.10 )	51.25 ( 23.41 )
Change from BL to Week 25	-20.20 ( 19.82 )	-22.14 ( 16.09 )	-5.63 ( 14.00 )

No statistical analyses for this end point

Secondary: Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age

Top of page

End point title

Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age ^[32]

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 and Week 25

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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	25	21	8
Units: score on a scale
arithmetic mean (standard deviation)	37.26 ( 16.17 )	29.30 ( 14.60 )	43.32 ( 7.47 )

Arm B vs. Arm C for Haem-A-QoL Total Score

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0297 ^[33]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

14.01

Confidence interval

level

95%

sides

2-sided

lower limit

1.44

upper limit

26.59

Notes
[33] - Not controlled for Type I error

Arm A vs. Arm C for Haem-A-QoL Total Score

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3281 ^[34]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

6.06

Confidence interval

level

95%

sides

2-sided

lower limit

-6.27

upper limit

18.4

Notes
[34] - Not controlled for Type I error

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age

Top of page

End point title

Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age ^[35]

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.

End point type

Secondary

End point timeframe

Baseline and Week 25

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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	25	21	8
Units: score on a scale
arithmetic mean (standard deviation)
Value at Baseline (BL)	49.15 ( 16.04 )	46.59 ( 12.58 )	42.05 ( 17.89 )
Change from BL to Week 25	-10.14 ( 16.17 )	-17.61 ( 14.60 )	-2.50 ( 7.47 )

No statistical analyses for this end point

Secondary: Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age

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End point title

Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age ^[36]

End point description

The Haemo-QoL-SF contains 35 items covering nine dimensions considered relevant for the adolescent’s (aged 12-17 years) health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The score ranges from 0 to 100, and a higher score is indicative of poorer HRQoL. According to the pre-specified statistical analysis plan, no statistical analyses were performed on the protocol-defined endpoints for the Haemo-QoL-SF due to the small number of adolescents randomized to Arms A, B and C.

End point type

Secondary

End point timeframe

Baseline and Week 25

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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	3	5	2
Units: score on a scale
arithmetic mean (full range (min-max))
Value at Baseline (BL)	44.5 (35.7 to 58.6)	35.7 (20.0 to 50.7)	44.7 (35.0 to 54.3)
Value at Week 25	32.9 (27.9 to 39.3)	27.6 (10.0 to 40.0)	21.5 (13.6 to 29.3)

No statistical analyses for this end point

Secondary: Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25

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End point title

Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25 ^[37]

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 and Week 25

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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	28	25	9
Units: score on a scale
arithmetic mean (standard deviation)	81.82 ( 23.19 )	85.94 ( 15.20 )	78.36 ( 20.68 )

Arm C vs. Arm A for EQ-5D-5L VAS

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6165 ^[38]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

-3.46

Confidence interval

level

95%

sides

2-sided

lower limit

-17.23

upper limit

10.31

Notes
[38] - Not controlled for Type I error

Arm C vs. Arm B for EQ-5D-5L VAS

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2797 ^[39]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

-7.58

Confidence interval

level

95%

sides

2-sided

lower limit

-21.48

upper limit

6.33

Notes
[39] - Not controlled for Type I error

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25

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End point title

Arms A, B, and C: Change from Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 ^[40]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 25

Notes
[40] - 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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	25	10
Units: score on a scale
arithmetic mean (standard deviation)
Value at Baseline (BL) (n=29,25,10)	74.59 ( 16.91 )	78.96 ( 12.91 )	84.50 ( 15.07 )
Change from BL to Week 25 (n=28,25,9)	4.82 ( 19.13 )	7.40 ( 16.67 )	-2.00 ( 13.27 )

No statistical analyses for this end point

Secondary: Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25

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End point title

Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25 ^[41]

End point description

The European Quality of Life 5-Dimensions-5 Levels Questionnaire (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 and Week 25

Notes
[41] - 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 is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	28	25	9
Units: score on a scale
arithmetic mean (standard deviation)	0.79 ( 0.27 )	0.82 ( 0.17 )	0.74 ( 0.35 )

Arm C vs. Arm A for EQ-5D-5L Index Utility

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.489 ^[42]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.09

Notes
[42] - Not controlled for Type I error

Arm C vs. Arm B for EQ-5D-5L Index Utility

Comparison groups

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W v Arm C (Control): No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2454 ^[43]

Method

ANCOVA

Parameter type

Difference in Adjusted Means

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.06

Notes
[43] - Not controlled for Type I error

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Index Utility Score at Week 25

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End point title

Arms A, B, and C: Change from Baseline in EQ-5D-5L Index Utility Score at Week 25 ^[44]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 25

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a comparison between the randomized arms only (Arms A, B, and C). Arm C: No Prophylaxis is presented as an analysis set because it only includes data from the first 24 weeks while the patients were not receiving prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	25	10
Units: score on a scale
arithmetic mean (standard deviation)
Value at Baseline (BL) (n=29,25,10)	0.68 ( 0.27 )	0.75 ( 0.20 )	0.76 ( 0.27 )
Change from BL to Week 25 (n=28,25,9)	0.08 ( 0.22 )	0.08 ( 0.21 )	0.02 ( 0.09 )

No statistical analyses for this end point

Secondary: Arm D: Change from Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age

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End point title

Arm D: Change from Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age ^[45]

End point description

The Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire contains 35 items covering nine dimensions considered relevant for the children’s health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The scores range from 0 to 100, and higher scores are indicative of poorer HRQoL.

End point type

Secondary

End point timeframe

Baseline and Week 25

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a single-group descriptive analysis of Arm D that only includes a subset of patients (8-12 years old) from this arm.

End point values	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW
Number of subjects analysed	6
Units: score on a scale
arithmetic mean (standard deviation)
PH Score: Baseline (BL) - Value at Visit (n=6)	67.71 ( 30.98 )
PH Score: Change from BL at Week 25 (n=5)	-53.75 ( 37.66 )
Total Score: BL - Value at Visit (n=6)	54.40 ( 19.68 )
Total Score: Change from BL at Week 25 (n=5)	-23.86 ( 17.84 )

No statistical analyses for this end point

Secondary: Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time

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End point title

Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time ^[46]

End point description

Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless of age, were collected using the Adapted Inhib-QoL with Aspects of Caregiver Burden questionnaire. The questionnaire comprises two parts. The first part asks the caregiver for his/her opinion on the child’s HRQoL (proxy HRQoL). The second part asks the caregiver to rate how the child's situation is for them (i.e., the impact of the child’s disease and treatment on the caregiver). Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. Scores range from 0 to 100, with lower scores reflective of better HRQoL. A total score is calculated as the sum of all of the items in the scale.

End point type

Secondary

End point timeframe

Baseline (Week 1) and Weeks 13 and 25

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a single-group descriptive analysis of Arm D only.

End point values	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW
Number of subjects analysed	10
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n = 10)	51.04 ( 10.47 )
Week 13 (n = 6)	29.85 ( 10.71 )
Week 25 (n = 1)	11.29 ( 0 )

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms

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End point title

Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms ^[47]

End point description

The number of participants experiencing at least one adverse event (AE), including all non-serious and serious AEs, is reported here. According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

End point type

Secondary

End point timeframe

From Baseline until primary cutoff date (at least 24 weeks): Arm C (Control) No Prophylaxis, median (range): 24.0 (23.9-28.0) weeks; Arms A & B Emicizumab, median (range): Arm A: 43.7 (28.1-60.3) weeks; Arm B: 46.1 (24.0-58.7) weeks

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a comparison of the adverse events that occurred in the randomized arms only (Arms A, B, and C) at the time of the primary data cutoff date.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm C (Control): No Prophylaxis
Number of subjects analysed	29	27	14
Units: Participants
Any AE, Any WHO Grade	25	19	2
AEs by Highest WHO Grade: Grade 1	10	6	2
AEs by Highest WHO Grade: Grade 2	12	12	0
AEs by Highest WHO Grade: Grade 3	3	1	0
AEs by Highest WHO Grade: Grade 4	0	0	0
AE with Fatal Outcome	0	0	0
Serious AE	2	1	0
AE Related to Treatment	12	10	0
Local Injection Site Reaction	4	5	0
Systemic Hypersens./Anaphylac(tic/toid) Reaction	0	1	0
Thromboembolic Event	0	0	0
Thrombotic Microangiopathy	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis

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End point title

Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis ^[48]

End point description

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[48] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Any Adverse Event (AE), Any WHO Grade	29	24	15	14
AEs by Highest WHO Grade: Grade 1	5	3	4	2
AEs by Highest WHO Grade: Grade 2	14	14	9	9
AEs by Highest WHO Grade: Grade 3	6	5	2	2
AEs by Highest WHO Grade: Grade 4	4	2	0	1
AE with Fatal Outcome	1	0	0	0
Serious AE	9	6	2	4
AE Related to Treatment	15	12	1	6

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis

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End point title

Number of Participants with at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis ^[49]

End point description

According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[49] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

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End point title

Number of Participants with at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis ^[50]

End point description

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[50] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Any Sys.Hypersens./Anaphylaxis Reaction, Any Grade	0	1	0	0
Event by Highest WHO Grade: Grade 1	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis

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End point title

Number of Participants with at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis ^[51]

End point description

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[51] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Any Thromboembolic Event (TE), Any WHO Grade	1	0	0	0
TEs by Highest WHO Grade: Grade 4	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis

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End point title

Number of Participants with at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis ^[52]

End point description

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[52] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

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End point title

Number of Participants with at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis ^[53]

End point description

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[53] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Any Injection-Site Reaction (ISR), Any WHO Grade	4	5	0	0
ISR by Highest WHO Grade: Grade 1	3	5	0	0
ISR by Highest WHO Grade: Grade 2	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Serum Chemistry Laboratory Abnormalities by Shift from Baseline to Highest WHO Grade Post-Baseline

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End point title

Number of Participants with Serum Chemistry Laboratory Abnormalities by Shift from Baseline to Highest WHO Grade Post-Baseline ^[54]

End point description

The number of participants with abnormal shifts in laboratory chemistry parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be 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; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator’s judgment. It was the investigator’s responsibility to review all laboratory findings. SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[54] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Corrected Calcium (Low), Normal to Grade 3	0	0	0	1
Corrected Calcium (Low), Normal to Grade 4	0	0	3	0
Glucose (Low), Normal to Grade 4	0	0	0	1
Glucose (High), Normal to Grade 3	1	0	0	0
Phosphorus (Low), Normal to Grade 3	0	1	0	0
Potassium (Low), Normal to Grade 4	0	0	1	0
Potassium (High), Normal to Grade 3	0	1	0	0
SGOT/AST (High), Normal to Grade 3	1	1	0	0
SGPT/ALT (High), Normal to Grade 3	0	1	2	0
Sodium (Low), Normal to Grade 4	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Hematology Laboratory Abnormalities by Shift from Baseline to Highest WHO Grade Post-Baseline

Top of page

End point title

Number of Participants with Hematology Laboratory Abnormalities by Shift from Baseline to Highest WHO Grade Post-Baseline ^[55]

End point description

The number of participants with abnormal shifts in laboratory hematology parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be 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; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator’s judgment. It was the investigator’s responsibility to review all laboratory findings.

End point type

Secondary

End point timeframe

From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

Notes
[55] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Participants
Hemoglobin (Low), Normal to Grade 4	2	0	0	0
Hemoglobin (Low), Normal to Grade 2	1	0	2	1
Platelet (Low), Normal to Grade 2	0	0	0	1

No statistical analyses for this end point

Secondary: Change from Baseline in Body Temperature Over Time

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End point title

Change from Baseline in Body Temperature Over Time ^[56]

End point description

The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). Safety Population 2 included all participants from all arms who received at least one dose of emicizumab. The number analyzed (n=) indicates those with evaluable data at a given timepoint. There is no recorded data for Arm C participants at Week 73 because they spent the first 24 weeks of the study on no prophylaxis (i.e., before receiving emicizumab). The value '9999' means there are no results to report (i.e., 0 patients with data).

End point type

Secondary

End point timeframe

Baseline and Weeks 5, 25, 49, and 73

Notes
[56] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: Celsius (C)
arithmetic mean (standard deviation)
Baseline (BL) - Value at Visit (n=29,27,14,15)	36.48 ( 0.43 )	36.57 ( 0.38 )	36.59 ( 0.33 )	36.45 ( 0.40 )
Change from BL at Week 5 (n=29,27,14,15)	-0.04 ( 0.46 )	-0.01 ( 0.40 )	0.09 ( 0.35 )	-0.11 ( 0.32 )
Change from BL at Week 25 (n=29,27,14,15)	-0.12 ( 0.53 )	0.04 ( 0.40 )	-0.03 ( 0.44 )	-0.12 ( 0.58 )
Change from BL at Week 49 (n=29,26,13,12)	-0.11 ( 0.47 )	-0.07 ( 0.43 )	-0.27 ( 0.27 )	-0.04 ( 0.37 )
Change from BL at Week 73 (n=29,26,0,11)	-0.10 ( 0.43 )	0.04 ( 0.43 )	-0.01 ( 0.35 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Change from Baseline in Pulse Rate Over Time

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End point title

Change from Baseline in Pulse Rate Over Time ^[57]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 5, 25, 49, and 73

Notes
[57] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: beats per minute
arithmetic mean (standard deviation)
Baseline (BL) - Value at Visit (n=29,27,14,15)	81.7 ( 10.3 )	78.9 ( 11.5 )	94.1 ( 11.7 )	88.1 ( 10.5 )
Change from BL at Week 5 (n=29,27,14,15)	1.6 ( 11.4 )	3.5 ( 11.3 )	-4.3 ( 11.0 )	-4.4 ( 9.6 )
Change from BL at Week 25 (n=29,27,14,15)	-2.0 ( 11.0 )	4.8 ( 13.6 )	-8.6 ( 12.7 )	-5.0 ( 8.7 )
Change from BL at Week 49 (n=29,26,13,11)	2.1 ( 12.2 )	5.0 ( 10.1 )	-8.4 ( 15.3 )	-7.6 ( 12.8 )
Change from BL at Week 73 (n=27,26,0,10)	2.4 ( 13.2 )	2.0 ( 13.5 )	-8.7 ( 14.9 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Change from Baseline in Respiratory Rate Over Time

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End point title

Change from Baseline in Respiratory Rate Over Time ^[58]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 5, 25, 49, and 73

Notes
[58] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: breaths per minute
arithmetic mean (standard deviation)
Baseline (BL) - Value at Visit (n=29,27,14,15)	19.9 ( 2.2 )	19.5 ( 2.5 )	20.4 ( 1.7 )	19.2 ( 2.6 )
Change from BL at Week 5 (n=29,27,14,15)	0.2 ( 2.3 )	-0.1 ( 1.7 )	-0.7 ( 1.7 )	-0.3 ( 1.8 )
Change from BL at Week 25 (n=29,27,14,15)	-0.6 ( 2.4 )	-0.3 ( 1.8 )	-0.4 ( 1.7 )	-0.2 ( 1.9 )
Change from BL at Week 49 (n=29,26,13,8)	-0.1 ( 2.7 )	0.1 ( 2.0 )	-0.3 ( 2.5 )	-0.2 ( 2.5 )
Change from BL at Week 73 (n=27,26,0,10)	-0.2 ( 2.6 )	-0.5 ( 2.1 )	-1.0 ( 2.4 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Change from Baseline in Systolic Blood Pressure Over Time

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End point title

Change from Baseline in Systolic Blood Pressure Over Time ^[59]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 5, 25, 49, and 73

Notes
[59] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: millimetres of mercury (mmHg)
arithmetic mean (standard deviation)
Baseline (BL) - Value at Visit (n=29,27,14,15)	123.6 ( 16.6 )	120.1 ( 12.4 )	96.3 ( 10.0 )	124.9 ( 11.3 )
Change from BL at Week 5 (n=29,27,14,15)	1.7 ( 12.4 )	0.6 ( 10.6 )	1.5 ( 12.5 )	-2.4 ( 10.7 )
Change from BL at Week 25 (n=29,27,14,15)	-1.1 ( 13.5 )	-0.8 ( 8.4 )	-0.7 ( 11.1 )	-0.4 ( 8.7 )
Change from BL at Week 49 (n=29,26,13,10)	-0.4 ( 12.6 )	-0.2 ( 8.4 )	2.4 ( 12.9 )	-2.0 ( 10.5 )
Change from BL at Week 73 (n=27,26,0,12)	0.2 ( 11.8 )	2.7 ( 9.2 )	4.3 ( 9.4 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Change from Baseline in Diastolic Blood Pressure Over Time

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End point title

Change from Baseline in Diastolic Blood Pressure Over Time ^[60]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 5, 25, 49, and 73

Notes
[60] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: millimetres of mercury (mmHg)
arithmetic mean (standard deviation)
Baseline (BL) - Value at Visit (n=29,27,14,15)	82.6 ( 14.5 )	79.1 ( 9.8 )	65.8 ( 7.7 )	82.4 ( 9.7 )
Change from BL at Week 5 (n=29,27,14,15)	1.1 ( 11.6 )	1.7 ( 9.0 )	-0.1 ( 10.2 )	-1.9 ( 9.2 )
Change from BL at Week 25 (n=29,27,14,15)	-0.4 ( 12.7 )	-2.4 ( 9.1 )	3.0 ( 9.5 )	-3.6 ( 8.1 )
Change from BL at Week 49 (n=29,26,13,10)	0.6 ( 8.9 )	-0.8 ( 8.8 )	-0.7 ( 11.8 )	0.6 ( 10.2 )
Change from BL at Week 73 (n=27,26,0,12)	1.5 ( 12.3 )	-0.5 ( 8.7 )	1.5 ( 11.9 )	9999 ( 9999 )

No statistical analyses for this end point

Secondary: Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status

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End point title

Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status ^[61]

End point description

Participants were considered anti-drug antibody (ADA)-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration, or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater than the titer of the baseline sample. Participants were considered ADA-negative if they were ADA-negative at baseline and all post-baseline samples were negative following drug administration, or if they were ADA-positive at baseline but did not have any post-baseline (following drug administration) samples with a titer that was at least 4-fold greater than the titer of the baseline sample.

End point type

Secondary

End point timeframe

Samples taken at Baseline and at prespecified times post-baseline from first dose of emicizumab until data cutoff date, median (range) time of exposure to emicizumab: All Arms: 196.14 (20.1-222.1) weeks; Arm D only: 64.14 (61.1-67.3) weeks

Notes
[61] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	14
Units: participants
ADA-Positive Status	4	4	0	0
ADA-Negative Status	25	23	15	14

No statistical analyses for this end point

Secondary: Plasma Trough Concentration (Ctrough) of Emicizumab

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End point title

Plasma Trough Concentration (Ctrough) of Emicizumab ^[62]

End point description

The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). The Pharmacokinetics Population included all participants from all arms who received at least one dose of emicizumab. One participant from Arm C was excluded from analysis due to a dosing protocol deviation. The number analyzed (n=) indicates those with evaluable data at a given timepoint. The value '9999' means there are no results to report (i.e., 0 patients with data).

End point type

Secondary

End point timeframe

Arms A & D, QW (up to Week 49 for Arm D only): Weeks 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, and 133; Arms B & C, Q4W: Weeks 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73, 85, 97, 109, 121, and 133

Notes
[62] - 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: Arm C: Emicizumab is presented as an analysis set because it only includes data after participants completed the first 24 weeks of no prophylaxis and switched to receiving emicizumab prophylaxis.

End point values	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W
Number of subjects analysed	29	27	15	13
Units: microgram per millilitre (μg/mL)
geometric mean (geometric coefficient of variation)
Week 2 (n=29,27,13,15)	12.5 ( 36.1 )	13.0 ( 29.1 )	16.0 ( 13.9 )	13.9 ( 37.4 )
Week 3 (n=29,27,13,15)	22.9 ( 31.9 )	24.1 ( 31.3 )	32.6 ( 15.7 )	28.2 ( 29.4 )
Week 4 (n=28,27,13,15)	32.5 ( 31.7 )	34.2 ( 32.2 )	47.3 ( 16.5 )	39.6 ( 26.5 )
Week 5 (n=28,27,13,15)	39.8 ( 30.0 )	41.5 ( 30.9 )	55.1 ( 13.3 )	41.7 ( 35.1 )
Week 7 (n=28,0,0,14)	38.8 ( 30.6 )	9999 ( 9999 )	55.4 ( 17.3 )	9999 ( 9999 )
Week 9 (n=28,27,13,15)	38.2 ( 31.6 )	35.1 ( 31.8 )	48.7 ( 19.9 )	37.6 ( 26.9 )
Week 13 (n=28,27,12,15)	37.0 ( 34.3 )	30.6 ( 41.4 )	47.4 ( 24.2 )	33.2 ( 35.4 )
Week 17 (n=28,27,13,12)	38.2 ( 31.3 )	30.5 ( 35.2 )	47.2 ( 23.6 )	30.0 ( 28.7 )
Week 21 (n=28,27,13,13)	37.8 ( 28.6 )	31.0 ( 40.2 )	46.7 ( 16.5 )	31.9 ( 25.7 )
Week 25 (n=28,27,13,15)	36.4 ( 32.7 )	32.1 ( 45.7 )	46.2 ( 25.3 )	32.9 ( 28.2 )
Week 33 (n=28,0,0,9)	37.1 ( 32.7 )	9999 ( 9999 )	43.4 ( 17.5 )	9999 ( 9999 )
Week 37 (n=0,24,13,0)	9999 ( 9999 )	31.4 ( 33.5 )	9999 ( 9999 )	34.7 ( 32.0 )
Week 41 (n=27,0,0,6)	40.4 ( 30.6 )	9999 ( 9999 )	46.4 ( 25.5 )	9999 ( 9999 )
Week 49 (n=27,26,12,5)	41.8 ( 31.1 )	33.0 ( 48.0 )	60.2 ( 11.2 )	34.5 ( 39.0 )
Week 61 (n=25,26,10,0)	42.8 ( 29.3 )	36.0 ( 49.0 )	9999 ( 9999 )	36.3 ( 32.2 )
Week 73 (n=24,24,11,0)	45.7 ( 41.6 )	37.5 ( 40.5 )	9999 ( 9999 )	34.5 ( 32.3 )
Week 85 (n=22,22,13,0)	42.7 ( 41.2 )	38.4 ( 45.1 )	9999 ( 9999 )	35.9 ( 36.4 )
Week 97 (n=23,26,11,0)	42.4 ( 31.1 )	35.6 ( 34.8 )	9999 ( 9999 )	39.4 ( 36.9 )
Week 109 (n=25,26,3,0)	45.4 ( 36.8 )	36.5 ( 35.3 )	9999 ( 9999 )	38.4 ( 15.1 )
Week 121 (n=18,18,0,0)	41.6 ( 36.0 )	35.8 ( 38.2 )	9999 ( 9999 )	9999 ( 9999 )
Week 133 (n=8,10,0,0)	50.3 ( 25.9 )	35.6 ( 29.7 )	9999 ( 9999 )	9999 ( 9999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the date of randomization or enrollment until the end of study (Arm C [Control] No Prophylaxis: up to 28 weeks; Arms A to C Emicizumab: up to 88 months; Arm D Emicizumab: up to 52.4 months)

Adverse event reporting additional description

After randomization (randomized arms A, B, and C) or initiation of study drug (non-randomized arm D), all adverse events were reported until the patient completed their last study visit. After this period, the investigator reported any serious adverse events that were believed to be related to prior study drug treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

28.0

Reporting group title

Arm C (Control): No Prophylaxis

Reporting group description

Reporting group title

Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Reporting group title

Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W

Reporting group description

After 24 weeks on no prophylaxis, participants were given the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

Reporting group title

Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW

Reporting group description

Reporting group title

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W

Reporting group description

Serious adverse events	Arm C (Control): No Prophylaxis	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 14 (0.00%)	9 / 29 (31.03%)	4 / 14 (28.57%)	2 / 15 (13.33%)	6 / 27 (22.22%)
number of deaths (all causes)	0	1	0	0	0
number of deaths resulting from adverse events	0	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Vascular disorders
Haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Shock haemorrhagic
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Mass
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrosis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Injury, poisoning and procedural complications
Limb fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Fracture
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Bone contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Cardio-respiratory arrest
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Iron deficiency anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (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
Eye disorders
Cataract
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Gastrointestinal disorders
Ileal ulcer
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Mallory-Weiss syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (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 fistula
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (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
Large intestine polyp
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (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
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Mouth haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (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
Rectal ulcer
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (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 and urinary disorders
Ureteric dilatation
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Ureterolithiasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (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
Haemophilic arthropathy
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm C (Control): No Prophylaxis	Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W	Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 14 (14.29%)	28 / 29 (96.55%)	14 / 14 (100.00%)	15 / 15 (100.00%)	24 / 27 (88.89%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	5	1	0	2
Haematoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	2 / 14 (14.29%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	0 / 14 (0.00%)	5 / 15 (33.33%)	2 / 27 (7.41%)
occurrences all number	0	10	0	7	2
Injection site reaction
subjects affected / exposed	0 / 14 (0.00%)	4 / 29 (13.79%)	0 / 14 (0.00%)	0 / 15 (0.00%)	5 / 27 (18.52%)
occurrences all number	0	7	0	0	29
Influenza like illness
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	1	0	0
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Chest discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	1
Reproductive system and breast disorders
Breast hyperplasia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 14 (0.00%)	4 / 29 (13.79%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	5	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	2	0	1	0
Bronchiectasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Pulmonary mass
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 14 (0.00%)	4 / 29 (13.79%)	0 / 14 (0.00%)	2 / 15 (13.33%)	0 / 27 (0.00%)
occurrences all number	0	8	0	2	0
Blood glucose increased
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	7	0	0	1
Blood uric acid increased
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	2 / 14 (14.29%)	4 / 15 (26.67%)	1 / 27 (3.70%)
occurrences all number	0	2	3	8	2
Alanine aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	6 / 14 (42.86%)	1 / 15 (6.67%)	7 / 27 (25.93%)
occurrences all number	0	9	14	1	14
Aspartate aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	4 / 14 (28.57%)	0 / 15 (0.00%)	6 / 27 (22.22%)
occurrences all number	0	9	7	0	12
Alanine aminotransferase abnormal
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Blood ketone body increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Aspartate aminotransferase abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	2
Bilirubin conjugated increased
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0	0
Differential white blood cell count abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
White blood cells urine positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
White blood cell count abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Neutrophil count abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Weight increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	1	1	0	2
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	2
Neutrophil count increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	2 / 14 (14.29%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	4	0	2
Ligament sprain
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	1	0	2
Limb injury
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Arthropod bite
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Animal bite
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Meniscus injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Closed globe injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Muscle strain
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Skin abrasion
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	1	0	2
Soft tissue injury
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	1
Palipitations
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	1	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	5	1	0	2
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	4	3	0	1
Head discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Syncope
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	4 / 29 (13.79%)	1 / 14 (7.14%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	4	1	1	1
Iron deficiency anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Splenomegaly
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	1	0	1
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 14 (0.00%)	4 / 29 (13.79%)	3 / 14 (21.43%)	0 / 15 (0.00%)	4 / 27 (14.81%)
occurrences all number	0	7	5	0	4
Constipation
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	4	1	0	0
Mouth ulceration
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Dyspepsia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Toothache
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	3	0	0	0
Abdominal distension
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	2 / 14 (14.29%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	2	1	0
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	2	0	0	2
Dental caries
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	1 / 14 (7.14%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	3	1	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	3	0	0	1
Gastritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	2 / 14 (14.29%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0
Colitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Chronic gastritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	1
Haemorrhoids
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	2 / 14 (14.29%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	2	0	1
Aphthous ulcer
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Tooth impacted
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	2
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	2 / 14 (14.29%)	2 / 15 (13.33%)	1 / 27 (3.70%)
occurrences all number	0	2	3	4	1
Gallbladder polyp
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Hepatic steatosis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	4 / 14 (28.57%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	1	4	1	1
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Dermatitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Rash
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	1	1	1	3
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Nephrolithiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	1
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Groin pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Muscular weakness
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	5 / 29 (17.24%)	0 / 14 (0.00%)	1 / 15 (6.67%)	4 / 27 (14.81%)
occurrences all number	0	5	0	1	4
Back pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Haemarthrosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	1	0	1
Haemophilic arthropathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	2 / 14 (14.29%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	11 / 29 (37.93%)	8 / 14 (57.14%)	10 / 15 (66.67%)	11 / 27 (40.74%)
occurrences all number	3	18	20	40	26
Nasopharyngitis
subjects affected / exposed	0 / 14 (0.00%)	3 / 29 (10.34%)	1 / 14 (7.14%)	0 / 15 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	5	1	0	3
Pharyngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	1 / 15 (6.67%)	3 / 27 (11.11%)
occurrences all number	0	0	1	2	3
Bronchitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	1 / 15 (6.67%)	2 / 27 (7.41%)
occurrences all number	0	0	1	3	2
Otitis media
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	0	0	1	1
Herpes zoster
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	1 / 15 (6.67%)	1 / 27 (3.70%)
occurrences all number	0	1	0	1	1
Tonsillitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	2 / 15 (13.33%)	1 / 27 (3.70%)
occurrences all number	0	1	0	4	2
Gingivitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	1	0	0	3
Viral infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Laryngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	2	0	1	0
Varicella
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	3	0	1	0
Influenza
subjects affected / exposed	0 / 14 (0.00%)	2 / 29 (6.90%)	0 / 14 (0.00%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0	0
Suspected COVID-19
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	2 / 14 (14.29%)	3 / 15 (20.00%)	1 / 27 (3.70%)
occurrences all number	0	1	3	3	1
COVID-19
subjects affected / exposed	0 / 14 (0.00%)	6 / 29 (20.69%)	5 / 14 (35.71%)	3 / 15 (20.00%)	7 / 27 (25.93%)
occurrences all number	0	6	5	3	8
Appendicitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	1 / 14 (7.14%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	1	1	1	0
Metabolism and nutrition disorders
Hyperuricaemia
subjects affected / exposed	0 / 14 (0.00%)	10 / 29 (34.48%)	4 / 14 (28.57%)	2 / 15 (13.33%)	10 / 27 (37.04%)
occurrences all number	0	17	8	3	13
Electrolyte imbalance
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	0	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 29 (0.00%)	1 / 14 (7.14%)	0 / 15 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	1	0	0
Hyperlipidaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	2 / 14 (14.29%)	0 / 15 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	1	2	0	2
Iron deficiency
subjects affected / exposed	0 / 14 (0.00%)	1 / 29 (3.45%)	0 / 14 (0.00%)	1 / 15 (6.67%)	0 / 27 (0.00%)
occurrences all number	0	1	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

20 Mar 2017

Protocol v2, the main changes to the protocol were as follows: - Update of the safety sections with the most recent safety information regarding 2 patients who developed thrombotic microangiopathy and 2 patients who developed thromboembolic events in Study BH29884. Both occurred in patients with hemophilia A with FVIII inhibitors receiving bypassing agents. Information on the requirements for laboratory monitoring of coagulation status following bypassing agent use was also updated. The section for risks associated with emicizumab was updated accordingly, and microangiopathic hemolytic anemia/thrombotic microangiopathy was newly classified as an AESI. An exclusion criterion to exclude patients at high risk to experience thrombotic microangiopathy was added. - Addition of guidance on the use of FVIII in conjunction with emicizumab. - Prohibition of the use of short-term prophylaxis with aPCC or PCC concomitantly with emicizumab in order to minimize the risk of thromboembolic and thrombotic microangiopathy events. - Replacement of the Wilcoxon rank sum test with the Van Elteren test as a back-up statistical method for the primary analysis to allow a stratified analysis to be performed. - The permitted treatment for breakthrough bleeds was specified with guidance regarding the use of concomitant bypassing agents in patients being treated with emicizumab, including dosage and requirements for laboratory monitoring, to minimize the risk of thromboembolic and thrombotic microangiopathy events.

30 Oct 2017

Protocol v3, the main changes to the protocol were as follows: - Safety findings related to thrombotic microangiopathy observed in Study BH29884 were updated. - Laboratory testing of prothrombin fragment 1+2 for monitoring of patients treated with emicizumab receiving bypassing agents concomitantly was removed. - Sample collection for the Research Biosample Repository was removed.

19 Jul 2019

Protocol v4, the main changes to the protocol were as follows: - An additional arm (Arm D) was added to the study to characterize the pharmacokinetics, efficacy, and safety of emicizumab prophylaxis in pediatric patients (aged <12 years) who have hemophilia A with inhibitors and previously receiving bypassing agent treatment. Arm D was planned to enroll approximately 15 patients. A schedule of activities was added. The study design and other applicable sections of the protocol were amended to reflect the addition of Arm D. - Efficacy, PK, PD, and safety information was added based on available data from Studies ACE002JP, BH29884, BH29992, BH30071, BO39182, and JO39881 to align with Emicizumab IB, Version 12. - Patients who were enrolled in Study BH29768 were eligible to enroll in this study, provided they met the eligibility criteria and were able to enroll at a participating site while the study was open for enrollment.

22 Apr 2023

Protocol v5 has been primarily amended to extend the study. The study will end 3 years after the last Arm D patient completes 1 year treatment and patients still having clinical benefit are transferred to a post-trial continued access solution per Roche Global Policy on Continued Access to Investigational Medicinal Products (see Sections 3.1 and 4.3.4). The study will end earlier, before 3 years after the last Arm D patient completes 1 year treatment, should the post-trial continued access solution be available earlier. Language has been added to clarify that collection of pharmacokinetic (PK)/anti-drug antibody (ADA)/Biomarker samples from Arm D patients will stop when the patient completes the study or after Week 49, whichever occurs first.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Model-Based Annualized Bleeding Rate for Treated Bleeds

Primary: Model-Based Annualized Bleeding Rate for Treated Bleeds

Primary: Mean Calculated Annualized Bleeding Rate for Treated Bleeds

Primary: Mean Calculated Annualized Bleeding Rate for Treated Bleeds

Primary: Median Calculated Annualized Bleeding Rate for Treated Bleeds

Primary: Median Calculated Annualized Bleeding Rate for Treated Bleeds

Secondary: Model-Based Annualized Bleeding Rate for All Bleeds

Secondary: Model-Based Annualized Bleeding Rate for All Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for All Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for All Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for All Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for All Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Secondary: Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Secondary: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds with Emicizumab Prophylaxis On-Study Versus with Previous Episodic Therapy Pre-Study

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Change from Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age

Secondary: Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age

Secondary: Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age

Secondary: Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25

Secondary: Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25

Secondary: Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25

Secondary: Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Index Utility Score at Week 25

Secondary: Arms A, B, and C: Change from Baseline in EQ-5D-5L Index Utility Score at Week 25

Secondary: Arm D: Change from Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age

Secondary: Arm D: Change from Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age

Secondary: Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time

Secondary: Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis

Secondary: Number of Participants with at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis

Secondary: Number of Participants with at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

Secondary: Number of Participants with at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

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