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Clinical Trial Results:
A Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Administration of Emicizumab in Hemophilia A Pediatric Patients with Inhibitors

Summary
EudraCT number	2016-000073-21
Trial protocol	ES DE GB FR IT
Global end of trial date

Results information
Results version number	v1
This version publication date	27 Apr 2019
First version publication date	27 Apr 2019
Other versions	v2

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

BH29992

ISRCTN number

US NCT number

NCT02795767

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001839-PIP01-15

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

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

Yes

Analysis stage

Interim

Date of interim/final analysis

30 Apr 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Apr 2018

Global end of trial reached?

Main objective of the trial

No formal hypothesis testing is planned in the study. All the analyses will be descriptive and be performed for each cohort separately. The main objectives of the study are to investigate the efficacy, safety, and pharmacokinetics of subcutaneous (SC) emicizumab administered at 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W in pediatric subjects with hemophilia A and factor VIII inhibitors who are currently receiving treatment with bypassing agents.

Protection of trial subjects

This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. An Informed Consent Form and Assent Form must be signed and dated by the pediatric subject’s legally authorized representative and the subject (when applicable) before his or her participation in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Jul 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Costa Rica: 1

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Japan: 9

Country: Number of subjects enrolled

South Africa: 6

Country: Number of subjects enrolled

Turkey: 8

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 24

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

Following completion of accrual to Cohort A: Emicizumab QW, enrollment was opened to Cohort B: Emicizumab Q2W and Cohort C: Emicizumab Q4W. Of note, enrollment remained open to Cohort A only for subjects who were <2 years old, and enrollment to Cohorts B and C was limited to subjects who were 2-11 years old.

Screening details

A total of 88 subjects with hemophilia A with FVIII inhibitors who were receiving treatment with bypassing agents were enrolled in the study, 68 in Cohort A: Emicizumab QW, 10 in Cohort B: Emicizumab Q2W, and 10 in Cohort C: Emicizumab Q4W.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A: Emicizumab QW

Arm description

Subjects received emicizumab at a loading dose of 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg QW SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra; ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg QW SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first. During the 52-week treatment period, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to have their emicizumab maintenance dose up-titrated to 3 mg/kg QW starting on Week 17.

Cohort B: Emicizumab Q2W

Arm description

Subjects received emicizumab at a loading dose of 3 mg/kg QW subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 3 mg/kg once every 2 weeks (Q2W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra; ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 mg/kg QW subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 3 mg/kg once every 2 weeks (Q2W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first. During the 52-week treatment period, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to have their emicizumab maintenance dose up-titrated to 3 mg/kg QW starting on Week 17.

Cohort C: Emicizumab Q4W

Arm description

Subjects received emicizumab at a loading dose of 3 mg/kg QW subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 6 mg/kg once every 4 weeks (Q4W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra; ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 mg/kg QW subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 6 mg/kg once every 4 weeks (Q4W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first. During the 52-week treatment period, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to have their emicizumab maintenance dose up-titrated to 3 mg/kg QW starting on Week 17.

Number of subjects in period 1	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Started	68	10	10
Dose Up-Titrated to 3 mg/kg QW	0	0	2
Completed 52 Weeks in Study	59	0	0
Discontinued from Study Treatment	2	0	1
Completed	0	0	0
Not completed	68	10	10
Received Commercial Emicizumab	2	-	-
Ongoing Study Treatment	66	10	9
Lack of efficacy	-	-	1

Baseline characteristics

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Reporting group title

Cohort A: Emicizumab QW

Reporting group description

Reporting group title

Cohort B: Emicizumab Q2W

Reporting group description

Reporting group title

Cohort C: Emicizumab Q4W

Reporting group description

Reporting group values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W	Total
Number of subjects	68	10	10	88
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	8	0	0	8
Children (2-11 years)	57	10	10	77
Adolescents (12-17 years)	3	0	0	3
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	6.2 ( 3.6 )	6.9 ( 3.2 )	7.9 ( 3.0 )	-
Sex: Female, Male
Units: Subjects
Female	0	0	0	0
Male	68	10	10	88
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	10	1	2	13
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	11	1	0	12
White	39	7	8	54
More than one race	2	0	0	2
Unknown or Not Reported	6	1	0	7
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	5	1	1	7
Not Hispanic or Latino	61	9	9	79
Unknown or Not Reported	2	0	0	2
Number of Subjects with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry
A target joint was defined as a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry.
Units: Subjects
0 Target Joints	44	3	7	54
1 Target Joint	9	6	1	16
>1 Target Joints	15	1	2	18

End points

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Reporting group title

Cohort A: Emicizumab QW

Reporting group description

Reporting group title

Cohort B: Emicizumab Q2W

Reporting group description

Reporting group title

Cohort C: Emicizumab Q4W

Reporting group description

Subject analysis set title

Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent

Subject analysis set type

Sub-group analysis

Subject analysis set description

This group includes historical data from subjects in the non-interventional study (NIS) BH29768 (NCT02476942) who had received prophylactic or episodic treatment with bypassing agents and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Cohort A of this study.

Subject analysis set title

Cohort A NIS Population: Emicizumab QW

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who had previously received episodic or prophylactic treatment with bypassing agents in NIS BH29768 (NCT02476942) and were enrolled in Cohort A of this study received emicizumab at a loading dose of 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg QW SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first.

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age ^[1] ^[2]

End point description

The number of treated bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[1] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[2] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[3]
Units: treated bleed rate per year
number (confidence interval 95%)	0.3 (0.17 to 0.50)

Notes
[3] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age ^[4] ^[5]

End point description

The number of all bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each subject stays in the study). 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[6]
Units: all bleed rate per year
number (confidence interval 95%)	3.2 (1.94 to 5.22)

Notes
[6] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age ^[7] ^[8]

End point description

The number of treated spontaneous bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each subject stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[7] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[9]
Units: treated spontaneous bleed rate per year
number (confidence interval 95%)	0.0 (0.0 to 0.1)

Notes
[9] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age ^[10] ^[11]

End point description

The number of treated joint bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each subject stays in the study). A "joint bleed" is defined as a bleed with type reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A “treated joint bleed” is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Only treated bleeds that fulfilled the 72-hour rule were included in the analysis of treated joint bleeds, excluding bleeds due to surgery/procedure.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[10] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[12]
Units: treated joint bleed rate per year
number (confidence interval 95%)	0.2 (0.08 to 0.29)

Notes
[12] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age ^[13] ^[14]

End point description

The number of treated target joint bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each subject stays in the study). A "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded. The number '99999' signifies that the model-based ABR and 95% CI were not estimable because too few events had occurred over the efficacy period to calculate values using the negative binomial regression model; 95.4% of subjects in this cohort had 0 treated target joint bleeds.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[13] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[14] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[15]
Units: treated target joint bleed rate per year
number (confidence interval 95%)	99999 (99999 to 99999)

Notes
[15] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age ^[16] ^[17]

End point description

The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each subject using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[16] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[18]
Units: treated bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)

Notes
[18] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age ^[19] ^[20]

End point description

The number of all bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each subject 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[19] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[21]
Units: all bleed rate per year
median (inter-quartile range (Q1-Q3))	0.6 (0.00 to 2.92)

Notes
[21] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age ^[22] ^[23]

End point description

The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each subject using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[22] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[24]
Units: treated spontaneous bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)

Notes
[24] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age ^[25] ^[26]

End point description

The number of treated joint bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each subject using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A "joint bleed" is defined as a bleed with type reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A “treated joint bleed” is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Only treated bleeds that fulfilled the 72-hour rule were included in the analysis of treated joint bleeds, excluding bleeds due to surgery/procedure.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[25] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[27]
Units: treated joint bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)

Notes
[27] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age ^[28] ^[29]

End point description

The number of treated target joint bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each subject using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[28] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[29] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[30]
Units: treated target joint bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)

Notes
[30] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohort A: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[31] ^[32]

End point description

The percentage of subjects by categorized number of treated bleeds over the efficacy period is presented here. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[31] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[33]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	76.9 (64.8 to 86.5)
0-3 Bleeds	100.0 (94.5 to 100.0)
0-10 Bleeds	100.0 (94.5 to 100.0)
>10 Bleeds	0.0 (0.0 to 5.5)

Notes
[33] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohort A: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[34] ^[35]

End point description

The percentage of subjects by categorized number of all bleeds over the efficacy period is presented here. 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[34] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[36]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	49.2 (36.6 to 61.9)
0-3 Bleeds	72.3 (59.8 to 82.7)
0-10 Bleeds	92.3 (83.0 to 97.5)
>10 Bleeds	7.7 (2.5 to 17.0)

Notes
[36] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohort A: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[37] ^[38]

End point description

The percentage of subjects by categorized number of treated spontaneous bleeds over the efficacy period is presented here. A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[37] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[38] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[39]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	96.9 (89.3 to 99.6)
0-3 Bleeds	100.0 (94.5 to 100.0)
0-10 Bleeds	100.0 (94.5 to 100.0)
>10 Bleeds	0.0 (0.0 to 5.5)

Notes
[39] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Top of page

End point title

Cohort A: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[40] ^[41]

End point description

The percentage of subjects by categorized number of treated joint bleeds over the efficacy period is presented here. A "joint bleed" is defined as a bleed with type reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A “treated joint bleed” is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Only treated bleeds that fulfilled the 72-hour rule were included in the analysis of treated joint bleeds, excluding bleeds due to surgery/procedure.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[40] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[42]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	84.6 (73.5 to 92.4)
0-3 Bleeds	100.0 (94.5 to 100.0)
0-10 Bleeds	100.0 (94.5 to 100.0)
>10 Bleeds	0.0 (0.0 to 5.5)

Notes
[42] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Top of page

End point title

Cohort A: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[43] ^[44]

End point description

The percentage of subjects by categorized number of treated target joint bleeds over the efficacy period is presented here. A "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

Notes
[43] - 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: No formal hypothesis testing was planned for this study. All statistical analyses are descriptive.
[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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. All available data from Cohorts B and C (efficacy period of about 6 months) were also to be analyzed and are reported as secondary end points.

End point values	Cohort A: Emicizumab QW
Number of subjects analysed	65 ^[45]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	95.4 (87.1 to 99.0)
0-3 Bleeds	100.0 (94.5 to 100.0)
0-10 Bleeds	100.0 (94.5 to 100.0)
>10 Bleeds	0.0 (0.0 to 5.5)

Notes
[45] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age ^[46]

End point description

End point type

Secondary

End point timeframe

From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy periods in Cohorts B and C were 21.29 (18.6-24.1) weeks and 19.86 (8.9-24.1) weeks, respectively.

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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[47]	10 ^[48]
Units: treated bleed rate per year
number (confidence interval 95%)	0.2 (0.03 to 1.72)	2.2 (0.69 to 6.81)

Notes
[47] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[48] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age ^[49]

End point description

End point type

Secondary

End point timeframe

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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[50]	10 ^[51]
Units: all bleed rate per year
number (confidence interval 95%)	1.5 (0.62 to 3.40)	3.8 (1.42 to 10.11)

Notes
[50] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[51] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age ^[52]

End point description

The number of treated spontaneous bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial (NB) regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., time that each subject stays on-study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded. The number '99999' signifies that model-based ABR and 95% CI were not estimable because too few events had occurred over the efficacy period to calculate values using the NB regression model; 100% of subjects in Cohort B had 0 treated spontaneous bleeds.

End point type

Secondary

End point timeframe

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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[53]	10 ^[54]
Units: treated spontaneous bleed rate per year
number (confidence interval 95%)	99999 (99999 to 99999)	0.8 (0.05 to 12.00)

Notes
[53] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[54] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age ^[55]

End point description

End point type

Secondary

End point timeframe

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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[56]	10 ^[57]
Units: treated joint bleed rate per year
number (confidence interval 95%)	0.2 (0.03 to 1.72)	1.7 (0.60 to 4.89)

Notes
[56] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[57] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age ^[58]

End point description

End point type

Secondary

End point timeframe

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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[59]	10 ^[60]
Units: treated target joint bleed rate per year
number (confidence interval 95%)	0.2 (0.03 to 1.72)	0.5 (0.05 to 5.88)

Notes
[59] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[60] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age ^[61]

End point description

End point type

Secondary

End point timeframe

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: This is a non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[62]	10 ^[63]
Units: treated bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 3.26)

Notes
[62] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[63] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age ^[64]

End point description

End point type

Secondary

End point timeframe

Notes
[64] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[65]	10 ^[66]
Units: all bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 2.81)	1.6 (0.00 to 4.84)

Notes
[65] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[66] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age ^[67]

End point description

End point type

Secondary

End point timeframe

Notes
[67] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[68]	10 ^[69]
Units: treated spontaneous bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 0.00)

Notes
[68] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[69] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age ^[70]

End point description

End point type

Secondary

End point timeframe

Notes
[70] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[71]	10 ^[72]
Units: treated joint bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 3.26)

Notes
[71] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[72] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age ^[73]

End point description

End point type

Secondary

End point timeframe

Notes
[73] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[74]	10 ^[75]
Units: treated target joint bleed rate per year
median (inter-quartile range (Q1-Q3))	0.0 (0.00 to 0.00)	0.0 (0.00 to 0.00)

Notes
[74] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[75] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[76]

End point description

End point type

Secondary

End point timeframe

Notes
[76] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[77]	10 ^[78]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	90.0 (55.5 to 99.7)	60.0 (26.2 to 87.8)
0-3 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
0-10 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
>10 Bleeds	0.0 (0.0 to 30.8)	0.0 (0.0 to 30.8)

Notes
[77] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[78] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[79]

End point description

End point type

Secondary

End point timeframe

Notes
[79] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[80]	10 ^[81]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	60.0 (26.2 to 87.8)	50.0 (18.7 to 81.3)
0-3 Bleeds	100.0 (69.2 to 100.0)	90.0 (55.5 to 99.7)
0-10 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
>10 Bleeds	0.0 (0.0 to 30.8)	0.0 (0.0 to 30.8)

Notes
[80] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[81] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[82]

End point description

End point type

Secondary

End point timeframe

Notes
[82] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[83]	10 ^[84]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	100.0 (69.2 to 100.0)	90.0 (55.5 to 99.7)
0-3 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
0-10 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
>10 Bleeds	0.0 (0.0 to 30.8)	0.0 (0.0 to 30.8)

Notes
[83] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[84] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[85]

End point description

End point type

Secondary

End point timeframe

Notes
[85] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[86]	10 ^[87]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	90.0 (55.5 to 99.7)	60.0 (26.2 to 87.8)
0-3 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
0-10 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
>10 Bleeds	0.0 (0.0 to 30.8)	0.0 (0.0 to 30.8)

Notes
[86] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[87] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

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End point title

Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age ^[88]

End point description

End point type

Secondary

End point timeframe

Notes
[88] - 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 non-randomized study that began by recruiting subjects only to Cohort A: Emicizumab QW; Cohorts B and C were added later in protocol version 4. Per protocol, primary analysis for all cohorts was to be performed 52 weeks after all subjects in the primary population of Cohort A had been enrolled or withdrawn prematurely, whichever occurred first. Results for Cohort A are reported as primary end points, while corresponding results for Cohorts B and C are reported as secondary end points.

End point values	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	10 ^[89]	10 ^[90]
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	90.0 (55.5 to 99.7)	90.0 (55.5 to 99.7)
0-3 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
0-10 Bleeds	100.0 (69.2 to 100.0)	100.0 (69.2 to 100.0)
>10 Bleeds	0.0 (0.0 to 30.8)	0.0 (0.0 to 30.8)

Notes
[89] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.
[90] - Analysis includes all treated subjects <12 years of age who were on same dose for at least 12 weeks.

No statistical analyses for this end point

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the Non-Interventional Study (NIS) Population

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End point title

Cohort A: Intra-Subject Comparison of the Model-Based ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the Non-Interventional Study (NIS) Population

End point description

This is an intra-subject comparison of the model-based annualized bleeding rate (ABR) for treated bleeds (i.e., number of treated bleeds over efficacy period using negative binomial regression model) on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). A “treated bleed” is a bleed directly followed by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and first treatment thereafter are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

Up to 24 weeks in NIS BH29768 (NCT02476942) prior to study entry and from Baseline to 52 weeks on this study; At primary completion date, the median (min-max) duration of the efficacy period in the NIS population was 88.57 (55.9-92.6) weeks.

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: treated bleed rate per year
number (confidence interval 95%)	19.9 (15.33 to 25.85)	0.2 (0.11 to 0.49)

Cohort A Intra-Subject ABR Ratio of Treated Bleeds

Statistical analysis description

This is an intra-subject analysis of a total of 18 subjects (not 36) from Cohort A of the ABR ratio of treated bleeds over two different periods: on study while receiving emicizumab QW prophylaxis versus before study entry while participating in NIS BH29768 (NCT02476942) and receiving prophylactic/episodic bypassing agents.

Comparison groups

Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent v Cohort A NIS Population: Emicizumab QW

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

ABR Ratio

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.023

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

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End point title

Cohort A: Intra-Subject Comparison of the Model-Based ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

End point description

This is an intra-subject comparison of the model-based annualized bleeding rate (ABR) for all bleeds (i.e., number of all bleeds over efficacy period using negative binomial regression model) on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: all bleed rate per year
number (confidence interval 95%)	31.9 (22.68 to 44.81)	3.3 (1.45 to 7.53)

Cohort A Intra-Subject ABR Ratio of All Bleeds

Statistical analysis description

This is an intra-subject analysis of a total of 18 subjects (not 36) from Cohort A of the ABR ratio of all bleeds over two different periods: on study while receiving emicizumab QW prophylaxis versus before study entry while participating in NIS BH29768 (NCT02476942) and receiving prophylactic/episodic bypassing agents.

Comparison groups

Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent v Cohort A NIS Population: Emicizumab QW

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

ABR Ratio

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.21

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

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End point title

Cohort A: Intra-Subject Comparison of the Calculated ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

End point description

This is an intra-subject comparison of the calculated ABR for treated bleeds (annualized per subject using the following formula: ABR = [number of bleeds/number of days during the efficacy period] x 365.25) on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). A “treated bleed” is a bleed directly followed by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and first treatment thereafter are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: treated bleed rate per year
median (inter-quartile range (Q1-Q3))	16.2 (11.49 to 25.78)	0.0 (0.00 to 0.56)

No statistical analyses for this end point

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

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End point title

Cohort A: Intra-Subject Comparison of the Calculated ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

End point description

This is an intra-subject comparison of the calculated annualized bleeding rate (ABR) for all bleeds (annualized for each subject using the following formula: ABR = [number of bleeds/number of days during the efficacy period] x 365.25) on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: all bleed rate per year
median (inter-quartile range (Q1-Q3))	21.3 (14.18 to 44.47)	1.1 (0.00 to 2.30)

No statistical analyses for this end point

Secondary: Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

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End point title

Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

End point description

This is an intra-subject comparison of the percentage of subjects by categorized number of treated bleeds over the efficacy period on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). A “treated bleed” is a bleed directly followed by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and first treatment thereafter are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	5.6 (0.1 to 27.3)	72.2 (46.5 to 90.3)
0-3 Bleeds	16.7 (3.6 to 41.4)	100.0 (81.5 to 100.0)
0-10 Bleeds	66.7 (41.0 to 86.7)	100.0 (81.5 to 100.0)
>10 Bleeds	33.3 (13.3 to 59.0)	0.0 (0.0 to 18.5)

No statistical analyses for this end point

Secondary: Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

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End point title

Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

End point description

This is an intra-subject comparison of the percentage of subjects by categorized number of all bleeds over the efficacy period on study versus pre-study in the NIS population who had previously participated in study BH29768 (NCT02476942). 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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

End point values	Cohort A NIS Population: Prophylactic/Episodic Bypassing Agent	Cohort A NIS Population: Emicizumab QW
Number of subjects analysed	18	18
Units: percentage of subjects
number (confidence interval 95%)
0 Bleeds	0.0 (0.0 to 18.5)	33.3 (13.3 to 59.0)
0-3 Bleeds	11.1 (1.4 to 34.7)	72.2 (46.5 to 90.3)
0-10 Bleeds	44.4 (21.5 to 69.2)	83.3 (58.6 to 96.4)
>10 Bleeds	55.6 (30.8 to 78.5)	16.7 (3.6 to 41.4)

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

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End point title

Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

End point description

End point type

Secondary

End point timeframe

From Baseline to 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	3	0 ^[91]	0 ^[92]
Units: treated bleed rate per year
number (confidence interval 95%)	0.8 (0.25 to 2.40)	( to )	( to )

Notes
[91] - None of the subjects enrolled in this cohort were ≥12 years of age.
[92] - None of the subjects enrolled in this cohort were ≥12 years of age.

No statistical analyses for this end point

Secondary: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

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End point title

Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

End point description

The number of all bleeds over the efficacy period is presented as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in followup times (i.e., the time that each subject stays in the study). 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 was implemented exactly as defined for the “treated bleeds” outcome measure. 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 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	3	0 ^[93]	0 ^[94]
Units: all bleed rate per year
number (confidence interval 95%)	1.4 (0.49 to 4.16)	( to )	( to )

Notes
[93] - None of the subjects enrolled in this cohort were ≥12 years of age.
[94] - None of the subjects enrolled in this cohort were ≥12 years of age.

No statistical analyses for this end point

Secondary: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

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End point title

Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

End point description

End point type

Secondary

End point timeframe

From Baseline to 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	3	0 ^[95]	0 ^[96]
Units: treated bleed rate per year
median (inter-quartile range (Q1-Q3))	0.9 (0.00 to 1.14)	( to )	( to )

Notes
[95] - None of the subjects enrolled in this cohort were ≥12 years of age.
[96] - None of the subjects enrolled in this cohort were ≥12 years of age.

No statistical analyses for this end point

Secondary: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

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End point title

Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects ≥12 Years of Age and <40 kg Body Weight

End point description

End point type

Secondary

End point timeframe

From Baseline to 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	3	0 ^[97]	0 ^[98]
Units: all bleed rate per year
median (inter-quartile range (Q1-Q3))	0.9 (0.00 to 2.84)	( to )	( to )

Notes
[97] - None of the subjects enrolled in this cohort were ≥12 years of age.
[98] - None of the subjects enrolled in this cohort were ≥12 years of age.

No statistical analyses for this end point

Secondary: Number of Treated Bleeds Over Time in Subjects with Dose Up-Titration

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End point title

Number of Treated Bleeds Over Time in Subjects with Dose Up-Titration

End point description

The number of treated bleeds over time was to be analyzed in subjects whose emicizumab maintenance dose was up-titrated to 3 mg/kg QW if they had experienced suboptimal bleeding control on emicizumab at steady-state, per protocol criteria. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	0 ^[99]	0 ^[100]	0 ^[101]
Units: treated bleeds

Notes
[99] - At the primary completion date, none of the subjects in this cohort had their dose up-titrated.
[100] - At the primary completion date, none of the subjects in this cohort had their dose up-titrated.
[101] - Because only 2 subjects had dose up-titrated, data could not be analyzed on a population level.

No statistical analyses for this end point

Secondary: Number of All Bleeds Over Time in Subjects with Dose Up-Titration

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End point title

Number of All Bleeds Over Time in Subjects with Dose Up-Titration

End point description

The number of all bleeds over time was to be analyzed in subjects whose emicizumab maintenance dose was up-titrated to 3 mg/kg QW if they had experienced suboptimal bleeding control on emicizumab at steady-state, per protocol criteria. 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 was implemented exactly as defined for the “treated bleeds” outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. Due to the smalll sample size at the primary completion date, data could not be analyzed on a population level. Data collection is ongoing, and results will be reported upon study completion.

End point type

Secondary

End point timeframe

From Baseline to 52 weeks

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	0 ^[102]	0 ^[103]	0 ^[104]
Units: all bleeds

Notes
[102] - At the primary completion date, none of the subjects in this cohort had dose up-titration.
[103] - At the primary completion date, none of the subjects in this cohort had their dose up-titration.
[104] - Because only 2 subjects had dose up-titration, data could not be analyzed on a population level.

No statistical analyses for this end point

Secondary: Change from Baseline Over Time in the Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score, as Completed by Treated Subjects ≥8 to <12 Years of Age

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End point title

Change from Baseline Over Time in the Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score, as Completed by Treated Subjects ≥8 to <12 Years of Age

End point description

The Haemo-QoL-SF is a self-reported questionnaire for children ≥8 years of age. It contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life: Physical Health, Feelings, View of Yourself, Family, Friends, Other People, Sports and School, Dealing with Hemophilia, and Treatment. Items are rated with five respective response options: never, seldom, sometimes, often, and always. The Total Score is derived from the scores for all domains and ranges from 0 to 100, with a lower score reflective of better health-related quality of life. The number '99999' signifies that a 95% confidence interval could not be calculated for data from a single subject. The number '999999' signifies that no data was available at a given timepoint.

End point type

Secondary

End point timeframe

Baseline (Week 1), Weeks 13, 25, 37, 49, and 57, and then every 24 weeks until end of study (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	22 ^[105]	6 ^[106]	6 ^[107]
Units: units on a scale
arithmetic mean (confidence interval 95%)
Baseline: value at visit (n=18,6,6)	33.37 (25.15 to 41.60)	25.60 (18.29 to 32.90)	25.12 (9.85 to 40.39)
Change from Baseline at Week 13 (n=18,6,5)	-7.02 (-12.08 to -1.96)	-9.17 (-15.59 to -2.75)	0.29 (-23.12 to 23.69)
Change from Baseline at Week 25 (n=18,1,1)	-9.17 (-15.97 to -2.37)	-21.43 (-99999 to 99999)	-39.29 (-99999 to 99999)
Change from Baseline at Week 37 (n=17,0,0)	-11.64 (-16.11 to -7.17)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 49 (n=17,0,0)	-9.62 (-13.59 to -5.65)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 57 (n=6,0,0)	-8.57 (-20.64 to 3.50)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 81 (n=7,0,0)	-10.31 (-23.04 to 2.43)	999999 (999999 to 999999)	999999 (999999 to 999999)

Notes
[105] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.
[106] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.
[107] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.

No statistical analyses for this end point

Secondary: Change from Baseline Over Time in the Haemo-QoL-SF Questionnaire Physical Health Domain Score, as Completed by Treated Subjects ≥8 to <12 Years of Age

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End point title

Change from Baseline Over Time in the Haemo-QoL-SF Questionnaire Physical Health Domain Score, as Completed by Treated Subjects ≥8 to <12 Years of Age

End point description

The Haemo-QoL-SF is a self-reported questionnaire for children ≥8 years of age. It contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life: Physical Health, Feelings, View of Yourself, Family, Friends, Other People, Sports and School, Dealing with Hemophilia, and Treatment. The Physical Health domain assesses hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The Physical Health domain score ranges from 0 to 100, with a lower score reflective of better physical health. The number '99999' signifies that a 95% confidence interval could not be calculated for data from a single subject. The number '999999' signifies that no data was available at a given timepoint.

End point type

Secondary

End point timeframe

Baseline (Week 1), Weeks 13, 25, 37, 49, and 57, and then every 24 weeks until end of study (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	22 ^[108]	6 ^[109]	6 ^[110]
Units: units on a scale
arithmetic mean (confidence interval 95%)
Baseline: value at visit (n=18,6,6)	29.51 (16.38 to 42.65)	30.21 (21.49 to 38.93)	19.79 (-7.23 to 46.81)
Change from Baseline at Week 13 (n=18,6,5)	-18.40 (-31.08 to -5.72)	-23.96 (-28.90 to -19.02)	3.75 (-46.12 to 53.62)
Change from Baseline at Week 25 (n=18,1,1)	-18.40 (-33.76 to -3.05)	-18.75 (-99999 to 99999)	-56.25 (-99999 to 99999)
Change from Baseline at Week 37 (n=17,0,0)	-21.32 (-36.61 to -6.04)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 49 (n=17,0,0)	-15.44 (-25.74 to -5.15)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 57 (n=6,0,0)	-16.67 (-35.98 to 2.64)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 81 (n=7,0,0)	-13.39 (-36.38 to 9.59)	999999 (999999 to 999999)	999999 (999999 to 999999)

Notes
[108] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.
[109] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.
[110] - Analysis includes all treated subjects ≥8 to <12 years who completed a sufficient number of items.

No statistical analyses for this end point

Secondary: Change from Baseline Over Time in the Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients with Inhibitors Including Aspects of Caregiver Burden (Adapted Inhib-QoL) Questionnaire Total Score, Treated Subjects <12 Years of Age

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End point title

Change from Baseline Over Time in the Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients with Inhibitors Including Aspects of Caregiver Burden (Adapted Inhib-QoL) Questionnaire Total Score, Treated Subjects <12 Years of Age

End point description

Proxy assessment of health-related quality of life (HRQoL) and aspects of caregiver burden were assessed using the Adapted Inhib-QoL questionnaire, which comprises two parts with a total of 30 questions. The first part asks the caregiver for his/her opinion on the child’s HRQoL and consists of two scales: Physical Health and Treatment. The second part asks the caregiver to rate the impact of the child's disease and treatment on them and consists of 6 scales (5 if the child does not have siblings): General Condition, Dealing with the Inhibitor, Perceive Treatment, Family life, Siblings, Contact with Others. Items are rated with five respective response options: never, seldom, sometimes, often, and all the time. The Total Score is derived from the individual scores of all of the domains and it ranges from 0 to 100, with lower scores reflective of better HRQoL. '99999' means 95% CI not calculated for data from 1 subject; '999999' means no data available at that timepoint.

End point type

Secondary

End point timeframe

Baseline (Week 1), Weeks 13, 25, 37, 49, and 57, and then every 24 weeks until end of study (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	65 ^[111]	10 ^[112]	10 ^[113]
Units: units on a scale
arithmetic mean (confidence interval 95%)
Baseline: value at visit (n=58,10,10)	43.10 (39.63 to 46.56)	40.56 (32.46 to 48.65)	31.45 (19.93 to 42.97)
Change from Baseline at Week 13 (n=58,10,9)	-19.76 (-23.55 to -15.96)	-21.46 (-27.21 to -15.72)	-9.24 (-21.69 to 3.21)
Change from Baseline at Week 25 (n=56,1,1)	-21.72 (-25.59 to -17.86)	-26.52 (-99999 to 99999)	-33.33 (-99999 to 99999)
Change from Baseline at Week 37 (n=53,0,0)	-21.60 (-25.29 to -17.91)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 49 (n=51,0,0)	-21.30 (-24.82 to -17.78)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 57 (n=22,0,0)	-22.93 (-26.89 to -18.97)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 81 (n=16,0,0)	-24.25 (-30.70 to -17.81)	999999 (999999 to 999999)	999999 (999999 to 999999)

Notes
[111] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items
[112] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items
[113] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items

No statistical analyses for this end point

Secondary: Change from Baseline Over Time in the Caregiver-Reported Adapted Inhib-QoL Questionnaire Physical Health Domain Score, Treated Subjects <12 Years of Age

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End point title

Change from Baseline Over Time in the Caregiver-Reported Adapted Inhib-QoL Questionnaire Physical Health Domain Score, Treated Subjects <12 Years of Age

End point description

Proxy assessment of health-related quality of life (HRQoL) and aspects of caregiver burden were assessed using the Adapted Inhib-QoL questionnaire, which comprises two parts with a total of 30 questions. The first part asks the caregiver for his/her opinion on the child’s HRQoL and consists of two scales: Physical Health and Treatment. The second part asks the caregiver to rate the impact the child's disease and treatment has on them and consists of 6 scales (5 if child does not have siblings): General Condition, Dealing with the Inhibitor, Perceive Treatment, Family life, Siblings, Contact with Others. Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. A total score is the sum of all of the items in the scale. The Physical Health domain score ranges from 0 to 100, with lower scores reflective of better physical health. '99999' means 95% CI not calculated for data from 1 subject; '999999' means no data available at that timepoint.

End point type

Secondary

End point timeframe

Baseline (Week 1), Weeks 13, 25, 37, 49, and 57, and then every 24 weeks until end of study (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	65 ^[114]	10 ^[115]	10 ^[116]
Units: units on a scale
arithmetic mean (confidence interval 95%)
Baseline: value at visit (n=58,10,10)	37.13 (31.69 to 42.57)	34.64 (18.13 to 51.16)	20.00 (2.41 to 37.59)
Change from Baseline at Week 13 (n=58,10,9)	-31.10 (-36.78 to -25.42)	-30.00 (-46.83 to -13.17)	-6.35 (-33.24 to 20.54)
Change from Baseline at Week 25 (n=56,1,1)	-31.06 (-36.37 to -25.74)	-28.57 (-99999 to 99999)	-64.29 (-99999 to 99999)
Change from Baseline at Week 37 (n=53,0,0)	-31.20 (-36.86 to -25.53)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 49 (n=51,0,0)	-28.29 (-34.23 to -22.36)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 57 (n=22,0,0)	-29.22 (-37.29 to -21.15)	999999 (999999 to 999999)	999999 (999999 to 999999)
Change from Baseline at Week 81 (n=16,0,0)	-30.36 (-42.85 to -17.87)	999999 (999999 to 999999)	999999 (999999 to 999999)

Notes
[114] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items
[115] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items
[116] - Includes all treated subjects <12 years with caregivers who completed a sufficient number of items

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event

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End point title

Number of Subjects with at Least One Adverse Event

End point description

The number of subjects experiencing at least one adverse event, including all non-serious and serious adverse events, are reported.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after study drug discontinuation; At the primary completion date, the median (min-max) duration of observation in Cohorts A, B, and C were 57.36 (17.9-92.6), 21.29 (18.6-24.1), and 20.71 (18.0-24.1) weeks, respectively.

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	63	9	10

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Grade ≥3 Adverse Event

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End point title

Number of Subjects with at Least One Grade ≥3 Adverse Event

End point description

The World Health Organization (WHO) toxicity grading scale was used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable.

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	11	1	3

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event Leading to Withdrawal From Treatment

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End point title

Number of Subjects with at Least One Adverse Event Leading to Withdrawal From Treatment

End point description

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event of Local Injection Site Reaction

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End point title

Number of Subjects with at Least One Adverse Event of Local Injection Site Reaction

End point description

Local adverse events that occurred within 24 hours after study drug administration and, in the investigator’s opinion, were judged to be related to study drug injection, were captured as an “injection-site reaction” on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a “local injection-site reaction.”

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	19	2	6

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event of Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction

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End point title

Number of Subjects with at Least One Adverse Event of Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction

End point description

Systemic hypersensitivity, anaphylaxis, or anaphylactoid reactions were identified by the investigator using Sampson's criteria, as defined in the protocol. At the primary completion date, one subject had reported two non-serious adverse events (cough and abdominal pain) that were identified as a potential case based on a Standardised MedDRA Queries (SMQ) search for Sampson's criteria. However, after medical review of the case, it was confirmed that this case was not indicative of systemic hypersensitivity, anaphylaxis, or anaphylactoid reaction.

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event of Thromboembolic Event

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End point title

Number of Subjects with at Least One Adverse Event of Thromboembolic Event

End point description

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with at Least One Adverse Event of Thrombotic Microangiopathy

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End point title

Number of Subjects with at Least One Adverse Event of Thrombotic Microangiopathy

End point description

End point type

Secondary

End point timeframe

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADA), Including Non-Neutralizing ADA and ADA with Neutralizing Potential

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End point title

Number of Subjects Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADA), Including Non-Neutralizing ADA and ADA with Neutralizing Potential

End point description

'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample. ADAs associated with consistent decline of emicizumab exposure (corroborated by associated loss of effect) were considered as having a neutralizing potential.

End point type

Secondary

End point timeframe

Predose (0 hour) at Weeks 1, 5, 17, 33, 49, 57; then every 12 weeks until end of study or 24 weeks after treatment discontinuation (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: subjects
Total ADA Negative	65	10	9
ADA Negative	61	10	9
ADA Negative (Treatment Unaffected)	4	0	0
Total ADA Positive	3	0	1
ADA Positive (Treatment Boosted)	0	0	0
ADA Positive (Treatment Induced)	3	0	1
ADA Positive with Neutralizing Potential	1	0	1
ADA Positive with Non-Neutralizing ADA	2	0	0

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

End point description

Pre-dose (trough) plasma concentrations of emicizumab were analyzed using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantitation was 0.1 micrograms per milliliter (μg/mL).

End point type

Secondary

End point timeframe

Predose (0 hour) at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 49, and 57; then every 12 weeks until end of study or 24 weeks after treatment discontinuation (up to approximately 152 weeks)

End point values	Cohort A: Emicizumab QW	Cohort B: Emicizumab Q2W	Cohort C: Emicizumab Q4W
Number of subjects analysed	68	10	10
Units: micrograms per milliliter (μg/mL)
arithmetic mean (standard deviation)
Week 1 (n=67,10,10)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Week 2 (n=66,10,10)	18.2 ( 5.5 )	17.0 ( 3.9 )	17.2 ( 4.1 )
Week 3 (n=67,10,9)	31.6 ( 5.6 )	31.7 ( 6.8 )	33.9 ( 5.8 )
Week 4 (n=67,10,10)	42.9 ( 8.0 )	42.4 ( 9.5 )	44.7 ( 7.0 )
Week 5 (n=66,10,9)	53.3 ( 10.6 )	51.8 ( 10.5 )	56.4 ( 12.3 )
Week 7 (n=68,10,8)	51.2 ( 10.5 )	51.5 ( 9.6 )	59.9 ( 24.6 )
Week 9 (n=67,10,9)	49.9 ( 9.7 )	51.9 ( 11.2 )	39.3 ( 16.7 )
Week 13 (n=67,10,9)	48.3 ( 13.3 )	45.3 ( 10.8 )	37.1 ( 10.6 )
Week 17 (n=67,10,8)	46.1 ( 11.3 )	48.7 ( 10.4 )	36.3 ( 6.1 )
Week 21 (n=65,5,4)	44.9 ( 11.0 )	49.8 ( 9.0 )	37.4 ( 16.9 )
Week 25 (n=65,1,0)	46.4 ( 11.4 )	33.3 ( 99999 )	999999 ( 999999 )
Week 29 (n=63,0,0)	47.4 ( 12.9 )	999999 ( 999999 )	999999 ( 999999 )
Week 33 (n=62,0,0)	50.9 ( 13.9 )	999999 ( 999999 )	999999 ( 999999 )
Week 37 (n=62,0,0)	50.4 ( 15.2 )	999999 ( 999999 )	999999 ( 999999 )
Week 41 (n=60,0,0)	47.3 ( 13.5 )	999999 ( 999999 )	999999 ( 999999 )
Week 49 (n=59,0,0)	48.8 ( 12.5 )	999999 ( 999999 )	999999 ( 999999 )
Week 57 (n=36,0,0)	49.3 ( 14.2 )	999999 ( 999999 )	999999 ( 999999 )
Week 69 (n=19,0,0)	49.6 ( 10.7 )	999999 ( 999999 )	999999 ( 999999 )
Week 81 (n=19,0,0)	51.2 ( 10.3 )	999999 ( 999999 )	999999 ( 999999 )
Week 93 (n=1,0,0)	49.9 ( 99999 )	999999 ( 999999 )	999999 ( 999999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline until the primary completion date (30-Apr-2018); at that time, the median (min-max) duration of observation in Cohorts A, B, and C were 57.36 (17.9-92.6) weeks, 21.29 (18.6-24.1) weeks, and 20.71 (18.0-24.1) weeks, respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Cohort A: Emicizumab QW

Reporting group description

Reporting group title

Cohort C: Emicizumab Q4W

Reporting group description

Reporting group title

Cohort B: Emicizumab Q2W

Reporting group description

Serious adverse events	Cohort A: Emicizumab QW	Cohort C: Emicizumab Q4W	Cohort B: Emicizumab Q2W
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 68 (20.59%)	2 / 10 (20.00%)	1 / 10 (10.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events
Investigations
Neutralising antibodies positive
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ligament sprain
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mouth injury
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Haemorrhage
subjects affected / exposed	1 / 68 (1.47%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Mouth haemorrhage
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscle haemorrhage
subjects affected / exposed	2 / 68 (2.94%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 68 (2.94%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Ketoacidosis
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort A: Emicizumab QW	Cohort C: Emicizumab Q4W	Cohort B: Emicizumab Q2W
Total subjects affected by non serious adverse events
subjects affected / exposed	62 / 68 (91.18%)	10 / 10 (100.00%)	9 / 10 (90.00%)
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	19 / 68 (27.94%)	6 / 10 (60.00%)	2 / 10 (20.00%)
occurrences all number	42	15	7
Pain
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Pyrexia
subjects affected / exposed	16 / 68 (23.53%)	3 / 10 (30.00%)	2 / 10 (20.00%)
occurrences all number	26	4	3
Swelling
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	17 / 68 (25.00%)	0 / 10 (0.00%)	4 / 10 (40.00%)
occurrences all number	24	0	4
Oropharyngeal pain
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	6	0	1
Rhinorrhoea
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Product issues
Device breakage
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Device malfunction
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Investigations
Indeterminable ABO blood type
subjects affected / exposed	1 / 68 (1.47%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	1	1	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	11 / 68 (16.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	63	0	0
Fall
subjects affected / exposed	9 / 68 (13.24%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	16	0	1
Head injury
subjects affected / exposed	2 / 68 (2.94%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	1
Joint injury
subjects affected / exposed	2 / 68 (2.94%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	3	0	1
Laceration
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Ligament sprain
subjects affected / exposed	6 / 68 (8.82%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	9	1	0
Limb injury
subjects affected / exposed	5 / 68 (7.35%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0
Skin abrasion
subjects affected / exposed	8 / 68 (11.76%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	15	0	0
Nervous system disorders
Headache
subjects affected / exposed	9 / 68 (13.24%)	2 / 10 (20.00%)	1 / 10 (10.00%)
occurrences all number	12	2	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 68 (2.94%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 68 (4.41%)	0 / 10 (0.00%)	2 / 10 (20.00%)
occurrences all number	3	0	2
Abdominal pain upper
subjects affected / exposed	4 / 68 (5.88%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	5	1	0
Constipation
subjects affected / exposed	1 / 68 (1.47%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Diarrhoea
subjects affected / exposed	12 / 68 (17.65%)	0 / 10 (0.00%)	2 / 10 (20.00%)
occurrences all number	14	0	2
Nausea
subjects affected / exposed	3 / 68 (4.41%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	3	1	0
Vomiting
subjects affected / exposed	13 / 68 (19.12%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	14	0	1
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	2 / 68 (2.94%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	3	1	0
Rash
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0
Rash pruritic
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Urticaria
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 68 (8.82%)	1 / 10 (10.00%)	1 / 10 (10.00%)
occurrences all number	12	7	1
Groin pain
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Limb discomfort
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Neck pain
subjects affected / exposed	0 / 68 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Pain in extremity
subjects affected / exposed	5 / 68 (7.35%)	3 / 10 (30.00%)	0 / 10 (0.00%)
occurrences all number	5	4	0
Infections and infestations
Bronchitis
subjects affected / exposed	5 / 68 (7.35%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0
Conjunctivitis
subjects affected / exposed	2 / 68 (2.94%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	5	1	0
Ear infection
subjects affected / exposed	5 / 68 (7.35%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0
Gastroenteritis
subjects affected / exposed	6 / 68 (8.82%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	6	0	0
Influenza
subjects affected / exposed	8 / 68 (11.76%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	12	0	1
Nasopharyngitis
subjects affected / exposed	27 / 68 (39.71%)	4 / 10 (40.00%)	2 / 10 (20.00%)
occurrences all number	43	5	6
Otitis media
subjects affected / exposed	6 / 68 (8.82%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	7	0	0
Rhinitis
subjects affected / exposed	2 / 68 (2.94%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	3	1	0
Sinusitis
subjects affected / exposed	1 / 68 (1.47%)	1 / 10 (10.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Tinea versicolour
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Tonsilitis
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	0	0
Tracheitis
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Upper respiratory tract infection
subjects affected / exposed	19 / 68 (27.94%)	2 / 10 (20.00%)	0 / 10 (0.00%)
occurrences all number	33	2	0
Varicella
subjects affected / exposed	4 / 68 (5.88%)	0 / 10 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 68 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Jul 2016

The key changes in Protocol Amendment 1 (Version 2) that modified the study design or analyses, along with a rationale for each change, are summarized as follows: - Due to the anticipated rapid enrollment of the study, recruitment was placed on a temporary halt after the first 20 subjects had enrolled until the Joint Monitoring Committee (JMC) released recommendations on the appropriateness of the maintenance dose; -Modified dose up-titration criteria to more precisely define the subpopulation who may stand to benefit from an increased dose of emicizumab; -Added additional efficacy objectives and endpoints to evaluate all bleeds (i.e., both treated and not treated with coagulation factors) given that some subjects may report bleeds that they did not treat, as well as spontaneous bleeds as additional assessments of efficacy; -Based on feasibility and desire to expand the safety database, the Sponsor increased the maximum number of pediatric subjects with hemophilia A with inhibitors who were previously treated with episodic or prophylactic bypassing agents from 40 to approximately 60. Additionally, if no subjects <2 years are included in the primary cohort (QW Arm), the primary analysis would still occur at the specified time. However, enrollment in the study may be left open exclusively for subjects <2 years in order to enroll up to 5 such subjects.; Removed activated partial thromboplastin time (aPTT) point-of-care testing using the CoaguChek Pro II in order to reduce burden on subjects and sites given the sizeable schedule of assessments; Provided the option for subjects to potentially combine emicizumab volumes (if necessary) from more than 1 vial into 1 syringe to reduce the number of subcutaneous injections they may require.

08 Dec 2016

The key changes in Protocol Amendment 2 (Version 3) that modified the study design or analyses, along with a rationale for each change, are summarized as follows: -Most recent information on safety findings of thromboembolic events and thrombotic microangiopathy (TMA) events observed in Study BH29884 was added, including requirements for laboratory monitoring of coagulation status following bypassing agent use; -TMA was newly classified as an adverse event of special interest, and an exclusion criterion to exclude patients at high risk to experience TMA (e.g., have a previous medical or family history of TMA) was added; -The permitted and prohibited treatment for control and prevention of bleeds was specified with guidance for use of bypassing agents in combination with emicizumab; -Additional efficacy objectives and endpoints to evaluate treated joint bleeds and treated target joint bleeds were added to the analyses.

01 Sep 2017

The key changes in Protocol Amendment 3 (Version 4) that modified the study design or analyses, along with a rationale for each change, are summarized as follows: -Two arms (designated as the Q2W Arm and Q4W Arm; subjects 2 to 11 years of age) were added to the study to investigate additional, less frequent emicizumab dosing schedules (Q2W and Q4W).; -Approximately 80 subjects were planned to be included in the study, with 60 subjects in the QW Arm and 20 subjects in the additional Q2W and Q4W arms (10 subjects each).; -The up-titration schema was modified with removal of the 2.25 mg/kg QW dosing level. This was based on an interim data review, and JMC recommendation characterizing exposure at 1.5 mg/kg QW in subjects 2 to 12 years of age to be similar to adolescent/adult patients. As such, the up-titration dose was the same used in adolescent/adult subjects (3 mg/kg QW). The efficacy endpoint was revised to characterize the efficacy of up-titration on an intra-subject level based on the basis of the number of bleeds over time. This was due to the small number of subjects that were up-titrated.; -A new safety risk associated with emicizumab was added as follows: Life-threatening bleeding due to unreliable standard coagulation tests and inhibitors assays in the setting of emicizumab. Coagulation laboratory tests (including, but not limited to, aPTT, one-stage factor VIII (FVIII) activity, and FVIII inhibitor measurement by Bethesda assay) are not reliable and are impacted by the presence of emicizumab and, therefore, did not reflect patients’ underlying hemostatic status accurately.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
28 Oct 2016	The initial emicizumab maintenance dose of 1.5 mg/kg QW was evaluated by the Study BH29992 Joint Monitoring Committee (JMC) during an interim data review. At that time, further enrollment in the study was on the prespecified, protocol-defined hold, pending JMC interim data review and recommendations. All available data (including safety, efficacy, and pharmacokinetics) from the first 20 subjects enrolled in Cohort A was assessed by the JMC to determine the appropriateness of the starting maintenance dose, as well as to decide whether the study could begin enrolling subjects <2 years of age. On 7 December 2016, the JMC recommended continuing enrollment of subjects in Cohort A at the maintenance dose of 1.5 mg/kg QW, as well as to open enrollment to subjects <2 years of age at that same maintenance dose.	07 Dec 2016

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

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Administration of Emicizumab in Hemophilia A Pediatric Patients with Inhibitors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Primary: Cohort A: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Model-Based Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for All Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Calculated Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of All Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Spontaneous Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohorts B and C: Percentage of Subjects by Categorized Number of Treated Target Joint Bleeds Over the Efficacy Period in Treated Subjects <12 Years of Age

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the Non-Interventional Study (NIS) Population

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the Non-Interventional Study (NIS) Population

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of the Model-Based ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of the Calculated ABR for All Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Secondary: Cohort A: Intra-Subject Comparison of Percentage of Subjects by Categorized Number of Treated Bleeds on Study Versus Pre-Study in Treated Subjects <12 Years of Age From the NIS Population

Clinical Trial Results:
A Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Administration of Emicizumab in Hemophilia A Pediatric Patients with Inhibitors