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

Among 22 studies testing emicizumab in Hemophilia A — 6 open to participants now, 8 under way, 3 of them phase 3. emicizumab · Hemophilia A.

Enrollment

6th of 22

85 · median 27

Started

2018

with 2 others

Phase 3

11 of 22

none open now

Registered

6th of 22

by date

Lead sponsor

10 of 22

Hoffmann-La Roche

Among the 22 studies testing emicizumab in Hemophilia A, this one is the 6th largest by enrollment, is one of 3 that started in 2018, is one of 11 in phase 3, and was the 6th registered.

Browse trials for

• Hemophilia A 844

Study arms

• Active comparator
  Arm C (Control): No Prophylaxis, Then Emicizumab

  Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm C will not receive any prophylactic treatment for at least 24 weeks. After 24 weeks, participants will have the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

  Drug: Emicizumab

• Experimental
  Arm A: Emicizumab Prophylaxis at 1.5 mg/kg QW

  Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm A will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 1.5 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

  Drug: Emicizumab

• Experimental
  Arm B: Emicizumab Prophylaxis at 6 mg/kg Q4W

  Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm B will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 6 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

  Drug: Emicizumab

• Experimental
  Arm D: Emicizumab Prophylaxis at 1.5 mg/kg QW

  Participants \<12 years old with hemophilia A and FVIII inhibitors who are enrolled to Arm D will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.

  Drug: Emicizumab

Interventions

• DrugEmicizumab

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

  Also known as: Hemlibra, RO5534262, RG6013, ACE910

Primary outcomes

1. Model-Based Annualized Bleeding Rate for Treated Bleeds

   The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

2. Mean Calculated Annualized Bleeding Rate for Treated Bleeds

   The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

3. Median Calculated Annualized Bleeding Rate for Treated Bleeds

   The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

Secondary outcomes

1. Model-Based Annualized Bleeding Rate for All Bleeds

   The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

   Time frame: From Baseline to at least 24 weeks

2. Mean Calculated Annualized Bleeding Rate for All Bleeds

   The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

   Time frame: From Baseline to at least 24 weeks

3. Median Calculated Annualized Bleeding Rate for All Bleeds

   The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

   Time frame: From Baseline to at least 24 weeks

4. Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

   The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

5. Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

   The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

6. Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

   The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

7. Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

   The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

8. Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

   The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

9. Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

   The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

   Time frame: From Baseline to at least 24 weeks

10. Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds

    The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

    Time frame: From Baseline to at least 24 weeks

11. Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

    The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

    Time frame: From Baseline to at least 24 weeks

12. Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

    The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

    Time frame: From Baseline to at least 24 weeks

13. Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study

    This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

    Time frame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)

14. Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study

    This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The ABR was calculated for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. "All bleeds" comprises both treated and non-treated bleeds, and the 72-hour rule was implemented separately for each type. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was calculated as a treatment-free period of 72 hours from the bleed itself.

    Time frame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)

15. Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age

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

    Time frame: Baseline and Week 25

16. Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain ranges from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health).

    Time frame: Baseline and Week 25

17. Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age

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

    Time frame: Baseline and Week 25

18. Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain ranges from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores and it ranges from 0 to 100, with lower scores reflective of better quality of life.

    Time frame: Baseline and Week 25

19. Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age

    The Haemo-QoL-SF contains 35 items covering nine dimensions considered relevant for the adolescent's (aged 12-17 years) health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The score ranges from 0 to 100, and a higher score is indicative of poorer HRQoL. According to the pre-specified statistical analysis plan, no statistical analyses were performed on the protocol-defined endpoints for the Haemo-QoL-SF due to the small number of adolescents randomized to Arms A, B and C.

    Time frame: Baseline and Week 25

20. Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25

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

    Time frame: Baseline and Week 25

21. Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25

    The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

    Time frame: Baseline and Week 25

22. Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25

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

    Time frame: Baseline and Week 25

23. Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25

    The European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life.

    Time frame: Baseline and Week 25

24. Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age

    The Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire contains 35 items covering nine dimensions considered relevant for the children's health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The scores range from 0 to 100, and higher scores are indicative of poorer HRQoL.

    Time frame: Baseline and Week 25

25. Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time

    Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless of age, were collected using the Adapted Inhib-QoL with Aspects of Caregiver Burden questionnaire. The questionnaire comprises two parts. The first part asks the caregiver for his/her opinion on the child's HRQoL (proxy HRQoL). The second part asks the caregiver to rate how the child's situation is for them (i.e., the impact of the child's disease and treatment on the caregiver). Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. Scores range from 0 to 100, with lower scores reflective of better HRQoL. A total score is calculated as the sum of all of the items in the scale.

    Time frame: Baseline (Week 1) and Weeks 13 and 25

26. Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms

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

    Time frame: From Baseline until primary cutoff date (at least 24 weeks): Arm C (Control) No Prophylaxis, median (range): 24.0 (23.9-28.0) weeks; Arms A & B Emicizumab, median (range): Arm A: 43.7 (28.1-60.3) weeks; Arm B: 46.1 (24.0-58.7) weeks

27. Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis

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

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

28. Number of Participants With at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

29. Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

30. Number of Participants With at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

31. Number of Participants With at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

32. Number of Participants With at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

33. Number of Participants With Serum Chemistry Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline

    The number of participants with abnormal shifts in laboratory chemistry parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings. SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

34. Number of Participants With Hematology Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline

    The number of participants with abnormal shifts in laboratory hematology parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings.

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

35. Change From Baseline in Body Temperature Over Time

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Baseline and Weeks 5, 25, 49, and 73

36. Change From Baseline in Pulse Rate Over Time

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Baseline, Weeks 5, 25, 49, and 73

37. Change From Baseline in Respiratory Rate Over Time

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Baseline, Weeks 5, 25, 49, and 73

38. Change From Baseline in Systolic Blood Pressure Over Time

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Baseline, Weeks 5, 25, 49, and 73

39. Change From Baseline in Diastolic Blood Pressure Over Time

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Baseline, Weeks 5, 25, 49, and 73

40. Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status

    Participants were considered anti-drug antibody (ADA)-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration, or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater than the titer of the baseline sample. Participants were considered ADA-negative if they were ADA-negative at baseline and all post-baseline samples were negative following drug administration, or if they were ADA-positive at baseline but did not have any post-baseline (following drug administration) samples with a titer that was at least 4-fold greater than the titer of the baseline sample.

    Time frame: Samples taken at Baseline and at prespecified times post-baseline from first dose of emicizumab until data cutoff date, median (range) time of exposure to emicizumab: All Arms: 196.14 (20.1-222.1) weeks; Arm D only: 64.14 (61.1-67.3) weeks

41. Plasma Trough Concentration (Ctrough) of Emicizumab

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

    Time frame: Arms A & D, QW (up to Week 49 for Arm D only): Weeks 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, and 133; Arms B & C, Q4W: Weeks 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73, 85, 97, 109, 121, and 133

Baseline characteristics

Study documents

• Study protocol ↗ · Apr 22, 2023
• Statistical analysis plan ↗ · Jul 22, 2019

PDFs hosted by the registry, ClinicalTrials.gov.

Individual participant data

Plan to share: Yes — For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing