HAVEN 1: A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02622321
Collaborator
Chugai Pharmaceutical (Industry)
113
44
4
60.5
2.6
0
Study Details
Study Description
Brief Summary
This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent participants will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than [<] 9 or greater than or equal to [>/=] 9 bleeds); Arm B participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Prophylactic bypassing agent participants will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last participant has enrolled in Arms A or B or until approximately 50 participants have enrolled in Arm C, whichever occurs first. Episodic bypassing agent participants who previously participated in the non-interventional study BH29768 (NCT02476942) who were unable to enroll in Arms A or B, or participants on prophylactic bypassing agents who were unable to enroll in Arm C, prior to their closure will have the opportunity to enroll in Arm D. Like participants in Arms A and C, Arm D participants will receive emicizumab prophylaxis from the start of the trial. All participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, preferably with recombinant activated factor VII (rFVIIa).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
113 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors
Actual Study Start Date
:
Nov 18, 2015
Actual Primary Completion Date
:
Oct 25, 2016
Actual Study Completion Date
:
Dec 1, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A: 1.5 mg/kg Emicizumab QW Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.
Other Names:
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Names:
Drug: aPCC
Participants will continue to receive aPCC.
Other Names:
|
| Active Comparator: Arm B (Control): No Prophylaxis, Then Emicizumab Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.
Other Names:
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Names:
Drug: aPCC
Participants will continue to receive aPCC.
Other Names:
|
| Experimental: Arm C: 1.5 mg/kg Emicizumab QW Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.
Other Names:
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Names:
Drug: aPCC
Participants will continue to receive aPCC.
Other Names:
|
| Experimental: Arm D: 1.5 mg/kg Emicizumab QW Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.
Other Names:
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Names:
Drug: aPCC
Participants will continue to receive aPCC.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Secondary Outcome Measures
- Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of all bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents [Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks]
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents [Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks]
This was an intra-participant comparison of the ABRs for treated bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
- Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of treated joint bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Bleeds due to surgery/procedure were excluded.
- Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents [Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks]
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm C participants who had previously received prophylactic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents [Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks]
This was an intra-participant comparison of the ABRs for treated bleeds in Arm C participants who had previously received bypassing agent prophylaxis during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
- Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of treated spontaneous bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of treated target joint bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)]
Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis [Week 25]
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: 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 range 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).
- Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis [Week 25]
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: 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 range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life.
- European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis [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 Visual Analog Scale. The Visual Analogue Scale 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.
- EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis [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 Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed).
- Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old) [Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)]
The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children's health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Baseline was defined as the last assessment prior to treatment. Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose; baseline for Arm B (Emi) is the same as Week 25 for Arm B (Control).
- Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)]
The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)]
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)]
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants [1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks]
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
- Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale [From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)]
Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated, only data before up-titration is included. aPCC = activated prothrombin complex concentrate; Hypersens.= hypersensitivity
- Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study [From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)]
'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample. ADA-positive samples were further analyzed for neutralizing capacity using a modified FVIII chromogenic assay; if also positive, they were considered neutralizing ADAs.
- Plasma Trough Concentrations of Emicizumab at Specified Timepoints [Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)]
Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose.
Eligibility Criteria
Criteria
Ages Eligible for Study:
12 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Body weight >/= 40 kilograms (kg) at the time of screening
-
Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor ( that is [i.e.], >/= 5 Bethesda Units [BU])
-
Documentation of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks
-
/= 6 bleeds in the last 24 weeks prior to screening (if on an episodic bypassing agent regimen) or >/=2 bleeds in the last 24 weeks prior to screening (if on a prophylactic bypassing agent regimen)
-
Adequate hematologic, hepatic and renal function
-
For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined highly effective contraceptive methods
Exclusion Criteria:
-
Participants with inherited or acquired bleeding disorder other than hemophilia A
-
Participants with ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with Factor VIII (FVIII), with the exception of participants who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis
-
Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
-
Participants with other conditions (for example [e.g.], certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
-
History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
-
Known human immunodeficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count < 200 cells per microliter (cells/mcL) within 24 weeks prior to screening
-
Use of systemic immunomodulators (e.g., interferon or rituximab) at enrolment or planned use during the study, with the exception of antiretroviral therapy
-
Participants who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous medical or family history of TMA), in the investigator's judgment
-
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the participant's safe participation in and completion of the study or interpretation of the study results
-
Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
-
Receipt of emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; An investigational drug concurrently
-
Unwillingness to use highly effective contraception methods for the specified duration in the protocol (females only, unless required otherwise by the local health authority)
-
Clinically significant abnormality on screening evaluations or laboratory tests that, in the opinion of the investigator, may pose an additional risk in administering study drug to the participant
-
Pregnancy or lactation, or intent to become pregnant during the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90010 |
| 2 | Santa Monica Oncology Center | Santa Monica | California | United States | 90403 |
| 3 | University of Colorado Denver, Children's Hospital | Aurora | Colorado | United States | 80045 |
| 4 | Winship Cancer Institute | Atlanta | Georgia | United States | 30322 |
| 5 | Boston Childrens Hospital | Boston | Massachusetts | United States | 02115 |
| 6 | Children's Hospital of Michigan; Pediatrics | Detroit | Michigan | United States | 48201 |
| 7 | Cornell Univ Medical College; Hematology-Oncolog | New York | New York | United States | 10021 |
| 8 | Oregon Health & Science Uni ; Dept of Pediatrics | Portland | Oregon | United States | 97201 |
| 9 | Pennsylvania State Hershey Medical Center; Division of Hematology/Oncology, H046 | Hershey | Pennsylvania | United States | 17033-0850 |
| 10 | Univ of TX Health Science Ctr; Gulf States Hemo and Throm Ctr | Houston | Texas | United States | 77030 |
| 11 | Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia | Seattle | Washington | United States | 98104 |
| 12 | Royal Prince Alfred Hospital; Haematology | Camperdown | New South Wales | Australia | 2050 |
| 13 | The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit | Melbourne | Victoria | Australia | 3004 |
| 14 | ICIC | San Jose | Costa Rica | 1000 | |
| 15 | Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique | Bron | France | 69677 | |
| 16 | CH de Bicetre; Centre de Traitement d' Hemophilie | Le Kremlin Bicetre | France | 94275 | |
| 17 | Hopital Cardiologique; Hematologie B | Lille | France | 59037 | |
| 18 | Groupe Hospitalier Necker Enfants Malades | Paris | France | 75015 | |
| 19 | Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin | Bonn | Germany | 53127 | |
| 20 | CTC North GmbH & Co. KG am Universitätsklinikum Hamburg-Eppendorf | Hamburg | Germany | 20251 | |
| 21 | Hämophilie-Zentrum Rhein Main GmbH | Mörfelden-Walldorf | Germany | 64546 | |
| 22 | IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi" | Milano | Lombardia | Italy | 20122 |
| 23 | AOU Careggi; SOD Malattie Emorragiche | Firenze | Toscana | Italy | 50134 |
| 24 | Nagoya University Hospital | Aichi | Japan | 466-8560 | |
| 25 | Hiroshima University Hospital | Hiroshima | Japan | 734-8551 | |
| 26 | Hyogo College of Medicine Hospital | Hyogo | Japan | 663-8501 | |
| 27 | St. Marianna University School of Medicine Hospital | Kanagawa | Japan | 216-8511 | |
| 28 | Hospital of the University of Occupational and Environmental Health,Japan | Kitakyushu-shi | Japan | 807-8556 | |
| 29 | Nara Medical University Hospital | Nara | Japan | 634-8522 | |
| 30 | Tokyo Medical University Hospital | Tokyo | Japan | 160-0023 | |
| 31 | Severance Hospital | Seoul | Korea, Republic of | 03722 | |
| 32 | Auckland City Hospital; Auckland Haemophilia Centre | Auckland | New Zealand | 1023 | |
| 33 | Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii | Gdansk | Poland | 80-952 | |
| 34 | SPSK Nr1 Klinika Hematoo&Transpl.Szpiku | Lublin | Poland | 20-081 | |
| 35 | ALVAMED Lekarskie Gabinety Specjalistyczne | Poznań | Poland | 60-549 | |
| 36 | Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych | Warsaw | Poland | 02-776 | |
| 37 | Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center | Johannesburg | South Africa | 2193 | |
| 38 | Hospital Universitario la Paz; Servicio de Hematologia | Madrid | Spain | 28046 | |
| 39 | Hospital Universitario Virgen del Rocio; Servicio de Hematologia | Sevilla | Spain | 41013 | |
| 40 | Hospital Universitario la Fe; Servicio de Hematologia | Valencia | Spain | 46026 | |
| 41 | National Taiwan Uni Hospital | Taipei City | Taiwan | 10041 | |
| 42 | Cardiff and Vale NHS Trust | Cardiff | United Kingdom | CF14 4XW | |
| 43 | St Thomas' Hospital; Haemostasis & Thromboisis Centre | London | United Kingdom | SE1 7EH | |
| 44 | Oxford University Hospitals NHS Trust - Churchill Hospital | Oxford | United Kingdom | OX3 7LE |
Sponsors and Collaborators
- Hoffmann-La Roche
- Chugai Pharmaceutical
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02622321
Other Study ID Numbers:
- BH29884
- 2015-002866-21
First Posted:
Dec 4, 2015
Last Update Posted:
Jun 24, 2021
Last Verified:
May 1, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 113 participants were enrolled in this study: 109 participants prior to the primary completion date plus a further 4 participants to Arm D of the study after the primary completion date. Participants in Arm A and Arm B were randomized in a 2:1 ratio; participants in Arm C and Arm D were enrolled without randomization. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis, Then Emicizumab | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Period Title: Overall Study | ||||
| STARTED | 35 | 18 | 49 | 11 |
| Received at Least One Dose of Treatment | 34 | 18 | 49 | 11 |
| Completed 24 Weeks in the Study | 31 | 18 | 49 | 11 |
| Dose Up-Titrated to 3 mg/kg QW | 2 | 0 | 3 | 2 |
| COMPLETED | 32 | 18 | 48 | 11 |
| NOT COMPLETED | 3 | 0 | 1 | 0 |
Baseline Characteristics
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis, Then Emicizumab | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Total of all reporting groups |
| Overall Participants | 35 | 18 | 49 | 11 | 113 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
35.8
(13.9)
|
37.2
(13.7)
|
25.6
(16.8)
|
39.0
(16.1)
|
31.9
(16.2)
|
| Age, Customized (Count of Participants) | |||||
| Adolescents (12-17 years) |
4
11.4%
|
2
11.1%
|
26
53.1%
|
0
0%
|
32
28.3%
|
| Adults (18-64 years) |
30
85.7%
|
15
83.3%
|
21
42.9%
|
10
90.9%
|
76
67.3%
|
| Elderly (65-84 years) |
1
2.9%
|
1
5.6%
|
2
4.1%
|
1
9.1%
|
5
4.4%
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Male |
35
100%
|
18
100%
|
49
100%
|
11
100%
|
113
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
4
11.4%
|
1
5.6%
|
12
24.5%
|
1
9.1%
|
18
15.9%
|
| Not Hispanic or Latino |
31
88.6%
|
17
94.4%
|
37
75.5%
|
10
90.9%
|
95
84.1%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
1
2%
|
0
0%
|
1
0.9%
|
| Asian |
10
28.6%
|
3
16.7%
|
8
16.3%
|
0
0%
|
21
18.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
1
5.6%
|
0
0%
|
0
0%
|
1
0.9%
|
| Black or African American |
4
11.4%
|
4
22.2%
|
3
6.1%
|
0
0%
|
11
9.7%
|
| White |
21
60%
|
10
55.6%
|
33
67.3%
|
11
100%
|
75
66.4%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
4
8.2%
|
0
0%
|
4
3.5%
|
| Number of Participants by the Number of Bleeds (<9 or ≥9) in the Last 24 Weeks Prior to Study Entry (Count of Participants) | |||||
| <9 Bleeds |
11
31.4%
|
5
27.8%
|
23
46.9%
|
6
54.5%
|
45
39.8%
|
| ≥9 Bleeds |
24
68.6%
|
13
72.2%
|
26
53.1%
|
5
45.5%
|
68
60.2%
|
Outcome Measures
| Title | Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-treat (ITT) population defined as all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Number (95% Confidence Interval) [treated bleeds per year] |
2.9
|
23.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (less than [<] 9 or greater than or equal to [>/=] 9) in the last 24 weeks prior to study entry as a stratification factor in the randomization. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.13 | |
| Confidence Interval |
(2-Sided) 95% 0.057 to 0.277 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of all bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Number (95% Confidence Interval) [all bleeds per year] |
5.5
|
28.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.20 | |
| Confidence Interval |
(2-Sided) 95% 0.102 to 0.375 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents |
|---|---|
| Description | This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm A (NIS): Previous Episodic Bypassing Agents |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm A participants who previously participated in NIS BH29768 (NCT02476942) and had received episodic bypassing agents during the NIS. |
| Measure Participants | 24 | 24 |
| Number (95% Confidence Interval) [all bleeds per year] |
4.1
|
37.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Non-Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.11 | |
| Confidence Interval |
(2-Sided) 95% 0.055 to 0.218 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents |
|---|---|
| Description | This was an intra-participant comparison of the ABRs for treated bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm A (NIS): Previous Episodic Bypassing Agents |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm A participants who previously participated in NIS BH29768 (NCT02476942) and had received episodic bypassing agents during the NIS. |
| Measure Participants | 24 | 24 |
| Number (95% Confidence Interval) [treated bleeds per year] |
1.7
|
21.6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Non-Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.08 | |
| Confidence Interval |
(2-Sided) 95% 0.031 to 0.198 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of treated joint bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Bleeds due to surgery/procedure were excluded. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Number (95% Confidence Interval) [treated joint bleeds per year] |
0.8
|
6.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0050 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.11 | |
| Confidence Interval |
(2-Sided) 95% 0.025 to 0.520 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents |
|---|---|
| Description | This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm C participants who had previously received prophylactic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768. |
| Arm/Group Title | Arm C: 1.5 mg/kg Emicizumab QW | Arm C (NIS): Previous Prophylactic Bypassing Agents |
|---|---|---|
| Arm/Group Description | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm C participants who previously participated in NIS BH29768 (NCT02476942) and had received prophylactic bypassing agents during the NIS. |
| Measure Participants | 24 | 24 |
| Number (95% Confidence Interval) [all bleeds per year] |
5.5
|
24.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Non-Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.23 | |
| Confidence Interval |
(2-Sided) 95% 0.119 to 0.435 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents |
|---|---|
| Description | This was an intra-participant comparison of the ABRs for treated bleeds in Arm C participants who had previously received bypassing agent prophylaxis during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were 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. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768. |
| Arm/Group Title | Arm C: 1.5 mg/kg Emicizumab QW | Arm Cnis: Previous Prophylactic Bypassing Agents |
|---|---|---|
| Arm/Group Description | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm C participants who previously participated in NIS BH29768 (NCT02476942) and had received prophylactic bypassing agents (rFVIIa or/and aPCC) during the NIS BH29768. |
| Measure Participants | 24 | 24 |
| Number (95% Confidence Interval) [treated bleeds per year] |
3.3
|
15.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0003 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Non-Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.21 | |
| Confidence Interval |
(2-Sided) 95% 0.089 to 0.486 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of treated spontaneous bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Number (95% Confidence Interval) [treated spontaneous bleeds per year] |
1.3
|
16.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.08 | |
| Confidence Interval |
(2-Sided) 95% 0.037 to 0.154 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of treated target joint bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Number (95% Confidence Interval) [treated target joint bleeds per year] |
0.1
|
3.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0002 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. | |
| Method | Stratified Wald Test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | ABR Ratio |
| Estimated Value | 0.05 | |
| Confidence Interval |
(2-Sided) 95% 0.009 to 0.227 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Treated Bleeds |
3.5
|
26.2
|
| All Bleeds |
6.3
|
30.8
|
| Treated Spontaneous Bleeds |
1.5
|
18.1
|
| Treated Joint Bleeds |
1.0
|
8.1
|
| Treated Target Joint Bleeds |
0.4
|
6.2
|
| Title | Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Treated Bleeds |
0.0
|
18.8
|
| All Bleeds |
2.0
|
30.2
|
| Treated Spontaneous Bleeds |
0.0
|
15.2
|
| Treated Joint Bleeds |
0.0
|
1.0
|
| Treated Target Joint Bleeds |
0.0
|
1.0
|
| Title | Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 35 | 18 |
| Treated Bleeds |
62.9
179.7%
|
5.6
31.1%
|
| All Bleeds |
37.1
106%
|
5.6
31.1%
|
| Treated Spontaneous Bleeds |
68.6
196%
|
11.1
61.7%
|
| Treated Joint Bleeds |
85.7
244.9%
|
50.0
277.8%
|
| Treated Target Joint Bleeds |
94.3
269.4%
|
50.0
277.8%
|
| Title | Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: 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 range 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 | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of adult participants (≥18 years old) in Arms A and B who responded to the questionnaire at Week 25. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 26 | 14 |
| Mean (Standard Deviation) [score on a scale] |
30.19
(26.59)
|
57.14
(23.35)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm. Analysis was performed using Analysis of Covariance (ANCOVA). | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0029 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Adjusted Mean Difference |
| Estimated Value | 21.55 | |
| Confidence Interval |
(2-Sided) 95% 7.89 to 35.22 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: 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 range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life. |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of adult participants (≥18 years old) in Arms A and B who responded to the questionnaire at Week 25. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 26 | 14 |
| Mean (Standard Deviation) [score on a scale] |
26.465
(18.666)
|
47.504
(17.435)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0019 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Adjusted Mean Difference |
| Estimated Value | 14.01 | |
| Confidence Interval |
(2-Sided) 95% 5.56 to 22.45 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | 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 Visual Analog Scale. The Visual Analogue Scale 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 | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of participants in Arms A and B who responded to the questionnaire at Week 25. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 30 | 16 |
| Mean (Standard Deviation) [score on a scale] |
83.8
(12.9)
|
76.4
(15.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0171 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Adjusted Mean Difference |
| Estimated Value | -9.72 | |
| Confidence Interval |
(2-Sided) 95% -17.62 to -1.82 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis |
|---|---|
| Description | 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 Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed). |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: all participants who were randomized to Arm A or Arm B. The number of participants analyzed is the number of participants in Arms A and B who responded to the questionnaire at Week 25. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis |
|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 30 | 16 |
| Mean (Standard Deviation) [score on a scale] |
0.83
(0.22)
|
0.60
(0.35)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis |
|---|---|---|
| Comments | Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction arm. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0014 |
| Comments | Statistical significance was controlled at a two-sided alpha level of 0.05. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Adjusted Mean Difference |
| Estimated Value | -0.16 | |
| Confidence Interval |
(2-Sided) 95% -0.25 to -0.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old) |
|---|---|
| Description | The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children's health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Baseline was defined as the last assessment prior to treatment. Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose; baseline for Arm B (Emi) is the same as Week 25 for Arm B (Control). |
| Time Frame | Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The number analyzed is the number of adolescent participants (12-17 years old) who responded to the questionnaire at baseline and Week 25. Arm D is excluded because no adolescents were enrolled in that arm. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 4 | 2 | 2 | 26 |
| Baseline |
34.643
(22.728)
|
37.143
(12.122)
|
30.000
(14.142)
|
30.714
(15.625)
|
| Week 25 |
33.095
(17.559)
|
30.000
(14.142)
|
12.143
(7.071)
|
19.286
(14.507)
|
| Title | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants |
|---|---|
| Description | The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This analysis set included all enrolled participants on the study. For Arm B, it only all participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 35 | 18 | 49 | 11 | 113 |
| Treated Bleeds |
1.9
|
0.6
|
3.2
|
1.5
|
2.4
|
| All Bleeds |
3.5
|
1.3
|
4.3
|
2.3
|
3.6
|
| Treated Spontaneous Bleeds |
0.6
|
0.1
|
2.1
|
0.8
|
1.3
|
| Treated Joint Bleeds |
0.5
|
0.1
|
0.4
|
0.4
|
0.4
|
| Treated Target Joint Bleeds |
0.1
|
0.01
|
0.3
|
0.3
|
0.2
|
| Title | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants |
|---|---|
| Description | The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 35 | 18 | 49 | 11 | 113 |
| Treated Bleeds |
2.9
|
0.6
|
3.3
|
1.6
|
2.6
|
| All Bleeds |
4.8
|
1.3
|
4.6
|
2.5
|
3.9
|
| Treated Spontaneous Bleeds |
1.2
|
0.2
|
2.2
|
0.9
|
1.5
|
| Treated Joint Bleeds |
0.9
|
0.1
|
0.4
|
0.4
|
0.5
|
| Treated Target Joint Bleeds |
0.4
|
0.1
|
0.3
|
0.4
|
0.3
|
| Title | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants |
|---|---|
| Description | The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. |
| Time Frame | From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 35 | 18 | 49 | 11 | 113 |
| Treated Bleeds |
0.3
|
0.0
|
0.0
|
0.0
|
0.0
|
| All Bleeds |
1.9
|
0.5
|
0.6
|
0.5
|
0.6
|
| Treated Spontaneous Bleeds |
0.0
|
0.0
|
0.0
|
0.0
|
0.0
|
| Treated Joint Bleeds |
0.0
|
0.0
|
0.0
|
0.0
|
0.0
|
| Treated Target Joint Bleeds |
0.0
|
0.0
|
0.0
|
0.0
|
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
3.9
|
| 13 to 24 Weeks |
2.2
|
| 25 to 36 Weeks |
0.9
|
| 37 to 48 Weeks |
0.3
|
| 49 to 60 Weeks |
0.4
|
| 61 to 72 Weeks |
0.5
|
| 73 to 84 Weeks |
0.6
|
| 85 to 96 Weeks |
0.4
|
| 97 to 108 Weeks |
0.5
|
| 109 to 120 Weeks |
0.0
|
| 121 to 132 Weeks |
0.4
|
| 133 to 144 Weeks |
0.5
|
| 145 to 156 Weeks |
0.4
|
| 157 to 168 Weeks |
0.2
|
| 169 to 180 Weeks |
0.2
|
| 181 to 192 Weeks |
0.0
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
0.0
|
| 13 to 24 Weeks |
0.0
|
| 25 to 36 Weeks |
0.0
|
| 37 to 48 Weeks |
0.0
|
| 49 to 60 Weeks |
0.0
|
| 61 to 72 Weeks |
0.0
|
| 73 to 84 Weeks |
0.0
|
| 85 to 96 Weeks |
0.0
|
| 97 to 108 Weeks |
0.0
|
| 109 to 120 Weeks |
0.0
|
| 121 to 132 Weeks |
0.0
|
| 133 to 144 Weeks |
0.0
|
| 145 to 156 Weeks |
0.0
|
| 157 to 168 Weeks |
0.0
|
| 169 to 180 Weeks |
0.0
|
| 181 to 192 Weeks |
0.0
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
6.2
|
| 13 to 24 Weeks |
3.4
|
| 25 to 36 Weeks |
1.5
|
| 37 to 48 Weeks |
1.4
|
| 49 to 60 Weeks |
1.1
|
| 61 to 72 Weeks |
1.0
|
| 73 to 84 Weeks |
1.3
|
| 85 to 96 Weeks |
1.0
|
| 97 to 108 Weeks |
1.2
|
| 109 to 120 Weeks |
0.9
|
| 121 to 132 Weeks |
0.8
|
| 133 to 144 Weeks |
0.5
|
| 145 to 156 Weeks |
0.8
|
| 157 to 168 Weeks |
0.3
|
| 169 to 180 Weeks |
0.8
|
| 181 to 192 Weeks |
0.2
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
0.0
|
| 13 to 24 Weeks |
0.0
|
| 25 to 36 Weeks |
0.0
|
| 37 to 48 Weeks |
0.0
|
| 49 to 60 Weeks |
0.0
|
| 61 to 72 Weeks |
0.0
|
| 73 to 84 Weeks |
0.0
|
| 85 to 96 Weeks |
0.0
|
| 97 to 108 Weeks |
0.0
|
| 109 to 120 Weeks |
0.0
|
| 121 to 132 Weeks |
0.0
|
| 133 to 144 Weeks |
0.0
|
| 145 to 156 Weeks |
0.0
|
| 157 to 168 Weeks |
0.0
|
| 169 to 180 Weeks |
0.0
|
| 181 to 192 Weeks |
0.0
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
2.2
|
| 13 to 24 Weeks |
1.3
|
| 25 to 36 Weeks |
0.4
|
| 37 to 48 Weeks |
0.2
|
| 49 to 60 Weeks |
0.1
|
| 61 to 72 Weeks |
0.2
|
| 73 to 84 Weeks |
0.2
|
| 85 to 96 Weeks |
0.1
|
| 97 to 108 Weeks |
0.3
|
| 109 to 120 Weeks |
0.0
|
| 121 to 132 Weeks |
0.1
|
| 133 to 144 Weeks |
0.0
|
| 145 to 156 Weeks |
0.4
|
| 157 to 168 Weeks |
0.2
|
| 169 to 180 Weeks |
0.2
|
| 181 to 192 Weeks |
0.0
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants |
|---|---|
| Description | The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. |
| Time Frame | 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All enrolled participants; for Arm B, it only includes participants who switched to emicizumab prophylaxis after having completed the first 24 weeks on study with no prophylaxis. The number analyzed includes participants with available data over each interval. |
| Arm/Group Title | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|
| Arm/Group Description | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 113 |
| 1 to 12 Weeks |
0.0
|
| 13 to 24 Weeks |
0.0
|
| 25 to 36 Weeks |
0.0
|
| 37 to 48 Weeks |
0.0
|
| 49 to 60 Weeks |
0.0
|
| 61 to 72 Weeks |
0.0
|
| 73 to 84 Weeks |
0.0
|
| 85 to 96 Weeks |
0.0
|
| 97 to 108 Weeks |
0.0
|
| 109 to 120 Weeks |
0.0
|
| 121 to 132 Weeks |
0.0
|
| 133 to 144 Weeks |
0.0
|
| 145 to 156 Weeks |
0.0
|
| 157 to 168 Weeks |
0.0
|
| 169 to 180 Weeks |
0.0
|
| 181 to 192 Weeks |
0.0
|
| 193 to 204 Weeks |
0.0
|
| 205 to 216 Weeks |
0.0
|
| 217 to 228 Weeks |
0.0
|
| 229 to 240 Weeks |
0.0
|
| Title | Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale |
|---|---|
| Description | Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated, only data before up-titration is included. aPCC = activated prothrombin complex concentrate; Hypersens.= hypersensitivity |
| Time Frame | From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population: All treated participants grouped by their assigned treatment. For Arm B, data collected while receiving episodic bypassing agents (no prophyalxis) for the first 24 weeks and 1.5 mg/kg emicizumab QW after Week 24 are reported separately under 'Arm B (Control): No Prophylaxis' and 'Arm B (Emi): 1.5 mg/kg Emicizumab QW', respectively. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Data reported represents data collected during emicizumab treatment only. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 34 | 18 | 18 | 49 | 11 |
| Any Adverse Event (AE) |
34
97.1%
|
9
50%
|
15
30.6%
|
46
418.2%
|
9
8%
|
| AE with Fatal Outcome |
0
0%
|
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
| Serious AE |
10
28.6%
|
4
22.2%
|
4
8.2%
|
9
81.8%
|
2
1.8%
|
| AE Leading to Withdrawal from Treatment |
2
5.7%
|
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
| AE Leading to Dose Mod./Interruption |
1
2.9%
|
0
0%
|
0
0%
|
5
45.5%
|
0
0%
|
| Grade ≥3 AE |
10
28.6%
|
4
22.2%
|
3
6.1%
|
7
63.6%
|
3
2.7%
|
| Related AE |
15
42.9%
|
0
0%
|
4
8.2%
|
13
118.2%
|
4
3.5%
|
| Local Injection Site Reaction |
9
25.7%
|
0
0%
|
3
6.1%
|
7
63.6%
|
4
3.5%
|
| Systemic Hypersens./Anaphylac(tic/toid) Reaction |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Thrombotic Microangiopathy (TMA) |
1
2.9%
|
0
0%
|
0
0%
|
2
18.2%
|
0
0%
|
| TMA Event Related to aPCC and Emicizumab |
1
2.9%
|
0
0%
|
0
0%
|
2
18.2%
|
0
0%
|
| Thromboembolic Event (TE) |
1
2.9%
|
1
5.6%
|
1
2%
|
1
9.1%
|
0
0%
|
| TE Event Related to aPCC and Emicizumab |
1
2.9%
|
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
| Title | Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study |
|---|---|
| Description | 'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample. ADA-positive samples were further analyzed for neutralizing capacity using a modified FVIII chromogenic assay; if also positive, they were considered neutralizing ADAs. |
| Time Frame | From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All emicizumab-treated participants included Arms A, C, and D and Arm B participants who switched to receive emicizumab (Arm B Emi). The overall number of participants analyzed is the number of participants with at least one post-baseline anti-drug antibody assessment. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Measure Participants | 33 | 18 | 49 | 11 |
| Total ADA Negative (Neg+Neg Unaffected) |
33
94.3%
|
18
100%
|
47
95.9%
|
11
100%
|
| ADA Negative, Negative |
33
94.3%
|
17
94.4%
|
46
93.9%
|
11
100%
|
| ADA Negative, Negative (Treatment Unaffected) |
0
0%
|
1
5.6%
|
1
2%
|
0
0%
|
| Total ADA Positive (Boosted + Induced) |
0
0%
|
0
0%
|
2
4.1%
|
0
0%
|
| ADA Positive, Positive (Treatment Boosted) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| ADA Positive, Positive (Treatment Induced) |
0
0%
|
0
0%
|
2
4.1%
|
0
0%
|
| ADA Positive with Neutralizing ADAs |
0
0%
|
0
0%
|
2
4.1%
|
0
0%
|
| Title | Plasma Trough Concentrations of Emicizumab at Specified Timepoints |
|---|---|
| Description | Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose. |
| Time Frame | Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. The number analyzed includes participants with PK samples at each timepoint. |
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | All Participants: 1.5 mg/kg Emicizumab QW |
|---|---|---|---|---|---|
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | This analysis set included all enrolled participants on the study. For Arm B, it only included participants starting after Week 24 on study when they crossed over to first receive prophylactic treatment with emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. |
| Measure Participants | 34 | 18 | 49 | 11 | 112 |
| Week 1 |
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
NA
(NA)
|
| Week 2 |
16.2
(4.4)
|
21.7
(10.6)
|
15.8
(5.5)
|
18.3
(6.5)
|
17.1
(6.6)
|
| Week 3 |
31.6
(7.3)
|
32.3
(10.4)
|
31.7
(8.3)
|
32.7
(13.0)
|
31.9
(8.8)
|
| Week 4 |
43.8
(12.2)
|
44.6
(18.6)
|
44.7
(11.5)
|
49.0
(13.5)
|
44.9
(13.2)
|
| Week 5 |
53.5
(15.1)
|
52.2
(14.2)
|
54.0
(13.2)
|
59.1
(14.6)
|
54.1
(14.0)
|
| Week 7 |
52.8
(16.2)
|
53.3
(18.0)
|
53.6
(14.3)
|
54.9
(9.2)
|
53.4
(14.9)
|
| Week 9 |
50.4
(12.4)
|
48.9
(16.7)
|
52.6
(15.7)
|
53.7
(13.8)
|
51.5
(14.7)
|
| Week 13 |
49.3
(13.4)
|
45.2
(16.2)
|
52.6
(15.0)
|
53.4
(14.0)
|
50.5
(14.7)
|
| Week 17 |
50.7
(15.0)
|
46.5
(17.4)
|
51.2
(14.9)
|
57.5
(16.9)
|
51.0
(15.6)
|
| Week 21 |
52.6
(17.4)
|
44.5
(15.4)
|
51.6
(17.1)
|
55.0
(13.7)
|
51.1
(16.6)
|
| Week 25 |
54.6
(19.1)
|
45.8
(18.6)
|
50.4
(16.8)
|
52.8
(14.1)
|
51.2
(17.6)
|
| Week 33 |
50.7
(17.2)
|
48.1
(21.1)
|
54.8
(16.7)
|
57.1
(15.2)
|
52.7
(17.5)
|
| Week 41 |
45.3
(13.7)
|
49.3
(25.9)
|
54.8
(23.4)
|
63.3
(19.4)
|
52.0
(21.6)
|
| Week 49 |
48.0
(12.3)
|
54.6
(27.6)
|
56.1
(22.2)
|
55.1
(18.7)
|
53.3
(20.5)
|
| Week 61 |
52.2
(16.3)
|
51.8
(33.4)
|
60.9
(27.7)
|
53.2
(13.8)
|
56.0
(24.8)
|
| Week 73 |
55.5
(14.9)
|
45.6
(26.2)
|
62.9
(24.9)
|
51.9
(13.0)
|
57.1
(22.0)
|
| Week 85 |
56.9
(18.3)
|
42.5
(34.4)
|
56.6
(22.7)
|
50.9
(12.5)
|
54.5
(22.7)
|
| Week 97 |
53.2
(15.2)
|
34.4
(26.4)
|
54.6
(20.0)
|
53.8
(16.9)
|
51.3
(19.9)
|
| Week 109 |
49.6
(15.9)
|
32.8
(31.4)
|
47.4
(12.4)
|
49.3
(12.8)
|
46.7
(17.6)
|
| Week 121 |
53.8
(16.3)
|
36.1
(33.6)
|
46.3
(12.5)
|
53.1
(5.0)
|
48.5
(19.7)
|
| Week 133 |
50.5
(15.9)
|
48.7
(29.4)
|
49.0
(18.5)
|
52.0
(NA)
|
49.8
(18.8)
|
| Week 145 |
51.3
(16.6)
|
38.2
(19.0)
|
44.0
(21.7)
|
49.5
(10.3)
|
47.4
(17.4)
|
| Week 157 |
58.0
(16.5)
|
45.5
(17.0)
|
55.4
(19.2)
|
55.3
(16.7)
|
|
| Week 169 |
55.0
(19.3)
|
43.2
(20.2)
|
50.8
(NA)
|
52.5
(18.7)
|
Adverse Events
| Time Frame | From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety Population: All treated subjects grouped by treatment (including after up-titration). For Arm B, data collected with episodic bypassing agents (no prophyalxis) for first 24 weeks and with 1.5 mg/kg emicizumab QW after Week 24 are reported separately under Arm B (Control): No Prophylaxis and Arm B (Emi): 1.5 mg/kg Emicizumab QW, respectively. | |||||||||
| Arm/Group Title | Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | |||||
| Arm/Group Description | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. The safety data reported here represents data collected from all Arm B participants during the first 24 weeks of 'no prophylaxis'; safety data from Arm B participants who switched to emicizumab after Week 24 are reported separately under Arm B (Emi): 1.5 mg/kg Emicizumab QW. | This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Data reported represents data collected during emicizumab treatment only. | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | |||||
All Cause Mortality |
||||||||||
| Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | 0/18 (0%) | 0/18 (0%) | 1/49 (2%) | 0/11 (0%) | |||||
Serious Adverse Events |
||||||||||
| Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 11/34 (32.4%) | 5/18 (27.8%) | 4/18 (22.2%) | 9/49 (18.4%) | 2/11 (18.2%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Iron deficiency anaemia | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Thrombotic microangiopathy | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||
| Gastrointestinal haemorrhage | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Gastric ulcer haemorrhage | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Large intestine polyp | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Rectal haemorrhage | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Tooth development disorder | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Upper gastrointestinal haemorrhage | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| General disorders | ||||||||||
| Chest pain | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Infections and infestations | ||||||||||
| Device related infection | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Urinary tract infection | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Cavernous sinus thrombosis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Sepsis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Gastroenteritis viral | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Meningitis bacterial | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Vascular device infection | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Device related sepsis | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Gastroenteritis | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||
| Subdural haemorrhage | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Road traffic accident | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||
| Muscle haemorrhage | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Haemarthrosis | 2/34 (5.9%) | 2 | 2/18 (11.1%) | 2 | 1/18 (5.6%) | 1 | 2/49 (4.1%) | 3 | 0/11 (0%) | 0 |
| Arthralgia | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Myalgia | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Osteonecrosis | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Soft tissue haemorrhage | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||
| Tumour haemorrhage | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Nervous system disorders | ||||||||||
| Headache | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Product Issues | ||||||||||
| Device loosening | 1/34 (2.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Psychiatric disorders | ||||||||||
| Intentional self-injury | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Delirium | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Renal and urinary disorders | ||||||||||
| Haematuria | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Subcapsular renal haematoma | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||
| Skin necrosis | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Vascular disorders | ||||||||||
| Thrombophlebitis superficial | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Haematoma | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Haemorrhage | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||||
| Arm A: 1.5 mg/kg Emicizumab QW | Arm B (Control): No Prophylaxis | Arm B (Emi): 1.5 mg/kg Emicizumab QW | Arm C: 1.5 mg/kg Emicizumab QW | Arm D: 1.5 mg/kg Emicizumab QW | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 33/34 (97.1%) | 9/18 (50%) | 15/18 (83.3%) | 42/49 (85.7%) | 9/11 (81.8%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Anaemia | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 2 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Iron deficiency anaemia | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 3 | 0/11 (0%) | 0 |
| Cardiac disorders | ||||||||||
| Arrhythmia | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Ear and labyrinth disorders | ||||||||||
| Ear discomfort | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Eye disorders | ||||||||||
| Vision blurred | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Cataract | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Gastrointestinal disorders | ||||||||||
| Abdominal pain upper | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Enteritis | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Large intestine polyp | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Toothache | 4/34 (11.8%) | 4 | 0/18 (0%) | 0 | 2/18 (11.1%) | 2 | 2/49 (4.1%) | 3 | 2/11 (18.2%) | 2 |
| Abdominal pain | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 2 | 0/11 (0%) | 0 |
| Dental caries | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 3/18 (16.7%) | 4 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Diarrhoea | 4/34 (11.8%) | 4 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 5/49 (10.2%) | 8 | 0/11 (0%) | 0 |
| Nausea | 4/34 (11.8%) | 5 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 3 | 0/11 (0%) | 0 |
| Vomiting | 3/34 (8.8%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 4/49 (8.2%) | 4 | 0/11 (0%) | 0 |
| Gastrooesophageal reflux disease | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Food poisoning | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Gastritis | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| General disorders | ||||||||||
| Chest pain | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Fatigue | 3/34 (8.8%) | 4 | 0/18 (0%) | 0 | 2/18 (11.1%) | 2 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Injection site reaction | 9/34 (26.5%) | 18 | 0/18 (0%) | 0 | 3/18 (16.7%) | 3 | 8/49 (16.3%) | 21 | 4/11 (36.4%) | 5 |
| Pyrexia | 2/34 (5.9%) | 2 | 1/18 (5.6%) | 1 | 2/18 (11.1%) | 2 | 8/49 (16.3%) | 10 | 1/11 (9.1%) | 1 |
| Device related thrombosis | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Catheter site pain | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Influenza like illness | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Pain | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Peripheral swelling | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Hepatobiliary disorders | ||||||||||
| Drug-induced liver injury | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Immune system disorders | ||||||||||
| Seasonal allergy | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Infections and infestations | ||||||||||
| Folliculitis | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Nasopharyngitis | 11/34 (32.4%) | 29 | 2/18 (11.1%) | 2 | 7/18 (38.9%) | 14 | 16/49 (32.7%) | 27 | 2/11 (18.2%) | 2 |
| Upper respiratory tract infection | 8/34 (23.5%) | 21 | 2/18 (11.1%) | 2 | 2/18 (11.1%) | 2 | 7/49 (14.3%) | 8 | 2/11 (18.2%) | 2 |
| Bronchitis | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 1/11 (9.1%) | 1 |
| Influenza | 1/34 (2.9%) | 2 | 0/18 (0%) | 0 | 2/18 (11.1%) | 2 | 10/49 (20.4%) | 10 | 0/11 (0%) | 0 |
| Gastroenteritis | 3/34 (8.8%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Herpes virus infection | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Rhinitis | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Urinary tract infection | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Cellulitis | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Device related infection | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Lower respiratory tract infection | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Sinusitis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 3/18 (16.7%) | 3 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||
| Post procedural constipation | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Procedural hypotension | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Procedural nausea | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Procedural pain | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 2/18 (11.1%) | 2 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Contusion | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Fall | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 2 |
| Fibula fracture | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Incision site swelling | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Ligament sprain | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Limb injury | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 1/49 (2%) | 1 | 1/11 (9.1%) | 1 |
| Rib fracture | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Skin abrasion | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 2/11 (18.2%) | 2 |
| Skin laceration | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Thermal burn | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Tibia fracture | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Tooth fracture | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Investigations | ||||||||||
| Blood glucose increased | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Blood creatine phosphokinase increased | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 4 | 1/11 (9.1%) | 1 |
| Body temperature increased | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| C-reactive protein increased | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Indeterminable ABO blood type | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 3 | 0/11 (0%) | 0 |
| Prothrombin fragment 1.2 increased | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 2 |
| Metabolism and nutrition disorders | ||||||||||
| Dehydration | 1/34 (2.9%) | 1 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Electrolyte imbalance | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Decreased appetite | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Hypercholesterolaemia | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||
| Arthralgia | 9/34 (26.5%) | 17 | 0/18 (0%) | 0 | 6/18 (33.3%) | 9 | 12/49 (24.5%) | 33 | 3/11 (27.3%) | 5 |
| Myalgia | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Arthropathy | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Back pain | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Groin pain | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Joint swelling | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 2 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Muscle spasms | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 2/49 (4.1%) | 2 | 0/11 (0%) | 0 |
| Musculoskeletal stiffness | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Pain in extremity | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 4/49 (8.2%) | 4 | 0/11 (0%) | 0 |
| Plantar fasciitis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Synovitis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||
| Skin papilloma | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Tumour haemorrhage | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Nervous system disorders | ||||||||||
| Headache | 6/34 (17.6%) | 9 | 1/18 (5.6%) | 1 | 4/18 (22.2%) | 4 | 13/49 (26.5%) | 22 | 3/11 (27.3%) | 3 |
| Dizziness | 4/34 (11.8%) | 4 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Migraine | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Neuropathy peripheral | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Product Issues | ||||||||||
| Device occlusion | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Psychiatric disorders | ||||||||||
| Insomnia | 1/34 (2.9%) | 1 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 2/49 (4.1%) | 2 | 1/11 (9.1%) | 1 |
| Renal and urinary disorders | ||||||||||
| Pollakiuria | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||
| Benign prostatic hyperplasia | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 1 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Cough | 5/34 (14.7%) | 5 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 3 | 0/11 (0%) | 0 |
| Oropharyngeal pain | 0/34 (0%) | 0 | 1/18 (5.6%) | 1 | 0/18 (0%) | 0 | 2/49 (4.1%) | 3 | 0/11 (0%) | 0 |
| Nasal congestion | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 2/11 (18.2%) | 2 |
| Rhinitis allergic | 4/34 (11.8%) | 4 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||
| Hair growth abnormal | 3/34 (8.8%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Rash | 2/34 (5.9%) | 2 | 1/18 (5.6%) | 1 | 1/18 (5.6%) | 1 | 1/49 (2%) | 1 | 0/11 (0%) | 0 |
| Dry skin | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 2 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Ecchymosis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Eczema | 3/34 (8.8%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Erythema | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 1/11 (9.1%) | 1 |
| Hand dermatitis | 2/34 (5.9%) | 3 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Neurodermatitis | 0/34 (0%) | 0 | 0/18 (0%) | 0 | 1/18 (5.6%) | 2 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Urticaria | 2/34 (5.9%) | 2 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 0/49 (0%) | 0 | 0/11 (0%) | 0 |
| Vascular disorders | ||||||||||
| Hypertension | 5/34 (14.7%) | 5 | 0/18 (0%) | 0 | 0/18 (0%) | 0 | 3/49 (6.1%) | 3 | 2/11 (18.2%) | 2 |
Limitations/Caveats
[Not Specified]
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.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-La Roche |
| Phone | 800-821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02622321
Other Study ID Numbers:
- BH29884
- 2015-002866-21
First Posted:
Dec 4, 2015
Last Update Posted:
Jun 24, 2021
Last Verified:
May 1, 2021