Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Model-Based Annualized Bleeding Rate for Treated Bleeds |
The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Mean Calculated Annualized Bleeding Rate for Treated Bleeds |
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Median Calculated Annualized Bleeding Rate for Treated Bleeds |
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Model-Based Annualized Bleeding Rate for All Bleeds |
The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Mean Calculated Annualized Bleeding Rate for All Bleeds |
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Median Calculated Annualized Bleeding Rate for All Bleeds |
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds |
The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds |
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds |
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Model-Based Annualized Bleeding Rate for Treated Joint Bleeds |
The number of treated joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds |
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Primary |
Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds |
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. |
From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks) |
|
| Secondary |
Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period |
|
At Years 4, 5, 6, 7, and 8 of follow-up |
|
| Secondary |
Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period |
|
At Years 5 and 8 of follow-up |
|
| Secondary |
Incidence and Severity of Adverse Events, With Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Incidence of Thromboembolic Events |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Incidence of Thrombotic Microangiopathy |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Incidence and Severity of of Injection Site Reactions, With Severity Determined According to WHO Toxicity Grading Scale |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Incidence of Adverse Events Leading to Study Drug Discontinuation |
|
From first dose of emicizumab until study completion (8 years) |
|
| Secondary |
Number of Participants According to Hematology and Serum Chemistry Laboratory Test Result Shifts From Baseline WHO Grade to the Highest WHO Grade Post-Baseline |
Laboratory parameters for hematology and blood chemistry were measured at baseline and over time, and the values were compared with a standard reference range. Values outside the standard reference range were considered laboratory abnormalities and graded according to the World Health Organization (WHO) toxicity grading scale, ranging from lowest (Grade 1) to greatest (Grade 4) deviation from standard in the direction indicated for the abnormality (i.e., below (Low) or above (High) the reference range; 'Not Low' and 'Not High' indicate values within the reference range). Participants were categorized according to their laboratory test result shift from baseline WHO grade to highest WHO grade at any point post-baseline (up to Week 53) for each parameter. 'Missing' indicates that the test result was not available. |
Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53 |
|
| Secondary |
Change From Baseline in Pulse Rate Over Time |
|
Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) |
|
| Secondary |
Change From Baseline in Respiratory Rate Over Time |
|
Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) |
|
| Secondary |
Change From Baseline in Body Temperature Over Time |
|
Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) |
|
| Secondary |
Change From Baseline in Systolic Blood Pressure Over Time |
|
Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) |
|
| Secondary |
Change From Baseline in Diastolic Blood Pressure Over Time |
|
Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) |
|
| Secondary |
Plasma Trough Concentrations (Ctrough) of Emicizumab |
|
Predose at Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53 |
|
| Secondary |
Incidence of Anti-Emicizumab Antibodies |
|
Weeks 1, 5, 17, 29, 41, and 53, and thereafter as clinically indicated until study completion (up to 8 years) |
|
| Secondary |
Incidence of De Novo Development of Factor VIII Inhibitors |
As per the protocol, after any 3 exposure days to FVIII or a block of FVIII exposure days (e.g., a block is defined as a minimum of two consecutive doses of FVIII) administered for treatment of a bleed, a surgical procedure, or other (e.g., preventative doses before activity), one plasma sample for anti-FVIII antibodies (for centralized analysis) had to be collected 14 days after the final dose of FVIII administered. |
As clinically indicated from baseline until study completion (up to 8 years) |
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