Clinical Trial Results:
A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors
Summary
|
|
EudraCT number |
2015-002866-21 |
Trial protocol |
DE ES GB PL FR IT |
Global end of trial date |
01 Dec 2020
|
Results information
|
|
Results version number |
v2(current) |
This version publication date |
12 Jun 2021
|
First version publication date |
04 Nov 2017
|
Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
BH29884
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02622321 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
F. Hoffmann-La Roche AG
|
||
Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
|
||
Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
|
||
Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-001839-PIP01-15 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
01 Dec 2020
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
01 Dec 2020
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
The main objective of this study was to evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents.
|
||
Protection of trial subjects |
The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Nov 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Australia: 4
|
||
Country: Number of subjects enrolled |
Costa Rica: 5
|
||
Country: Number of subjects enrolled |
France: 7
|
||
Country: Number of subjects enrolled |
Germany: 6
|
||
Country: Number of subjects enrolled |
United Kingdom: 5
|
||
Country: Number of subjects enrolled |
Italy: 9
|
||
Country: Number of subjects enrolled |
Japan: 12
|
||
Country: Number of subjects enrolled |
New Zealand: 3
|
||
Country: Number of subjects enrolled |
Poland: 9
|
||
Country: Number of subjects enrolled |
South Africa: 6
|
||
Country: Number of subjects enrolled |
Korea, Republic of: 1
|
||
Country: Number of subjects enrolled |
Spain: 6
|
||
Country: Number of subjects enrolled |
Taiwan: 4
|
||
Country: Number of subjects enrolled |
United States: 36
|
||
Worldwide total number of subjects |
113
|
||
EEA total number of subjects |
37
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
32
|
||
Adults (18-64 years) |
76
|
||
From 65 to 84 years |
5
|
||
85 years and over |
0
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Recruitment
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Screening details |
A total of 113 participants were enrolled in this study: 109 participants prior to the primary completion date plus a further 4 participants to Arm D of the study after the primary completion date. Participants in Arm A and Arm B were randomized in a 2:1 ratio; participants in Arm C and Arm D were enrolled without randomization. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Arm A: 1.5 mg/kg Emicizumab QW | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
RO5534262
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
ACE910
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Arm B (Control): No Prophylaxis | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
RO5534262
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
ACE910
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Arm C: 1.5 mg/kg Emicizumab QW | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
RO5534262
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
ACE910
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Arm D: 1.5 mg/kg Emicizumab QW | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Emicizumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
RO5534262
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
ACE910
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
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: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. [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: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. [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: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. [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: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. [5] - 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: Participants who withdrew from treatment were still considered to have completed the study if they subsequently completed the safety follow-up visit 24 weeks after discontinuation. For up-titration: After at least 24 weeks on prophylactic emicizumab, individual subjects who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm A: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B (Control): No Prophylaxis
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm C: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm D: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Arm A: 1.5 mg/kg Emicizumab QW
|
||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||
Reporting group title |
Arm B (Control): No Prophylaxis
|
||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||
Reporting group title |
Arm C: 1.5 mg/kg Emicizumab QW
|
||
Reporting group description |
Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||
Reporting group title |
Arm D: 1.5 mg/kg Emicizumab QW
|
||
Reporting group description |
Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||
Subject analysis set title |
Arm A (NIS): Previous Episodic Bypassing Agents
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm A participants who previously participated in NIS BH29768 (NCT02476942) and had received episodic bypassing agents during the NIS.
|
||
Subject analysis set title |
Arm C (NIS): Previous Prophylactic Bypassing Agents
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This arm includes data collected before entry into this study (assessed prospectively in a non-interventional study [NIS]) from Arm C participants who previously participated in NIS BH29768 (NCT02476942) and had received prophylactic bypassing agents during the NIS.
|
||
Subject analysis set title |
Arm B (Emi): 1.5 mg/kg Emicizumab QW
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This arm includes Arm B participants who switched to emicizumab prophylaxis after having first completed at least 24 weeks on study of no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study.
|
||
Subject analysis set title |
All Participants: 1.5 mg/kg Emicizumab QW
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set includes all enrolled participants on the study. For Arm B, it only includes participants starting after study Week 24 when they crossed over to first receive prophylactic treatment with emicizumab (i.e., Arm B (Emi): 1.5 mg/kg Emicizumab QW). Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.
|
|
|||||||||||||
End point title |
Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [1] | ||||||||||||
End point description |
The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. The Intent-to-treat (ITT) population was defined as all participants who were randomized to Arm A or Arm B.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
||||||||||||
Notes [1] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (less than [<] 9 or greater than or equal to [>/=] 9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.13
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.057 | ||||||||||||
upper limit |
0.277 | ||||||||||||
Notes [2] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [3] | ||||||||||||
End point description |
The number of all bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. The Intent-to-treat (ITT) population was defined as all participants who were randomized to Arm A or Arm B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
||||||||||||
Notes [3] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [4] | ||||||||||||
Method |
Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.102 | ||||||||||||
upper limit |
0.375 | ||||||||||||
Notes [4] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents [5] | ||||||||||||
End point description |
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
|
||||||||||||
Notes [5] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm A NIS) and on study (Arm A).
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm A (NIS): Previous Episodic Bypassing Agents
|
||||||||||||
Number of subjects included in analysis |
48
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [6] | ||||||||||||
Method |
Non-Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.055 | ||||||||||||
upper limit |
0.218 | ||||||||||||
Notes [6] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents [7] | ||||||||||||
End point description |
This was an intra-participant comparison of the ABRs for treated bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
|
||||||||||||
Notes [7] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm A NIS) and on study (Arm A).
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm A (NIS): Previous Episodic Bypassing Agents
|
||||||||||||
Number of subjects included in analysis |
48
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [8] | ||||||||||||
Method |
Non-Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.08
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.031 | ||||||||||||
upper limit |
0.198 | ||||||||||||
Notes [8] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [9] | ||||||||||||
End point description |
The number of treated joint bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Bleeds due to surgery/procedure were excluded. The Intent-to-treat (ITT) population was defined as all participants who were randomized to Arm A or Arm B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
||||||||||||
Notes [9] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.005 [10] | ||||||||||||
Method |
Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.11
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.025 | ||||||||||||
upper limit |
0.52 | ||||||||||||
Notes [10] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents [11] | ||||||||||||
End point description |
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm C participants who had previously received prophylactic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm C NIS) and on study (Arm C).
|
||||||||||||
Comparison groups |
Arm C: 1.5 mg/kg Emicizumab QW v Arm C (NIS): Previous Prophylactic Bypassing Agents
|
||||||||||||
Number of subjects included in analysis |
48
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [12] | ||||||||||||
Method |
Non-Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.23
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.119 | ||||||||||||
upper limit |
0.435 | ||||||||||||
Notes [12] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents [13] | ||||||||||||
End point description |
This was an intra-participant comparison of the ABRs for treated bleeds in Arm C participants who had previously received bypassing agent prophylaxis during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
This intra-participant comparison of ABR for treated bleeds between arms was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm C NIS) and on study (Arm C).
|
||||||||||||
Comparison groups |
Arm C: 1.5 mg/kg Emicizumab QW v Arm C (NIS): Previous Prophylactic Bypassing Agents
|
||||||||||||
Number of subjects included in analysis |
48
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0003 [14] | ||||||||||||
Method |
Non-Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.21
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.089 | ||||||||||||
upper limit |
0.486 | ||||||||||||
Notes [14] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [15] | ||||||||||||
End point description |
The number of treated spontaneous bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. The Intent-to-treat (ITT) population was defined as all participants who were randomized to Arm A or Arm B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [16] | ||||||||||||
Method |
Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.08
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.037 | ||||||||||||
upper limit |
0.154 | ||||||||||||
Notes [16] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
|||||||||||||
End point title |
Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [17] | ||||||||||||
End point description |
The number of treated target joint bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose. The Intent-to-treat (ITT) population was defined as all participants who were randomized to Arm A or Arm B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
53
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0002 [18] | ||||||||||||
Method |
Stratified Wald Test | ||||||||||||
Parameter type |
ABR Ratio | ||||||||||||
Point estimate |
0.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.009 | ||||||||||||
upper limit |
0.227 | ||||||||||||
Notes [18] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure. |
|
||||||||||||||||||||||||||||
End point title |
Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [19] | |||||||||||||||||||||||||||
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 were excluded. ITT population.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
|||||||||||||||||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [20] | |||||||||||||||||||||||||||
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 were excluded. ITT population.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
|||||||||||||||||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Percentage of Participants with 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis [21] | |||||||||||||||||||||||||||
End point description |
Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded. ITT population.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
|
|||||||||||||||||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis [22] | ||||||||||||
End point description |
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). ITT population. Number of subjects analyzed=adult participants with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 25
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Notes [23] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25 [24] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25 |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term. Analysis was performed using Analysis of Covariance (ANCOVA).
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
40
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0029 [25] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
21.55
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
7.89 | ||||||||||||
upper limit |
35.22 | ||||||||||||
Notes [25] - Statistical significance was controlled at a two-sided alpha level of 0.05. |
|
|||||||||||||
End point title |
Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis [26] | ||||||||||||
End point description |
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life. ITT population. Number of subjects analyzed=adult participants with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Notes [27] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25 [28] - Adult participants (≥18 years old) who responded to the questionnaire at Week 25 |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
40
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0019 [29] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
14.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
5.56 | ||||||||||||
upper limit |
22.45 | ||||||||||||
Notes [29] - Statistical significance was controlled at a two-sided alpha level of 0.05. |
|
|||||||||||||
End point title |
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis [30] | ||||||||||||
End point description |
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. ITT population. Number of subjects analyzed=participants with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 25
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Notes [31] - Participants who responded to the questionnaire at Week 25 [32] - Participants who responded to the questionnaire at Week 25 |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
46
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0171 [33] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-9.72
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-17.62 | ||||||||||||
upper limit |
-1.82 | ||||||||||||
Notes [33] - Statistical significance was controlled at a two-sided alpha level of 0.05. |
|
|||||||||||||
End point title |
EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis [34] | ||||||||||||
End point description |
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed). ITT population. Number of subjects analyzed=participants with available data for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 25
|
||||||||||||
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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||
|
|||||||||||||
Notes [35] - Participants who responded to the questionnaire at Week 25 [36] - Participants who responded to the questionnaire at Week 25 |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
|
||||||||||||
Comparison groups |
Arm A: 1.5 mg/kg Emicizumab QW v Arm B (Control): No Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
46
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0014 [37] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Adjusted Mean Difference | ||||||||||||
Point estimate |
-0.16
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.25 | ||||||||||||
upper limit |
-0.07 | ||||||||||||
Notes [37] - Statistical significance was controlled at a two-sided alpha level of 0.05. |
|
|||||||||||||||||||||||||||||||||||||
End point title |
Hemophilia-Specific Quality of Life – Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old) | ||||||||||||||||||||||||||||||||||||
End point description |
The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Baseline was defined as the last assessment prior to treatment. Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
Notes [38] - Adolescent participants (12-17 years old) [39] - Adolescent participants (12-17 years old) [40] - Adolescent participants (12-17 years old) [41] - None of the participants in Arm D were adolescents (12-17 years old). [42] - Adolescent participants (12-17 years old) |
|||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [43] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 were excluded.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [43] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [44] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 were excluded.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [44] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants [45] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 were excluded.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [45] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds per 12-Week Intervals Over Time, All Enrolled Participants | ||||||||||||||||||||||||||||||||||||||||||||||||
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 whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
|
||||||||||||||||||||||||||||||||||||||||||||||||
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, and 229-240 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Safety Summary of the Overall Percentage of Participants with at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated, only data before up-titration is included. aPCC = activated prothrombin complex concentrate; Hypersens.= hypersensitivity
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study [46] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample. ADA-positive samples were further analyzed for neutralizing capacity using a modified FVIII chromogenic assay; if also positive, they were considered neutralizing ADAs.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [46] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Plasma Trough Concentrations of Emicizumab at Specified Timepoints [47] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. Here, n=participants with available data for this endpoint at specified timepoints for each arm (Arms A, C, D, B (Emi), and All Participants, respectively). Because Arm B (Emi) participants switched to emicizumab prophylaxis after Week 24, Study Weeks for Arm B (Emi) are expressed relative to first emicizumab dose in the results table. Here, '99999' represents no data available because the measurements were all below the LLOQ; '999999' represents data not available because standard deviation not calculable for a single participant; '9999999' represents data not available because no samples were collected.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [47] - 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 main efficacy comparisons were planned for the randomized participants in Arm A: 1.5 mg/kg Emicizumab QW and Arm B: No Prophylaxis (control arm; prior to switch to emicizumab after 24 weeks). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety Population: All treated subjects grouped by treatment (including after up-titration). For Arm B, data collected with episodic bypassing agents (no prophyalxis) for first 24 weeks and with 1.5 mg/kg emicizumab QW after Week 24 are reported separately under Arm B (Control): No Prophylaxis and Arm B (Emi): 1.5 mg/kg Emicizumab QW, respectively.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm A: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B (Control): No Prophylaxis
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. The safety data reported here represents data collected from all Arm B participants during the first 24 weeks of 'no prophylaxis'; safety data from Arm B participants who switched to emicizumab after Week 24 are reported separately under Arm B (Emi): 1.5 mg/kg Emicizumab QW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B (Emi): 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
This arm includes Arm B participants who switched to emicizumab prophylaxis after having first completed at least 24 weeks on study of no prophylaxis. After Week 24, emicizumab was administered at a loading dose of 3 mg/kg once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Safety data reported here represents data collected during emicizumab treatment only. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm C: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm D: 1.5 mg/kg Emicizumab QW
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||
Substantial protocol amendments (globally) |
|||||||
Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
21 Apr 2016 |
The main changes were as follows:
- The planned number of participants to be enrolled in Arm C was increased from approximately 10-20 to 30-50, to enable the collection of additional safety and efficacy data from participants previously treated with prophylactic bypassing agents; - An additional emicizumab treatment arm (Arm D) was added, to enroll participants on episodic bypassing agents who had participated in NIS BH29768 but were unable to enroll in time to either Arm A or Arm B. This arm enabled the collection of additional efficacy, safety, pharmacokinetic, and pharmacodynamic data and plasma samples for the development and validation of in vitro diagnostic assay(s) suitable for participants receiving emicizumab treatment; - A secondary endpoint was added to compare all bleeds (i.e., treated with coagulation factors or not treated) as an additional assessment of efficacy given that some participants might have reported bleeds they did not treat; A planned interim analysis by the independent Data Monitoring Committee (iDMC), scheduled to occur during the execution of the primary efficacy period, was removed. This was due to the anticipated rapid completion of enrollment (i.e., approximately 7 months) and the very short time
interval between the interim and primary analyses; - An option was provided for participants who were approved to up-titrate their dose to potentially combine emicizumab volumes from more than 1 vial into 1 syringe to reduce the number of subcutaneous injections they required. |
||||||
30 Nov 2016 |
The main changes were as follows: - The permitted treatment for breakthrough bleeds was specified with guidance regarding the use of concomitant bypassing agents in participants being treated with emicizumab, as well as additional local and central laboratory assessments, in order to minimize the risk and monitor for thromboembolic and thrombotic microangiopathy events; - The use of short-term prophylaxis with aPCC concomitantly with emicizumab was prohibited, in order to minimize the risk of thromboembolic and thrombotic microangiopathy events; Microangiopathic hemolytic anemia/ thrombotic microangiopathy was newly classified as an adverse event of special interest (AESI), and an exclusion criterion to exclude participants at high risk to experience thrombotic microangiopathy was added; - A new efficacy objective to evaluate the clinical effect of emicizumab prophylaxis on the number of spontaneous bleeds over time (spontaneous bleed rate) was added, because this is a bleed category that is impacted by an effective treatment. |
||||||
Interruptions (globally) |
|||||||
Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |