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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03020160
• Collaborator: Chugai Pharmaceutical (Industry)
• Enrollment: 48
• Locations: 17
• Arms: 2
• Actual Duration (Months): 64.9
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This multicenter, open-label, non-randomized study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK) run-in part followed by an expansion part.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Drug: Emicizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients With Hemophilia A
• Actual Study Start Date: Jan 30, 2017
• Actual Primary Completion Date: Dec 15, 2017
• Actual Study Completion Date: Jun 29, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Emicizumab: Expansion Part Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Drug: Emicizumab; Emicizumab will be administered according to dose and schedule described in respective arms. Upon implementation of protocol Version 5, treatment duration will be extended. During this study prolongation, participants will have the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.; Other Names: Hemlibra RO5534262 ACE910
Experimental: Emicizumab: PK Run-in Part Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Drug: Emicizumab; Emicizumab will be administered according to dose and schedule described in respective arms. Upon implementation of protocol Version 5, treatment duration will be extended. During this study prolongation, participants will have the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.; Other Names: Hemlibra RO5534262 ACE910

Outcome Measures

Primary Outcome Measures

1. Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds [From Baseline to at least 24 weeks]

   The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

2. Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds [From Baseline to at least 24 weeks]

   The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the "treated bleeds" outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

3. Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds [From Baseline to at least 24 weeks]

   The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.

4. Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds [From Baseline to at least 24 weeks]

   The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as "joint" and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A "treated joint bleed" is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.

5. Expansion Part: Annualized Bleeding Rate (ABR) 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 as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.

Secondary Outcome Measures

1. Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age) [Baseline, Week 25]

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

2. Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score [Baseline, Week 25]

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

3. Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age) [Baseline, Week 25]

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

4. Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score [Baseline, Week 25]

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

5. Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age) [Baseline, Week 25]

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

6. Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score [Baseline, Week 25]

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

7. Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score [Baseline, Week 25]

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

8. Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [Baseline, Week 25]

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

9. Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [Baseline, Week 25]

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

10. Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks [Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)]

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

11. Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks [Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)]

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

12. Expansion Part: Number of Days Hospitalized [From Baseline until at least 24 weeks of treatment through to study completion (up to approximately 4 years)]

    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks); all participants had completed at least 24 weeks of treatment.

13. Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey [Predose at Week 17]

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

14. PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

15. PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

16. PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

17. PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

18. PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

19. PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab [Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)]

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

20. Expansion Part: Minimum Observed Plasma Concentration (Cmin) of Emicizumab [Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, and once every 12 weeks from Week 25 to study completion (up to approximately 4 years)]

21. Number of Participants With At Least One Adverse Event [From Baseline to study completion (up to approximately 4 years)]

    The number of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

22. Number of Participants With Grade ≥3 Adverse Events [From Baseline to study completion (up to approximately 4 years)]

    The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

23. Number of Participants With Adverse Events Leading to Withdrawal From Treatment [From Baseline to study completion (up to approximately 4 years)]

    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

24. Number of Participants With Adverse Events of Changes From Baseline in Vital Signs [From Baseline to study completion (up to approximately 4 years)]

    The number of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

25. Number of Participants With Adverse Events of Changes From Baseline in Physical Examination Findings [From Baseline to study completion (up to approximately 4 years)]

    Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

26. Number of Participants With Adverse Events of Abnormal Laboratory Values [From Baseline to study completion (up to approximately 4 years)]

    The number of participants with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries. It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

27. Number of Participants With Local Injection-Site Reactions [From Baseline to study completion (up to approximately 4 years)]

    Local adverse events that occurred within 24 hours after study drug administration and, in the investigator's opinion, were judged to be related to study drug injection, were captured as an "injection-site reaction" on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a "local injection-site reaction." At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

28. Number of Participants With Thromboembolic Events [From Baseline to study completion (up to approximately 4 years)]

    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

29. Number of Participants With Thrombotic Microangiopathy [From Baseline to study completion (up to approximately 4 years)]

    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

30. Number of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions [From Baseline to study completion (up to approximately 4 years)]

    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

31. Number of Participants With Anti-Drug Antibodies to Emicizumab [Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)]

    A validated ELISA method was used to analyze the levels of anti-drug antibodies to emicizumab in blood plasma samples. A sample was considered positive for anti-drug antibodies if the test result reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

32. Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies [Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)]

    The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Body weight greater than or equal to (>/=) 40 kilograms (kg) at screening

• Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors

• Participants using rFVIIa or willing to switch to recombinant activated factor VII (rFVIIa) as primary bypassing agent for the treatment of breakthrough bleeds

• FVIII inhibitor test during screening with titer results available prior to first administration of study drug

• Participants without FVIII inhibitors, that is with less than (<) 0.6 Bethesda unit per milliliter [BU/mL];< 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL, who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor greater than (>) 0.6 BU/mL (> 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI

• Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

• Inherited or acquired bleeding disorder other than hemophilia A

• Ongoing or planned ITI therapy; participants in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration

• History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment

• Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment

• Previous (within the last 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 (for example, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis

• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection

• Known HIV infection with cluster of differentiation (CD) 4 cells counts <200 cells per microliter (cells/mcL)

• Use of systemic immunomodulators (for example, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy

• Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the participant

• Pregnancy or lactation or intention to become pregnant during the study

• Women with a positive serum pregnancy test result within 7 days prior to initiation of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis	Sacramento	California	United States	95817
2	Indiana Hemophilia & Thrombosis center	Indianapolis	Indiana	United States	46260
3	University of Michigan, C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
4	Univ of N Carolina Chapel Hill; Hematology/Oncology	Chapel Hill	North Carolina	United States	27514
5	Royal Brisbane Hospital; Clinical Haematology	Brisbane	Queensland	Australia	4029
6	Royal Adelaide Hospital; Haematology Clinical Trials	Adelaide	South Australia	Australia	5000
7	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
8	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
9	Hokkaido University Hospital	Hokkaido		Japan	060-8648
10	Nara Medical University Hospital	Nara		Japan	634-8522
11	National Center for Child Health and Development	Tokyo		Japan	157-8535
12	Tokyo Medical University Hospital	Tokyo		Japan	160-0023
13	Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych	Warsaw		Poland	02-776
14	Uniwersytecki Szpital Kliniczny; Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku	Wrocław		Poland	50-367
15	Hospital Universitario la Paz; Servicio de Hematologia	Madrid		Spain	28046
16	Hospital Universitario Virgen del Rocio; Servicio de Hematologia	Sevilla		Spain	41013
17	Hospital Universitario la Fe; Servicio de Hematologia	Valencia		Spain	46026

Sponsors and Collaborators

• Hoffmann-La Roche
• Chugai Pharmaceutical

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Jul 25, 2017
• Statistical Analysis Plan - Jun 20, 2017

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03020160
• Other Study ID Numbers: BO39182; 2016-001094-33
• First Posted: Jan 13, 2017
• Last Update Posted: Jul 29, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hemophilia A

Study Results

Participant Flow

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

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Period Title: Overall Study
STARTED	7	41
Completed 24 Weeks in the Study	7	41
COMPLETED	0	0
NOT COMPLETED	7	41

Baseline Characteristics

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part	Total
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Total of all reporting groups
Overall Participants	7	41	48
Age (Count of Participants)
<=18 years	1 14.3%	3 7.3%	4 8.3%
Between 18 and 65 years	6 85.7%	35 85.4%	41 85.4%
>=65 years	0 0%	3 7.3%	3 6.3%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	7 100%	41 100%	48 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%	2 4.9%	3 6.3%
Not Hispanic or Latino	6 85.7%	38 92.7%	44 91.7%
Unknown or Not Reported	0 0%	1 2.4%	1 2.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 28.6%	8 19.5%	10 20.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.4%	1 2.1%
White	5 71.4%	31 75.6%	36 75%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 2.4%	1 2.1%
Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry (Count of Participants)
0 Target Joints	1 14.3%	16 39%	17 35.4%
1 Target Joint	2 28.6%	8 19.5%	10 20.8%
>1 Target Joints	4 57.1%	17 41.5%	21 43.8%

Outcome Measures

1. Primary Outcome

Title	Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds
Description	The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.
Time Frame	From Baseline to at least 24 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number (95% Confidence Interval) [treated bleed rate per year]	2.4

2. Primary Outcome

Title	Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds
Description	The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the "treated bleeds" outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time Frame	From Baseline to at least 24 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number (95% Confidence Interval) [all bleed rate per year]	4.5

3. Primary Outcome

Title	Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds
Description	The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.
Time Frame	From Baseline to at least 24 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number (95% Confidence Interval) [treated spontaneous bleed rate per year]	0.6

4. Primary Outcome

Title	Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds
Description	The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as "joint" and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A "treated joint bleed" is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.
Time Frame	From Baseline to at least 24 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number (95% Confidence Interval) [treated joint bleed rate per year]	1.7

5. Primary Outcome

Title	Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds
Description	The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.
Time Frame	From Baseline to at least 24 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number (95% Confidence Interval) [treated target joint bleed rate per year]	1.0

6. Secondary Outcome

Title	Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age)
Description	The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	38
Mean (95% Confidence Interval) [units on a scale]	-13.62

7. Secondary Outcome

Title	Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score
Description	The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	38
Number [percentage of participants]	67.6 965.7%

8. Secondary Outcome

Title	Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age)
Description	The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	38
Mean (95% Confidence Interval) [units on a scale]	-15.14

9. Secondary Outcome

Title	Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score
Description	The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	38
Number [percentage of participants]	67.6 965.7%

10. Secondary Outcome

Title	Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age)
Description	The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	3
Mean (Standard Deviation) [units on a scale]	-8.10 (6.48)

11. Secondary Outcome

Title	Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score
Description	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Mean (95% Confidence Interval) [units on a scale]	5.53

12. Secondary Outcome

Title	Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score
Description	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number [percentage of participants]	35.0 500%

13. Secondary Outcome

Title	Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
Description	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Mean (95% Confidence Interval) [units on a scale]	0.06

14. Secondary Outcome

Title	Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
Description	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Number [percentage of participants]	47.5 678.6%

15. Secondary Outcome

Title	Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks
Description	Participants enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here for each time point as the proportion of the number of days away from work to the expected number of days at work.
Time Frame	Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Baseline	0.05
Week 13	0.00
Week 25	0.01

16. Secondary Outcome

Title	Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks
Description	Participants enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school.
Time Frame	Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Baseline	0.12
Week 13	0.00
Week 25	0.03

17. Secondary Outcome

Title	Expansion Part: Number of Days Hospitalized
Description	At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks); all participants had completed at least 24 weeks of treatment.
Time Frame	From Baseline until at least 24 weeks of treatment through to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Mean (Standard Deviation) [days]	0 (0)

18. Secondary Outcome

Title	Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey
Description	The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.
Time Frame	Predose at Week 17

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Prefer the New Emicizumab SC Treatment	100 1428.6%
Prefer My Old Hemophilia Treatment (IV)	0.0 0%
Have No Preference	0.0 0%

19. Secondary Outcome

Title	PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	6.95
After Sixth Dose (Weeks 21-25)	6.98

20. Secondary Outcome

Title	PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	31.8 (19.3)
After Sixth Dose (Weeks 21-25)	62.7 (17.3)

21. Secondary Outcome

Title	PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	663 (19.6)
After Sixth Dose (Weeks 21-25)	1420 (20.7)

22. Secondary Outcome

Title	PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	1490 (27.2)

23. Secondary Outcome

Title	PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	29.5 (38.5)

24. Secondary Outcome

Title	PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab
Description	Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated.
Time Frame	Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: PK Run-In Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7
After First Dose (Weeks 1-5)	10.7 (23.9)
After Sixth Dose (Weeks 21-25)	11.1 (20.8)

25. Secondary Outcome

Title	Expansion Part: Minimum Observed Plasma Concentration (Cmin) of Emicizumab
Time Frame	Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, and once every 12 weeks from Week 25 to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	41
Week 1	NA (NA)
Week 2	16.0 (36.8)
Week 3	29.8 (30.5)
Week 4	41.3 (32.4)
Week 5	48.8 (32.2)
Week 9	40.4 (45.7)
Week 13	38.8 (48.8)
Week 17	36.1 (53.8)
Week 21	37.4 (48.5)
Week 25	37.7 (52.8)

26. Secondary Outcome

Title	Number of Participants With At Least One Adverse Event
Description	The number of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	7 100%	30 73.2%

27. Secondary Outcome

Title	Number of Participants With Grade ≥3 Adverse Events
Description	The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	1 14.3%	1 2.4%

28. Secondary Outcome

Title	Number of Participants With Adverse Events Leading to Withdrawal From Treatment
Description	At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

29. Secondary Outcome

Title	Number of Participants With Adverse Events of Changes From Baseline in Vital Signs
Description	The number of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

30. Secondary Outcome

Title	Number of Participants With Adverse Events of Changes From Baseline in Physical Examination Findings
Description	Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

31. Secondary Outcome

Title	Number of Participants With Adverse Events of Abnormal Laboratory Values
Description	The number of participants with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries. It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

32. Secondary Outcome

Title	Number of Participants With Local Injection-Site Reactions
Description	Local adverse events that occurred within 24 hours after study drug administration and, in the investigator's opinion, were judged to be related to study drug injection, were captured as an "injection-site reaction" on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a "local injection-site reaction." At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	1 14.3%	9 22%

33. Secondary Outcome

Title	Number of Participants With Thromboembolic Events
Description	At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

34. Secondary Outcome

Title	Number of Participants With Thrombotic Microangiopathy
Description	At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

35. Secondary Outcome

Title	Number of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions
Description	At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	From Baseline to study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

36. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies to Emicizumab
Description	A validated ELISA method was used to analyze the levels of anti-drug antibodies to emicizumab in blood plasma samples. A sample was considered positive for anti-drug antibodies if the test result reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab. The number analyzed indicates those with both baseline and post-baseline assessments.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

37. Secondary Outcome

Title	Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies
Description	The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Time Frame	Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

The analysis included all participants who received at least one dose of emicizumab.

Arm/Group Title	Emicizumab: PK Run-In Part	Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.	Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
Measure Participants	7	41
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	From Baseline until the clinical cut-off date (15-Dec-2017) for the primary analysis (median observation time was 43.71 weeks [range: 41.7-45.7 weeks])
Arm/Group Title	Emicizumab: PK Run-In Part		Emicizumab: Expansion Part
Arm/Group Description	Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.		Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
All Cause Mortality
	Emicizumab: PK Run-In Part		Emicizumab: Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/41 (0%)
Serious Adverse Events
	Emicizumab: PK Run-In Part		Emicizumab: Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/7 (0%)		1/41 (2.4%)
Vascular disorders
Hypertension	1/7 (14.3%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Emicizumab: PK Run-In Part		Emicizumab: Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		30/41 (73.2%)
Blood and lymphatic system disorders
Splenomegaly	0/7 (0%)		1/41 (2.4%)
Thrombocytopenia	0/7 (0%)		1/41 (2.4%)
Cardiac disorders
Atrioventricular block first degree	0/7 (0%)		1/41 (2.4%)
Endocrine disorders
Goitre	0/7 (0%)		1/41 (2.4%)
Eye disorders
Eczema eyelids	1/7 (14.3%)		0/41 (0%)
Cataract	0/7 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	1/7 (14.3%)		0/41 (0%)
Dyspepsia	1/7 (14.3%)		0/41 (0%)
Aphthous ulcer	0/7 (0%)		1/41 (2.4%)
Dental caries	0/7 (0%)		1/41 (2.4%)
Diarrhoea	0/7 (0%)		1/41 (2.4%)
Faeces discoloured	0/7 (0%)		1/41 (2.4%)
General disorders
Injection site reaction	1/7 (14.3%)		9/41 (22%)
Asthenia	0/7 (0%)		1/41 (2.4%)
Chills	0/7 (0%)		1/41 (2.4%)
Fatigue	0/7 (0%)		2/41 (4.9%)
Injection site pain	0/7 (0%)		1/41 (2.4%)
Malaise	0/7 (0%)		1/41 (2.4%)
Pain	0/7 (0%)		1/41 (2.4%)
Pyrexia	0/7 (0%)		2/41 (4.9%)
Hepatobiliary disorders
Cholelithiasis	1/7 (14.3%)		0/41 (0%)
Liver disorder	0/7 (0%)		1/41 (2.4%)
Infections and infestations
Device related infection	1/7 (14.3%)		0/41 (0%)
Ear infection	1/7 (14.3%)		0/41 (0%)
Pharyngitis	1/7 (14.3%)		0/41 (0%)
Upper respiratory tract infection	2/7 (28.6%)		3/41 (7.3%)
Chronic sinusitis	0/7 (0%)		1/41 (2.4%)
Gastroenteritis	0/7 (0%)		1/41 (2.4%)
Gastroenteritis viral	0/7 (0%)		1/41 (2.4%)
Nasopharyngitis	0/7 (0%)		11/41 (26.8%)
Oral herpes	0/7 (0%)		1/41 (2.4%)
Otitis media	0/7 (0%)		1/41 (2.4%)
Urinary tract infection	0/7 (0%)		1/41 (2.4%)
Injury, poisoning and procedural complications
Contusion	1/7 (14.3%)		0/41 (0%)
Post procedural inflammation	1/7 (14.3%)		0/41 (0%)
Tongue injury	1/7 (14.3%)		0/41 (0%)
Fall	0/7 (0%)		1/41 (2.4%)
Joint injury	0/7 (0%)		1/41 (2.4%)
Laceration	0/7 (0%)		1/41 (2.4%)
Ligament sprain	0/7 (0%)		1/41 (2.4%)
Muscle strain	0/7 (0%)		1/41 (2.4%)
Road traffic accident	0/7 (0%)		1/41 (2.4%)
Venomous sting	0/7 (0%)		1/41 (2.4%)
Wound	0/7 (0%)		1/41 (2.4%)
Investigations
Glycosylated haemoglobin increased	0/7 (0%)		1/41 (2.4%)
Metabolism and nutrition disorders
Hyperglycaemia	0/7 (0%)		1/41 (2.4%)
Iron deficiency	0/7 (0%)		1/41 (2.4%)
Vitamin B12 deficiency	0/7 (0%)		1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/7 (28.6%)		8/41 (19.5%)
Back pain	2/7 (28.6%)		1/41 (2.4%)
Myalgia	1/7 (14.3%)		1/41 (2.4%)
Osteitis	1/7 (14.3%)		0/41 (0%)
Joint lock	1/7 (14.3%)		0/41 (0%)
Musculoskeletal chest pain	1/7 (14.3%)		0/41 (0%)
Osteoarthritis	2/7 (28.6%)		0/41 (0%)
Synovitis	1/7 (14.3%)		2/41 (4.9%)
Temporomandibular joint syndrome	1/7 (14.3%)		0/41 (0%)
Tendon disorder	1/7 (14.3%)		0/41 (0%)
Muscle contracture	0/7 (0%)		1/41 (2.4%)
Neck pain	0/7 (0%)		2/41 (4.9%)
Pain in extremity	0/7 (0%)		4/41 (9.8%)
Pain in jaw	0/7 (0%)		1/41 (2.4%)
Nervous system disorders
Headache	2/7 (28.6%)		5/41 (12.2%)
Dizziness	0/7 (0%)		2/41 (4.9%)
Hypoaesthesia	0/7 (0%)		1/41 (2.4%)
Presyncope	0/7 (0%)		1/41 (2.4%)
Psychiatric disorders
Insomnia	0/7 (0%)		1/41 (2.4%)
Sleep disorder	0/7 (0%)		1/41 (2.4%)
Renal and urinary disorders
Dysuria	0/7 (0%)		1/41 (2.4%)
Hydronephrosis	0/7 (0%)		1/41 (2.4%)
Nephrolithiasis	0/7 (0%)		2/41 (4.9%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/7 (0%)		1/41 (2.4%)
Genital tract inflammation	0/7 (0%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/7 (0%)		1/41 (2.4%)
Cough	0/7 (0%)		1/41 (2.4%)
Oropharyngeal pain	0/7 (0%)		1/41 (2.4%)
Rhinorrhea	0/7 (0%)		1/41 (2.4%)
Skin and subcutaneous tissue disorders
Dermatitis	0/7 (0%)		1/41 (2.4%)
Erythema	0/7 (0%)		1/41 (2.4%)
Erythema nodosum	0/7 (0%)		1/41 (2.4%)
Psoriasis	0/7 (0%)		1/41 (2.4%)
Rash	0/7 (0%)		1/41 (2.4%)
Vascular disorders
Hypertension	1/7 (14.3%)		0/41 (0%)
Aneurysm	0/7 (0%)		1/41 (2.4%)

Limitations/Caveats

Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.