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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

The World Health Organization (WHO) Toxicity Grading Scale was used for assessing adverse event (AE) severity. For AEs that are not specifically listed in the WHO Toxicity Grading Scale, a Grade 3 AE is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a Grade 4 AE is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE; the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

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

According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. In order to assess the causality of an AE, investigators used their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an AE is considered to be related to the study drug, indicating "yes" or "no" accordingly.

The number 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 was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. All of the adverse events reported here were assessed independently by the investigator as not related to treatment with emicizumab.

Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events.

An abnormal laboratory value was defined as a laboratory test result outside of the normal range for hematology or serum chemistry parameters. The WHO toxicity grading scale, which ranges from Grades 1 to 4 (least severe to most severe, respectively; Grade 0 is within normal range), was used for assessing the severity of laboratory abnormalities and adverse events (WHO 2003). Not every laboratory abnormality qualified as an adverse event; an abnormality was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. In this study, any laboratory value changes were transient and returned to baseline for all participants.

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."

Hypercoagulation and thromboembolic events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers educated patients/caregivers to recognize the signs and symptoms of potential thromboembolism (i.e., dyspnea, chest pain, leg pain or swelling, etc.) and to ensure that they understood the importance of seeking appropriate medical attention.

Thrombotic microangiopathy is used to describe a group of disorders with clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage that can include the kidneys, gastrointestinal system, or central nervous system, etc. Thrombotic microangiopathy events were to be reported as serious adverse events or adverse events of special interest.

Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, including anaphylaxis and anaphylactic reactions, may occur. These events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers (HCP) instructed patients and caregivers how to recognize the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an HCP or seek emergency care in case of any such occurrence.

A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies (ADAs) to emicizumab in blood plasma samples. Participants were considered ADA-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ADA response).

The 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.

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.

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.

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.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.

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 v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.