Hemophilia A
Conditions
Brief summary
This multicenter, open-label, Phase 3 study with randomized and non-randomized arms is designed to investigate the efficacy, safety, and pharmacokinetics of emicizumab in participants with hemophilia A regardless of factor VIII (FVIII) inhibitor status. Participants greater than or equal to (≥)12 years old who received episodic therapy with FVIII or bypassing agents prior to study entry and experienced at least 5 bleeds over the prior 24 weeks will be randomized in a 2:2:1 ratio to the following regimens: Arm A: Emicizumab prophylaxis at 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg QW SC; Arm B: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 6 mg/kg once every 4 weeks (Q4W) SC; and Arm C: No prophylaxis (control arm). In addition, pediatric participants less than (\<)12 years old with hemophilia A and FVIII inhibitors who received episodic therapy with bypassing agents prior to study entry will be enrolled to Arm D: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 1.5 mg/kg QW SC.
Interventions
DRUGEmicizumab
Emicizumab will be administered via subcutaneous (SC) injection, as described for each treatment arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for Arms A, B, and C: * Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors * Aged 12 years or older at the time of informed consent * Body weight ≥40 kilograms (kg) at the time of screening * Participants without FVIII inhibitors (\<0.6 Bethesda unit per milliliter \[BU/mL\]) who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and have no evidence of inhibitor recurrence (permanent or temporary) * Documentation of the details of episodic therapy (FVIII or bypassing agents) and of number of bleeding episodes for at least the last 24 weeks and ≥5 bleeds in the last 24 weeks prior to study entry * Adequate hematologic, hepatic, and renal function * For women of child bearing potential: agreement to remain abstinent or use a protocol defined contraceptive measure during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug Inclusion Criteria for Arm D: * Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor (i.e., ≥5 BU/mL) * Children \<12 years old at time of informed consent * Body weight \>3 kg at time of informed consent * Requires treatment with bypassing agents * Adequate hematologic, hepatic, and renal function * For female participants who are of childbearing potential, follow the same contraception criteria as listed above for Arms A, B, and C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Model-Based Annualized Bleeding Rate for Treated Bleeds | From Baseline to at least 24 weeks | The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Mean Calculated Annualized Bleeding Rate for Treated Bleeds | From Baseline to at least 24 weeks | The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Median Calculated Annualized Bleeding Rate for Treated Bleeds | From Baseline to at least 24 weeks | The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Model-Based Annualized Bleeding Rate for All Bleeds | From Baseline to at least 24 weeks | The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
| Mean Calculated Annualized Bleeding Rate for All Bleeds | From Baseline to at least 24 weeks | The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
| Median Calculated Annualized Bleeding Rate for All Bleeds | From Baseline to at least 24 weeks | The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
| Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds | From Baseline to at least 24 weeks | The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | From Baseline to at least 24 weeks | The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | From Baseline to at least 24 weeks | The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Model-Based Annualized Bleeding Rate for Treated Joint Bleeds | From Baseline to at least 24 weeks | The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds | From Baseline to at least 24 weeks | The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds | From Baseline to at least 24 weeks | The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds | From Baseline to at least 24 weeks | The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | From Baseline to at least 24 weeks | The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | From Baseline to at least 24 weeks | The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days) | This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
| Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days) | This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The ABR was calculated for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. "All bleeds" comprises both treated and non-treated bleeds, and the 72-hour rule was implemented separately for each type. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was calculated as a treatment-free period of 72 hours from the bleed itself. |
| Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age | 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. |
| Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | 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). |
| Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age | 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. |
| Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | 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. |
| Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Baseline and Week 25 | The Haemo-QoL-SF contains 35 items covering nine dimensions considered relevant for the adolescent's (aged 12-17 years) health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The score ranges from 0 to 100, and a higher score is indicative of poorer HRQoL. According to the pre-specified statistical analysis plan, no statistical analyses were performed on the protocol-defined endpoints for the Haemo-QoL-SF due to the small number of adolescents randomized to Arms A, B and C. |
| Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25 | 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. |
| Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Baseline and Week 25 | The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The 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. |
| Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25 | Baseline and Week 25 | The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term. |
| Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Baseline and Week 25 | The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. |
| Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age | Baseline and Week 25 | The Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire contains 35 items covering nine dimensions considered relevant for the children's health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The scores range from 0 to 100, and higher scores are indicative of poorer HRQoL. |
| Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time | Baseline (Week 1) and Weeks 13 and 25 | Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless of age, were collected using the Adapted Inhib-QoL with Aspects of Caregiver Burden questionnaire. The questionnaire comprises two parts. The first part asks the caregiver for his/her opinion on the child's HRQoL (proxy HRQoL). The second part asks the caregiver to rate how the child's situation is for them (i.e., the impact of the child's disease and treatment on the caregiver). Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. Scores range from 0 to 100, with lower scores reflective of better HRQoL. A total score is calculated as the sum of all of the items in the scale. |
| Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms | From Baseline until primary cutoff date (at least 24 weeks): Arm C (Control) No Prophylaxis, median (range): 24.0 (23.9-28.0) weeks; Arms A & B Emicizumab, median (range): Arm A: 43.7 (28.1-60.3) weeks; Arm B: 46.1 (24.0-58.7) weeks | 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. |
| Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | 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. |
| Number of Participants With at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With Serum Chemistry Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | The number of participants with abnormal shifts in laboratory chemistry parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings. SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase |
| Number of Participants With Hematology Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline | From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months | The number of participants with abnormal shifts in laboratory hematology parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings. |
| Change From Baseline in Body Temperature Over Time | Baseline and Weeks 5, 25, 49, and 73 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
| Change From Baseline in Pulse Rate Over Time | Baseline, Weeks 5, 25, 49, and 73 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
| Change From Baseline in Respiratory Rate Over Time | Baseline, Weeks 5, 25, 49, and 73 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
| Change From Baseline in Systolic Blood Pressure Over Time | Baseline, Weeks 5, 25, 49, and 73 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
| Change From Baseline in Diastolic Blood Pressure Over Time | Baseline, Weeks 5, 25, 49, and 73 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
| Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status | Samples taken at Baseline and at prespecified times post-baseline from first dose of emicizumab until data cutoff date, median (range) time of exposure to emicizumab: All Arms: 196.14 (20.1-222.1) weeks; Arm D only: 64.14 (61.1-67.3) weeks | Participants were considered anti-drug antibody (ADA)-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration, or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater than the titer of the baseline sample. Participants were considered ADA-negative if they were ADA-negative at baseline and all post-baseline samples were negative following drug administration, or if they were ADA-positive at baseline but did not have any post-baseline (following drug administration) samples with a titer that was at least 4-fold greater than the titer of the baseline sample. |
| Plasma Trough Concentration (Ctrough) of Emicizumab | Arms A & D, QW (up to Week 49 for Arm D only): Weeks 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, and 133; Arms B & C, Q4W: Weeks 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73, 85, 97, 109, 121, and 133 | The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis). |
Countries
China, Hong Kong, Malaysia, Thailand
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 76 patients were screened for eligibility, 6 of whom were deemed ineligible, and 70 participants were randomized to this study (Arms A, B, and C). Arm D was added later in a protocol amendment (Version 4) after the study had already started. For Arm D, a total of 16 patients were screened and 15 patients were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Arm C: No Prophylaxis (Control), Then Emicizumab Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm C did not receive any prophylactic treatment for at least 24 weeks (Control). After 24 weeks, participants had the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study. | 14 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm A received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study. | 29 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who were randomized to Arm B received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 6 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study. | 27 |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW Participants \<12 years old with hemophilia A and FVIII inhibitors who were enrolled to Arm D received prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for the first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks of treatment, participants were allowed to continue receiving emicizumab until marketing authorization, as part of this study or a separate extension study, as long as they derived clinical benefit. Participants continued to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study. | 15 |
| Total | 85 |
Baseline characteristics
| Characteristic | Arm C: No Prophylaxis (Control), Then Emicizumab | Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Total |
|---|---|---|---|---|---|
| Age, Continuous | 27.5 Years STANDARD_DEVIATION 10.9 | 32.2 Years STANDARD_DEVIATION 12 | 28.6 Years STANDARD_DEVIATION 13.5 | 7.5 Years STANDARD_DEVIATION 2.2 | 25.9 Years STANDARD_DEVIATION 14.2 |
| Age, Customized ≥18 to <65 Years Old | 12 Participants | 26 Participants | 20 Participants | 0 Participants | 58 Participants |
| Age, Customized <18 Years Old | 2 Participants | 3 Participants | 6 Participants | 15 Participants | 26 Participants |
| Age, Customized ≥65 Years Old | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Categorical Number of Bleeds (<9 or ≥9) in the Past 24 Weeks Prior to Study Entry <9 Bleeds | 3 Participants | 7 Participants | 6 Participants | 5 Participants | 21 Participants |
| Categorical Number of Bleeds (<9 or ≥9) in the Past 24 Weeks Prior to Study Entry ≥9 Bleeds | 11 Participants | 22 Participants | 21 Participants | 10 Participants | 64 Participants |
| Factor VIII (FVIII) Inhibitor Status at Study Entry FVIII Inhibitor Negative (Non-Inhibitor) | 11 Participants | 24 Participants | 20 Participants | 0 Participants | 55 Participants |
| Factor VIII (FVIII) Inhibitor Status at Study Entry FVIII Inhibitor Positive | 3 Participants | 5 Participants | 7 Participants | 15 Participants | 30 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants | 29 Participants | 27 Participants | 15 Participants | 85 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 14 Participants | 29 Participants | 27 Participants | 15 Participants | 85 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 29 Participants | 27 Participants | 15 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 1 / 29 | 0 / 27 | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 2 / 14 | 28 / 29 | 24 / 27 | 14 / 14 | 15 / 15 |
| serious Total, serious adverse events | 0 / 14 | 9 / 29 | 6 / 27 | 4 / 14 | 2 / 15 |
Outcome results
Primary
Mean Calculated Annualized Bleeding Rate for Treated Bleeds
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Mean Calculated Annualized Bleeding Rate for Treated Bleeds | 43.7 Treated bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Bleeds | 1.4 Treated bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Mean Calculated Annualized Bleeding Rate for Treated Bleeds | 1.5 Treated bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Bleeds | 1.2 Treated bleeds per year |
Primary
Median Calculated Annualized Bleeding Rate for Treated Bleeds
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Median Calculated Annualized Bleeding Rate for Treated Bleeds | 45.3 Treated bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Bleeds | 0.0 Treated bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Median Calculated Annualized Bleeding Rate for Treated Bleeds | 0.0 Treated bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Bleeds | 0.0 Treated bleeds per year |
Primary
Model-Based Annualized Bleeding Rate for Treated Bleeds
The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Model-Based Annualized Bleeding Rate for Treated Bleeds | 27.0 Treated bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Bleeds | 1.0 Treated bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Model-Based Annualized Bleeding Rate for Treated Bleeds | 1.0 Treated bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Bleeds | 1.2 Treated bleeds per year |
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.016, 0.084]Stratified Wald test
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.015, 0.082]Stratified Wald test
Secondary
Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age
The Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire contains 35 items covering nine dimensions considered relevant for the children's health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The scores range from 0 to 100, and higher scores are indicative of poorer HRQoL.
Time frame: Baseline and Week 25
Population: This outcome measure was only applicable for participants enrolled in Arm D. The number analyzed for each visit represents the number of participants who responded to the questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age | Physical Health Score: Baseline (BL) - Value at Visit | 67.71 score on a scale | Standard Deviation 30.98 |
| Arm C (Control): No Prophylaxis | Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age | Physical Health Score: Change from BL at Week 25 | -53.75 score on a scale | Standard Deviation 37.66 |
| Arm C (Control): No Prophylaxis | Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age | Total Score: Baseline (BL) Value at Visit | 54.40 score on a scale | Standard Deviation 19.68 |
| Arm C (Control): No Prophylaxis | Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age | Total Score: Change from BL at Week 25 | -23.86 score on a scale | Standard Deviation 17.84 |
Secondary
Arm D: Change From Baseline in the Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Score Over Time
Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless of age, were collected using the Adapted Inhib-QoL with Aspects of Caregiver Burden questionnaire. The questionnaire comprises two parts. The first part asks the caregiver for his/her opinion on the child's HRQoL (proxy HRQoL). The second part asks the caregiver to rate how the child's situation is for them (i.e., the impact of the child's disease and treatment on the caregiver). Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. Scores range from 0 to 100, with lower scores reflective of better HRQoL. A total score is calculated as the sum of all of the items in the scale.
Time frame: Baseline (Week 1) and Weeks 17, 29, 37, and 49, every 12 weeks during extension phase, and study completion (up to 48 months)
Secondary
Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25
The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.
Time frame: Baseline and Week 25
Population: Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25 | 0.74 score on a scale | Standard Deviation 0.35 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25 | 0.79 score on a scale | Standard Deviation 0.27 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25 | 0.82 score on a scale | Standard Deviation 0.17 |
p-value: 0.48995% CI: [-0.18, 0.09]ANCOVA
p-value: 0.245495% CI: [-0.22, 0.06]ANCOVA
Secondary
Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25
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 and Week 25
Population: Participants randomized to Arms A, B, and C. The number analyzed represents participants who provided responses at Baseline and Week 25.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25 | 78.36 score on a scale | Standard Deviation 20.68 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25 | 81.82 score on a scale | Standard Deviation 23.19 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25 | 85.94 score on a scale | Standard Deviation 15.2 |
p-value: 0.616595% CI: [-17.23, 10.31]ANCOVA
p-value: 0.279795% CI: [-21.48, 6.33]ANCOVA
Secondary
Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age
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 and 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age | 43.32 score on a scale | Standard Deviation 7.47 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age | 37.26 score on a scale | Standard Deviation 16.17 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age | 29.30 score on a scale | Standard Deviation 14.6 |
p-value: 0.328195% CI: [-6.27, 18.4]ANCOVA
p-value: 0.029795% CI: [1.44, 26.59]ANCOVA
Secondary
Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age
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 and 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age | 42.53 score on a scale | Standard Deviation 14 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age | 27.85 score on a scale | Standard Deviation 19.82 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age | 24.20 score on a scale | Standard Deviation 16.09 |
p-value: 0.051595% CI: [-0.1, 29.46]ANCOVA
p-value: 0.020495% CI: [2.97, 33.68]ANCOVA
Secondary
Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25
The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life.
Time frame: Baseline and Week 25
Population: Participants randomized to Arms A, B, and C. The number analyzed indicates the number of participants who responded to the questionnaire scale at a given timepoint. For the change from baseline analysis, only participants who responded at both Baseline and Week 25 were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Value at Baseline (BL) | 0.76 score on a scale | Standard Deviation 0.27 |
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Change from BL to Week 25 | 0.02 score on a scale | Standard Deviation 0.09 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Value at Baseline (BL) | 0.68 score on a scale | Standard Deviation 0.27 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Change from BL to Week 25 | 0.08 score on a scale | Standard Deviation 0.22 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Value at Baseline (BL) | 0.75 score on a scale | Standard Deviation 0.2 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25 | Change from BL to Week 25 | 0.08 score on a scale | Standard Deviation 0.21 |
Secondary
Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25
The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The 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.
Time frame: Baseline and Week 25
Population: The number analyzed indicates the number of participants who responded to the questionnaire scale at a given timepoint. For the change from baseline analysis, only participants who responded at both Baseline and Week 25 were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Value at Baseline (BL) | 84.50 score on a scale | Standard Deviation 15.07 |
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Change from BL to Week 25 | -2.00 score on a scale | Standard Deviation 13.27 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Value at Baseline (BL) | 74.59 score on a scale | Standard Deviation 16.91 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Change from BL to Week 25 | 4.82 score on a scale | Standard Deviation 19.13 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Value at Baseline (BL) | 78.96 score on a scale | Standard Deviation 12.91 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25 | Change from BL to Week 25 | 7.40 score on a scale | Standard Deviation 16.67 |
Secondary
Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age
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).
Time frame: Baseline and 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Absolute Value at Baseline (BL) | 51.25 score on a scale | Standard Deviation 23.41 |
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -5.63 score on a scale | Standard Deviation 14 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Absolute Value at Baseline (BL) | 50.60 score on a scale | Standard Deviation 20.38 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -20.20 score on a scale | Standard Deviation 19.82 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Absolute Value at Baseline (BL) | 42.14 score on a scale | Standard Deviation 14.1 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -22.14 score on a scale | Standard Deviation 16.09 |
Secondary
Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age
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.
Time frame: Baseline and 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Value at Baseline (BL) | 42.05 score on a scale | Standard Deviation 17.89 |
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -2.50 score on a scale | Standard Deviation 7.47 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Value at Baseline (BL) | 49.15 score on a scale | Standard Deviation 16.04 |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -10.14 score on a scale | Standard Deviation 16.17 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Value at Baseline (BL) | 46.59 score on a scale | Standard Deviation 12.58 |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age | Change from BL to Week 25 | -17.61 score on a scale | Standard Deviation 14.6 |
Secondary
Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age
The Haemo-QoL-SF contains 35 items covering nine dimensions considered relevant for the adolescent's (aged 12-17 years) health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The score ranges from 0 to 100, and a higher score is indicative of poorer HRQoL. According to the pre-specified statistical analysis plan, no statistical analyses were performed on the protocol-defined endpoints for the Haemo-QoL-SF due to the small number of adolescents randomized to Arms A, B and C.
Time frame: Baseline and Week 25
Population: Only adolescents (aged 12-17 years) randomized to Arms A, B, and C were included in this analysis. The number analyzed represents participants who provided responses at Baseline and Week 25.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Baseline (BL) | 44.7 score on a scale |
| Arm C (Control): No Prophylaxis | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Week 25 | 21.5 score on a scale |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Baseline (BL) | 44.5 score on a scale |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Week 25 | 32.9 score on a scale |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Baseline (BL) | 35.7 score on a scale |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age | Value at Week 25 | 27.6 score on a scale |
Secondary
Change From Baseline in Body Temperature Over Time
Time frame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary
Change From Baseline in Diastolic Blood Pressure Over Time
Time frame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary
Change From Baseline in Pulse Rate Over Time
Time frame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary
Change From Baseline in Respiratory Rate Over Time
Time frame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary
Change From Baseline in Systolic Blood Pressure Over Time
Time frame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary
Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study
This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The ABR was calculated for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. All bleeds comprises both treated and non-treated bleeds, and the 72-hour rule was implemented separately for each type. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was calculated as a treatment-free period of 72 hours from the bleed itself.
Time frame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)
Population: A total of 4 participants, pooled from Arm A and Arm B (2 per Arm), who participated in the NIS BH29768 before entering this study were included for this intraparticipant analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | 39.67 All bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | 2.04 All bleeds per year |
Secondary
Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study
This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)
Population: A total of 4 participants, pooled from Arm A and Arm B (2 per Arm), who participated in the NIS BH29768 before entering this study were included for this intraparticipant analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | 13.02 Treated bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study | 0.24 Treated bleeds per year |
Secondary
Mean Calculated Annualized Bleeding Rate for All Bleeds
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As all bleeds comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Mean Calculated Annualized Bleeding Rate for All Bleeds | 53.0 All bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for All Bleeds | 2.7 All bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Mean Calculated Annualized Bleeding Rate for All Bleeds | 3.1 All bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for All Bleeds | 3.8 All bleeds per year |
Secondary
Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as joint based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 25.5 Treated joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 1.0 Treated joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 0.8 Treated joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 0.1 Treated joint bleeds per year |
Secondary
Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a treatment for bleed) with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 30.9 Treated spontaneous bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.5 Treated spontaneous bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.6 Treated spontaneous bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.6 Treated spontaneous bleeds per year |
Secondary
Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 15.6 Treated target joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.7 Treated target joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.5 Treated target joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.0 Treated target joint bleeds per year |
Secondary
Median Calculated Annualized Bleeding Rate for All Bleeds
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As all bleeds comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Median Calculated Annualized Bleeding Rate for All Bleeds | 56.7 All bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for All Bleeds | 1.5 All bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Median Calculated Annualized Bleeding Rate for All Bleeds | 1.9 All bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for All Bleeds | 2.1 All bleeds per year |
Secondary
Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as joint based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 10.9 Treated joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 0.0 Treated joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 0.0 Treated joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds | 0.0 Treated joint bleeds per year |
Secondary
Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a treatment for bleed) with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 21.8 Treated spontaneous bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.0 Treated spontaneous bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.0 Treated spontaneous bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.0 Treated spontaneous bleeds per year |
Secondary
Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 6.5 Treated target joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.0 Treated target joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.0 Treated target joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.0 Treated target joint bleeds per year |
Secondary
Model-Based Annualized Bleeding Rate for All Bleeds
The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As all bleeds comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Model-Based Annualized Bleeding Rate for All Bleeds | 41.1 All bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for All Bleeds | 1.9 All bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Model-Based Annualized Bleeding Rate for All Bleeds | 2.1 All bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for All Bleeds | 3.8 All bleeds per year |
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.026, 0.084]Stratified Wald test
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.028, 0.092]Stratified Wald test
Secondary
Model-Based Annualized Bleeding Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as joint based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Model-Based Annualized Bleeding Rate for Treated Joint Bleeds | 17.7 Treated joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Joint Bleeds | 0.7 Treated joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Model-Based Annualized Bleeding Rate for Treated Joint Bleeds | 0.6 Treated joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Joint Bleeds | 0.1 Treated joint bleeds per year |
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.017, 0.102]Stratified Wald test
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.013, 0.084]Stratified Wald test
Secondary
Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a treatment for bleed) with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds | 23.6 Treated spontaneous bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.4 Treated spontaneous bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.5 Treated spontaneous bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds | 0.6 Treated spontaneous bleeds per year |
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.006, 0.053]Stratified Wald test
Comparison: H0 (null hypothesis): ABR Ratio = 1; versus, H1 (alternative hypothesis): ABR Ratio ≠ 1p-value: <0.000195% CI: [0.007, 0.059]Stratified Wald test
Secondary
Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a treatment for bleed. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Time frame: From Baseline to at least 24 weeks
Population: All participants, which includes those randomized to Arms A, B, and C, and those enrolled in Arm D of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm C (Control): No Prophylaxis | Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds | 8.6 Treated target joint bleeds per year |
| Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.4 Treated target joint bleeds per year |
| Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W | Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds | 0.3 Treated target joint bleeds per year |
| Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW | Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds | NA Treated target joint bleeds per year |
p-value: <0.000195% CI: [0.016, 0.163]Stratified Wald test
p-value: <0.000195% CI: [0.011, 0.122]ABR Ratio
Secondary
Number of Participants With Adverse Events by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Adverse Events Leading to Study Drug Discontinuation
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Anti-Emicizumab Antibodies
Time frame: QW: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter until study completion; Q4W: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, and every 12 weeks thereafter until study completion (up to 85 months)
Secondary
Number of Participants With Hematology Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Injection-Site Reactions by Severity, According to the WHO Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Serum Chemistry Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Severe Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Thromboembolic Events by Severity, According to the WHO Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Number of Participants With Thrombotic Microangiopathy by Severity, According to the WHO Toxicity Grading Scale
Time frame: From Baseline until end of study (up to 85 months)
Secondary
Plasma Trough Concentration (Ctrough) of Emicizumab
Time frame: QW: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter to study completion; Q4W: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, and every 12 weeks thereafter to study completion (up to 85 months)