A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors

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

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

Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.

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

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

Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.

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

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

Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.

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

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

Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.

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

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

Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

Time frame: Baseline, Week 25

Population: Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

Time frame: Baseline, Week 25

Population: Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.

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

Time frame: Baseline, Week 25

Population: Adult participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.

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

Time frame: Baseline, Week 25

Population: Adult participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.

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

Time frame: Week 25

Population: The pre-specified efficacy objective was the comparison of Haemo-QoL-SF scores at Week 25 in adolescents who were previously on episodic treatment (i.e., randomized to Arms A, B, or C). Because there was a total of just one adolescent randomized to this study (in Arm C), statistical analyses could not be performed and no data is reported.

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

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

Population: Intra-participant comparison in the NIS population previously treated with episodic FVIII (NISE), which includes all participants who had received episodic FVIII in NIS BH29768 prior to study entry in Arms A and B (pooled data).

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

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

Population: Intra-participant comparison in the NIS population previously treated with FVIII prophylaxis (NISP), which includes all participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry in Arm D.

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

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

Population: Intra-participant comparison in the NIS population previously treated with episodic FVIII (NISE), which includes all participants who had received episodic FVIII in NIS BH29768 prior to study entry in Arms A and B (pooled data).

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

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

Population: Intra-participant comparison in the NIS population previously treated with FVIII prophylaxis (NISP), which includes all participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry in Arm D.

The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.

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

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.

The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.

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

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.

The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v4), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. The number analyzed includes participants with available data over each interval.

The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.

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

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C, it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study.

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

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

Population: The All Emicizumab Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: All participants in Arms A, B, and D who received at least one dose of emicizumab and all participants in Arm C (Control) who started the no prophylaxis study period. Participants in Arm C (Emi) are those from Arm C who switched after 24 weeks no prophylaxis to receive emicizumab prophylaxis (2 were excluded who did not switch at the time of analysis).

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

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

Population: The All Emicizumab Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab).

Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms severe and serious are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated and those who opted for a change in dosing regimen (after implementation of protocol v4), only AEs that occurred before either one of those events are included. Hypersens.= hypersensitivity; Mod. = modification

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

Population: All Emicizumab Participants, which includes all participants who received emicizumab on the study. For Arm C (Emi), it only includes participants who crossed over to receive prophylactic treatment with emicizumab after first completing 24 weeks of no prophylaxis on study (1 participant was excluded because they were lost to follow-up before Week 24 and did not receive emicizumab).

Trough plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm C (Control) switched from no prophylaxis to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm C (Emi) are expressed relative to first emicizumab dose.

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

Population: The Pharmacokinetics (PK) Population includes all participants in Arms A, B, C (Emi), and D treated with emicizumab who had at least one post-dose emicizumab concentration result; 1 was excluded from Arm C (Emi) (lost to follow-up before Week 24 and had not switched to emicizumab). Number analyzed represents participants per study arm with available samples at each specified timepoint.