A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

Overview

This is a phase IIIb, single arm, open-label, multi-center study to evaluate the safety and tolerability of emicizumab in participants with congenital hemophilia A who have documented inhibitors against Factor VIII (FVIII) at enrollment. Approximately 200 participants, aged 12 or older, will be enrolled in this study and are expected to be enrolled at approximately 85 sites globally. Participants will receive an initial weekly dose of prophylactic emicizumab subcutaneously for 4 weeks, followed by a weekly maintenance dose subcutaneously for the remainder of the 2-year treatment period.

Full Title of Study: “A Single-Arm, Multicenter Phase IIIB Clinical Trial to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 19, 2020

Interventions

  • Drug: Emicizumab
    • Initial dosing will be 3 mg/kg/week subcutaneously for 4 weeks; Maintenance dosing will follow at 1.5 mg/kg/week subcutaneously for the remainder of the 2-year treatment period

Arms, Groups and Cohorts

  • Experimental: 1.5 mg/kg Emicizumab QW
    • Participants will receive initial weekly doses of prophylactic emicizumab subcutaneously for 4 weeks, followed by maintenance doses consisting of half the initial dose, administered subcutaneously for the remainder of the 2-year treatment period

Clinical Trial Outcome Measures

Primary Measures

  • Overall Summary of the Number of Participants With Adverse Events, Severity Assessed According to the World Health Organization (WHO) Toxicity Grading Scale
    • Time Frame: From Baseline until study completion (up to 2 years)
    • 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. aPCC = activated prothrombin complex concentrate
  • Adverse Events (AEs) Rates Per 100 Patient-Years for All-Grade AEs, Serious AEs, and Grade ≥3 AEs
    • Time Frame: From Baseline until study completion (up to 2 years)
    • 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. The AE rate per 100 patient-years was computed as follows: AE Rate = (Number of AEs observed/ Total patient-years at risk)*100. Total patient-years at risk is the sum over all patients of the time intervals (in years) between start of study therapy (study day 1) and the end of follow up.
  • Number of Participants by Hematology and Biochemistry Laboratory Parameter Test Results as Shifts From the WHO Toxicity Grade at Baseline to the Worst WHO Toxicity Grade Post-Baseline
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • The World Health Organization (WHO) toxicity grading scale was used for determining the severity of laboratory abnormalities (i.e., test results outside of the reference range) for hematology and biochemistry parameters; Grade 0 is normal and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). Not every laboratory abnormality qualified as an adverse event (AE). A laboratory test result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator’s judgment. Baseline was defined as the last available assessment prior to first receipt of study drug. Abs = absolute count; SGOT/AST = aspartate aminotransferase; SGPT/ALT = alanine aminotransferase
  • Change From Baseline in Body Temperature at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.
  • Change From Baseline in Systolic Blood Pressure at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.
  • Change From Baseline in Diastolic Blood Pressure at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.
  • Change From Baseline in Pulse Rate at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.
  • Change From Baseline in Respiratory Rate at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.
  • Change From Baseline in Body Weight at Specified Timepoints
    • Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)
    • Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

Secondary Measures

  • Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • The number of bleeds over the efficacy period was analyzed as an ABR using a negative binomial regression model. Treated bleeds: bleeds followed by a hemophilia medication reported to be a “Treatment for bleed”. All bleeds: included both treated and non-treated bleeds. Treated joint bleeds: treated bleeds where bleed type was “joint bleed” accompanied by at least one of following symptoms: “increased swelling or warmth of the skin over the joint”, “increasing pain” or “decreased range of motion or difficulty using the joint compared with baseline”. Treated target joint bleeds: treated joint bleeds that occurred in a target joint, defined as a joint in which ≥3 treated joint bleeds occurred during the 24 weeks prior to study entry. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. For all bleed types, bleeds due to surgery/procedure were excluded. Bleeds occurring after dose up-titration have been excluded.
  • Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] 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: bleeds followed by a hemophilia medication reported to be a “Treatment for bleed”. All bleeds: included both treated and non-treated bleeds. Treated joint bleeds: treated bleeds where bleed type was “joint bleed” accompanied by at least one of following symptoms: “increased swelling or warmth of the skin over the joint”, “increasing pain” or “decreased range of motion or difficulty using the joint compared with baseline”. Treated target joint bleeds: treated joint bleeds that occurred in a target joint, defined as a joint in which ≥3 treated joint bleeds occurred during the 24 weeks prior to study entry. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. For all types, bleeds due to surgery/procedure and bleeds occurring after dose up-titration were excluded.
  • Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] 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: bleeds followed by a hemophilia medication reported to be a “Treatment for bleed”. All bleeds: included both treated and non-treated bleeds. Treated joint bleeds: treated bleeds where bleed type was “joint bleed” accompanied by at least one of following symptoms: “increased swelling or warmth of the skin over the joint”, “increasing pain” or “decreased range of motion or difficulty using the joint compared with baseline”. Treated target joint bleeds: treated joint bleeds that occurred in a target joint, defined as a joint in which ≥3 treated joint bleeds occurred during the 24 weeks prior to study entry. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. For all types, bleeds due to surgery/procedure and bleeds occurring after dose up-titration were excluded.
  • Percentage of Participants by the Categorized Number of Bleeds for Treated Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • Treated bleeds: bleeds followed by a hemophilia medication reported to be a “Treatment for bleed”. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Percentage of Participants by the Categorized Number of Bleeds for All Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • All bleeds: included both treated and non-treated bleeds. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Percentage of Participants by the Categorized Number of Bleeds for Treated Spontaneous Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for Treated Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: bleeds followed by a hemophilia medication reported to be a “Treatment for bleed”. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for All Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds: included both treated and non-treated bleeds. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds
    • Time Frame: From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)
    • The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Total Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. The Total Score is based on the scores for each domain and ranges from 0 to 100, with lower scores reflective of better quality of life.
  • Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Total Score at Specified Timepoints
    • Time Frame: At 3, 6, 12, and 18 months
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. The Total Score is based on the scores for each domain and ranges from 0 to 100, with lower scores reflective of better quality of life. An improvement larger than the responder threshold was defined as a decrease from baseline of at least 7 points in the Haem-A-QoL Total score.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Specified Timepoints
    • Time Frame: At 3, 6, 12, and 18 months
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life. An improvement larger than the responder threshold was defined as a decrease from baseline of at least 10 points in the Haem-A-QoL Physical Health domain score.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Treatment Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Work and School Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Dealing With Hemophilia Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Feelings Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Family Planning Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Future Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Partnership and Sexuality Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Sports and Leisure Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire View of Yourself Domain Score at Specified Timepoints, Adult Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a ‘not applicable’ option. Scale scores for each domain range from 0 to 100, with lower scores reflective of better quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. The Total Score is derived from the scores for all domains and scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Specified Timepoints
    • Time Frame: At 3, 6, 12, and 18 months
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. The Total Score is derived from the scores for all domains and scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life. An improvement larger than the responder threshold was defined as a decrease of at least 5 points in the Haemo-QoL-SF Total score.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Physical Health Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Physical Health Domain Score at Specified Timepoints
    • Time Frame: At 3, 6, 12, and 18 months
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life. An improvement larger than the responder threshold was defined as a decrease of at least 10 points in the Haemo-QoL-SF Physical Health domain score.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Treatment Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Sports and School Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Dealing With Hemophilia Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Feelings Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Family Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Friends Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Other People Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire View of Yourself Domain Score at Specified Timepoints, Adolescent Participants
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The Haemo-QoL-SF was designed as a series of age-related questionnaires to measure health-related quality of life in children and adolescents (12-17 year olds) with hemophilia. This version contains 35 items and covers nine domains considered relevant for children’s health-related quality of life: physical health, treatment, sports and school, dealing with hemophilia, feelings, family, friends, other people, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always. Scale scores range from 0 to 100, with a lower score reflective of better health-related quality of life.
  • Change From Baseline in the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) Index Utility Score at Specified Timepoints
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The EQ-5D-5L is a generic, self-reported, preference-based health utility measure that consists of six questions and is used to assess health status and inform pharmacoeconomic evaluations. The index utility score is based on the participant’s assessment of their health on five scales: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It ranges from -0.224 to 1, with 0 corresponding to death and 1 corresponding to full health; negative values correspond to health states worse than death. Higher scores indicate better quality of life.
  • Change From Baseline in the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) Quality-of-Life Visual Analogue Scale (VAS) Score at Specified Timepoints
    • Time Frame: Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months)
    • The EQ-5D-5L is a generic, self-reported, preference-based health utility measure that consists of six questions and is used to assess health status and inform pharmacoeconomic evaluations. The visual analogue scale (VAS) ranges from 0 to 100 points, on which the participant self-assesses their current health status; 0 being the worst health you can imagine and 100 being the best health you can imagine. Higher scores are reflective of better health.
  • Percentage of Participants Who Preferred the New Emicizumab Treatment or the Old Hemophilia Treatment, or Without Treatment Preference, as Assessed by the EmiPref Questionnaire
    • Time Frame: Month 3
    • The EmiPref questionnaire asked participants to specify the treatment they would prefer to continue to receive after receiving treatment with their previous episodic or prophylactic regimen and subcutaneous (SC) emicizumab, or if they had no preference. The 95% confidence intervals were calculated for one sample binomial using the Pearson-Clopper method.
  • Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) Against Emicizumab at Anytime Post-Baseline
    • Time Frame: Baseline (Week 1), Week 5, and at 3, 6, 9, 12, and 18 months, and at early termination/study completion (up to 24 months)
    • ‘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.
  • Mean Trough Plasma Concentrations of Emicizumab at Specified Timepoints
    • Time Frame: Pre-dose at Weeks 2, 3, and 5, Months 3, 6, 12, and 18, and at treatment discontinuation (up to 2 years)
    • The trough concentration is a measure of the plasma concentration of a study drug at the end of of the dosage interval.

Participating in This Clinical Trial

Inclusion Criteria

  • As per investigator's judgement, a willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the patient-reported outcome (PRO) questionnaires and bleed diaries through the use of an electronic device or paper – Aged 12 years or older at the time of informed consent – Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII – Documented treatment with bypassing agents or FVIII concentrates in the last 6 months (on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day before starting emicizumab – Adequate hematologic, hepatic, and renal function – For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of <1% per year during the treatment period and for at least five elimination half-lives (24 weeks) after the last dose of emicizumab Exclusion Criteria:

  • Inherited or acquired bleeding disorder other than hemophilia A – Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy (prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-hour washout period prior to the first emicizumab administration – History of illicit drug or alcohol abuse within 12 months prior to screening, as per the investigator's judgment – High risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA), as per the investigator's judgment – Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease – Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or thrombosis – History of clinically significant hypersensitivity reaction associated with monoclonal antibody therapies or components of the emicizumab injection – Known human immunodeficiency virus (HIV) infection with CD4 count <200 cells/μL within 6 months prior to screening – Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of antiretroviral therapy – 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 patient's safe participation in and completion of the study or interpretation of the study results – Receipt of: Emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within five half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or five half-lives, whichever is shorter; or, Any concurrent investigational drug. – Pregnancy or lactation, or intent to become pregnant during the study – Positive serum pregnancy test result within 7 days prior to initiation of emicizumab (females only)

Gender Eligibility: All

Minimum Age: 12 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hoffmann-La Roche
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Clinical Trials, Study Director, Hoffmann-La Roche

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