Clinical Trial Results:
A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients with Hemophilia A
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Summary
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EudraCT number |
2016-001094-33 |
Trial protocol |
ES PL BE |
Global end of trial date |
29 Jun 2022
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Results information
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Results version number |
v2(current) |
This version publication date |
29 Dec 2022
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First version publication date |
20 Dec 2018
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BO39182
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03020160 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Study Acronym: HAVEN 4 | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Jun 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Jun 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objectives of the Pharmacokinetics (PK) Run-In and the Expansion Parts of this study are the following:
PK Run-In Part Objectives:
- To investigate the pharmacokinetics (PK) of emicizumab after single and multiple (every 4 weeks [Q4W]) subcutaneous (SC) administration of 6 milligrams per kilogram (mg/kg)
- To assess the safety and tolerability of emicizumab after 6 mg/kg Q4W SC administration
Expansion Part Objectives:
- To evaluate the clinical effect of prophylactic emicizumab on the number of treated bleeds over time, all bleeds over time, joint bleeds over time, target joint bleeds over time, and spontaneous bleeds over time
- To evaluate the health-related quality of life, health status, and patient preference for treatment regimen
- To evaluate the overall safety of emicizumab given Q4W in patients with hemophilia A
- To characterize the pharmacokinetics of multiple Q4W doses of 6mg/kg emicizumab
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Protection of trial subjects |
This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. Each study subject or their legally authorized representative was required to read and sign an Informed Consent Form or an Informed Assent Form (ages 12-17), as applicable.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Jan 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
6 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 5
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
Japan: 8
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Country: Number of subjects enrolled |
Poland: 6
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Country: Number of subjects enrolled |
Spain: 14
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Country: Number of subjects enrolled |
United States: 11
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Worldwide total number of subjects |
48
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EEA total number of subjects |
24
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
4
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Adults (18-64 years) |
41
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
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Pre-assignment
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Screening 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. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Emicizumab: PK Run-In Cohort | ||||||||||||||||||||||||
Arm description |
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 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. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
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Investigational medicinal product code |
B02BX06
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Other name |
Hemlibra
RO5534262
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks, with no loading dose, for a minimum of 24 weeks.
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Arm title
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Emicizumab: Expansion Cohort | ||||||||||||||||||||||||
Arm description |
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 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. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
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Investigational medicinal product code |
B02BX06
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Other name |
Hemlibra
RO5534262
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
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 for a minimum of 24 weeks.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Emicizumab dose up-titration and change of dosing regimen were not study milestones that applied to all participants, but rather only to those who met the criteria for/opted for such changes to their dosing. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Emicizumab dose up-titration and change of dosing regimen were not study milestones that applied to all participants, but rather only to those who met the criteria for/opted for such changes to their dosing. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Emicizumab dose up-titration and change of dosing regimen were not study milestones that applied to all participants, but rather only to those who met the criteria for/opted for such changes to their dosing. [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Emicizumab dose up-titration and change of dosing regimen were not study milestones that applied to all participants, but rather only to those who met the criteria for/opted for such changes to their dosing. |
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Baseline characteristics reporting groups
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Reporting group title |
Emicizumab: PK Run-In Cohort
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Reporting group description |
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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Emicizumab: Expansion Cohort
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Reporting group description |
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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Emicizumab: PK Run-In Cohort
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Reporting group description |
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 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. | ||
Reporting group title |
Emicizumab: Expansion Cohort
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Reporting group description |
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 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. | ||
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End point title |
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds [1] [2] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
From Baseline to at least 24 weeks
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds [3] [4] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
From Baseline to at least 24 weeks
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds [5] [6] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
From Baseline to at least 24 weeks
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive. [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds [7] [8] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
From Baseline to at least 24 weeks
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive. [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds [9] [10] | ||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
From Baseline to at least 24 weeks
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive. [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score [11] | ||||||||
End point description |
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. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 25
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| Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Change from Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Subjects (≥18 Years of Age) [12] | ||||||||
End point description |
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. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 25
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| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Change from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Subjects (≥18 Years of Age) [13] | ||||||||
End point description |
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. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
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End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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|
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| No statistical analyses for this end point | |||||||||
|
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End point title |
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 [14] | ||||||||
End point description |
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 subject'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. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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|
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score [15] | ||||||||
End point description |
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. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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|
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Expansion Part: Change from Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Subjects (12-17 Years of Age) [16] | ||||||||
End point description |
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. The analysis included all adolescent subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25. Given the small number of adolescent subjects, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score [17] | ||||||||
End point description |
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 subject'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. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [18] | ||||||||
End point description |
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. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Expansion Part: Change from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [19] | ||||||||
End point description |
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. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 25
|
||||||||
| Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Expansion Part: Proportion of Days Away from Work to Expected Days at Work in the Previous Four Weeks [20] | ||||||||||||||
End point description |
Subjects 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 as the proportion of the number of days away from work to the expected number of days at work. The number of subjects who were working and completed the questionnaire at Baseline, Week 13, and Week 25 is reported in brackets.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Predose at Baseline, Weeks 13 and 25
|
||||||||||||||
| Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Expansion Part: Proportion of Days Away from School to Expected Days at School in the Previous Four Weeks [21] | ||||||||||||||
End point description |
Subjects 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. The number of subjects who were enrolled in school and completed the questionnaire at Baseline, Week 13, and Week 25 is reported in brackets.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Predose at Baseline, Weeks 13 and 25
|
||||||||||||||
| Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||
End point title |
Expansion Part: Number of Days Hospitalized [22] | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks)
|
||||||||
| Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Expansion Part: Percentage of Subjects 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 [23] | ||||||||||||||
End point description |
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the subject’s preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Predose at Week 17
|
||||||||||||||
| Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||
End point title |
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab [24] | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
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|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab [25] | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
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|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab [26] | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
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|
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| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab [27] | ||||||||||||
End point description |
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 (as indicated by the entered value '99999').
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
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|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab [28] | ||||||||||||
End point description |
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, as indicated by the entered value '99999'.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
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|
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| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab [29] | ||||||||||||
End point description |
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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The study plan was to evaluate pharmacokinetic (PK) parameters of emicizumab only in the PK Run-In cohort of the study. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
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End point title |
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints [30] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The analysis included all subjects enrolled in the PK run-in part of the study. The value 'n =' represents the number of subjects with an evaluable sample at a given time point. '999999' indicates that plasma concentration could not be estimated because samples were below the lower limit of quantification (BLQ).
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The plasma concentrations of emicizumab over time for the PK Run-In and Expansion cohorts are reported under separate endpoints because of the differences in sampling schedules between the two cohorts. |
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|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints [31] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The analysis included all subjects enrolled in the expansion part of the study. The value 'n =' represents the number of subjects with an evaluable sample at a given time point. '999999' indicates that plasma concentration could not be estimated because samples were below the lower limit of quantification (BLQ).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Predose on Day 1 of 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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The plasma concentrations of emicizumab over time for the PK Run-In and Expansion cohorts are reported under separate endpoints because of the differences in sampling schedules between the two cohorts. |
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|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Percentage of Subjects with at Least One Adverse Event | ||||||||||||||||||
End point description |
The percentage of subjects 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. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
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End point title |
Percentage of Subjects with at Least One Grade ≥3 Adverse Event | ||||||||||||
End point description |
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. The analysis included all subjects who received at least 1 dose of emicizumab
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Adverse Event Leading to Withdrawal from Treatment | ||||||||||||
End point description |
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. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Percentage of Subjects with at Least One Adverse Event Related to Study Treatment | |||||||||||||||||||||||||||||||||||||||
End point description |
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. The analysis included all subjects who received at least one dose of emicizumab.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Percentage of Subjects with at Least One Adverse Event of Changes from Baseline in Vital Signs | |||||||||||||||||||||
End point description |
The percentage of subjects 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. The analysis included all subjects who received at least one dose of emicizumab.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Adverse Event of Changes from Baseline in Physical Examination Findings | ||||||||||||
End point description |
Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percentage of Subjects with at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline Grade 3 or 4 | ||||||||||||||||||||||||
End point description |
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 subjects. The analysis included all subjects who received at least 1 dose of emicizumab.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Local Injection-Site Reaction | ||||||||||||
End point description |
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.” The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Thromboembolic Event | ||||||||||||
End point description |
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. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Thrombotic Microangiopathy | ||||||||||||
End point description |
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. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study | ||||||||||||
End point description |
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. Subjects 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). The analysis included all subjects who received at least one dose of emicizumab. The number of subjects analyzed indicates those with both baseline and post-baseline assessments.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction | ||||||||||||
End point description |
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. The analysis included all subjects who received at least one dose of emicizumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With De Novo Development of Anti-Factor VIII (FVIII) Antibodies | ||||||||||||
End point description |
The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A subject 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. The analysis included all subjects who were FVIII inhibitor-negative at baseline and had received at least one dose of emicizumab during the study.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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)
|
||||||||||||
|
|||||||||||||
| Notes [32] - Only subjects who were FVIII inhibitor-negative at baseline were included. [33] - Only subjects who were FVIII inhibitor-negative at baseline were included. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
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 [34] | ||||||||||||||||||
End point description |
The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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)
|
||||||||||||||||||
| Notes [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
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 [35] | ||||||||||||||||||
End point description |
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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)
|
||||||||||||||||||
| Notes [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
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 [36] | ||||||||||||||||||
End point description |
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (≥) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration or change of dosing regimen were excluded.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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)
|
||||||||||||||||||
| Notes [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time [37] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time [38] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds per 12-Week Intervals Over Time [39] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds per 12-Week Intervals Over Time [40] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
|
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End point type |
Secondary
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End point timeframe |
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
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| Notes [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time [41] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
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End point type |
Secondary
|
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End point timeframe |
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
|
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| Notes [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time [42] | ||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants 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.
|
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End point type |
Secondary
|
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End point timeframe |
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
|
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| Notes [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Emicizumab: PK Run-In Cohort
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Reporting group description |
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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Emicizumab: Expansion Cohort
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Reporting group description |
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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Nov 2016 |
Protocol amendment 1 (version 2) included safety information on thromboembolic and thrombotic microangiopathy events observed in Study BH29884, as well as refinement of the study efficacy objectives. All subject enrollment commenced under this version of the protocol. |
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25 Jul 2017 |
Protocol amendment 2 (version 3) included updated information on safety findings of thrombotic microangiopathy in Study BH29884 and ways to mitigate risks. Key changes to the protocol that modified the study design or analyses in this amendment, along with a rationale for each change, are summarized: -Updated safety findings of thrombotic microangiopathy observed in Study BH29884; -Clarification on activated prothrombin complex concentrate (aPCC) use was added: aPCC in combination with emicizumab were to be avoided completely in patients who had the option of using other bypassing agents to treat bleeds; -Clarification about anti-fibrinolytics use was added: Anti-fibrinolytics in combination with recombinant activated factor VII were to be used with caution and avoided in combination with aPCC or Byclot; -Clarification regarding laboratory monitoring of coagulation status after any bypassing agent use was added; -Definition of "joint bleeds" was modified from the ISTH definition because of lack of clarity. The previous definition of "joint bleed" required the reporting of a combination of an “unusual sensation (aura) in the joint” and another joint bleed symptom (e.g., decreased range of motion) as per the bleed/medication questionnaire. The definition of "joint bleed" was redefined as bleeds with bleed type “joint bleed” reported with at least one of the symptoms of joint bleed as per the questionnaire except for the symptom “unusual sensation (aura) in the joint” reported alone; -New safety risk associated with emicizumab was added for life-threatening bleeding due to unreliable standard coagulation tests and inhibitors assays in the setting of emicizumab; -The sample size section was aligned with the approved statistical analysis plan. |
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25 May 2018 |
Protocol amendment 3 (version 4) has been amended to clarify the requirements for emicizumab up-titration, to revise the length of the study, and update the exploratory biomarker testing beyond Week 24. Changes to the protocol, along with a rationale for each change, are summarized: -To align with other studies in the emicizumab program, additional options for dose up-titration (if medically indicated) per investigator's judgment and in agreement with the Medical Monitor were added.; -The total length of the study has been extended from 20 months to 4 years to ensure patients continued access to emicizumab until its marketing authorization and commercial availability of emicizumab dosing regimen of every 4 weeks in individual countries.; -To further strengthen safety monitoring for special situations that may or may not result in an adverse event, instructions regarding the reporting of overdose (accidental or intentional), medication error, drug abuse, or drug misuse have been added.; -In order to assess coagulation status in patients on prophylactic emicizumab who received FVIII or bypassing agents and to assess the performance of different FVIII assays in measuring FVIII activity when emicizumab is present in blood with other coagulation factors, additional biomarker blood samples will be obtained from patients during hospitalization, e.g., because of surgery, severe bleedings, and at the time of hospital visits.; -To align with other studies in the emicizumab program, additional clarification has been added on adverse event reporting for patients who experience a worsening of hemophilia.; -Testing of the FIX antigen and FX antigen after Week 24 will no longer be conducted as no changes induced by emicizumab in these biomarkers have been observed across the emicizumab program. |
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20 Dec 2019 |
Protocol amendment 4 (version 5) has been amended primarily to extend study duration to enable collection of long-term safety and efficacy data; patients will be able to continue in the study until 5 years after the last patient is enrolled. Changes to the protocol, along with a rationale for each change, are summarized: -The duration of the study has been extended to enable the collection of additional safety and efficacy data, including data on adverse events and anti-drug antibody development. Thromboembolic events and thrombotic microangiopathy, both protocol-defined adverse events of special interest, have been reported when an average cumulative dose of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was co-administered with emicizumab. Continued collection of data related to concomitant hemophilia medications, emicizumab administration, and bleeds will contribute to a better understanding of these adverse events of special interest should they occur. The total length of the study has been extended, from screening of the first patient to the end of study, from 4 years to 6 years accordingly.; -The opportunity to switch to a preferred dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/ kg every 4 weeks) during study prolongation has been added to provide the same flexibility in choosing preferred dosing regimen as with
commercial product.; -The definition for end of study for an individual patient has been modified to include a switch to commercially available product.; -Text has been modified and relocated to account for the fact that special situations
(i.e., overdoses, medication errors, drug abuse, and drug misuse) are not required to be reported within 24 hours. Note that serious adverse events associated with special situations are still required to be reported within 24 hours. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution. | |||
