Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A (NCT NCT03020160)

NCT ID: NCT03020160

Last Updated: 2023-01-11

Results Overview

The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

48 participants

Primary outcome timeframe

From Baseline to at least 24 weeks

Results posted on

2023-01-11

Participant Flow

A total of 7 patients were screened and enrolled in the PK run-in cohort of the study. For the expansion cohort, a total of 44 patients were screened, 41 of whom were enrolled.

Participant milestones

Participant milestones
Measure	Emicizumab: PK Run-In Cohort Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Overall Study STARTED	7	41
Overall Study Completed 24 Weeks in the Study	7	41
Overall Study Emicizumab Dose Was Up-Titrated	0	4
Overall Study Opted for a Change in Emicizumab Dosing Regimen	0	1
Overall Study COMPLETED	6	41
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Emicizumab: PK Run-In Cohort Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: Expansion Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Total n=48 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	35 Participants n=7 Participants	41 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	41 Participants n=7 Participants	48 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	38 Participants n=7 Participants	44 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	8 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants	31 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry 0 Target Joints	1 Participants n=5 Participants	16 Participants n=7 Participants	17 Participants n=5 Participants
Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry 1 Target Joint	2 Participants n=5 Participants	8 Participants n=7 Participants	10 Participants n=5 Participants
Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry >1 Target Joints	4 Participants n=5 Participants	17 Participants n=7 Participants	21 Participants n=5 Participants
Number of Participants by Hemophilia A Severity at Baseline Mild	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Number of Participants by Hemophilia A Severity at Baseline Moderate	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Number of Participants by Hemophilia A Severity at Baseline Severe	7 Participants n=5 Participants	40 Participants n=7 Participants	47 Participants n=5 Participants
Number of Participants by Factor VIII Inhibitor Status at Baseline Factor VIII Inhibitor Positive	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Number of Participants by Factor VIII Inhibitor Status at Baseline Factor VIII Inhibitor Negative	4 Participants n=5 Participants	36 Participants n=7 Participants	40 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Baseline to at least 24 weeks

Population: The analysis included all participants enrolled in the expansion part of the study.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds	—	2.4 treated bleed rate per year Interval 1.38 to 4.28

PRIMARY outcome

Timeframe: From Baseline to at least 24 weeks

Population: The analysis included all participants enrolled in the expansion part of the study.

The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (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 participant 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.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds	—	4.5 all bleed rate per year Interval 3.1 to 6.6

PRIMARY outcome

Timeframe: From Baseline to at least 24 weeks

Population: The analysis included all participants enrolled in the expansion part of the study.

The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (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 participant 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.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds	—	0.6 treated spontaneous bleed rate per year Interval 0.27 to 1.53

PRIMARY outcome

Timeframe: From Baseline to at least 24 weeks

Population: The analysis included all participants enrolled in the expansion part of the study.

The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (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 participant 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). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds	—	1.7 treated joint bleed rate per year Interval 0.82 to 3.68

PRIMARY outcome

Timeframe: From Baseline to at least 24 weeks

Population: The analysis included all participants enrolled in the expansion part of the study.

The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (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 participant 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.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds	—	1.0 treated target joint bleed rate per year Interval 0.31 to 3.26

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all adult participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=37 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age)	—	-13.62 units on a scale Interval -18.36 to -8.88

SECONDARY outcome

Timeframe: Baseline, Week 25

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=37 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score	—	67.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 25

The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=37 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age)	—	-15.14 units on a scale Interval -22.44 to -7.83

SECONDARY outcome

Timeframe: Baseline, Week 25

The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=37 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score	—	67.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all adolescent participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=3 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age)	—	-8.10 units on a scale Standard Deviation 6.48

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=40 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score	—	5.53 units on a scale Interval 1.15 to 9.9

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=40 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score	—	35.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=40 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score	—	0.06 units on a scale Interval 0.03 to 0.1

SECONDARY outcome

Timeframe: Baseline, Week 25

Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.

The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=40 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score	—	47.5 percentage of participants

SECONDARY outcome

Timeframe: Predose at Baseline, Weeks 13 and 25

Population: The analysis included all participants enrolled in the expansion part of the study who were working and completed the questionnaire at Baseline, Week 13, and Week 25.

Participants enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here for each time point as the proportion of the number of days away from work to the expected number of days at work.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=28 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks Baseline	—	0.05 away/expected work days Interval 0.01 to 0.1
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks Week 13	—	0.00 away/expected work days Interval 0.0 to 0.0
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks Week 25	—	0.01 away/expected work days Interval 0.0 to 0.02

SECONDARY outcome

Timeframe: Predose at Baseline, Weeks 13 and 25

Population: The analysis included all participants enrolled in the expansion part of the study who were enrolled in school and completed the questionnaire at Baseline, Week 13, and Week 25.

Participants enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=10 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks Baseline	—	0.12 away/expected school days Interval 0.01 to 0.24
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks Week 13	—	0.00 away/expected school days Interval 0.0 to 0.0
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks Week 25	—	0.03 away/expected school days Interval 0.0 to 0.1

SECONDARY outcome

Timeframe: From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks)

Population: The analysis included all participants enrolled in the expansion part of the study.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Number of Days Hospitalized	—	0 days Standard Deviation 0

SECONDARY outcome

Timeframe: Predose at Week 17

Population: The analysis included all participants enrolled in the expansion part of the study.

The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=41 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey Have No Preference	—	0.0 percentage of participants Interval 0.0 to 8.6
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey Prefer the New Emicizumab SC Treatment	—	100 percentage of participants Interval 91.4 to 100.0
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey Prefer My Old Hemophilia Treatment (IV)	—	0.0 percentage of participants Interval 0.0 to 8.6

SECONDARY outcome

Timeframe: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25

Population: The analysis included all participants enrolled in the PK Run-In part of the study.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab After First Dose (Weeks 1-5)	—	6.95 day Interval 3.99 to 7.18
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab After Sixth Dose (Weeks 21-25)	—	6.98 day Interval 6.9 to 14.03

SECONDARY outcome

Population: The analysis included all participants enrolled in the PK Run-In part of the study.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab After First Dose (Weeks 1-5)	—	31.8 μg/mL Geometric Coefficient of Variation 19.3
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab After Sixth Dose (Weeks 21-25)	—	62.7 μg/mL Geometric Coefficient of Variation 17.3

SECONDARY outcome

Population: The analysis included all participants enrolled in the PK Run-In part of the study.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab After First Dose (Weeks 1-5)	—	663 day*μg/mL Geometric Coefficient of Variation 19.6
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab After Sixth Dose (Weeks 21-25)	—	1420 day*μg/mL Geometric Coefficient of Variation 20.7

SECONDARY outcome

Population: The analysis included all participants enrolled in the PK Run-In part of the study. t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, dependent PK parameters, such as AUC\[0-inf\], could not be estimated after the sixth dose of emicizumab.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab After First Dose (Weeks 1-5)	—	1490 day*μg/mL Geometric Coefficient of Variation 27.2

SECONDARY outcome

Population: The analysis included all participants enrolled in the PK Run-In part of the study. t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, t1/2 could not be determined after the sixth dose of emicizumab.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab After First Dose (Weeks 1-5)	—	29.5 day Geometric Coefficient of Variation 38.5

SECONDARY outcome

Population: The analysis included all participants enrolled in the PK Run-In part of the study.

Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab After First Dose (Weeks 1-5)	—	10.7 mL/h Geometric Coefficient of Variation 23.9
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab After Sixth Dose (Weeks 21-25)	—	11.1 mL/h Geometric Coefficient of Variation 20.8

SECONDARY outcome

Timeframe: Week 1 Day 1 predose and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, and 25, and every 12 weeks thereafter to Week 265

Population: The analysis included all participants enrolled in the PK Run-In part of the study. The number analyzed represents the number of participants with an evaluable sample at a given time point.

Outcome measures

Outcome measures
Measure	Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.	Emicizumab: PK Run-In Cohort n=7 Participants Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study.
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 73	—	39.7 μg/mL Geometric Coefficient of Variation 22.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 85	—	38.0 μg/mL Geometric Coefficient of Variation 29.2
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 97	—	43.6 μg/mL Geometric Coefficient of Variation 17.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 109	—	37.7 μg/mL Geometric Coefficient of Variation 13.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 121	—	39.6 μg/mL Geometric Coefficient of Variation 19.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 1, Day 1 - Predose	—	NA μg/mL Geometric Coefficient of Variation NA Concentration could not be estimated because samples were below the lower limit of quantification (BLQ).
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 1, Day 1 - 8 hours	—	7.0 μg/mL Geometric Coefficient of Variation 71.7
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 1, Day 3	—	20.6 μg/mL Geometric Coefficient of Variation 51.2
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 1, Day 5	—	26.5 μg/mL Geometric Coefficient of Variation 29.7
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 2, Day 8	—	29.4 μg/mL Geometric Coefficient of Variation 25.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 2, Day 11	—	27.7 μg/mL Geometric Coefficient of Variation 21.9
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 3, Day 15	—	26.3 μg/mL Geometric Coefficient of Variation 20.5
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 3, Day 18	—	24.1 μg/mL Geometric Coefficient of Variation 21.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 4, Day 22	—	22.0 μg/mL Geometric Coefficient of Variation 14.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 4, Day 25	—	20.6 μg/mL Geometric Coefficient of Variation 15.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 5	—	18.5 μg/mL Geometric Coefficient of Variation 18.2
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 6	—	47.4 μg/mL Geometric Coefficient of Variation 13.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 7	—	42.1 μg/mL Geometric Coefficient of Variation 18.3
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 8	—	35.4 μg/mL Geometric Coefficient of Variation 22.5
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 9	—	28.2 μg/mL Geometric Coefficient of Variation 18.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 11	—	55.9 μg/mL Geometric Coefficient of Variation 20.4
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 13	—	34.6 μg/mL Geometric Coefficient of Variation 24.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 15	—	52.0 μg/mL Geometric Coefficient of Variation 17.0
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 17	—	36.7 μg/mL Geometric Coefficient of Variation 16.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 19	—	50.8 μg/mL Geometric Coefficient of Variation 32.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 21	—	34.5 μg/mL Geometric Coefficient of Variation 25.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 22	—	62.2 μg/mL Geometric Coefficient of Variation 17.5
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 23	—	56.5 μg/mL Geometric Coefficient of Variation 19.0
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 24	—	47.9 μg/mL Geometric Coefficient of Variation 28.7
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 25	—	39.2 μg/mL Geometric Coefficient of Variation 25.3
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 37	—	34.0 μg/mL Geometric Coefficient of Variation 15.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 49	—	34.7 μg/mL Geometric Coefficient of Variation 23.2
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 61	—	41.1 μg/mL Geometric Coefficient of Variation 25.9
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 133	—	37.5 μg/mL Geometric Coefficient of Variation 14.2
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 145	—	34.8 μg/mL Geometric Coefficient of Variation 13.1
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 157	—	35.0 μg/mL Geometric Coefficient of Variation 20.7
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 181	—	45.4 μg/mL Geometric Coefficient of Variation 14.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 193	—	37.9 μg/mL Geometric Coefficient of Variation 21.5
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 205	—	45.4 μg/mL Geometric Coefficient of Variation 21.0
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 217	—	45.3 μg/mL Geometric Coefficient of Variation 11.3
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 229	—	52.1 μg/mL Geometric Coefficient of Variation 18.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 241	—	45.6 μg/mL Geometric Coefficient of Variation 13.6
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 253	—	40.4 μg/mL Geometric Coefficient of Variation 13.8
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints Week 265	—	42.4 μg/mL Geometric Coefficient of Variation 16.5

SECONDARY outcome

Timeframe: Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73. 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, and 253

Population: The analysis included all participants enrolled in the Expansion part of the study. The number analyzed represents the number of participants with an evaluable sample at a given time point.