Hemophilia A
Conditions
Brief summary
This multicenter, open-label, non-randomized study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK) run-in part followed by an expansion part.
Interventions
DRUGEmicizumab
Emicizumab will be administered according to dose and schedule described in respective arms. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol Version 5 (20-Dec-2019), treatment duration was extended. During this study prolongation, participants had the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.
Sponsors
Chugai Pharmaceutical
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight greater than or equal to (\>/=) 40 kilograms (kg) at screening * Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors * Participants using rFVIIa or willing to switch to recombinant activated factor VII (rFVIIa) as primary bypassing agent for the treatment of breakthrough bleeds * FVIII inhibitor test during screening with titer results available prior to first administration of study drug * Participants without FVIII inhibitors, that is with less than (\<) 0.6 Bethesda unit per milliliter \[BU/mL\];\< 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL, who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor greater than (\>) 0.6 BU/mL (\> 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* Inherited or acquired bleeding disorder other than hemophilia A * Ongoing or planned ITI therapy; participants in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration * History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment * Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment * Previous (within the last 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease * Other conditions (for example, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis * History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection * Known HIV infection with cluster of differentiation (CD) 4 cells counts \<200 cells per microliter (cells/mcL) * Use of systemic immunomodulators (for example, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy * Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the participant * Pregnancy or lactation or intention to become pregnant during the study * Women with a positive serum pregnancy test result within 7 days prior to initiation of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds | From Baseline to at least 24 weeks | The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a treated bleed if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a treatment for bleed, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded. |
| Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds | From Baseline to at least 24 weeks | The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As all bleeds comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the treated bleeds outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
| Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds | From Baseline to at least 24 weeks | The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as spontaneous if there is no other known contributing factor such as trauma or procedure/surgery. A treated spontaneous bleed is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded. |
| Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds | From Baseline to at least 24 weeks | The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A joint bleed is defined as a bleed with type reported as joint and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A treated joint bleed is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure. |
| Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds | From Baseline to at least 24 weeks | The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A target joint bleed is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A treated target joint bleed is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score | Baseline, Week 25 | The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement. |
| Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score | Baseline, Week 25 | The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement. |
| Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score | Baseline, Week 25 | The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement. |
| Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score | Baseline, Week 25 | The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement. |
| Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks | Predose at Baseline, Weeks 13 and 25 | Participants enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here for each time point as the proportion of the number of days away from work to the expected number of days at work. |
| Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks | Predose at Baseline, Weeks 13 and 25 | Participants enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school. |
| Expansion Part: Number of Days Hospitalized | From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks) | — |
| Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey | Predose at Week 17 | The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference. |
| PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | — |
| PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | — |
| PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | — |
| PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | — |
| PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | — |
| PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab | Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25 | Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated. |
| PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1 Day 1 predose and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, and 25, and every 12 weeks thereafter to Week 265 | — |
| Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73. 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, and 253 | — |
| Number of Participants With at Least One Adverse Event | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | The number of participants experiencing at least one adverse event (AE), including all non-serious and serious AEs, is reported here. According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Grade ≥3 Adverse Event | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | The World Health Organization (WHO) Toxicity Grading Scale was used for assessing adverse event (AE) severity. For AEs that are not specifically listed in the WHO Toxicity Grading Scale, a Grade 3 AE is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a Grade 4 AE is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE; the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE. |
| Number of Participants With at Least One Adverse Event Related to Study Treatment | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. In order to assess the causality of an AE, investigators used their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an AE is considered to be related to the study drug, indicating yes or no accordingly. |
| Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | The number of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. All of the adverse events reported here were assessed independently by the investigator as not related to treatment with emicizumab. |
| Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. |
| Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | An abnormal laboratory value was defined as a laboratory test result outside of the normal range for hematology or serum chemistry parameters. The WHO toxicity grading scale, which ranges from Grades 1 to 4 (least severe to most severe, respectively; Grade 0 is within normal range), was used for assessing the severity of laboratory abnormalities and adverse events (WHO 2003). Not every laboratory abnormality qualified as an adverse event; an abnormality was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. In this study, any laboratory value changes were transient and returned to baseline for all participants. |
| Number of Participants With at Least One Local Injection-Site Reaction | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | Local adverse events that occurred within 24 hours after study drug administration and, in the investigator's opinion, were judged to be related to study drug injection, were captured as an injection-site reaction on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a local injection-site reaction. |
| Number of Participants With at Least One Thromboembolic Event | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | Hypercoagulation and thromboembolic events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers educated patients/caregivers to recognize the signs and symptoms of potential thromboembolism (i.e., dyspnea, chest pain, leg pain or swelling, etc.) and to ensure that they understood the importance of seeking appropriate medical attention. |
| Number of Participants With at Least One Thrombotic Microangiopathy | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | Thrombotic microangiopathy is used to describe a group of disorders with clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage that can include the kidneys, gastrointestinal system, or central nervous system, etc. Thrombotic microangiopathy events were to be reported as serious adverse events or adverse events of special interest. |
| Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction | From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months) | Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, including anaphylaxis and anaphylactic reactions, may occur. These events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers (HCP) instructed patients and caregivers how to recognize the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an HCP or seek emergency care in case of any such occurrence. |
| Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study | Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months) | A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies (ADAs) to emicizumab in blood plasma samples. Participants were considered ADA-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ADA response). |
| Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies | Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months) | The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. |
| Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] 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 or change of dosing regimen were excluded. |
| Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] 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 or change of dosing regimen were excluded. |
| Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] 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 or change of dosing regimen were excluded. |
| Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age) | Baseline, Week 25 | The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement. |
| Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 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, 229-240, 241-252, and 253-264 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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen. |
| Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score | Baseline, Week 25 | The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement. |
| Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age) | Baseline, Week 25 | The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement. |
| Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score | Baseline, Week 25 | The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement. |
| Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age) | Baseline, Week 25 | The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution. |
Countries
Australia, Belgium, Japan, Poland, Spain, United States
Participant flow
Pre-assignment details
A total of 7 patients were screened and enrolled in the PK run-in cohort of the study. For the expansion cohort, a total of 44 patients were screened, 41 of whom were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Emicizumab: PK Run-In Cohort Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks (Q4W), with no loading dose, for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study. | 7 |
| Emicizumab: Expansion Cohort Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks (Q4W) for at least 24 weeks. Upon implementation of protocol version 5 (20-Dec-2019), each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab SC 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the study. | 41 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Emicizumab: PK Run-In Cohort | Emicizumab: Expansion Cohort | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 35 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 38 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Number of Participants by Factor VIII Inhibitor Status at Baseline Factor VIII Inhibitor Negative | 4 Participants | 36 Participants | 40 Participants |
| Number of Participants by Factor VIII Inhibitor Status at Baseline Factor VIII Inhibitor Positive | 3 Participants | 5 Participants | 8 Participants |
| Number of Participants by Hemophilia A Severity at Baseline Mild | 0 Participants | 1 Participants | 1 Participants |
| Number of Participants by Hemophilia A Severity at Baseline Moderate | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants by Hemophilia A Severity at Baseline Severe | 7 Participants | 40 Participants | 47 Participants |
| Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry 0 Target Joints | 1 Participants | 16 Participants | 17 Participants |
| Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry 1 Target Joint | 2 Participants | 8 Participants | 10 Participants |
| Number of Participants with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry >1 Target Joints | 4 Participants | 17 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 8 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 31 Participants | 36 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 41 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 41 |
| other Total, other adverse events | 7 / 7 | 37 / 41 |
| serious Total, serious adverse events | 2 / 7 | 8 / 41 |
Outcome results
Primary
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds
The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As all bleeds comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the treated bleeds outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time frame: From Baseline to at least 24 weeks
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds | 4.5 all bleed rate per year |
Primary
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds
The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a treated bleed if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a treatment for bleed, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.
Time frame: From Baseline to at least 24 weeks
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds | 2.4 treated bleed rate per year |
Primary
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A joint bleed is defined as a bleed with type reported as joint and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A treated joint bleed is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.
Time frame: From Baseline to at least 24 weeks
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds | 1.7 treated joint bleed rate per year |
Primary
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as spontaneous if there is no other known contributing factor such as trauma or procedure/surgery. A treated spontaneous bleed is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.
Time frame: From Baseline to at least 24 weeks
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds | 0.6 treated spontaneous bleed rate per year |
Primary
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A target joint bleed is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A treated target joint bleed is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.
Time frame: From Baseline to at least 24 weeks
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds | 1.0 treated target joint bleed rate per year |
Secondary
Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score | 0.06 units on a scale |
Secondary
Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score | 5.53 units on a scale |
Secondary
Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age)
The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all adult participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age) | -15.14 units on a scale |
Secondary
Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age)
The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all adult participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age) | -13.62 units on a scale |
Secondary
Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age)
The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
Time frame: Baseline, Week 25
Population: The analysis included all adolescent participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age) | -8.10 units on a scale | Standard Deviation 6.48 |
Secondary
Expansion Part: Number of Days Hospitalized
Time frame: From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks)
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Number of Days Hospitalized | 0 days | Standard Deviation 0 |
Secondary
Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score
The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all adult participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score | 67.6 percentage of participants |
Secondary
Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score
The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a not applicable option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all adult participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score | 67.6 percentage of participants |
Secondary
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.
Time frame: Predose at Week 17
Population: The analysis included all participants enrolled in the expansion part of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey | Prefer the New Emicizumab SC Treatment | 100 percentage of participants |
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey | Prefer My Old Hemophilia Treatment (IV) | 0.0 percentage of participants |
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey | Have No Preference | 0.0 percentage of participants |
Secondary
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score | 47.5 percentage of participants |
Secondary
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Time frame: Baseline, Week 25
Population: The analysis included all participants enrolled in the expansion part of the study. The number analyzed represents participants who completed the questionnaire at Baseline and Week 25.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score | 35.0 percentage of participants |
Secondary
Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints
Time frame: Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73. 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, and 253
Population: The analysis included all participants enrolled in the Expansion part of the study. The number analyzed represents the number of participants with an evaluable sample at a given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1 | NA μg/mL | — |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 2 | 16.0 μg/mL | Geometric Coefficient of Variation 36.8 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 3 | 29.8 μg/mL | Geometric Coefficient of Variation 30.5 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 4 | 41.3 μg/mL | Geometric Coefficient of Variation 32.4 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 5 | 48.8 μg/mL | Geometric Coefficient of Variation 32.2 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 9 | 40.4 μg/mL | Geometric Coefficient of Variation 45.7 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 13 | 38.9 μg/mL | Geometric Coefficient of Variation 49.1 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 17 | 36.1 μg/mL | Geometric Coefficient of Variation 53.8 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 21 | 37.4 μg/mL | Geometric Coefficient of Variation 48.3 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 25 | 37.6 μg/mL | Geometric Coefficient of Variation 52.5 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 37 | 39.6 μg/mL | Geometric Coefficient of Variation 49.9 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 49 | 40.2 μg/mL | Geometric Coefficient of Variation 48.4 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 61 | 38.7 μg/mL | Geometric Coefficient of Variation 51.7 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 73 | 42.1 μg/mL | Geometric Coefficient of Variation 51.2 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 85 | 36.4 μg/mL | Geometric Coefficient of Variation 50.8 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 97 | 35.6 μg/mL | Geometric Coefficient of Variation 49.5 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 145 | 36.5 μg/mL | Geometric Coefficient of Variation 51.7 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 157 | 47.3 μg/mL | Geometric Coefficient of Variation 36 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 169 | 41.7 μg/mL | Geometric Coefficient of Variation 41.9 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 181 | 45.1 μg/mL | Geometric Coefficient of Variation 47.9 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 193 | 48.6 μg/mL | Geometric Coefficient of Variation 47 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 205 | 46.0 μg/mL | Geometric Coefficient of Variation 48.2 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 217 | 43.9 μg/mL | Geometric Coefficient of Variation 47.8 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 229 | 50.2 μg/mL | Geometric Coefficient of Variation 43.1 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 241 | 36.2 μg/mL | Geometric Coefficient of Variation 46.5 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 253 | 38.8 μg/mL | Geometric Coefficient of Variation 46.6 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 109 | 33.0 μg/mL | Geometric Coefficient of Variation 63.6 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 121 | 32.5 μg/mL | Geometric Coefficient of Variation 60.5 |
| Emicizumab: Expansion Cohort | Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 133 | 33.7 μg/mL | Geometric Coefficient of Variation 49 |
Secondary
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks
Participants enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school.
Time frame: Predose at Baseline, Weeks 13 and 25
Population: The analysis included all participants enrolled in the expansion part of the study who were enrolled in school and completed the questionnaire at Baseline, Week 13, and Week 25.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks | Baseline | 0.12 away/expected school days |
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks | Week 13 | 0.00 away/expected school days |
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks | Week 25 | 0.03 away/expected school days |
Secondary
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks
Participants enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here for each time point as the proportion of the number of days away from work to the expected number of days at work.
Time frame: Predose at Baseline, Weeks 13 and 25
Population: The analysis included all participants enrolled in the expansion part of the study who were working and completed the questionnaire at Baseline, Week 13, and Week 25.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks | Baseline | 0.05 away/expected work days |
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks | Week 13 | 0.00 away/expected work days |
| Emicizumab: Expansion Cohort | Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks | Week 25 | 0.01 away/expected work days |
Secondary
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 5.1 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 4.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 3.1 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 2.5 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 2.2 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 3.5 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 1.8 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 2.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 2.4 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 1.6 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 2.2 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 1.2 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 2.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 2.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 2.3 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 1.7 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 1.9 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 1.4 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 1.7 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 1.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 2.4 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 2.6 All bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
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 or change of dosing regimen were excluded.
Time frame: From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Bleeds | 2.0 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | All Bleeds | 3.0 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Spontaneous Bleeds | 0.7 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Joint Bleeds | 1.3 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Target Joint Bleeds | 0.6 bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 2.3 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 2.5 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 1.5 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 1.9 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 1.3 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 2.7 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 1.1 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 1.4 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 2.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 1.4 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 1.8 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 1.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 1.6 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 2.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 2.1 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 1.3 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 1.7 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 1.4 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 1.2 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 1.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 2.4 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 2.6 Treated bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 0.4 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 1.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 0.1 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 0.3 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 0.2 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 0.1 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 0.2 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 0.4 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 0.4 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 0.4 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 1.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 1.8 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 0.7 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 0.5 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 0.2 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 0.8 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 0.0 Treated spontaneous bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 4.3 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 0.0 All bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 4.3 All bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
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 or change of dosing regimen were excluded.
Time frame: From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Bleeds | 0.6 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | All Bleeds | 1.2 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Spontaneous Bleeds | 0.0 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Joint Bleeds | 0.3 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Target Joint Bleeds | 0.0 bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 4.3 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 0.0 Treated bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 0.0 Treated bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time
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 with dose up-titration or a change in emicizumab dosing regimen (after implementation of protocol v5), the efficacy period ended the day before the first day on the up-titrated dose or changed dosing regimen.
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, 229-240, 241-252, and 253-264 weeks
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study. The number analyzed includes participants with available data over each interval.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 1 to 12 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 13 to 24 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 25 to 36 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 37 to 48 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 49 to 60 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 61 to 72 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 73 to 84 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 85 to 96 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 97 to 108 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 109 to 120 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 121 to 132 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 145 to 156 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 157 to 168 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 169 to 180 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 193 to 204 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 205 to 216 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 217 to 228 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 229 to 240 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 241 to 252 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 253 to 264 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 133 to 144 Weeks | 0.0 Treated spontaneous bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time | 181 to 192 Weeks | 0.0 Treated spontaneous bleeds per year |
Secondary
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
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 or change of dosing regimen were excluded.
Time frame: From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Population: The analysis includes all participants in the Expansion Cohort who received emicizumab on the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Bleeds | 1.9 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | All Bleeds | 2.9 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Spontaneous Bleeds | 0.5 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Joint Bleeds | 1.2 bleeds per year |
| Emicizumab: Expansion Cohort | Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds | Treated Target Joint Bleeds | 0.5 bleeds per year |
Secondary
Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study
A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies (ADAs) to emicizumab in blood plasma samples. Participants were considered ADA-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ADA response).
Time frame: Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab. The number analyzed indicates those with both baseline and post-baseline assessments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study | 1 Participants |
Secondary
Number of Participants With at Least One Adverse Event
The number of participants experiencing at least one adverse event (AE), including all non-serious and serious AEs, is reported here. According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event | Any Adverse Event (AE) | 7 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event | Serious AE | 2 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event | Any Adverse Event (AE) | 39 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event | Serious AE | 8 Participants |
Secondary
Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment
According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization \[WHO\] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment | 0 Participants |
Secondary
Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings
Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings | 0 Participants |
Secondary
Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs
The number of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. All of the adverse events reported here were assessed independently by the investigator as not related to treatment with emicizumab.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Hypertension | 2 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Pyrexia | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Tachycardia | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Hypertension | 4 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Pyrexia | 4 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs | Tachycardia | 1 Participants |
Secondary
Number of Participants With at Least One Adverse Event Related to Study Treatment
According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. In order to assess the causality of an AE, investigators used their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an AE is considered to be related to the study drug, indicating yes or no accordingly.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Injection Site Reaction | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Erythema | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Presyncope | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Incorrect Dose Administered | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Chills | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Accidental Overdose | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Rash | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Iron Deficiency Anaemia | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Any Adverse Event Related to Study Treatment | 2 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Iron Deficiency Anaemia | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Any Adverse Event Related to Study Treatment | 14 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Injection Site Reaction | 9 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Chills | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Presyncope | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Rash | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Erythema | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Incorrect Dose Administered | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Adverse Event Related to Study Treatment | Accidental Overdose | 1 Participants |
Secondary
Number of Participants With at Least One Grade ≥3 Adverse Event
The World Health Organization (WHO) Toxicity Grading Scale was used for assessing adverse event (AE) severity. For AEs that are not specifically listed in the WHO Toxicity Grading Scale, a Grade 3 AE is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a Grade 4 AE is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. The terms severe and serious are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE; the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Grade ≥3 Adverse Event | 2 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Grade ≥3 Adverse Event | 7 Participants |
Secondary
Number of Participants With at Least One Local Injection-Site Reaction
Local adverse events that occurred within 24 hours after study drug administration and, in the investigator's opinion, were judged to be related to study drug injection, were captured as an injection-site reaction on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a local injection-site reaction.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Local Injection-Site Reaction | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Local Injection-Site Reaction | 9 Participants |
Secondary
Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4
An abnormal laboratory value was defined as a laboratory test result outside of the normal range for hematology or serum chemistry parameters. The WHO toxicity grading scale, which ranges from Grades 1 to 4 (least severe to most severe, respectively; Grade 0 is within normal range), was used for assessing the severity of laboratory abnormalities and adverse events (WHO 2003). Not every laboratory abnormality qualified as an adverse event; an abnormality was reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. In this study, any laboratory value changes were transient and returned to baseline for all participants.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Aspartate Aminotransferase (AST) - High | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Calcium, Corrected - Low | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Phosphorus - Low | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Sodium - High | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Sodium - High | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Aspartate Aminotransferase (AST) - High | 1 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Phosphorus - Low | 2 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4 | Calcium, Corrected - Low | 1 Participants |
Secondary
Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, including anaphylaxis and anaphylactic reactions, may occur. These events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers (HCP) instructed patients and caregivers how to recognize the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an HCP or seek emergency care in case of any such occurrence.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction | 0 Participants |
Secondary
Number of Participants With at Least One Thromboembolic Event
Hypercoagulation and thromboembolic events were to be reported as serious adverse events or adverse events of special interest. Healthcare providers educated patients/caregivers to recognize the signs and symptoms of potential thromboembolism (i.e., dyspnea, chest pain, leg pain or swelling, etc.) and to ensure that they understood the importance of seeking appropriate medical attention.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Thromboembolic Event | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Thromboembolic Event | 0 Participants |
Secondary
Number of Participants With at Least One Thrombotic Microangiopathy
Thrombotic microangiopathy is used to describe a group of disorders with clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage that can include the kidneys, gastrointestinal system, or central nervous system, etc. Thrombotic microangiopathy events were to be reported as serious adverse events or adverse events of special interest.
Time frame: From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Population: The analysis included all participants who received at least one dose of emicizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Thrombotic Microangiopathy | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With at Least One Thrombotic Microangiopathy | 0 Participants |
Secondary
Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies
The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold.
Time frame: Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months)
Population: The analysis included all participants who were FVIII inhibitor-negative at baseline and had received at least one dose of emicizumab during the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Emicizumab: Expansion Cohort | Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies | 0 Participants |
| Emicizumab: Expansion Cohort | Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies | 0 Participants |
Secondary
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab
Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated.
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab | After First Dose (Weeks 1-5) | 10.7 mL/h | Geometric Coefficient of Variation 23.9 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab | After Sixth Dose (Weeks 21-25) | 11.1 mL/h | Geometric Coefficient of Variation 20.8 |
Secondary
PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study. t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, t1/2 could not be determined after the sixth dose of emicizumab.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab | After First Dose (Weeks 1-5) | 29.5 day | Geometric Coefficient of Variation 38.5 |
Secondary
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab | After First Dose (Weeks 1-5) | 663 day*μg/mL | Geometric Coefficient of Variation 19.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab | After Sixth Dose (Weeks 21-25) | 1420 day*μg/mL | Geometric Coefficient of Variation 20.7 |
Secondary
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study. t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, dependent PK parameters, such as AUC\[0-inf\], could not be estimated after the sixth dose of emicizumab.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab | After First Dose (Weeks 1-5) | 1490 day*μg/mL | Geometric Coefficient of Variation 27.2 |
Secondary
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab | After First Dose (Weeks 1-5) | 31.8 μg/mL | Geometric Coefficient of Variation 19.3 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab | After Sixth Dose (Weeks 21-25) | 62.7 μg/mL | Geometric Coefficient of Variation 17.3 |
Secondary
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints
Time frame: Week 1 Day 1 predose and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, and 25, and every 12 weeks thereafter to Week 265
Population: The analysis included all participants enrolled in the PK Run-In part of the study. The number analyzed represents the number of participants with an evaluable sample at a given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1, Day 1 - Predose | NA μg/mL | — |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1, Day 1 - 8 hours | 7.0 μg/mL | Geometric Coefficient of Variation 71.7 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1, Day 3 | 20.6 μg/mL | Geometric Coefficient of Variation 51.2 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 1, Day 5 | 26.5 μg/mL | Geometric Coefficient of Variation 29.7 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 2, Day 8 | 29.4 μg/mL | Geometric Coefficient of Variation 25.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 2, Day 11 | 27.7 μg/mL | Geometric Coefficient of Variation 21.9 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 3, Day 15 | 26.3 μg/mL | Geometric Coefficient of Variation 20.5 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 3, Day 18 | 24.1 μg/mL | Geometric Coefficient of Variation 21.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 4, Day 22 | 22.0 μg/mL | Geometric Coefficient of Variation 14.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 4, Day 25 | 20.6 μg/mL | Geometric Coefficient of Variation 15.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 5 | 18.5 μg/mL | Geometric Coefficient of Variation 18.2 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 6 | 47.4 μg/mL | Geometric Coefficient of Variation 13.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 7 | 42.1 μg/mL | Geometric Coefficient of Variation 18.3 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 8 | 35.4 μg/mL | Geometric Coefficient of Variation 22.5 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 9 | 28.2 μg/mL | Geometric Coefficient of Variation 18.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 11 | 55.9 μg/mL | Geometric Coefficient of Variation 20.4 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 13 | 34.6 μg/mL | Geometric Coefficient of Variation 24.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 15 | 52.0 μg/mL | Geometric Coefficient of Variation 17 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 17 | 36.7 μg/mL | Geometric Coefficient of Variation 16.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 19 | 50.8 μg/mL | Geometric Coefficient of Variation 32.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 21 | 34.5 μg/mL | Geometric Coefficient of Variation 25.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 22 | 62.2 μg/mL | Geometric Coefficient of Variation 17.5 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 23 | 56.5 μg/mL | Geometric Coefficient of Variation 19 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 24 | 47.9 μg/mL | Geometric Coefficient of Variation 28.7 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 25 | 39.2 μg/mL | Geometric Coefficient of Variation 25.3 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 37 | 34.0 μg/mL | Geometric Coefficient of Variation 15.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 49 | 34.7 μg/mL | Geometric Coefficient of Variation 23.2 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 61 | 41.1 μg/mL | Geometric Coefficient of Variation 25.9 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 73 | 39.7 μg/mL | Geometric Coefficient of Variation 22.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 85 | 38.0 μg/mL | Geometric Coefficient of Variation 29.2 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 97 | 43.6 μg/mL | Geometric Coefficient of Variation 17.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 109 | 37.7 μg/mL | Geometric Coefficient of Variation 13.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 121 | 39.6 μg/mL | Geometric Coefficient of Variation 19.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 133 | 37.5 μg/mL | Geometric Coefficient of Variation 14.2 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 145 | 34.8 μg/mL | Geometric Coefficient of Variation 13.1 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 157 | 35.0 μg/mL | Geometric Coefficient of Variation 20.7 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 181 | 45.4 μg/mL | Geometric Coefficient of Variation 14.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 193 | 37.9 μg/mL | Geometric Coefficient of Variation 21.5 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 205 | 45.4 μg/mL | Geometric Coefficient of Variation 21 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 217 | 45.3 μg/mL | Geometric Coefficient of Variation 11.3 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 229 | 52.1 μg/mL | Geometric Coefficient of Variation 18.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 241 | 45.6 μg/mL | Geometric Coefficient of Variation 13.6 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 253 | 40.4 μg/mL | Geometric Coefficient of Variation 13.8 |
| Emicizumab: Expansion Cohort | PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints | Week 265 | 42.4 μg/mL | Geometric Coefficient of Variation 16.5 |
Secondary
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab
Time frame: Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Population: The analysis included all participants enrolled in the PK Run-In part of the study.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Emicizumab: Expansion Cohort | PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab | After First Dose (Weeks 1-5) | 6.95 day |
| Emicizumab: Expansion Cohort | PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab | After Sixth Dose (Weeks 21-25) | 6.98 day |