Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants

Hemophilia A Clinical Trial

— HAVEN 5  

Official title:

A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03315455
• Other study ID #: YO39309
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 26, 2018
• Est. completion date: May 31, 2025

Study information

• Verified date: April 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 85
• Est. completion date: May 31, 2025
• Est. primary completion date: August 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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 Exclusion Criteria:

Exclusion Criteria for Arms A, B, and C:

• Inherited or acquired bleeding disorder other than hemophilia A
• At high risk for thrombotic microangiopathy, in the investigator's judgment
• History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
• Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
• Other conditions that may increase risk of bleeding or thrombosis
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Known human immuno-deficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count <200 cells/microliter (cells/mcL) within 24 weeks prior to screening. Participants with HIV infection who have CD4 >200 cells/mcL and meet all other criteria are eligible
• Use of systemic immunomodulators at enrollment or planned use during the study, with the exception of anti-retroviral therapy
• Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
• Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
• Receipt of: Emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; A non-hemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter
• Pregnant or lactating, or intending to become pregnant during the study

Exclusion Criteria for Arm D:

• Inherited or acquired bleeding disorder other than hemophilia A
• Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment with FVIII
• Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
• Other diseases that may increase risk of bleeding or thrombosis
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
• At high risk for thrombotic microangiopathy, in the investigator's judgment
• Use of systemic immunomodulators at enrollment or planned use during the study
• Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
• Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood products (or any standard-of-care treatment for a life-threatening condition)
• Receipt of: Emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; A non-hemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter
• Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
• Pregnant or lactating, or intending to become pregnant during the study

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Drug:
• Emicizumab
Emicizumab will be administered via subcutaneous (SC) injection, as described for each treatment arm.

Locations

Country	Name	City	State
China	Beijing Children's Hospital, Capital Medical University; rheumatism	Beijing City
China	Peking Union Medical College Hospital	Beijing City
China	Xiangya Hospital of Centre-South University	Changsha
China	Southern Medical University Nanfang Hospital	Guangdong Province Guangzhou City
China	Ruijin Hospital Shanghai Jiaotong University School of Medicine; hemotology	Shanghai City
China	Tianjin Institute of Hematology & Blood Diseases Hospital	Tianjin
China	Tongji Hosp, Tongji Med. Col, Huazhong Univ. of Sci. & Tech	Wuhan
China	Xiehe Hospital, Tongji Medical College Huazhong University of Science & Technology	Wuhan
Hong Kong	Queen Mary Hospital; Department of Pediatrics & Adolescent Medicine	Hong kong
Hong Kong	Prince of Wales Hospital; Department of Pediatrics	Shatin
Malaysia	Penang General Hospital; Department of Medicine	Pulau Pinang	Penang
Malaysia	Queen Elizabeth Hospital	Shah Alam	Selangor
Thailand	Ramathibodi Hospital	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

China,  Hong Kong,  Malaysia,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	From Baseline to at least 24 weeks
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.	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)
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.	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)
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.	Baseline and Week 25
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).	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline and Week 25
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.	Baseline (Week 1) and Weeks 17, 29, 37, and 49, every 12 weeks during extension phase, and study completion (up to 48 months)
Secondary	Number of Participants With Adverse Events by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale		From Baseline until end of study (up to 85 months)
Secondary	Number of Participants With Adverse Events Leading to Study Drug Discontinuation		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		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		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		From Baseline until end of study (up to 85 months)
Secondary	Number of Participants With Severe Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions		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		From Baseline until end of study (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		From Baseline until end of study (up to 85 months)
Secondary	Change From Baseline in Body Temperature Over Time		Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary	Change From Baseline in Pulse Rate Over Time		Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary	Change From Baseline in Respiratory Rate Over Time		Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary	Change From Baseline in Systolic Blood Pressure Over Time		Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary	Change From Baseline in Diastolic Blood Pressure Over Time		Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
Secondary	Number of Participants With Anti-Emicizumab Antibodies		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	Plasma Trough Concentration (Ctrough) of Emicizumab		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)