Clinical trial NCT03020160
Conditions: Hemophilia A
Sponsor: Hoffmann-La Roche
Start date: 2017-01-30; Completion date: 2022-06-29
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, open-label, non-randomized study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK) run-in part followed by an expansion part.

Detailed description:

Arms: arm 1: Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks, with no loading dose, for at least 24 weeks. arm 2: Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks for at least 24 weeks.
Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: Emicizumab will be administered according to dose and schedule described in respective arms. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol Version 5 (20-Dec-2019), treatment duration was extended. During this study prolongation, participants had the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
F. Hoffmann-La Roche Ltd of Basel, Switzerland, and Chugai Pharmaceutical Co. Ltd.* of Tokyo, Japan, will 
act as co-sponsors of this global study. However, it may be implemented in individual countries by 
Roche’s local affiliates, including Genentech, Inc. in the United States, or Chugai Pharmaceutical Co. 
Ltd.* in South Korea, Taiwan, and Japan. The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is 
provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
*Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan. The specific details of the 
legal/regulatory entity within the relevant country are provided within the clinical trial agreement with the 
Investigator/Institution and the Clinical Trial Application with the Competent Authority.
Emicizumab—F. Hoffmann-La Roche Ltd
Protocol BO39182, Version 5
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III STUDY 
TO EVALUATE THE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF EMICIZUMAB GIVEN 
EVERY 4 WEEKS (Q4W) IN PATIENTS WITH 
HEMOPHILIA A
PROTOCOL NUMBER:
BO39182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-001094-33
IND NUMBER:
122954
NCT NUMBER:
NCT03020160
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd.
DATE FINAL:
Version 1: 24 March 2016
DATES AMENDED:
Version 2: 19 November 2016
Version 3:  25 July 2017
Version 4:  25 May 2018
Version 5:  See electronic date stamp below.
 
20-Dec-2019 01:00:41
Title
Approver's Name
Date and Time (UTC)


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PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Protocol BO39182 has been amended primarily to extend study duration to enable 
collection of long-term safety and efficacy data; patients will be able to continue in the 
study until 5 years after the last patient is enrolled.  Changes to the protocol, along with 
a rationale for each change, are summarized below:

The duration of the study has been extended to enable the collection of additional 
safety and efficacy data, including data on adverse events and anti-drug antibody 
development.  Thromboembolic events and thrombotic microangiopathy, both 
protocol-defined adverse events of special interest, have been reported when an 
average cumulative dose of 100 U/kg/24 hours of activated prothrombin complex 
concentrate (aPCC) was co-administered with emicizumab.  Continued collection of 
data related to concomitant hemophilia medications, emicizumab administration, and 
bleeds will contribute to a better understanding of these adverse events of special 
interest should they occur.  The total length of the study has been extended, from 
screening of the first patient to the end of study, from 4 years to 6 years accordingly
(Sections 3.1.2 and 3.2).

The opportunity to switch to a preferred dosing regimen (1.5 mg/kg weekly, 3 mg/kg 
every 2 weeks, or 6 mg/ kg every 4 weeks) during study prolongation has been 
added to provide the same flexibility in choosing preferred dosing regimen as with 
commercial product (Section 3.1.2 and 4.3.2.1).

The definition for end of study for an individual patient has been modified to include a 
switch to commercially available product (Section 3.2).
Additional changes made to the protocol are as follows:

The Background and Safety sections have been updated, including information 
regarding a fourth case of thromboembolic event observed in the Phase IIIb study 
MO39129 of prophylactic emicizumab in patients with congenital hemophilia A who 
have inhibitors (Sections 1.2.2, 1.3, and 5.1.2.3).

Language has been added to clarify that continued use of antiplatelet and 
anticoagulation treatment is allowed if deemed medically necessary (Section 4.4.2).

Text has been modified and relocated to account for the fact that special situations 
(i.e., overdoses, medication errors, drug abuse, and drug misuse) are not required to 
be reported within 24 hours (Sections 5.3.5.12 and 5.4).  Note that serious adverse 
events associated with special situations are still required to be reported within 
24 hours.

A global change has been made to update the Medical Monitor and emergency 
contact information (Section 5.4.1).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable) (Section 7.6).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).


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
Language has been revised to clarify that data posting will include clinical trial 
registries and to clarify that redacted Clinical Study Reports and other summary 
reports will be made available upon request (Section 9.6).

Appendix 8 (Anaphylaxis Precautions) has been added for alignment with the Roche 
protocol template.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol.


Emicizumab—F. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 22
1.1
Background on Hemophilia A ................................................ 22
1.1.1
Management.......................................................................... 22
1.2
Background on Emicizumab.................................................. 25
1.2.1
Molecule and Preclinical Data ............................................... 25
1.2.2
Clinical Experience ................................................................ 26
1.3
Study Rationale and Benefit-Risk Assessment...................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 31
2.1
Pharmacokinetic Run-In Phase ............................................. 31
2.1.1
Objectives.............................................................................. 31
2.2
Expansion Phase................................................................... 31
2.2.1
Efficacy Objectives ................................................................ 31
2.2.2
Safety Objectives................................................................... 32
2.2.3
Pharmacokinetic Objective .................................................... 32
2.2.4
Exploratory Pharmacodynamic Biomarker 
Objective................................................................................ 32
3.
STUDY DESIGN......................................................................................... 33
3.1
Description of the Study......................................................... 33
3.1.1
PK Run-In Part ...................................................................... 33
3.1.2
Expansion Part ...................................................................... 33
3.2
End of Study and Length of Study......................................... 37
3.3
Rationale for Study Design.................................................... 37
3.3.1
Rationale for Emicizumab Dose and Schedule...................... 38
3.3.2
Rationale for Patient Population ............................................ 40
3.3.3
Rationale for Biomarker Assessments................................... 40
3.3.4
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 41


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4.
MATERIALS AND METHODS .................................................................... 42
4.1
Patients.................................................................................. 42
4.1.1
Inclusion Criteria.................................................................... 42
4.1.2
Exclusion Criteria................................................................... 43
4.2
Method of Treatment Assignment.......................................... 44
4.3
Study Treatment.................................................................... 45
4.3.1
Formulation, Packaging, and Handling.................................. 45
4.3.2
Dosage, Dose Adjustments, Administration, and 
Compliance............................................................................ 45
4.3.2.1
Subcutaneous Emicizumab ................................................... 45
4.3.3
Investigational Medicinal Product Accountability ................... 47
4.3.4
Post-Study Access to Emicizumab........................................ 47
4.4
Concomitant Therapy ............................................................ 48
4.4.1
Permitted Therapy................................................................. 48
4.4.2
Prohibited Therapy ................................................................ 49
4.5
Study Assessments ............................................................... 50
4.5.1
Informed Consent Forms and Screening Log........................ 51
4.5.2
Medical History and Demographic Data ................................ 51
4.5.3
Physical Examinations........................................................... 51
4.5.4
Vital Signs.............................................................................. 51
4.5.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 52
4.5.5.1
Pharmacokinetic Samples ..................................................... 53
4.5.6
Electrocardiograms................................................................ 54
4.5.7
Patient-Reported Outcomes .................................................. 54
4.5.8
Bleed Definitions.................................................................... 56
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 57
4.6.1
Patient Discontinuation.......................................................... 57
4.6.2
Study Treatment Discontinuation........................................... 58
4.6.3
Study and Site Discontinuation.............................................. 58
5.
ASSESSMENT OF SAFETY....................................................................... 59
5.1
Safety Plan ............................................................................ 59
5.1.1
Patient Selection.................................................................... 59


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5.1.2
Risks Associated with Emicizumab ....................................... 59
5.1.2.1
Injection-Site Reactions......................................................... 59
5.1.2.2
Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid Reaction......................................................... 59
5.1.2.3
Hypercoagulation and Thromboembolic Events .................... 60
5.1.2.4
Thrombotic Microangiopathy ................................................. 61
5.1.2.5
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
Associated with Emicizumab ................................................. 62
5.1.3
Management of Specific Adverse Events .............................. 63
5.1.4
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab .......................................................... 64
5.2
Safety Parameters and Definitions ........................................ 64
5.2.1
Adverse Events ..................................................................... 64
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 65
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 66
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 66
5.3.1
Adverse Event Reporting Period ........................................... 66
5.3.2
Eliciting Adverse Event Information....................................... 67
5.3.3
Assessment of Severity of Adverse Events ........................... 67
5.3.4
Assessment of Causality of Adverse Events ......................... 67
5.3.5
Procedures for Recording Adverse Events............................ 68
5.3.5.1
Injection-Site Reactions......................................................... 68
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 68
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 69
5.3.5.4
Persistent or Recurrent Adverse Events................................ 69
5.3.5.5
Abnormal Laboratory Values ................................................. 69
5.3.5.6
Abnormal Vital Sign Values ................................................... 70
5.3.5.7
Abnormal Liver Function Tests.............................................. 71
5.3.5.8
Deaths ................................................................................... 71
5.3.5.9
Preexisting Medical Conditions.............................................. 71


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5.3.5.10
Lack of Efficacy or Worsening of Hemophilic 
Bleeds.................................................................................... 72
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 72
5.3.5.12
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 73
5.3.5.13
Patient-Reported Outcome Data ........................................... 75
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 75
5.4.1
Emergency Medical Contacts................................................ 76
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 76
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 76
5.4.2.2
Events That Occur after Study Drug Initiation........................ 76
5.4.3
Reporting Requirements for Pregnancies.............................. 77
5.4.3.1
Pregnancies in Female Patients............................................ 77
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 77
5.4.3.3
Abortions ............................................................................... 77
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 77
5.5
Follow-Up of Patients after Adverse Events .......................... 77
5.5.1
Investigator Follow-Up........................................................... 77
5.5.2
Sponsor Follow-Up ................................................................ 78
5.6
Adverse Events that Occur after the Adverse 
Event Reporting Period.......................................................... 78
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and
Ethics Committees................................................................. 78
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 79
6.1
Determination of Sample Size ............................................... 79
6.2
Summaries of Conduct of Study............................................ 79
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 79
6.4
Efficacy Analyses .................................................................. 79
6.4.1
Efficacy Endpoints................................................................. 79
6.4.2
Patient-Reported Outcomes .................................................. 80
6.5
Safety Analyses..................................................................... 80


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6.6
Pharmacokinetic Analyses..................................................... 81
6.7
Immunogenicity Analyses...................................................... 82
6.8
Exploratory Analyses............................................................. 82
6.9
Interim analysis...................................................................... 82
6.9.1
Planned Interim Analysis ....................................................... 82
6.9.2
Optional Interim Analysis....................................................... 82
7.
DATA COLLECTION AND MANAGEMENT ............................................... 82
7.1
Data Quality Assurance......................................................... 82
7.2
Electronic Case Report Forms............................................... 83
7.3
Electronic Patient-Reported Outcome Data........................... 83
7.4
Source Data Documentation.................................................. 84
7.5
Use of Computerized Systems .............................................. 84
7.6
Retention of Records............................................................. 84
8.
ETHICAL CONSIDERATIONS.................................................................... 85
8.1
Compliance with Laws and Regulations ................................ 85
8.2
Informed Consent.................................................................. 85
8.3
Institutional Review Board or Ethics Committee.................... 86
8.4
Confidentiality........................................................................ 87
8.5
Financial Disclosure .............................................................. 87
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 87
9.1
Study Documentation ............................................................ 87
9.2
Protocol Deviations................................................................ 87
9.3
Site Inspections ..................................................................... 88
9.4
Administrative Structure......................................................... 88
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 88
9.6
Protocol Amendments ........................................................... 89
10. REFERENCES ........................................................................................... 90


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LIST OF TABLES
Table 1
Guidelines for Management of Specific Adverse Events ............ 63
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 67
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 34
Figure 2
Simulated Plasma Emicizumab Concentration over Time 
(Q4W Dosing) ............................................................................. 39
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................... 95
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples................................................................... 104
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of 
Laboratory Abnormalities and Adverse Events ......................... 111
Appendix 4
Clinical Criteria for Diagnosing Anaphylaxis.............................. 118
Appendix 5
Haemo-QoL-SF (United States/English) ................................... 119
Appendix 6
Haem-A-QoL (United States/English) ....................................... 121
Appendix 7
EQ-5D-5L (United Kingdom/English) ........................................ 128
Appendix 8
Anaphylaxis Precautions........................................................... 130


EmicizumabF. Hoffmann-La Roche Ltd
10/Protocol BO39182, Version 5
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL STUDY TO 
EVALUATE THE EFFICACY, SAFETY, 
PHARMACOKINETICS AND 
PHARMACODYNAMICS OF EMICIZUMAB GIVEN 
EVERY 4 WEEKS (Q4W) IN PATIENTS WITH 
HEMOPHILIA A
PROTOCOL NUMBER:
BO39182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-001094-33
IND NUMBER:
122954
NCT NUMBER:
NCT03020160
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
your local study monitor.


EmicizumabF. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III STUDY TO 
EVALUATE THE EFFICACY, SAFETY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF EMICIZUMAB GIVEN EVERY 
4 WEEKS (Q4W) IN PATIENTS WITH HEMOPHILIA A
PROTOCOL NUMBER:
BO39182
VERSION NUMBER:
5
EUDRACT NUMBER:
2016-001094-33
IND NUMBER:
122954
NCT NUMBER:
NCT03020160
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase III
INDICATION:
Hemophilia A
SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd.
Objectives and Endpoints
Pharmacokinetic Run-In Phase Objectives
The objectives of the pharmacokinetic run-in are as follows:

To investigate the pharmacokinetics of emicizumab after single and multiple (every 4 weeks 
[Q4W]) subcutaneous (SC) administration of 6 mg/kg

To assess the safety and tolerability of emicizumab after Q4W SC administration of 6 mg/kg 

To explore the prophylactic effect of emicizumab in maintaining adequate control of 
bleeding

To investigate the effect of emicizumab on pharmacodynamic (PD) markers including, but 
not limited to, aPTT, thrombin generation, and factor VIII (FVIII) activity
Expansion Phase
Efficacy Objectives
The efficacy objectives are as follows:

To evaluate the efficacy of prophylactic emicizumab in maintaining adequate control of 
bleeding

To evaluate the clinical effect of prophylactic emicizumab on the number of joint bleeds over 
time

To evaluate the clinical effect of prophylactic emicizumab on the number of target joint 
bleeds over time (target joints are defined as joints with 3 bleeds occurring in the same 
joint over the last 24 weeks prior to study entry)

To evaluate the clinical effect of prophylactic emicizumab on the number of all bleeds 
(i.e., those treated and untreated with coagulation factors) over time

To evaluate the clinical effect of prophylactic emicizumab on the number of spontaneous 
bleeds over time (spontaneous bleed rate)


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
To evaluate the health-related quality of life (HRQoL) of patients according to Haem-A-QoL 
(18y) or Haemo-QoL_SF (ages 1217) scores after 24 weeks 

To evaluate the health status of patients according to EuroQoL 5-Dimension, 5Level
Questionnaire (EQ-5D-5L) scores after 24 weeks 

To assess preference for emicizumab regimen compared with previous regimen used 

To assess the number of days away from school/work

To assess the number of days hospitalized
Safety Objectives
The safety objectives of this study are to evaluate the overall safety of emicizumab given Q4W 
in patients with hemophilia A based on the following endpoints:

The incidence and severity of adverse events

The incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs

Incidence of laboratory abnormalities

Incidence and severity of injection-site reactions

Incidence of adverse events leading to drug discontinuation

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events

Incidence of thrombotic microangiopathy

The incidence and clinical significance of anti-emicizumab antibodies

The incidence of de novo development of FVIII inhibitors (non-inhibitor population)
Pharmacokinetic Objective
The pharmacokinetic (PK) objective of this study is as follows:

To characterize the pharmacokinetics of multiple Q4W SC doses of 6 mg/kg emicizumab 
Exploratory Pharmacodynamic Biomarker Objective
The exploratory PD biomarker objective is as follows:

To investigate the effect of Q4W doses of emicizumab on PD parameters, including, but not 
limited to, aPTT, thrombin generation and FVIII activity at timepoints throughout the study
Study Design
Description of Study
Study BO39182 is a multicenter, open-label, non-randomized study designed to investigate the 
efficacy, pharmacokinetics, safety, and pharmacodynamics of emicizumab (6 mg/kg) 
administered in a Q4W dosing regimen.  Patients with hemophilia A with or without inhibitors 
against FVIII will be enrolled.  The study consists of two parts:  a PK run-in part followed by an 
expansion part.
PK Run-In-Part
In the PK run-in part, a full PK profile will be measured in the first 6 enrolled patients during the 
first 4 weeks to characterize the pharmacokinetics of a single SC dose of 6 mg/kg emicizumab 
in patients with hemophilia A.  After the first and second emicizumab administration, an intense 
PK sampling will occur.  A reduced PK sampling schedule will be used to characterize repeated 
Q4W SC administration from Week 9 to Week 21.  After the sixth injection at Week 21, PK 
sampling frequency will be increased to characterize steady-state pharmacokinetics 
(see protocol).
An analysis of the data collected when all 6 patients in the PK run-in cohort have been followed 
for at least 6 weeks will be performed to assess whether the mean PK profile is as predicted 
(i.e., lower limit of 95% CI of the predicted mean PK profile) after repeated 6 mg/kg SC 
administration Q4W.  In addition to PK, safety will be assessed in order to establish whether the 


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expansion cohort can be opened.  This analysis will be conducted by a Roche internal group of 
representatives from Clinical Pharmacology, Clinical Science, Clinical Safety, and Statistics; no 
formal Internal Monitoring Committee (IMC) will be set up.
Expansion Part
An expansion phase will be conducted to further investigate the efficacy, pharmacokinetics, 
safety, and pharmacodynamics in a cohort of 40 patients.  These patients will start with loading 
doses of 3 mg/kg QW 4, followed by a maintenance dose of 6 mg/kg Q4W for at least 
24 weeks overall.  These patients will undergo PK sampling to investigate trough concentrations 
(Ctrough) and samples (predose) will be drawn as per the schedule of assessments (see protocol).
The primary analysis (descriptive analyses of the study objectives) will be conducted either after 
the last enrolled patient completes the 24-week treatment period, is lost to follow-up, or has 
withdrawn, whichever occurs first.  
During the study, individual bleeds will be captured as they occur while HRQoL, health status, 
patients’ preference and days of school or work missed will be assessed as outlined in the 
schedule of assessments in protocol. Patients (or their legally authorized representative) will be 
asked on a weekly basis to record via their electronic, handheld device whether a bleed has 
occurred and whether treatment for a bleed or treatment to prevent a bleed has been given.
Physical examinations, vital signs, ECG, and laboratory assessments will be performed as 
detailed in the schedule of assessments (see protocol) and will be the same for all patients 
receiving emicizumab, regardless of whether they are enrolled in the PK run-in cohort or the 
expansion cohort.  Adverse events will be captured on an ongoing basis, as they occur during 
the study.
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have already 
occurred).  There is clinical experience in the ongoing Phase I/II clinical studies with the 
treatment of over 60 breakthrough bleeds in patients receiving emicizumab with either FVIII or 
bypassing agents.  FVIII, aPCC, or recombinant activated factor VII (rFVIIa) do not interfere with 
emicizumab PK assessments and no safety signals have been observed when breakthrough 
bleeds were treated with standard-of-care regimens during Phase I/II studies.  However, in the 
ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with FVIII 
inhibitors), 3 events of TMA and 2 thromboembolic events were observed in patients who 
concomitantly used repeated doses of aPCC for the treatment of breakthrough bleeds.  
Therefore, it is recommended that breakthrough bleeds in the inhibitor population are treated 
with rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should be 
avoided. In addition, caution should be taken if anti-fibrinolytics are used in conjunction with 
rFVIIa in patients who are receiving emicizumab, and the use of anti-fibrinolytics is prohibited in 
conjunction with aPCC or Byclot.
Therefore, a washout period of 72 hours prior to the first emicizumab dose in this study is 
required for patients receiving prior aPCC or Byclot.  Also a washout period of 72 hours for 
patients who were previously receiving ITI is required prior to the first emicizumab 
administration.  Patients may require dosing with FVIII or for the treatment of potential 
breakthrough bleeds (see protocol), especially for the time period until steady-state 
concentrations of emicizumab have been reached.
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation) will be collected as 
per the schedule of assessments and always coupled with a PK assessment for days where PK 
and PD samples are to be drawn.  As values for many tests are normalized by even low plasma 
concentrations of emicizumab, a variety of assay formats (one-stage, chromogenic) and 
modifications (pre-dilution of patient plasma) will be investigated for assessment of PD 
response at higher emicizumab plasma concentrations.  It is not expected that these biomarkers 
will be used to guide the selection of patients to be treated with emicizumab.  However, these 
biomarkers may be used to identify a future assay for the monitoring of emicizumab activity.  In 
addition, factor IX (FIX) and factor X (FX) antigen levels will be monitored.
Biomarkers related to thromboembolism (e.g., D-dimer, prothrombin fragment 1.2) and 
immunologic biomarkers (i.e., anti-emicizumab antibodies and anti-FVIII antibodies) will be 
measured as per the schedule of assessments (see protocol). 
Breakthrough bleeds will be treated with appropriate coagulation products with either FVIII 
(non-inhibitor patients) or rFVIIa (inhibitor patients) at the lowest expected dose to achieve 


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hemostasis and captured as they occur.  When a bleed has occurred, patients (or their legally 
authorized representative) will be required to report bleed information, including site of bleed, 
type of bleed, time of each individual bleed (day, start time), symptoms of bleed, and treatment 
for bleed (e.g., other than emicizumab in case of breakthrough bleeds).  The reason for the use 
of coagulation products (e.g., FVIII or rFVIIa) will be documented (e.g., bleeding, preventative 
dose before activity).  Thorough documentation of the treatments for bleeds will be requested, 
including agent, start time, dose, route of administration, and number of infusions needed to 
treat the bleed.  For patients with inhibitors against FVIII who receive bypassing agents, local 
and central laboratory assessments are required to monitor the risk for thromboembolic events 
or TMA as per the schedule of assessments. 
All patients, irrespective of the cohort assigned, who continue to derive clinical benefit will be 
given the opportunity to continue receiving prophylactic emicizumab either within this study or 
as part of a future extension study according to Roche policy on post-study drug access.  After 
24 weeks on prophylactic emicizumab, all patients will be able to continue on their 6 mg/kg 
Q4W maintenance dose or may be provided the option to increase their dose to 3 mg/kg QW if 
they meet protocol-defined criteria of suboptimal response.  Suboptimal response is defined as 
follows: 

2 qualifying bleeds within 24 weeks while on prophylactic emicizumab
Qualifying bleeds are defined as spontaneous, verified by investigator (e.g., by imaging or 
physical examination), and occurring while on prophylactic emicizumab at steady state (after the 
Week 5 visit for expansion cohort/after Week 17 visit for PK run-in cohort).  These patients must 
receive approval from the Medical Monitor to increase their dose to 3 mg/kg QW.
If the investigator believes that a specific patient warrants dose escalation based on a different 
reason, he or she may discuss the case with the Medical Monitor for consideration and potential 
approval.
Upon implementation of protocol Version 5, treatment duration will be extended until 5 years 
after the last patient is enrolled to enable the collection of additional safety and efficacy data.  
During this study prolongation, each patient may choose a preferred emicizumab dosing 
regimen among those permitted (i.e., emicizumab 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg 
Q4W) and continue on that dosing regimen until discontinuation from the study.  
Instructions for switching the dosing regimen are outlined in the protocol.
Patients who discontinue emicizumab will be followed for 24 weeks after the last emicizumab 
dose.
Number of Patients
Approximately 46 patients with congenital hemophilia A previously treated with either FVIII or 
bypassing agents will be enrolled in the study (6 patients in the PK run-in phase and 40 patients 
in the expansion phase). 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (consent/assent will be taken as appropriate)

Aged 12 years

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the patient-reported outcome (PRO) questionnaires 
and bleed diaries through the use of an electronic device 

Body weight 40 kg at screening 

Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors 

Patients using rFVIIa or willing to switch to rFVIIa as primary bypassing agent for the 
treatment of breakthrough bleeds

FVIII inhibitor test during screening with titer results available prior to first administration of 
study drug


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
Patients without FVIII inhibitors (0.6 BU/mL; 1.0 BU/mL only for laboratories with an 
historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) who completed successful 
ITI must have done so at least 5 years before screening and must have no evidence of 
inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor 0.6 
BU/mL (1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor 
detection of 1.0 BU/mL) since ITI

For patients to be enrolled into PK run-in cohort:
Current episodic treatment (FVIII or bypassing agents) at the time of entry into this 
study and documentation of details of episodic treatment for at least 24 weeks prior to 
entry into this study

For patients to be enrolled into the expansion cohort:
Documentation of details of prophylactic or episodic treatment (FVIII or bypassing 
agents) and the number of bleeding episodes for at least 24 weeks prior to entry into 
this study
For patients on an episodic regimen, 5 bleeds in the prior 24 weeks, regardless of 
inhibitor status

Adequate hematologic function, defined as a platelet count 100,000/L and hemoglobin 
8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5 age-adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT 3 age-adapted ULN 
at the time of screening, and no clinical signs or known laboratory/radiographic evidence 
consistent with cirrhosis 

Adequate renal function, defined as serum creatinine 2.5 age-adapted ULN and 
creatinine clearance 30 mL/min by Cockcroft-Gault formula 

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use highly effective contraceptive methods that result in a 
failure rate of 1% per year during the treatment period and for at least 5 elimination 
half-lives (24 weeks) after the last dose of study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (1 year of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus)
Examples of highly effective contraceptive methods with a failure rate of 1% per year 
include proper use of combined oral or injected hormonal contraceptives, bilateral 
tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods such as a 
condom and a cervical cap) may be combined to achieve a failure rate of 1% per 
year.  Barrier methods must always be supplemented with the use of a non-lipid-based 
spermicide
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods for contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

Ongoing or planned ITI therapy; patients in whom ITI has failed will be eligible with a 
72-hour washout period prior to the first emicizumab administration.

History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment

Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment


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
Previous (within the last 12 months) or current treatment for thromboembolic disease (with 
the exception of previous catheter-associated thrombosis for which anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease

Other conditions (e.g., certain autoimmune diseases) that may currently increase the risk of 
bleeding or thrombosis

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 

Known HIV infection with CD4 counts 200 cells/L
HIV infection with CD4 counts 200 cell/L permitted

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy

Concomitant disease, condition, significant abnormality on screening evaluations or 
laboratory tests, or treatment that could interfere with the conduct of the study, or that would, 
in the opinion of the investigator/co-investigator, pose an additional unacceptable risk in 
administering study drug to the patient  

Receipt of any of the following:
Emicizumab in a prior investigational study
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter
Any other investigational drug currently being administered or planned to be 
administered 

Inability to comply with the study protocol in the opinion of the investigator

Pregnancy or lactation or intention to become pregnant during the study

Women with a positive serum pregnancy test result within 7 days prior to initiation of study 
drug
End of Study
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (last patient last visit [LPLV]), as defined by any of the following criteria:

Completion of at least 24 weeks of emicizumab treatment and either transfer to a separate 
extension study to receive further emicizumab as per Roche Global Policy on Continued 
Access to Investigational Medicinal Products or switch to commercially available product
OR

Completion of the end-of-study safety follow-up visit 24 weeks after discontinuing 
emicizumab
OR

Withdrawal of consent 
OR

Lost to follow-up
Length of Study
The length of the study for an individual patient will be: 

Screening period up to 4 weeks

Treatment and observation period at least 24 weeks 

For patients who discontinue emicizumab treatment, safety follow-up visit 24 weeks after 
discontinuing emicizumab


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The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
The emicizumab regimen being tested is 3 mg/kg QW for 4 weeks followed by 6 mg/kg Q4W 
subcutaneously for 24 weeks.  All patients with suboptimal control may have the option to 
increase the dose to 3 mg/kg QW after 24 weeks, with approval from the Medical Monitor
Non-Investigational Medicinal Products
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening to the study completion/discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF page. 
Concomitant use of the following drugs and therapies will be permitted:

For patients in the expansion cohort who are on FVIII prophylaxis, they may continue their 
regular FVIII prophylaxis until the second emicizumab loading dose in order to avoid bleeds 
before adequate emicizumab level is reached.  Concomitant routine FVIII prophylaxis is not 
otherwise permissible during the study.

Drugs intended to control bleeds, including FVIII concentrates (non-inhibitor patients) or 
rFVIIa (inhibitor patients), should be used at the lowest dose expected to achieve 
hemostasis.  Given that circulating emicizumab may increase patients’ coagulation potential, 
the doses required to achieve hemostasis may be lower than the FVIII or bypassing agent 
doses used prior to starting the study.
Caution should be taken for patients who are using rFVIIa (e.g., consideration of using no 
more than 90 g/kg rFVIIa as an initial dose).
Use of aPCC in combination with emicizumab should be avoided completely in patients 
who have the option of using other bypassing agents to treat bleeds.  In the event that 
aPCC is the only available bypassing agent, the lowest dose expected to achieve 
hemostasis should be prescribed with no more than 50 units/kg of aPCC to be administered 
as an initial dose.  For patients receiving aPCC prior to study entry, a washout period of 
72 hours prior to first emicizumab dosing is required.
Other bypassing agents (e.g., Byclot) should be avoided.  In cases where such agents are 
the only available bypassing agent, the lowest dose expected to achieve hemostasis should 
be prescribed, with no more than the lowest dose described in the prescribing information 
to be administered as an initial dose (e.g., no more than 60 g/kg of Byclot).  For patients 
receiving Byclot prior to study entry, a washout period of 72 hours prior to first emicizumab 
dosing is required.
Exact dose and schedule of FVIII or bypassing agents should be discussed with patients at 
the beginning and throughout the study.  Repeated dosing of FVIII, rFVIIa, aPCC, or other 
bypassing agents should be performed only under medical supervision and consideration 
should be given to verifying bleeds prior to repeated dosing.  For rFVIIa, aPCC, and other 
bypassing agents, laboratory monitoring by additional local and central laboratory 
assessments should be performed as per the schedule of assessments.

Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab.

Drugs and therapies to treat adverse events and use of topical antiseptics, anesthetics, eye 
drops, and so on, that are not considered to result in systemic exposure

Drugs to treat an existing medical condition ongoing at study entry that do not violate the 
eligibility criteria (e.g., anti-retroviral therapy for HIV infections)


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Statistical Methods
Primary Analysis
The efficacy objective is to evaluate the clinical effect of 6 mg/kg emicizumab Q4W based on 
the number of bleeds over time. 
The analyses will be performed using a negative binomial regression model, which accounts for 
different follow-up times, with the patient’s number of bleeds as a function of the time that each 
patient stays in the study included as an offset in the model.  
The number of bleeds will be also annualized (Annualized Bleeding RateABR) for each 
patient using the following formula: 
In case the negative binomial model does not converge the above formula will be used as the 
sole method of analysis.
The clinical effect of prophylactic emicizumab on the number of bleeds, joint bleeds, target joint 
bleeds, spontaneous bleeds and all bleeds (i.e., those treated and untreated with coagulation 
factors) over time will be evaluated.
The number of bleeds, sites of bleeds, and types of bleeds will be summarized for all patients 
and listed for each patient individually.  Several exploratory analyses will be conducted to 
characterize the type, location, duration, frequency, and pattern of bleeds.  For continuous 
endpoints, descriptive statistics will be calculated and categorical endpoints will be 
characterized through frequency tables. 
The primary final analysis will be performed 24 weeks after the last enrolled patient started 
treatment or has withdrawn prematurely, whichever occurs first.  
Safety Analyses
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including complete 
blood count with differential and platelet counts), ECGs, vital signs, anti-drug antibodies (ADAs), 
and de novo anti-FVIII inhibitors.
To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate thesaurus level, 
and toxicity grade.  
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading scale.
Pharmacokinetic Analyses
PK Run-In Cohort
PK parameters of emicizumab will be estimated using non-compartmental methods after the 
first and the sixth injections and include:

Tmax: Time to maximum observed plasma concentration

Cmax: Maximum observed plasma concentration

AUC: Area under the plasma concentrationtime curve over a dosing interval 

AUC0-inf: Area under the plasma concentrationtime curve between time zero (predose) 
extrapolated to infinity (only for the first injection)

t½: Apparent terminal half-life

CL/F and CLss/F: Apparent Clearance
Concentration data and calculated PK parameters for emicizumab will be presented in individual 
listings, summary tables (including descriptive statistics: mean, geometric means, medians, 
ranges, standard deviations, and coefficients of variation) and graphs (including concentration 
versus time plots on linear and semi-logarithmic scales) as appropriate.  


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Expansion Cohort
For all patients, predose (trough) plasma concentrations of emicizumab will be presented 
descriptively, including arithmetic and geometric means, median, range, standard deviations, 
and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
gender, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as area under the curve, will be derived from individual post-hoc predictions.  
Data may be pooled with data from previous Phase I/II studies and completed Phase III studies.  
These analyses will be reported in a dedicated report.
Immunogenicity Analyses
The immunogenicity analyses will include patients with at least one predose and one postdose 
ADA assessment.
The numbers and proportions of ADA-positive patients and ADA-negative patients during both 
the treatment and follow-up periods will be summarized.  Patients are considered to be ADA 
positive if they are ADA negative at baseline but develop an ADA response following study drug 
administration (treatment-induced ADA response), or if they are ADA positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater (i.e., 0.60 titer units) 
than the titer of the baseline sample (treatment-enhanced ADA response).  Patients are 
considered to be ADA negative if they are ADA negative at baseline and all post-baseline 
samples are negative, or if they are ADA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints will be 
analyzed and reported descriptively via subgroup analyses.
Exploratory Analyses
PD parameters (e.g., aPTT, parameters derived from thrombin generation, FVIII activity) will be 
presented using summary statistics, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation.
Determination of Sample Size
The sample size of 6 patients for the PK run-in cohort is considered appropriate to assess 
pharmacokinetics and safety to allow for an informed decision to open the subsequent 
expansion cohort with 40 additional patients.
The overall sample size of 40 patients in the expansion cohort is based primarily on clinical 
considerations taking into account the limited number of patients with hemophilia A. 
Planned Interim Analysis
An analysis of pharmacokinetics and safety will occur when the first 6 patients have been on 
treatment for 6 weeks.  On the basis of the results for pharmacokinetics and safety 
(e.g., lower limit of 95% CI of the predicted mean PK profile, no severe unexpected safety 
findings), the study will proceed with the expansion cohort.
This analysis will be conducted by a Roche internal group of representatives from Clinical 
Pharmacology, Clinical Science, Clinical Safety and Statistics; no formal IMC will be set up.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
annualized bleeding rate
ADA
anti-drug antibody
aHUS
atypical hemolytic uremic syndrome
aPCC
activated prothrombin complex concentrate
AUC
area under the concentrationtime curve
AUC
area under the concentrationtime curve over a dosing 
interval
Cavg,ss
average steady-state concentration
Cmax
maximum concentration observed
Ctrough
steady-state concentration at end of dosing interval
CVAD
central venous access device
cyFcR
cynomolgus monkey Fcreceptor
cyFcRn
cynomolgus monkey neonatal Fc receptor
EC
Ethics Committee
eCRF
electronic Case Report Form
EQ-5D-5L
European Quality of Life 5-Dimension, 5-Level 
questionnaire
EDC
electronic data capture
FDA
Food and Drug Administration
FEIBA
Factor Eight Inhibitor Bypassing Activity
FIX
factor IX
FIX:Ag
factor IX antigen
FIXa
activated factor IX
FVIII
factor VIII
FX
factor X
FX:Ag
factor X antigen
HCP
healthcare provider
hFcR
human Fcreceptor
hFcRn
human neonatal Fc receptor
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IgG4
immunoglobulin G4
IMP
investigational medicinal product
IND
Investigational New Drug (application)


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Abbreviation
Definition
IRB
Institutional Review Board
ITI
immune tolerance induction
IV
intravenous
LPLV
last patient, last visit
MAD
multiple ascending dose
MN
mobile nursing
MRI
magnetic resonance imaging
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic
PK
pharmacokinetic
PRO
patient-reported outcome
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
QW
weekly
Q2W
every 2 weeks
Q4W
every 4 weeks
rFVIII
recombinant factor VIII
rFVIIa
recombinant activated factor VII
SAD
single ascending dose
t1/2
half-life
TMA
thrombotic microangiopathy
tmax
time to maximum plasma concentration
ULN
upper limit of normal
VAS
visual analog scale


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1.
BACKGROUND
1.1
BACKGROUND ON HEMOPHILIA A 
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; 
Franchini and Mannucci 2013).  
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the 
Xq28 region of the X chromosome.  It occurs almost exclusively in men having one 
defective copy of the relevant gene on their X chromosome.  Because an affected male 
will transmit a normal Y chromosome to all his sons and an abnormal X chromosome to 
all his daughters, his sons will not be affected and all of his daughters will be carriers.  
The offspring of a female carrier will have a 50% chance to receive a mutated FVIII gene; 
thus, hemophilia A will be transmitted to half the male infants and half of female infants 
will be carriers.  Females who are carriers of hemophilia A may experience bleeding 
symptoms similar to those seen in men with mild hemophilia A, as approximately 10% of 
carriers have a FVIII activity less than 35% (Plug and Mauser-Bunschoten 2006).  Rarely, 
women can have more severe bleeding symptoms requiring treatment and may develop 
FVIII inhibitors.  Approximately 30% of patients with hemophilia A do not have a family 
history of the disorder; these cases arise from spontaneous FVIII gene mutations.  
The absence or functional deficiency of FVIII leads to a lifelong bleeding tendency.  
Common clinical signs of hemophilia A include easy bruising; prolonged bleeding after 
trauma or surgery; spontaneous bleeding into joints, muscles, or soft tissues; and 
intracranial hemorrhage.  The severity of the disease roughly correlates with the residual 
endogenous level of FVIII activity.  Approximately 68% of people with hemophilia A have 
moderate (25%) or severe (43%) forms, characterized by FVIII activity levels 5% or 
1%, respectively, leading to frequent bleeding events (bleeds) with the sequelae of 
musculoskeletal complications (e.g., arthropathy), local functional deficits, hemorrhagic 
shock, neurocognitive defects, or even death (World Federation of Hemophilia 2013).  
1.1.1
Management
Prophylactic FVIII replacement therapy (i.e., administered on a scheduled basis with the 
intent to prevent bleeds) has been proven to minimize bleeding events and 
complications (Manco-Johnson et al. 2007).  Since the 1990s, recombinant FVIII (rFVIII) 
concentrates have been standard-of-care treatment options for patients with 
hemophilia A (Kingdon and Lundblad 2002).  Treatment regimens to achieve optimal 
prevention of bleeding events vary individually; some patients tolerate trough FVIII levels 
of 1%, whereas, others require higher nadir FVIII levels to achieve the desired 
therapeutic outcome (Ahnstrom et al. 2004; Collins et al. 2010).  Current prophylactic 
regimens commonly use intravenous (IV) infusion therapy administered three times 
weekly; other regimens use every other day administration (Shapiro 2013). 


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Prophylactic FVIII replacement therapy has been recognized as superior to episodic 
treatment of symptomatic bleeds for several decades (Khawaji et al. 2012), and was 
adopted by national and international organizations as the desired treatment approach.  
However, the burden of treatment (Eton et al. 2013; Mair and May 2014) is 
extraordinarily onerous, as adequate prophylaxis requires a lifetime of self-administered 
IV infusion of FVIII 34 times each week.  In addition to the obvious toll on the quality of 
patients’ quality of life (Teal et al. 2014), this burden results in suboptimal care for many 
who elect to avoid routine prophylaxis, despite its medical advantage 
(Geraghty et al. 2006; Lindvall et al. 2006, De Moerloose et al. 2008; Collins et al. 2014; 
Oldenburg 2015).  Thus, episodic therapy is a standard-of-care for many patients with 
hemophilia in developed countries, where approximately one-third to one-half of the 
patients use FVIII on demand and avoid continuous prophylaxis.  For example, a recent 
analysis reveals that in North America and Europe, only 44.3% of 1238 patients with 
severe hemophilia A are treated with routine FVIII prophylaxis 
(Oldenburg and Brackmann 2014).  Similarly, prophylaxis was routinely offered to adults 
in only 18 of 35 European countries surveyed, and in 12 out of those 18 countries, 50% 
or fewer adults received FVIII prophylaxis (O'Mahony et al. 2013).  In addition to 
treatment burden, other reasons including venous access and cost concerns underlie 
this problem (Gringeri et al. 2012), which contributes to hemophilia-associated long-term 
morbidity.
Although patients on FVIII prophylaxis experience a low number of bleeds, magnetic 
resonance imaging (MRI) scans demonstrated progressive arthropathy in up to 
two-thirds of patients who receive an adequate primary prophylaxis regimen.  These 
changes begin within the first decade of life and involve clinically “bleed-free” joints 
(Kraft et al. 2012, Olivieri et al. 2012).  Accordingly, 40% of men in the third decade of 
life reported presence of a target joint, reduced mobility, or chronic pain 
(Fischer et al. 2013, Noone et al. 2013).  These findings indicate that FVIII prophylaxis 
delays, but does not completely prevent, long-term skeletal morbidity (Oldenburg 2015).  
This is in part due to the challenges of adherence and in part due to micro-bleeds 
associated with low FVIII trough levels (Ljung and Gretenkort 2015).  Due to the short 
half-life of FVIII, current prophylaxis regimens aim at maintaining FVIII levels at a trough 
of 1%, which restore hemostasis for only part of the time (Valentino et al. 2012).  A 
study of patients with varying severities of hemophilia suggests that protection from joint 
bleeds occurs only at continuous FVIII levels over 12% (Den Uijl et al. 2011), and 
achieving higher FVIII activity, though difficult to accomplish with current regimens, has 
been recognized as a goal for optimal care in a position paper from the World Federation 
of Hemophilia (Skinner 2012).  
Routine IV FVIII therapy relies on venous cannulation skills of patients and their care 
providers (Hacker et al. 2001).  In particular, this issue plagues the care of children with 
hemophilia, in whom central venous access devices (CVADs [i.e., port-a-caths]) have 
been used regularly to overcome technical difficulties.  Although CVADs make 


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prophylaxis feasible in young children, they are associated with complications, including 
mechanical failure, dehiscence of the skin over the reservoir, infection, and thrombosis 
(Ewenstein et al. 2004).  A recent prospective study reported that 183 lines were 
implanted in 99 patients and that 41% of patients had at least one infectious episode.  
The median time to line removal was 483 days (IQR: 1431071) (Rodriguez et al. 2015).  
A Finnish retrospective study similarly reported that 47% of 106 catheters implanted in 
58 patients had to be removed because of a complication (Vepsalainen et al. 2015).  In 
addition, significant healthcare provider (HCP) efforts are required to manage optimal 
treatment solutions and to overcome identified issues (Schrijvers et al. 2013).  Thus, 
both the disease and its treatment affect patients’ HRQoL.
The development of inhibitory alloantibodies (inhibitors) occurs in approximately 20%30% 
of patients with severe hemophilia A and in 3%13% of those with moderate or mild 
disease (Franchini and Mannucci 2013).  Inhibitors neutralize the activity of endogenous 
FVIII as well as of FVIII administered as replacement therapy.  For patients with a history 
of a high-titer (5 BU/mL) inhibitor following a re-challenge with FVIII administration 
(high-responding inhibitor), the only hemostatic options currently available are 
prothrombotic coagulation factors that augment other parts of the coagulation cascade 
(i.e., “bypassing agents”).  Bypassing products include factor eight inhibitor bypassing 
activity (FEIBA), an activated prothrombin complex concentrate (aPCC; FEIBA will be 
henceforth referred to as aPCC), and NovoSeven® (recombinant activated human FVIIa 
[rFVIIa]; NovoSeven® will be henceforth referred to as rFVIIa) (Srivastava et al. 2013).  
Both have been used as prophylaxis to prevent bleeding in patients with inhibitors 
against FVIII (“inhibitor patients”); however, the only available product for this indication 
in most countries is aPCC.  Of note, treatment of patients with congenital hemophilia A 
of any severity with high-titer inhibitors is similar, and their endogenous severity, as 
defined based on FVIII activity at diagnosis (mild, moderate, or severe), is no longer 
prognostic of their clinical phenotype and risk of bleeding.
aPCC may be associated with side effects, such as thromboembolic events, 
hypersensitivity reactions, myocardial infarction, and disseminated intravascular 
coagulation.  Both aPCC and rFVIIa are administered intravenously, with aPCC 
prophylaxis requiring every-other-day dosing and rFVIIa requiring daily (or more frequent) 
dosing.
The development of effective prophylactic treatment options with decreased 
immunogenicity and less frequent dosing requirements is important to reduce the time 
and burden associated with frequent IV dosing and the impact of the disease on aspects 
of physical health and other areas of function.  A study assessing the relationship 
between self-reported adherence to prophylaxis and health outcomes (HRQoL and 
bleeding episodes) showed that poorer adherence with prophylaxis was associated with 
a greater number of self-reported bleeding episodes, more days of work/school missed 
among pediatric patients, and lower physical health status scores among pediatric 
patients (Krishnan et al. 2015).  Adherence to prophylaxis by patients with hemophilia A, 


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defined as the extent to which a person’s behavior corresponds to agreed 
recommendations by a healthcare provider (WHO 2003), ranges from 44% to 87% 
(Llewellyn et al. 2003; De Moerloose et al. 2008; Ho et al. 2013).  In a Dutch study 
investigating patient behavior impacting adherence to prophylactic treatment, patients 
were asked about their experience with and adherence to administration of prophylaxis.  
Remarkably, some patients willingly chose non-adherence because they did not want to 
adapt their activities to hemophilia, and they were prepared to accept the consequences 
of their decision.  Patients noted the difficulties of regular prophylaxis due to inadequate 
routine and the complexity of the needed self-management skills including planning, 
management of the treatment of bleeds, forgetfulness, stock management, and 
overruling activities in life (Schrijvers et al. 2015).  There is a true need for therapeutics 
that have reliable efficacy, a long half-life, low treatment burden, and ease of 
administration to prevent bleeding in and minimize long-term morbidity of individuals with 
hemophilia A.
1.2
BACKGROUND ON EMICIZUMAB
1.2.1
Molecule and Preclinical Data
Emicizumab (also known as RO5534262 and ACE910) is a recombinant, humanized, 
bispecific, immunoglobulin G4 (IgG4) monoclonal antibody that binds with moderate 
affinity to activated factor IX (FIXa) and factor X (FX), mimicking the co-factor function of 
FVIII.  In patients with hemophilia A, hemostasis can be restored irrespective of the 
presence of FVIII inhibitors, as emicizumab shares no sequence homology with FVIII.  
In addition, emicizumab offers the possibility of subcutaneous (SC) administration, 
removing the need for venous access.  Finally, because the pharmacokinetic (PK) 
properties of this antibody are expected to enable marked extension of the dosing 
interval to once weekly, every 2 weeks, or every 4 weeks, this novel compound has the 
potential to dramatically change the treatment of patients with hemophilia A with and 
without FVIII inhibitors who are in need of effective, safe, and low burden prophylactic 
therapy.
Binding studies of emicizumab to cynomolgus monkey factor IX (FIX) and FX showed 
a similar affinity as to the human factors.  Mechanistic in vitro studies were conducted 
in human and cynomolgus FVIII-neutralized plasma and in various coagulation 
factor-specific assay-testing systems, which revealed that emicizumab shortened aPTT 
and promoted thrombin generation.  Emicizumab bound to human Fcreceptor (hFcR), 
cynomolgus monkey Fcreceptor (cyFcR), human neonatal Fc receptor (hFcRn), and 
cynomolgus monkey neonatal Fc receptor (cyFcRn) with similar affinities as a 
humanized IgG4 reference antibody, natalizumab.
In vivo pharmacology experiments in cynomolgus monkeys were conducted in a 
hemophilia A model where endogenous FVIII levels were neutralized by a FVIII-specific 
monoclonal antibody.  This model mimics essential characteristics of patients with 
hemophilia A and was used to test in vivo pharmacodynamics and efficacy under 


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spontaneous or local trauma-induced bleeding conditions.  In summary, emicizumab 
demonstrated the ability to significantly reduce bleeding tendency under both sets of 
conditions.
Potential prothrombotic risks associated with emicizumab-induced FVIII mimetic activity 
were further explored in an in vivo cynomolgus monkey venous stasis model.  In this 
model, thrombus formation in the presence of emicizumab was compared with that in the 
presence of FVIII or bypassing agents (rFVIIa or aPCC).  Thrombus formation with 
emicizumab did not markedly exceed formation observed with rFVIIa, aPCC, or FVIII.
The pharmacokinetics/toxicokinetics of emicizumab were assessed in cynomolgus 
monkeys after single and multiple doses were administered intravenously and via the 
intended clinical SC route.  After a single IV dose of 6 mg/kg emicizumab in male 
cynomolgus monkeys, the plasma clearance was 3.62 mL/day/kg and the terminal 
plasma half-life (t1/2) of emicizumab was 19.4 days.  The single SC administration study 
(dose levels: 0.06, 0.6, and 6 mg/kg) indicated slow (time to maximum plasma 
concentration [tmax]:  3.005.33 days) and complete absorption (bioavailability:  102% at 
6 mg/kg).  The IV and SC multiple dosing studies (toxicokinetic monitoring) revealed a 
t1/2 in the range of 14.930.8 days.  Overall, exposures in terms of maximum plasma 
concentration (Cmax) and area under the concentrationtime curve (AUC) increased in an 
approximately dose proportional manner.
A subfraction of the cynomolgus monkeys treated with repeated doses of emicizumab 
showed the formation of anti-emicizumab antibodies (which is expected with humanized 
monoclonal antibodies) with few animals also showing neutralizing antibodies.
Aspects of acute as well as repeated-dose toxicity including local tolerance assessment 
were evaluated in cynomolgus monkeys in 4-, 13-, and 26-week SC dose toxicity studies 
(at doses up to 30 mg/kg weekly) and a 4-week IV dose toxicity study (at doses up to 
100 mg/kg weekly).  No toxicologically relevant changes attributable to SC or IV 
administration of emicizumab were observed; the no observed adverse effect level 
(NOAEL) was the highest tested dose in each toxicity study.
See the RO5543262 (Emicizumab) Investigator's Brochure for additional details on 
nonclinical studies with emicizumab.
1.2.2
Clinical Experience
Currently available experience with emicizumab in humans includes data from one 
completed Phase I study (ACE001JPLast Patient Last Visit on 17 April 2015) and its 
ongoing extension, a Phase I/II study (ACE002JP).  ACE001JP was a single study 
conducted in 3 parts, including both healthy subjects (Part A and Part B) and patients 
with hemophilia A (Part C).  The objective of Parts A and B in healthy subjects was to 
investigate the tolerability, safety, PK, and pharmacodynamic (PD) response of 
SC-administered emicizumab in adult Japanese and Caucasian men and to evaluate for 


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racial differences, if any, in their PK and PD response.  Healthy male volunteers aged 
2044 were eligible for enrollment.  A total of 64 healthy volunteers were enrolled in 
Parts A and B from August 2012 to April 2013.  In Part C, the objective was to 
investigate the tolerability, safety, PK, and PD response of SC administered emicizumab 
in patients with hemophilia A.  Patients were eligible for enrollment if they were 
1259 years of age, 40 kg in weight, had a diagnosis of severe congenital 
hemophilia A, and had documentation of bleeds and/or treatment with coagulation factor 
in the last 6 months.  For those with inhibitors, patients must have had 6 bleeds in the 
6 months prior to enrollment, and for those without inhibitors, patients were required to 
have received 150 lifetime doses of FVIII replacement, including in the last 6 months.  
A total of 18 patients with hemophilia A were enrolled from May 2013 to June 2014. 
Parts A and B of Study ACE001JP (completed) consisted of a randomized, 
placebo-controlled, single ascending dose (SAD) study, which was conducted in 
Japanese (n40; Part A) and Caucasian (n24; Part B) healthy men; 48 subjects 
received a single SC injection of 0.001 mg/kg to 1 mg/kg of emicizumab and 16 subjects 
received a single SC injection of placebo.  Part C of Study ACE001JP was an open-label, 
multiple ascending dose (MAD) study in 18 Japanese patients with hemophilia A, both 
with and without inhibitors.  Of note, patients received concurrent coagulation factor 
products to control breakthrough bleeds.  Of the 18 patients in Part C of 
Study ACE001JP, 6 patients were dosed with 0.3 mg/kg/week SC following a single 
loading dose of 1 mg/kg SC, 6 patients were dosed with 1 mg/kg/week SC following a 
single loading dose of 3 mg/kg, and 6 patients received 3 mg/kg/week of emicizumab 
without a loading dose.  
Study ACE002JP is an extension study that allows patients enrolled in Part C of 
Study ACE001JP to continue treatment with emicizumab.  In order to be eligible for the 
extension study, patients must have completed 12 weeks of assigned treatment in 
Study ACE001JP and had bleeds prior to study entry.  Seventeen of 18 patients in 
Part C of Study ACE001JP completed the 12-week treatment period.  One patient 
discontinued the treatment and moved to the post-discontinuation follow-up period.  A 
total of 16 of the 17 patients who completed the 12-week treatment period subsequently 
enrolled into extension Study ACE002JP, and 1 of the 17 patients moved to the 
post-treatment observation period of Study ACE001JP.  Thus, the ongoing extension 
study, ACE002JP, includes 6 patients from the 0.3 mg/kg/week group, 5 patients from 
the 1 mg/kg/week group, and 5 patients from the 3 mg/kg/week group of 
Study ACE001JP.  The investigator discontinued emicizumab for 1 adolescent patient 
with mild local injection-site reactions and a pre-study history of allergic reactions.  
Another patient, who had a pre-enrollment annualized bleeding rate (ABR) 0 on FVIII 
prophylaxis, was not allowed to enroll in the extension study due to a health authority 
requirement for a history of bleeds pre-enrollment.  As Study ACE002JP allows for dose 
escalation in patients with a suboptimal response but no significant toxicity on their 


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current emicizumab dose, 2 of 6 patients eventually had their dose escalated from 
0.3 mg/kg/week to 1 mg/kg/week and then to 3 mg/kg/week. 
Data from the completed Parts A, B, and C of Study ACE001JP and interim data from 
Study ACE002JP (as of the cutoff date of 17 April 2015) are presented here; for further 
updated information, consult the current RO5534262 (Emicizumab) Investigator’s 
Brochure.  All continuing patients in Study ACE002JP have been observed for at least 
96, 72, or 48 weeks in the 0.3, 1, and 3 mg/kg/week dosing groups, respectively, except 
for 1 patient in the 3 mg/kg/week group who has only been followed for 44 weeks.  
The median age and body mass index (BMI) of the healthy volunteers across the dose 
groups in Part A ranged from 25.535.5 years and 20.2821.44 kg/m2, respectively.  In 
Part B, the median age ranged from 28.530.5 years, and the median BMI ranged from 
21.6022.56 kg/m2 across the dose groups.  Among the 0.3, 1, and 3 mg/kg/week 
groups in Part C, the median age was 32, 30, and 33 years, respectively; the median 
BMI was 22.54, 22.87, and 22.31 kg/m2, respectively.  There were 5 adolescent patients 
(1218 years):  1 patient (17 years old) in the 0.3 mg/kg/week group; 2 patients 
(12 years old and 18 years old) in the 1 mg/kg/week group; and 2 patients (12 years old 
and 18 years old) in the 3 mg/kg/week group.  There were 11 patients with inhibitors:  
4 patients in the 0.3 mg/kg/week group; 4 patients in the 1 mg/kg/week group; and 
3 patients in the 3 mg/kg/week group.  All patients in Part C of Study ACE001JP have 
completed the treatment period and have either subsequently enrolled in the extension 
Study ACE002JP (16 of 18 patients) or moved to the follow-up or observation period 
(2 of 18 patients).   
In the 0.3 mg/kg/week cohort, 1 patient transitioned to the observation period of the 
ACE001JP study after 12 weeks of treatment and restarted the study treatment in the 
ACE002JP study at the increased dose of 1 mg/kg/week, approximately 35 weeks later.  
Another patient in the 0.3 mg/kg/week cohort had his dose increased in Study 
ACE002JP after completing 12 weeks of treatment in Study ACE001JP.  Both of these 
patients eventually had their dose further increased to 3 mg/kg/week.  A third patient in 
this group started to receive 1 mg/kg/week just prior to the data cutoff.  At the data cutoff 
date of 17 April 2015, 6 patients in the 0.3 mg/kg/week group, 5 patients in the 
1 mg/kg/week group, and 5 patients in 3 mg/kg/week group have continued emicizumab 
treatment in Study ACE002JP.
The efficacy parameter of ABR was calculated by annualizing the number of bleeds that 
required treatment with coagulation factor products during the 6 months prior to study 
enrollment and during the treatment period after first emicizumab administration.  During 
the 6 months before study enrollment, the patients without inhibitors had received FVIII 
prophylactic replacement therapy, while the patients with inhibitors had received 
episodic therapy and/or prophylactic therapy with bypassing agents.  


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During the course of emicizumab administration, the ABR decreased in all patients 
compared with the ABR prior to study enrollment, regardless of whether or not they had 
inhibitors, with the exception of 1 patient without inhibitors in the 3 mg/kg/week group.  
This patient, who was previously on FVIII prophylaxis, had a baseline ABR of 0 and 
maintained an ABR of 0 during treatment with emicizumab.  In the 0.3 mg/kg/week group, 
the ABR reduction ranged from 22.8%100% in all patients.  In the 1 mg/kg/week group, 
the ABR reduction ranged from 78.9%100% in all patients (excluding the patients who 
were dose escalated from the 0.3 mg/kg/week group).  In the 3 mg/kg/week group, the 
ABR reduction ranged from 86.4%100% in all patients (excluding the patient with the 
baseline ABR of 0 and patients who were dose escalated from the 1 mg/kg/week group). 
Emicizumab was safe and well tolerated in patients (see the Investigator's Brochure).in 
the Phase I/II studies.  The majority of adverse events were of mild intensity, except for 
5 moderate adverse events (upper respiratory tract infection, bipolar I disorder, 
hemophilia [i.e., left hip joint bleeding due to hemophilia], headache, and asthma) and 
2 severe adverse events (appendicitis and mesenteric hematoma).  Both severe events 
were considered to be serious adverse events and not related to emicizumab 
administration.  A total of 7 patients reported injection-site reactions (including erythema,
hematoma, rash, pain, discomfort and pruritus).  All injection-site reactions were of mild 
intensity.  Besides injection-site reactions, the most frequently reported adverse events 
(4 patients) were nasopharyngitis, pharyngitis, dental caries, excoriation, and 
headache. There were no dose dependent increases in adverse events, and the 
majority of the adverse events were not considered related to emicizumab.  Treatment 
was discontinued for 1 patient with injection-site erythema in the 1 mg/kg weekly group; 
the event was mild in intensity and resolved.  This same patient also reported one 
non-related serious adverse event (hemophilia [i.e., left hip joint bleeding due to 
hemophilia]) approximately 24 weeks after the last dose of study drug.  In the Phase I/II 
studies, no thromboembolic adverse events have been reported when emicizumab has 
been administered alone or concomitantly with FVIII products or bypassing agents as 
episodic therapy.
As of May 2019, in the ongoing Phase III Study BH29884 (adolescent and adult patients 
with hemophilia A with FVIII inhibitors), thrombotic microangiopathy (TMA) was observed 
in 3 patients receiving emicizumab and bypassing agents; and 2 cases of 
thromboembolic events were observed in 2 patients receiving emicizumab and 
bypassing agents.  In addition, 1 patient experienced a serious adverse event of acute 
myocardial infarction in Phase IIIb study MO39129, a single-arm study of prophylactic 
emicizumab in patients with congenital hemophilia A who have persistent inhibitors 
against FVIII.  For more details, refer to Sections 5.1.2.3 and 5.1.2.4 and the current 
RO5534262 (Emicizumab) Investigator's Brochure.
Emicizumab exhibited linear PK after single SC administration.  Following single SC 
injection, its mean elimination t1/2 (45 weeks) was similar to that of other human IgG 
antibodies.  Furthermore, comparison of PK profiles between Japanese and Caucasian 


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healthy volunteers did not reveal racial differences.  In patients with hemophilia A, 
emicizumab trough plasma concentrations increased in a dose-proportional manner with 
weekly dosing to achieve a plateau after approximately 12 weeks in the first two dosing 
groups, in which a loading dose was administered, and after approximately 24 weeks in 
the highest dose group, in which no initial loading dose was administered.
Until the cutoff in April 2018 in four Phase III clinical trials of emicizumab (Studies 
BH29884, BH29992, BH30071, and BO39182), 5% of patients tested positive for 
anti-drug antibodies (ADAs) to emicizumab and 1% of patients developed ADAs with 
neutralizing potential (based on declining pharmacokinetics).  A similar safety profile 
was observed in patients, irrespective of the presence of ADAs.  One patient who 
developed ADAs with neutralizing potential experienced loss of efficacy after 5 weeks of 
treatment and discontinued emicizumab treatment.  For further updated information, 
consult the current RO5534262 (Emicizumab) Investigator’s Brochure.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This study is designed to evaluate the efficacy, safety, pharmacokinetics, 
pharmacodynamics, HRQoL, and patient preference of emicizumab given every 4 weeks 
(Q4W) SC in patients with hemophilia A irrespective of FVIII inhibitor status, supported 
by the mode of action of emicizumab and the observation from Phase I/II studies of 
similar pharmacokinetics, efficacy, and safety between the inhibitor and non-inhibitor 
populations.  
In the Phase I/II study (ACE001JP) 18 Japanese patients with hemophilia A, either with 
or without inhibitors, were treated with emicizumab at three different dosing regimens 
(0.3 mg/kg/week, 1 mg/kg/week, and 3 mg/kg/week).  During the course of emicizumab 
administration, the ABR significantly decreased in all patients compared with the ABR 
prior to study enrollment, regardless of inhibitor status, with the exception of 1 patient 
without inhibitors in the 3 mg/kg/week group (see Section 1.2.2).
The dosing regimen investigated in this study (3 mg/kg weekly [QW]4 followed by 
6 mg/kg Q4W) is being investigated to provide an option for patients to receive 
emicizumab every 4 weeks, while still delivering the same cumulative dose as the 
1.5 mg/kg QW or 3 mg/kg every 2 weeks (Q2W) regimens currently being investigated in 
other Phase III studies.  The Q4W regimen of 6 mg/kg is expected to result in a similar 
exposure (average steady-state concentration [Cavg,ss]) as the 1.5 mg/kg QW and  
3 mg/kg Q2W regimens despite higher Cmax and lower Ctrough levels at steady state 
(see Section 3.3).  
Emicizumab was well tolerated in the Phase I/II studies.  The majority of adverse events 
were of mild intensity, with the most common being injection-site reactions.  The majority 
of the adverse events were not considered related to emicizumab.  In these studies, no 
thromboembolic or systemic hypersensitivity adverse events were observed; however, in 
the ongoing Phase III Study BH29884, 3 cases of TMA and 2 thromboembolic events 


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were observed in 5 patients on emicizumab who received bypassing agents for the 
treatment of breakthrough bleeds.  Three out of these 5 patients have fully recovered,
while 1 patient’s condition has improved and 1 patient has died due to severe rectal 
bleeding. In addition, 1 patient experienced a serious adverse event of acute myocardial 
infarction in Study MO39129 (see Sections 5.1.2.3 and Section 5.1.2.4 and the current 
RO5534262 [Emicizumab] Investigator’s Brochure).  
The safety is additionally supported by a NOAEL of 30 mg/kg/week in cynomolgus 
monkeys.  The data from this preclinical study estimate the maximum dose of 3 mg/kg 
QW used in the Phase I/II study was associated with a 10.3-fold and 11.2-fold safety 
margin based on Cmax and AUC, respectively, while the dose of 6 mg/kg Q4W 
investigated in the present study is predicted to be associated with corresponding 
17.4- and 22.5-fold safety margins. 
2.
OBJECTIVES AND ENDPOINTS
2.1
PHARMACOKINETIC RUN-IN PHASE
2.1.1
Objectives
The objectives of the PK run-in are as follows:

To investigate the pharmacokinetics of emicizumab after single and multiple (Q4W) 
SC administration of 6 mg/kg

To assess the safety and tolerability of emicizumab after Q4W SC administration of 
6 mg/kg 

To explore the prophylactic effect of emicizumab in maintaining adequate control of 
bleeding

To investigate the effect of emicizumab on PD markers including, but not limited to,
aPTT, thrombin generation, and FVIII activity
2.2
EXPANSION PHASE
2.2.1
Efficacy Objectives
The efficacy objectives are as follows:

To evaluate the efficacy of prophylactic emicizumab in maintaining adequate control 
of bleeding

To evaluate the clinical effect of prophylactic emicizumab on the number of joint 
bleeds over time

To evaluate the clinical effect of prophylactic emicizumab on the number of target 
joint bleeds over time (target joints are defined as joints with 3 bleeds occurring in 
the same joint over the last 24 weeks prior to study entry)

To evaluate the clinical effect of prophylactic emicizumab on the number of all 
bleeds (i.e., those treated and untreated with coagulation factors) over time

To evaluate the clinical effect of prophylactic emicizumab on the number of 
spontaneous bleeds over time (spontaneous bleed rate)


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
To evaluate the HRQoL of patients according to Haem-A-QoL (18y) or 
Haemo-QoL_SF (ages 1217) scores after 24 weeks 

To evaluate the health status of patients according to EuroQoL 5-Dimension, 
5-Level Questionnaire (EQ-5D-5L) scores after 24 weeks 

To assess preference for emicizumab regimen compared with previous regimen 
used 

To assess the number of days away from school/work

To assess the number of days hospitalized
2.2.2
Safety Objectives
The safety objectives of this study are to evaluate the overall safety of emicizumab given 
Q4W in patients with hemophilia A based on the following endpoints:

The incidence and severity of adverse events

The incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs

Incidence of laboratory abnormalities

Incidence and severity of injection-site reactions

Incidence of adverse events leading to drug discontinuation

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events

Incidence of thrombotic microangiopathy 

The incidence and clinical significance of anti-emicizumab antibodies

The incidence of de novo development of FVIII inhibitors (non-inhibitor population)
2.2.3
Pharmacokinetic Objective
The PK objective of this study is as follows:

To characterize the pharmacokinetics of multiple Q4W SC doses of 6 mg/kg 
emicizumab 
2.2.4
Exploratory Pharmacodynamic Biomarker Objective
The exploratory PD biomarker objective is as follows:

To investigate the effect of Q4W doses of emicizumab on PD parameters, including,
but not limited to, aPTT, thrombin generation and FVIII activity at timepoints 
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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study BO39182 is a multicenter, open-label, non-randomized study designed to 
investigate the efficacy, pharmacokinetics, safety, and pharmacodynamics of 
emicizumab (6 mg/kg) administered in a Q4W dosing regimen.  Patients with hemophilia 
A with or without inhibitors against FVIII will be enrolled.  The study consists of two parts:  
a PK run-in part followed by an expansion part.  
3.1.1
PK Run-In Part
In the PK run-in part, a full PK profile will be measured in the first 6 enrolled patients 
during the first 4 weeks to characterize the pharmacokinetics of a single SC dose of 
6 mg/kg emicizumab in patients with hemophilia A.  After the first and second 
emicizumab administration, an intense PK sampling will occur.  A reduced PK sampling 
schedule will be used to characterize repeated Q4W SC administration from Week 9 to 
Week 21.  After the sixth injection at Week 21, PK sampling frequency will be increased 
to characterize steady-state pharmacokinetics (see Appendix 2).  
An analysis of the data collected when all 6 patients in the PK run-in cohort have been 
followed for at least 6 weeks will be performed to assess whether the mean PK profile is 
as predicted (i.e., lower limit of 95% CI of the predicted mean PK profile) after 
repeated 6 mg/kg SC administration Q4W.  In addition to PK, safety will be assessed in 
order to establish whether the expansion cohort can be opened.  This analysis will be 
conducted by a Roche internal group of representatives from Clinical Pharmacology, 
Clinical Science, Clinical Safety, and Statistics; no formal Internal Monitoring Committee 
(IMC) will be set up. 
3.1.2
Expansion Part
An expansion phase will be conducted to further investigate the efficacy, 
pharmacokinetics, safety, and pharmacodynamics in a cohort of 40 patients.  These 
patients will start with loading doses of 3 mg/kg QW 4, followed by a maintenance dose 
of 6 mg/kg Q4W for at least 24 weeks overall.  These patients will undergo PK sampling 
to investigate trough concentrations (Ctrough) and samples (predose) will be drawn as per 
the schedule of assessments (see Appendix 2). 




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Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have 
already occurred).  There is clinical experience in the ongoing Phase I/II clinical studies 
with the treatment of over 60 breakthrough bleeds in patients receiving emicizumab with 
either FVIII or bypassing agents.  FVIII, aPCC, or rFVIIa do not interfere with 
emicizumab PK assessments and no safety signals have been observed when 
breakthrough bleeds were treated with standard-of-care regimens during Phase I/II 
studies.  However, in the ongoing Phase III Study BH29884 (adolescent and adult 
patients with hemophilia A with FVIII inhibitors), 3 events of TMA and 2 thromboembolic 
events were observed in patients who concomitantly used repeated doses of aPCC for 
the treatment of breakthrough bleeds (see Sections 5.1.2.3 and 5.1.2.4).  Therefore, it is 
recommended that breakthrough bleeds in the inhibitor population are treated with 
rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should be 
avoided (see Section 4.4.1). In addition, caution should be taken if anti-fibrinolytics are 
used in conjunction with rFVIIa in patients who are receiving emicizumab, and the use of 
anti-fibrinolytics is prohibited in conjunction with aPCC or Byclot® (see Sections 4.4.1
and 4.4.2).
Therefore, a washout period of 72 hours prior to the first emicizumab dose in this study
is required for patients receiving prior aPCC or Byclot.  Also a washout period of 
72 hours for patients who were previously receiving ITI is required prior to the first 
emicizumab administration.  Patients may require dosing with FVIII or for the treatment 
of potential breakthrough bleeds (see Section 4.4.1), especially for the time period until 
steady-state concentrations of emicizumab have been reached. 
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation) will be 
collected as per the schedule of assessments and always coupled with a PK 
assessment for days where PK and PD samples are to be drawn (see Appendix 2).  As 
values for many tests are normalized by even low plasma concentrations of emicizumab, 
a variety of assay formats (one-stage, chromogenic) and modifications (pre-dilution of 
patient plasma) will be investigated for assessment of PD response at higher 
emicizumab plasma concentrations.  It is not expected that these biomarkers will be 
used to guide the selection of patients to be treated with emicizumab.  However, these 
biomarkers may be used to identify a future assay for the monitoring of emicizumab 
activity.  In addition, FIX and FX antigen levels will be monitored.
Biomarkers related to thromboembolism (e.g., D-dimer, prothrombin fragment 1.2) and 
immunologic biomarkers (i.e., anti-emicizumab antibodies and anti-FVIII antibodies) will 
be measured as per the schedule of assessments (see Appendix 1). 
Breakthrough bleeds will be treated with appropriate coagulation products with either 
FVIII (non-inhibitor patients) or rFVIIa (inhibitor patients) at the lowest expected dose to 
achieve hemostasis and captured as they occur (see Section 4.4.1).  When a bleed has 
occurred, patients (or their legally authorized representative) will be required to report 
bleed information, including site of bleed, type of bleed, time of each individual bleed 


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(day, start time), symptoms of bleed, and treatment for bleed (e.g., other than 
emicizumab in case of breakthrough bleeds).  The reason for the use of coagulation 
products (e.g., FVIII or rFVIIa) will be documented (e.g., bleeding, preventative dose 
before activity).  Thorough documentation of the treatments for bleeds will be requested, 
including agent, start time, dose, route of administration, and number of infusions 
needed to treat the bleed.  For patients with inhibitors against FVIII who receive
bypassing agents, local and central laboratory assessments are required to monitor the 
risk for thromboembolic events or TMA as per the schedule of assessments 
(see Appendix 1 and Appendix 2).  
All patients, irrespective of the cohort assigned, who continue to derive clinical benefit 
will be given the opportunity to continue receiving prophylactic emicizumab either within 
this study or as part of a future extension study according to Roche policy on post-study 
drug access (see Section 4.3.4).  After 24 weeks on prophylactic emicizumab, all 
patients will be able to continue on their 6 mg/kg Q4W maintenance dose or may be 
provided the option to increase their dose to 3 mg/kg QW if they meet protocol-defined 
criteria of suboptimal response. Suboptimal response is defined as follows:

2 qualifying bleeds within 24 weeks while on prophylactic emicizumab 
Qualifying bleeds are defined as spontaneous, verified by investigator (e.g., by imaging 
or physical examination), and occurring while on prophylactic emicizumab at steady 
state (after the Week 5 visit for expansion cohort/after Week 17 visit for PK run-in cohort).  
These patients must receive approval from the Medical Monitor to increase their dose to 
3 mg/kg QW (see Section 4.3.2).
If the investigator believes that a specific patient warrants dose escalation based on a 
different reason, he or she may discuss the case with the Medical Monitor for 
consideration and potential approval.
Upon implementation of protocol Version 5, treatment duration will be extended until 
5 years after the last patient is enrolled to enable the collection of additional safety and 
efficacy data. During this study prolongation, each patient may choose a preferred 
emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg QW, 3 
mg/kg Q2W, or 6 mg/kg Q4W) and continue on that dosing regimen until 
discontinuation from the study. Instructions for switching the dosing regimen are 
outlined in Section 4.3.2.1. 
Patients who discontinue emicizumab will be followed for 24 weeks after the last 
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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last remaining patient has 
completed the last visit (last patient last visit [LPLV]), as defined by any of the following 
criteria:

Completion of at least 24 weeks of emicizumab treatment and either transfer to a 
separate extension study to receive further emicizumab as per Roche Global Policy 
on Continued Access to Investigational Medicinal Products or switch to 
commercially available product
OR

Completion of the end-of-study safety follow-up visit 24 weeks after discontinuing 
emicizumab
OR

Withdrawal of consent 
OR

Lost to follow-up  
The length of the study for an individual patient will be: 

Screening period up to 4 weeks

Treatment and observation period at least 24 weeks 

For patients who discontinue emicizumab treatment, safety follow-up visit 24 weeks 
after discontinuing emicizumab
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
3.3
RATIONALE FOR STUDY DESIGN
The Sponsor proposes a multicenter, non-randomized Phase III clinical study that will 
enroll patients aged 12 years or older with severe hemophilia A, irrespective of inhibitor 
status.  The study consists of a PK run-in cohort and an expansion cohort (see Figure 1) 
and will investigate a Q4W dosing regimen that would provide patients with a treatment 
option that requires less frequent dosing while providing a similar exposure compared 
with the emicizumab 1.5 mg/kg QW and emicizumab 3 mg/kg Q2W regimens that are 
currently under investigation.  
The PK run-in cohort of 6 patients will provide substantial knowledge on 
pharmacokinetics (e.g., dose linearity and SC absorption) and will inform about 
preliminary safety and efficacy.  As the patients will not receive a loading dose in this 
cohort and bleeds might not be optimally controlled by emicizumab at the study start, 
this cohort is restricted to patients previously receiving episodic treatment with either
FVIII or bypassing agents.


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The expansion cohort of 40 patients will investigate pharmacokinetics, safety, and 
efficacy in patients receiving a loading dose of 3 mg/kg QW 4 followed by a 
maintenance dose of 6 mg/kg Q4W.  This cohort will be open for patients who are on 
either episodic or prophylactic treatment prior to study. 
The Q4W regimen option is investigated in this study in order to help address current 
challenges concerning the limited adherence to prophylaxis of 44%87% in patients with 
hemophilia A (Llewellyn et al. 2003; De Moerloose et al. 2008; Ho et al. 2013).  As major 
factors for limited adherence to prophylaxis are inadequate routine and the complexity of 
the needed self-management skills including planning, forgetfulness, and stock 
management (Schrijvers et al. 2015), a SC Q4W dosing regimen might address these 
challenges and reduce the treatment burden for patients with hemophilia A assigned to 
prophylaxis treatment (see Section 1.1). 
3.3.1
Rationale for Emicizumab Dose and Schedule
Phase III dosing regimens have been proposed based on modeling and simulation of the 
PK and efficacy data from patients participating in Part C of Study ACE001JP and in 
Study ACE002JP. 
Single- and multiple-dose pharmacokinetics of emicizumab were characterized in 
Phase I and Phase II studies at doses up to 1 mg/kg and 3 mg/kg, respectively.  After a 
single dose, the emicizumab plasma concentrations peaked 12 weeks after dosing.  
Plasma concentrations subsequently decreased with a mean elimination half-life (t1/2) of 
28.334.4 days, without clear differences among doses.  Emicizumab exhibited linear 
PK, with exposure increasing in proportion to the dose.  After multiple doses, in patients 
with hemophilia A, emicizumab trough plasma concentrations increased in a 
dose-proportional manner with weekly dosing to achieve a plateau after approximately 
12 weeks in groups in which a single loading dose was administered and after 
approximately 24 weeks in the highest dose group, in which no initial loading dose was 
administered.
The exposure/response relationship of emicizumab (predicted plasma concentration at 
the time of bleeding event/bleeding event) was previously characterized with repeated 
time-to-event (RTTE) modeling.  Simulations suggested that a median ABR of 1 is 
achieved for emicizumab trough plasma concentrations 16 g/mL and a median ABR 
of 0 for emicizumab trough plasma concentrations 45 g/mL.  To achieve this level, 
once-weekly loading doses of 3 mg/kg for the first 4 weeks followed by QW maintenance 
doses of 1.5 mg/kg or Q2W maintenance doses of 3 mg/kg have been recommended for 
the other Phase III studies. 
A dose of 6 mg/kg Q4W is equivalent in terms of cumulative dose to the dose levels of 
1.5 mg QW or 3 mg/kg Q2W that are being evaluated in the other Phase III studies.  
Assuming linear PK up to 6 mg/kg, model-based simulations were used to explore 
whether a Q4W dosing regimen could provide sufficient efficacy.  Simulations showed 


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that a once-weekly loading dose of 3 mg/kg for the first 4 weeks, followed by an every 
4-week maintenance dose of 6 mg/kg would provide a steady-state Cmax and AUCof 
78.120.9 g/mL and 1570447 day·g/mL, respectively.  While more than half of the 
patients would not be expected to have a trough level of 45 g/mL at steady state, the 
simulated ABR distribution was similar to the planned dosing regimens of other Phase III 
studies.  This Q4W dosing regimen is, therefore, expected to maintain similar efficacy to 
the QW and Q2W dosing regimens.  
Figure 2
Simulated Plasma Emicizumab Concentration over Time (Q4W 
Dosing)
Q4W every 4 weeks.
Notes:  Once-weekly loading dose of 3 mg/kg for first 4 weeks followed by every 4 weeks 
maintenance dose of 6 mg/kg was applied.
X-axis time after first emicizumab administration (week). 
Y-axis plasma emicizumab concentration (g/mL).  
Dots and solid linesimulated median plotted at each trough sampling timepoint.  
Shaded areasimulated 5- to 95-percentile range.  
Broken linetarget exposure level of 45 g/mL. 
Time after first RO5534262 administration (week)
Plasma RO5534262 concentration (ug/mL)
0
20
40
60
80
100
0
4
8
12
16
20
24
3 mg/kg once weekly for first 4 weeks followed by 6 mg/kg once 4-weekly


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Overall, a Q4W dosing regimen with 6 mg/kg is expected to provide favorable safety and 
efficacy in patients with hemophilia A with or without inhibitors. 
3.3.2
Rationale for Patient Population
This study will include patients with hemophilia A, irrespective of the presence of FVIII 
inhibitors.  The mode of action of emicizumab is identical in the inhibitor and 
non-inhibitor populations, and data from Phase I/II studies did not show a difference in 
pharmacokinetics, safety, or efficacy between patients with or without inhibitors against 
FVIII.  Ideally, a representative variety of patients with hemophilia A should be enrolled 
in this Q4W study (e.g., to include 1012 patients with inhibitors out of the total of 
approximately 46 patients) in order to investigate further PK in both inhibitor and 
non-inhibitor populations.  
For the PK run-in part only, patients on an episodic treatment regimen at time of 
enrollment are allowed to enter because, in this cohort (who do not receive loading 
dose), the likelihood of breakthrough bleeds is higher based on the steady state 
concentrations of emicizumab, which are expected to be reached after only 24 weeks. 
Although the severity of a patient’s hemophilia A is directly related to the FVIII activity, 
inter-patient variability may exist based on level of physical activity, bleeding history, and 
other features.  Therefore, patients previously treated with episodic FVIII or bypassing 
agents will be required to have at least 5 bleeds in the last 24 weeks prior to study entry 
to be eligible for enrollment into the expansion cohort.  This requirement is intended to 
select a group of patients with hemophilia A who have a high, unmet medical need and 
to enable evaluation of adequate control of bleeding in this population.  Patients who 
have been on previous prophylactic treatment can enroll (in the expansion phase only) 
without any requirement for a certain bleed number because these patients’ bleeds 
should be well controlled through receiving their current standard of care.  In order to
exclude patients who might have a higher chance to show an immune response to 
foreign protein regimens (e.g., FVIII), patients without FVIII inhibitors (0.6 BU/mL;
1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection 
of 1.0 BU/mL) who completed successful immune tolerance induction (ITI) at least 
5 years before screening must have no evidence of inhibitor recurrence (permanent or 
temporary), indicated by detection of an inhibitor, FVIII half-life 6 hours, or FVIII 
recovery 66% since ITI (Antun et al. 2015).
3.3.3
Rationale for Biomarker Assessments
Biomarkers to measure the PD effect of emicizumab on hemostasis have not been fully 
validated to date and require further testing to determine which assays and technical 
conditions are most suitable for use with emicizumab treatment.  Plasma samples will be 
collected for PD biomarker assessment in parallel with PK samples at all clinic visits to 
demonstrate evidence of biologic activity of emicizumab in patients and to support 
evaluation of the Q4W dosing regimen.  These PD biomarkers include, but are not 


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limited to, coagulation assays such as aPTT, thrombin generation, and FVIII activity 
assays.  All of these assays were previously shown in the Phase I/II study to exhibit a 
dose-response relationship to emicizumab concentration (for more information, see the 
RO5534262 [Emicizumab] Investigator’s Brochure).  The aPTT assay will be run both in 
standard form and with a modification to ensure that the assay range covers all levels of 
emicizumab exposure.  In addition, clot waveform analysis may be run as an exploratory 
PD coagulation assay.  Exploratory plasma biomarkers will include factor IX antigen 
(FIX:Ag) and factor X antigen (FX:Ag) to assess whether drug treatment causes a 
change in the circulating levels of these coagulation factors, which are the binding 
targets of emicizumab, and may include measurement of other coagulation or 
hemophilia-related factors as well.  Finally, remaining plasma samples will be banked for 
future emicizumab-related research and will be stored for no longer than 5 years after 
study closure.  No whole-blood samples will be collected except as used for local safety 
laboratory tests, and no DNA analysis will be performed in this study.  
3.3.4
Rationale for Patient-Reported Outcome Assessments
HRQoL is an important outcome in the care of patients with hemophilia 
(Brown et al. 2009).  HRQoL in patients with hemophilia is multifaceted and impacted by 
disease symptoms (i.e., pain, bleeding), treatment (i.e., prophylactic and on-demand), 
anxiety (around infusions), and limitations in daily activities. 
The goal of measuring HRQoL is to quantify the benefit of treatment from the patient 
perspective.  Previous studies with adolescent patients treated with prophylactic 
regimens have reported improvements in physical health, feelings, view of self, family 
relations, friend relations, perceived support, relation with others, participation in sports, 
dealing with hemophilia, views of treatment, views of the future, and relationships 
(Santagostino et al. 2014).  Improvements in physical health, feelings, view of self, and 
participation in work and school have also been observed in adults treated with 
prophylactic regimens (Stasyshyn et al. 2014).
The inclusion of HRQoL measures in the current study will allow for the longitudinal 
assessment of the impact of prophylactic treatment with emicizumab in adolescents and 
adults with hemophilia A and an evaluation of any changes from their baseline 
assessment.
The study will also include a measure designed to capture patient preference with 
treatment.  Previous studies have noted that patients express preference for treatments 
that do not have negative effects (e.g., pain that results from infusions), are not time 
consuming, are not inconvenient, and have a goal of achieving a “normal life” 
(Cimino et al. 2014).  The inclusion of a fit-for-purpose preference survey after treatment 
with emicizumab will provide information on whether SC is preferred to IV administration 
and explore potential underlying reasons. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 46 patients with congenital hemophilia A previously treated with either 
FVIII or bypassing agents will be enrolled in the study (6 patients in the PK run-in phase 
and 40 patients in the expansion phase). 
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (consent/assent will be taken as appropriate)

Aged 12 years

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the patient-reported outcome (PRO) 
questionnaires and bleed diaries through the use of an electronic device 

Body weight 40 kg at screening 

Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors 

Patients using rFVIIa or willing to switch to rFVIIa as primary bypassing agent for 
the treatment of breakthrough bleeds

FVIII inhibitor test during screening with titer results available prior to first 
administration of study drug

Patients without FVIII inhibitors (0.6 BU/mL; 1.0 BU/mL only for laboratories with 
an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) who completed 
successful ITI must have done so at least 5 years before screening and must have 
no evidence of inhibitor recurrence (permanent or temporary) indicated by detection 
of an inhibitor 0.6 BU/mL (1.0 BU/mL only for laboratories with an historical 
sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI

For patients to be enrolled into PK run-in cohort:
Current episodic treatment (FVIII or bypassing agents) at the time of entry 
into this study and documentation of details of episodic treatment for at 
least 24 weeks prior to entry into this study

For patients to be enrolled into the expansion cohort:
Documentation of details of prophylactic or episodic treatment (FVIII or 
bypassing agents) and the number of bleeding episodes for at least 
24 weeks prior to entry into this study
For patients on an episodic regimen, 5 bleeds in the prior 24 weeks, 
regardless of inhibitor status

Adequate hematologic function, defined as a platelet count 100,000/L and 
hemoglobin 8 g/dL (4.97 mmol/L) at the time of screening


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
Adequate hepatic function, defined as total bilirubin 1.5age-adapted upper limit 
of normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT 
3age-adapted ULN at the time of screening, and no clinical signs or known 
laboratory/radiographic evidence consistent with cirrhosis 

Adequate renal function, defined as serum creatinine 2.5age-adapted ULN and 
creatinine clearance 30 mL/min by Cockcroft-Gault formula 

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use highly effective contraceptive methods that result in 
a failure rate of 1% per year during the treatment period and for at least 
5 elimination half-lives (24 weeks) after the last dose of study drug
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (1 year of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus)
Examples of highly effective contraceptive methods with a failure rate of 
1% per year include proper use of combined oral or injected hormonal 
contraceptives, bilateral tubal ligation, male sterilization, hormone-releasing 
intrauterine devices, and copper intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) 
may be combined to achieve a failure rate of 1% per year.  Barrier 
methods must always be supplemented with the use of a non-lipid-based 
spermicide
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods for 
contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

Ongoing or planned ITI therapy; patients in whom ITI has failed will be eligible with a 
72-hour washout period prior to the first emicizumab administration

History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment

Patients who are at high risk for TMA (e.g., have a previous medical or family history 
of TMA), in the investigator’s judgment

Previous (within the last 12 months) or current treatment for thromboembolic 
disease (with the exception of previous catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic 
disease


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
Other conditions (e.g., certain autoimmune diseases) that may currently increase 
the risk of bleeding or thrombosis

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Planned surgery (excluding minor procedures such as tooth extraction or incision 
and drainage) during the study 

Known HIV infection with CD4 counts 200 cells/L
HIV infection with CD4 counts 200 cell/L permitted

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use 
during the study, with the exception of anti-retroviral therapy

Concomitant disease, condition, significant abnormality on screening evaluations or 
laboratory tests, or treatment that could interfere with the conduct of the study, or 
that would, in the opinion of the investigator/co-investigator, pose an additional 
unacceptable risk in administering study drug to the patient  

Receipt of any of the following:
Emicizumab in a prior investigational study
An investigational drug to treat or reduce the risk of hemophilic bleeds
within 5 half-lives of last drug administration
A nonhemophilia-related investigational drug within last 30 days or 
5 half-lives, whichever is shorter
Any other investigational drug currently being administered or planned to 
be administered 

Inability to comply with the study protocol in the opinion of the investigator

Pregnancy or lactation or intention to become pregnant during the study

Women with a positive serum pregnancy test result within 7 days prior to initiation of 
study drug
4.2
METHOD OF TREATMENT ASSIGNMENT 
The study is open label and consists of two cohorts and two parts:  a PK run-in part and 
an expansion part.  The first 6 patients will be assigned to the PK run-in part.  An 
analysis of pharmacokinetics and safety will be conducted for these patients when the 
last patient has reached 6 weeks’ treatment duration.  Until this analysis, recruitment is 
paused and will be re-opened to recruit into the expansion cohort only if the safety and 
PK data of the PK run-in cohort support the study to proceed as planned.  


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4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is emicizumab (RO5534262).
4.3.1
Formulation, Packaging, and Handling
Emicizumab (RO5534262) will be supplied by the Sponsor as a sterile liquid for SC 
injection, contains no preservatives, and requires storage at 28° Celsius (do not freeze 
and protect from light).  Each single-use vial contains 150 mg (nominal) of emicizumab 
at pH 6.0.  The Drug Product is formulated as 150 mg/mL emicizumab in 150 mmol/L 
arginine, 0.5 mg/mL poloxamer 188, 20 mmol/L histidineaspartic acid buffer (pH 6.0).  
For further information on the formulation and handling of emicizumab, see the 
Investigator's Brochure. In order to minimize the number of injections for patients in 
certain weight categories, the administration per single injection of up to 2 mL of drug 
product solution will be permitted.  This will require pooling of emicizumab drug product 
solution from up to two 1-mL vials into a single syringe using a new transfer needle for 
each vial.  The detailed procedure for vial pooling is described in the Instructions for 
Use.
4.3.2
Dosage, Dose Adjustments, Administration, and Compliance
4.3.2.1
Subcutaneous Emicizumab
The emicizumab regimen being tested is 3 mg/kg QW for 4 weeks followed by 6 mg/kg
Q4W subcutaneously for 24 weeks. For patients on 6 mg/kg Q4W who missed a dose, 
emicizumab should be administered as soon as possible but no later than 14 days from 
planned administration day. If more than 14 days have passed, the patient should take 
the next dose of emicizumab at the next scheduled date. In all cases, the study 
medication dosing will proceed in accordance with the original dosing schedule.
All patients with suboptimal control of bleeding (2 qualifying bleeds within 24 weeks on 
emicizumab treatment) may have the opportunity to increase their emicizumab 
maintenance dose to 3 mg/kg QW starting at Week 25, if they receive approval from the 
Medical Monitor (see Section 3.1.2). 
If the investigator believes that a specific patient warrants dose escalation based on a 
different reason, he or she may discuss the case with the Medical Monitor for 
consideration and potential approval.
An increase of the emicizumab dose to 3 mg/kg QW can occur at the next scheduled 
emicizumab administration of the initial regimen (4 weeks from the last dose of a Q4W 
regimen).  


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The option to go back to a lower dose regimen as per investigator and patient discretion 
will remain and a decrease of the emicizumab dose from 3 mg/kg QW to a regimen that 
is 6 mg/kg Q4W or 3 mg/kg Q2W or 1.5 mg/kg QW is allowed.  A change from 3 mg/kg 
QW to 6 mg/kg Q4W can be initiated 2 weeks after the last dose; whereas, a change 
from 3 mg/kg QW to 3 mg/kg Q2W or 1.5 mg/kg QW can be initiated at the next 
scheduled treatment of the QW dosing regimen.
During study prolongation, each patient may choose a preferred emicizumab dosing 
regimen among those permitted (i.e., emicizumab 1.5 mg/kg QW, 3 mg/kg Q2W, or 
6 mg/kg Q4W) and continue on that dosing regimen until discontinuation from the 
study.  A change from 6 mg/kg Q4W to 1.5 mg/kg QW or 3 mg/kg Q2W can be 
initiated at the next scheduled treatment of the Q4W dosing regimen. A patient may 
switch dosing regimens only once.  However, if the investigator believes that a patient 
warrants an additional change in dosing regimen, he or she may discuss the case with 
the Medical Monitor for consideration and potential approval.
For patients in the PK run-in cohort, all drug administrations in Weeks 125 will be 
conducted at the investigational site by an HCP.  Patients who remain in the study after 
Week 25 will have the option to self-administer emicizumab at home if patient’s ability to 
self-administer the study drug is documented in the source data, except on days when 
PK assessment is planned (see Appendix 2). On these days, emicizumab should be 
administered at the investigational site after the PK sample has been drawn.
Patients in the expansion cohort will also need to come to the site at all times of drug 
administration in Weeks 125 because predose PK and PD samples have to be drawn.  
Therefore, all SC injections will be performed at the site until Week 25 (unless mobile 
nursing [MN] is implemented; see Section 4.5).  However, unassisted self-administration 
of the drug at the investigational site will be supported for patients in the expansion 
cohort, and patients remaining in the study after Week 25 might have the option to 
self-administer emicizumab at home. On days when PK samples are to be collected 
(see Appendix 2), emicizumab should be administered at the investigational site after the 
PK sample has been drawn.
Patients/caregivers will be required to complete in-person, instructional training on how 
to administer emicizumab as an SC injection.  Patients/caregivers will be taught to 
perform the injections utilizing the Instructions for Use document.  They will observe at 
least one SC injection performed by an HCP and will need to successfully administer at 
least one SC injection under an HCP’s watch prior to starting unassisted 
self-administration.  
Details on the devices to be used for study medication withdrawal from vial and SC 
injection are provided in the Pharmacy Manual.


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Any dose modification will be determined from emicizumab data entered into the 
electronic, handheld device. Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.12.
Patients will be observed for a minimum of 60 minutes after the first three doses as 
described in Section 5.1.2.2.  Patients/caregivers will be instructed on how to recognize 
signs/symptoms of hypersensitivity (including anaphylaxis) and obtain emergency care 
in the event of such reactions occurring.  Each site will have the discretion to provide 
additional training or include additional observation (e.g., after the fourth and fifth doses), 
if deemed appropriate, and each patient/caregivers will be able to ask any question he or 
she may have prior to being deemed capable of performing SC emicizumab injections.  
If, despite additional training, the investigator determines that the patient/caregivers is 
unable to inject emicizumab, a trained and proficient caregiver or HCP should be 
identified to administer the SC injections.
Patients and/or the caregivers will be provided with alert cards, which they will be 
requested to carry at all times.  These will include guidance on recognizing 
signs/symptoms of thromboembolic events or allergic/anaphylactic/anaphylactoid 
reactions and how to obtain emergency care. 
The Sponsor is currently evaluating the option to provide MN support during the study 
for patients in the expansion cohort (see Section 4.5). 
4.3.3
Investigational Medicinal Product Accountability
Emicizumab, the only IMP in this study, is required for completion of this study and will 
be provided by the Sponsor.  Accountability for each vial is required throughout the study.  
The study site will acknowledge receipt of IMPs, using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Emicizumab 
The Sponsor will offer post-study access to the study drug (emicizumab) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.


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A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or would not 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for patients with hemophilia A

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for hemophilia A

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
4 weeks prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF page.  Medications given to treat a bleed (e.g., rFVIIa or aPCC) will 
be reported only via the electronic, handheld device, except for FVIII taken in the week 
prior to starting emicizumab by patients without inhibitors to FVIII who will continue their 
prior FVIII prophylaxis until the second loading dose of emicizumab.  For these patients 
only, FVIII treatments taken in the week prior to the first dose of emicizumab will be 
recorded on the Concomitant Medication eCRF page.
4.4.1
Permitted Therapy
Concomitant use of the following drugs and therapies will be permitted:

For patients in the expansion cohort who are on FVIII prophylaxis, they may 
continue their regular FVIII prophylaxis until the second emicizumab loading dose in 
order to avoid bleeds before adequate emicizumab level is reached.  Concomitant 
routine FVIII prophylaxis is not otherwise permissible during the study. 


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
Drugs intended to control bleeds, including FVIII concentrates (non-inhibitor patients) 
or rFVIIa (inhibitor patients), should be used at the lowest dose expected to achieve 
hemostasis.  Given that circulating emicizumab may increase patients’ coagulation 
potential, the doses required to achieve hemostasis may be lower than the FVIII or 
bypassing agent doses used prior to starting the study.
Caution should be taken for patients who are using rFVIIa (e.g., consideration of 
using no more than 90 g/kg rFVIIa as an initial dose).
Use of aPCC in combination with emicizumab should be avoided completely in 
patients who have the option of using other bypassing agents to treat bleeds. In 
the event that aPCC is the only available bypassing agent, the lowest dose 
expected to achieve hemostasis should be prescribed with no more than 
50 units/kg of aPCC to be administered as an initial dose.  For patients receiving 
aPCC prior to study entry, a washout period of 72 hours prior to first emicizumab 
dosing is required.
Other bypassing agents (e.g., Byclot) should be avoided.  In cases where such 
agents are the only available bypassing agent, the lowest dose expected to 
achieve hemostasis should be prescribed, with no more than the lowest dose 
described in the prescribing information to be administered as an initial dose 
(e.g., no more than 60 g/kg of Byclot).  For patients receiving Byclot prior to 
study entry, a washout period of 72 hours prior to first emicizumab dosing is 
required.

Exact dose and schedule of FVIII or bypassing agents should be discussed with 
patients at the beginning and throughout the study.  Repeated dosing of FVIII, 
rFVIIa, aPCC, or other bypassing agents should be performed only under medical 
supervision and consideration should be given to verifying bleeds prior to repeated 
dosing. For rFVIIa, aPCC, and other bypassing agents, laboratory monitoring by 
additional local and central laboratory assessments should be performed as per the 
schedule of assessments (see Appendix 1).

Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in 
patients receiving emicizumab.

Drugs and therapies to treat adverse events and use of topical antiseptics, 
anesthetics, eye drops, and so on, that are not considered to result in systemic 
exposure 

Drugs to treat an existing medical condition ongoing at study entry that do not 
violate the eligibility criteria (e.g., anti-retroviral therapy for HIV infections)
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited for at least 4 weeks prior to initiation of 
study treatment, during the study, and until last observation (except for aPCC and 
Byclot that require a washout period of 72 hours prior to study treatment and can be 
used for the treatment of breakthrough bleeds during the study as per guidance in 
Section 4.4.1):


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
Drugs that would affect hemostasis (e.g., aspirin, non-steroidal anti-inflammatory 
drugs that are not selective or preferential COX-2 inhibitors, or anticoagulants [other 
than to flush, dwell, or de-clot a venous access device])
Drugs intended to control bleeding episodes or used in the context of minor 
surgery (e.g., tooth extraction) or injuries (e.g., concussion) to prevent 
deterioration or given if deemed medically necessary for management of certain 
conditions (e.g., post cardiac surgery) are permitted.

Systemic immunomodulators (e.g., rituximab, interferon) other than anti-retroviral 
therapy 

Elective surgery (excluding minor procedures such as tooth extraction or incision 
and drainage as well as emergency surgeries)

Use of other investigational drugs

Use of aPCC for short-term prophylaxis
Use of concomitant prophylactic regimen with FVIII or rFVIIa (short-term 
prophylaxis [e.g., around the time of surgery], however, is permitted)

Use of anti-fibrinolytics in conjunction with aPCC or Byclot
If prohibited therapy is administered for any reason, it should be recorded on the eCRF.  
If prohibited treatment is prescribed or considered medically necessary, the Medical 
Monitor should be consulted to discuss any changes in the benefit/risk and determine 
whether the patient should continue on the study.
4.5
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study.
The Sponsor may consider providing MN support.  If the Sponsor decides to provide MN 
support, at applicable sites and for patients in the expansion cohort only, certain study 
assessments during the study may be performed by an MN professional at the patient's 
home or another suitable location, such as his or her school or office, to improve access 
and convenience for patients participating in the study.  The Sponsor may select a 
healthcare company that will be responsible for providing MN services for participating 
sites (the MN vendor).  The MN vendor will be responsible for ensuring that all MN 
professionals are licensed, qualified, and in good standing, as per applicable regulations, 
and that appropriate background checks have been performed.  If the investigator at a 
participating site determines that MN services are appropriate for a patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient’s site.  MN visits will be scheduled on 
specified visit days, to allow for relevant assessments to be performed by the MN 
professional.  


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.  
For adolescents (i.e., 1217 years of age), an Informed Assent Form will be completed 
instead.  Parents or legally authorized representatives of adolescents will also complete 
an Informed Consent Form.
All screening evaluations must be completed within 4 weeks prior to the first dose and 
reviewed to confirm that patients meet all eligibility criteria before enrollment.  The 
investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, procedures, use of alcohol and 
drugs of abuse within the past year, and medication allergies.  In particular, sites should 
record whether the patient has any history of prior ITI, anaphylaxis, or known 
thrombophilia.  It should also include all medication taken in the 4 weeks prior to 
enrollment (including prescription, over-the-counter, and herbal/homeopathic remedies 
and therapies).  Finally, all bleed information (i.e., start date, cause, type, location), 
number of school/work days missed, and number of days hospitalized during the 
24 weeks prior to study entry should be documented.
Demographic data will include age, sex, and self-reported race and ethnicity.
4.5.3
Physical Examinations
A complete physical examination should include, but not necessarily be limited to, the 
evaluation of head, eye, ear, nose, and throat and include cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems, 
height, and weight.  Any abnormality identified during screening should be recorded on 
the General Medical History and Baseline Conditions eCRF.  Subsequently, a targeted 
(i.e., musculoskeletal, dermatological) and/or symptom-driven examination should be 
conducted as noted in the schedule of assessments or as clinically indicated.  New or 
worsened abnormalities from screening should be recorded as adverse events, if 
appropriate.
4.5.4
Vital Signs
Vital signs will include measurement of heart and respiratory rate, temperature, and 
systolic and diastolic blood pressure and should be recorded before study drug 
administration.  Frequency of vital sign assessments should follow the schedule of 
assessments but may also be taken anytime as unscheduled assessments as judged by 
the investigator.


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4.5.5
Laboratory, Biomarker, and Other Biological Samples
Local laboratory assessments will be performed as indicated on the schedule of 
assessments.  On days of study drug administration, laboratory samples should be 
drawn before the administration of study drug.  In the PK run-in, no deviation from 
defined drug administration visits is allowed until Week 25.  Deviations from the 
schedule of assessments of 2 days are acceptable after Week 25 in the PK run-in 
cohort. For the expansion cohort, deviations from the schedule of assessments of 
2 days are acceptable; however, predose PK and PD sample collection and drug 
administration should coincide.  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells], mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width)

Serum chemistries (sodium, potassium, glucose, blood urea nitrogen, creatinine, 
calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine 
aminotransferase, aspartate aminotransferase, and alkaline phosphatase) 

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening and within 7 days 
prior to initiation of study medication, if applicable
Urine pregnancy tests will be performed at specified subsequent visits.  If a 
urine pregnancy test result is positive, it must be confirmed by a serum 
pregnancy test.
In the event of use of a bypassing agent, the following local laboratory tests will be 
performed within 2448 hours of initial bypassing agent administration so the 
investigator may monitor for potential thromboembolic events and thrombotic 
microangiopathy:  platelet count, serum creatinine, LDH, and schistocytes. A plasma 
sample should also be provided for local and central laboratory monitoring of 
prothrombin fragment 12, fibrinogen and D-dimer.  If the test for prothrombin fragment 
12 is not available at the site, the sample should be sent to the local reference 
laboratory, if available.  For patients who require multiple doses of bypassing agents, 
laboratory monitoring should be performed every 2448 hours thereafter until 
2448 hours following the last dose of bypassing agents.  If applicable, laboratory results 
should be recorded in the Following Treatment with Bypassing Agents eCRF.
The following samples will be sent to the Sponsor or a designee for centralized analysis:

Plasma samples for PK analysis

Plasma samples for immunogenicity assessment (anti-drug antibody [ADA])


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
Plasma samples for anti-FVIII antibody measurement (inhibitor titer) will be sent to 
the Sponsor throughout the study, with the exception of the test needed at 
screening for patients who do not have a documented inhibitor test result within 
4 weeks prior to enrollment, per inclusion criteria (see Section 4.1.1).

Plasma for PD and exploratory PD biomarker assessments (aPTT, PT, FVIII activity, 
thrombin generation, FIX:Ag, FX:Ag, and others as listed in Appendix 2).

Plasma aliquot for central laboratory assessment of fibrinogen, D dimer, and 
prothrombin fragment 1.2, collected after administration of bypassing agents (as 
listed in Appendix 1, schedule of assessments, in the footnotes).  This sample is 
addition to the local laboratory monitoring after bypassing agent use as described 
above.
For patients who have received FVIII or bypassing agents during hospitalization 
(e.g., because of surgery, treatment for severe bleeds, etc.) or on the day of an 
unscheduled visit at investigational site, further blood samples will be collected as 
follows:

Plasma samples for PK analysis

Plasma for exploratory PD biomarker assessments:  FVIII activity (human 
chromogenic test) and thrombin generation assay)
For patients who have received FVIII, FVIII activity will be also measured using 
a bovine chromogenic test.
The blood sampling should be performed within 30 minutes to 24 hours after FVIII or 
bypassing agent administration on days hospitalized or attendance at investigational site.  
In case patient receives multiple administrations of coagulation factors, blood sampling 
should be performed after each administration. If multiple administrations occur on the 
same day, only one blood sample should be drawn per day. For patients who have 
received FVIII or bypassing agents on the day of scheduled visits, this analysis will be 
performed as part of PK and PD analyses.  Therefore, no additional blood sampling is 
required. In certain instances, blood draws may be performed by an MN professional 
(see Section 4.5).
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling Manual. 
4.5.5.1
Pharmacokinetic Samples
Blood samples for determination of plasma concentrations of emicizumab will be 
collected as specified in the schedule of assessments (see Appendix 1) and will be sent 
to the Sponsor or a designee for centralized analysis.
Emicizumab plasma concentrations will be measured by a specific and validated 
enzyme-linked immunosorbent assay (ELISA) method.  For blood draws, when the PK 
assessment is scheduled for the same nominal time as another scheduled assessment, 
the PK sample will take precedence.


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Details on sampling procedures, sample storage, and shipment are given in the Sample 
Handling Manual.
4.5.6
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1). 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  The following parameters will be 
obtained (and reported by the instrument): QT, RR, HR, QTcB, QTcF, PR and QRS and 
T- and U-wave morphology.  ECG recordings must be performed after the patient has 
been resting in a supine position for at least 10 minutes.
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
Any ECG changes that are associated with symptoms or lead to a change in study 
treatment or concomitant treatment, or discontinuation from study treatment must be 
reported as an adverse event on the adverse event eCRF.  The investigator or designee 
must review, sign, and date all ECG tracings.  The ECG may be repeated if investigator 
deems it appropriate.  Paper copies will be kept as part of the patient’s permanent study 
file at the site.  During the study, the Sponsor may request copies of ECGs to be 
submitted to the Sponsor or a Central Vendor.  Centralized ECG reading and 
interpretations will not be performed unless safety concerns arise.
4.5.7
Patient-Reported Outcomes
A data collection modality via an electronic, handheld device will be employed.  To 
capture PRO data during study treatment, patients will complete the HRQoL, health 
status, preference questionnaires, and questions related to the number of missed days 
of school or work electronically at study sites during the specified visits.  The instructions 
for completing the PRO questionnaires electronically will be provided by the investigator 
staff.  The data will be transmitted via a pre-specified transmission method (e.g., Web or 
wireless) automatically after entry to a centralized database at the electronic, handheld 
device vendor.  The data can be accessed securely by appropriate study personnel via 
the Internet.  In case the device is not available, paper questionnaires might be used. 
HRQoL
The Haem-A-QoL and the Haemo-QoL-SF will be used to measure HRQoL in adults and 
adolescents, respectively (see Appendix 5 and Appendix 6).  The Haem-A-QoL was 
designed for adult patients with hemophilia.  It consists of 46 items comprising 


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10 dimensions (physical health, feelings, view, sport and leisure time, work and school, 
dealing, treatment, future, family planning, and relationships/partners) and a scale 
representing total score.  Items are rated along 5 response options, although for some 
items there is also a ‘not applicable’ option (von Mackensen and Gringeri 2005; 2010). 
The Haemo-QoL has been developed in a series of age-related questionnaires to 
measure health-related quality of life in children and adolescents with hemophilia 
(Bullinger et al. 2002; von Mackensen and Bullinger 2004; Pollak et al. 2006).  These 
versions include a 77-item long form, a 35-item as well as a 16-item short form, and an 
8-item index form.  The short version for older children (817 years) containing 35 items 
was selected for adolescents in this study. This version covers nine dimensions 
considered relevant for the children’s HRQoL (physical health, feelings, view of yourself, 
family, friends, other people, sports and school, dealing with hemophilia and treatment).  
Items are rated with five respective response options: never, seldom, sometimes, often, 
and always.  Higher scores for both HRQoL measures are indicative of poorer HRQoL. 
Health Status
The EQ-5D-5L (see Appendix 7), is a self-reported health status questionnaire that 
consists of six questions used to calculate a health utility score for use in health 
economic analysis (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; 
Janssen et al. 2013).  There are two components to the EQ-5D-5L:  a five-item health 
state profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale (VAS) that measures health state.  
Published weighting systems allow for creation of a single summary score.  Overall 
scores range from 0 to 1, with low scores representing a higher level of dysfunction.  The 
EQ-5D-5L will be utilized in this study for economic modeling.
Missed Days of School or Work
Patients will also be asked to document the number of days of school or work missed in 
the previous 4 weeks at the timepoints outlined in the schedule of assessments 
(see Appendix 1).
Patient Preference
Patient preference will be assessed through the Preference Survey, which asks patients 
to report which treatment they would prefer to continue to receive after having been 
treated with IV FVIII or bypassing agents (episodic or prophylaxis) prior to study entry 
and SC emicizumab during the study.  Patients who express a preference are then 
asked to identify which reasons may have influenced their decision and indicate the top 
three reasons for their choice.  Patients will complete this questionnaire at Week 17 on 
emicizumab. 


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4.5.8
Bleed Definitions
Definition of a Bleed
For the purpose of the efficacy analyses, a standardized definition of bleed, adapted 
from criteria defined by the Subcommittee on Standards and Criteria, FVIII/FIX 
subcommittee of the International Society of Thrombosis and Hemostasis, and similar to 
that used in a recent clinical study, will be utilized in this study (Blanchette et al. 2014; 
Mahlangu et al. 2014). 

An event is considered a bleed if coagulation factors are administered to treat signs 
or symptoms of bleeding (e.g., pain, swelling, etc.). An additional definition of all 
reported bleeds (irrespective of treatment with coagulation factors) will be applied 
for a separate analysis.

Bleeds starting from the first sign of bleed and ending 72 hours after the last 
treatment for the bleed, within which any symptoms of bleeding at the same location 
or injections are 72 hours apart, are considered the same bleed.

Any injection to treat the bleed, taken 72 hours after the preceding injection, is 
considered the first injection to treat a new bleed at the same location.

Any bleed at a different location is considered a separate bleed regardless of time 
from last injection.
Definitions of Bleed Sites

Target joints:  defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and 
ankle) into which repeated bleeds occur (frequency of 3 bleeds into the same joint 
over the last 24 weeks prior to study entry)

Joint bleeds are defined as bleeds with bleed type “joint bleed” reported via the 
bleed/medication questionnaire with at least one of the following symptoms:
Increasing swelling or warmth of the skin over the joint
Increasing pain
Progressive loss of range of motion or difficulty in using the limb as 
compared with baseline

Muscle bleeds (sites as per the bleed/medication questionnaire)

Other (sites as per the bleed/medication questionnaire)
Definitions of Bleed Types
In addition, the assessment of a bleed will be separated into spontaneous bleeds, 
traumatic bleeds and bleeds related to procedure/surgery.  Both spontaneous bleeds 
(i.e., the occurrence of hemorrhage where neither the patient nor a caregiver can identify 
a reason) and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such 
as trauma, “strenuous” activity, or “overuse”) will be collected.


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
Spontaneous bleeds:  Bleeds should be classified as spontaneous if a patient 
records a bleed when there is no known contributing factor such as definite trauma, 
antecedent “strenuous” activity or “overuse.”  The determination of what constitutes 
“strenuous” or “overuse” will be at the discretion of the patient.  For example, light 
jogging may be considered “non-strenuous” while sprinting may be considered 
“strenuous,” lifting of weights for a short period of time may be considered 
“moderate use” while repetitive weightlifting may be considered “overuse.” 

Traumatic bleeds:  Bleeds should be classified as traumatic if a patient records a 
bleed when there is a known or believed reason for the bleed.  For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 
obvious injury, the bleed would be recorded as a traumatic bleed because, although 
no injury occurred, there was antecedent “strenuous” activity.  Bleeds subsequent to 
injuries would certainly be classified as traumatic.  

Bleeds related to procedure/surgery:  such as hematomas resulting from any 
surgeries or invasive procedures (e.g., tooth extractions, venipuncture, or SC drug 
administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy, etc.) would not be counted 
as bleeds.  Bleeds related to procedure/surgery are not associated with any trauma 
except procedure/surgery-induced trauma.  
Patients (or their legally authorized representative) will complete a bleed/medication 
questionnaire weekly and whenever a bleed occurs via an electronic, handheld device.  
For each bleeding episode, they will provide information on the above topics as well as 
on the medication used to treat the bleed.  Hemophilia medications that were taken will 
also be collected through the bleed/medication questionnaire.  If the electronic, handheld 
device is not available, a paper questionnaire might be used.  Investigators will review 
the bleed and bleed medication data as per the schedule of assessments 
(see Appendix 1) and have the option to correct or complete these in agreement with the 
patient via a Data Request Form process or via a Web-based portal, once implemented.  
The Sponsor will have view-access only but will do a review of the bleed and bleed 
medication data as per the Medical Data Review Plan.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient’s inability or unwillingness to comply with protocol requirements 
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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients participating in the PK run-in cohort who withdraw from 
the study will be replaced if they withdraw prior to being in the study for 6 weeks.  
Patients participating in the expansion cohort who withdraw at any time will not be 
replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience the following:

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
If the patient discontinues study treatment, bleed and bleed medication data should be 
provided by the patient via the electronic handheld device until the safety follow-up visit 
(24 weeks after last study drug administration).
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Emicizumab is currently in clinical development and is not approved.  Thus, the 
complete safety profile is not known at this time.  The safety plan for this study is 
designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below.  Please refer to the RO5534262 
(Emicizumab) Investigator’s Brochure for a complete summary of safety information. 
5.1.1
Patient Selection
The inclusion and exclusion criteria in this study are designed to select patients who are 
not at increased risk based on the current understanding of the investigational 
medication.  See Section 4.1.1 and Section 4.1.2 for full inclusion and exclusion criteria, 
respectively.
5.1.2
Risks Associated with Emicizumab
5.1.2.1
Injection-Site Reactions
In the completed and ongoing Japanese studies, injection-site reactions have been 
observed in some patients with hemophilia A.  These local injection-site reactions 
included injection-site erythema, injection-site hematoma, injection-site rash, 
injection-site discomfort, injection-site pain, and injection-site pruritus.  All local
injection-site reactions were of mild intensity.  Further details of the observed 
injection-site reactions are available in the RO5534262 (Emicizumab) Investigator’s 
Brochure.
Directions for emicizumab administration should be followed as outlined in Section 4.3.2. 
5.1.2.2
Hypersensitivity Reaction, Anaphylaxis, Anaphylactoid 
Reaction
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, 
including anaphylaxis and anaphylactic reactions, may occur.  In completed and ongoing 
clinical studies of emicizumab, no severe hypersensitivity reactions have been reported.  
These events should be reported as serious adverse events or adverse events of special 
interest as described in Sections 5.2.2 and 5.2.3, respectively.
HCPs administering the study medication in the clinic must be trained in the appropriate 
administration procedures, be able to recognize the signs and symptoms associated with 
potential hypersensitivity, anaphylactic, and anaphylactoid reactions, and should be 
familiar with Sampson’s criteria for defining anaphylaxis (Sampson et al. 2006; see 
Appendix 3, Appendix 4, and Appendix 8).  HCPs should also instruct patients how to 
recognize the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid 
reactions and to contact an HCP or seek emergency care in case of any such 
occurrence.  Patients/caregivers will also receive two alert cards to remind them of this 
information and these instructions should any of these reactions occur. 


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For patients with a previous history of a clinically significant hypersensitivity reaction, 
after each of the first three doses, the site will call the patient 24 hours after each dose to 
assess the status of the patient.  Additional precautions following each of these doses 
may also be considered, including having an extended observation period or IV access 
prior to dosing, etc.  The investigator may include these or other precautions, as deemed 
appropriate. 
5.1.2.3
Hypercoagulation and Thromboembolic Events
As of May 2019, four thromboembolic events have been observed in 4 patients receiving 
emicizumab, as follows. One event of Grade 1 device occlusion (non-serious) was 
reported in 1 patient (Study BH29884). The event resolved and was assessed by the 
investigator as not related to emicizumab. Also in Study BH29884, 2 patients 
experienced a total of two serious thromboembolic adverse events (thrombophlebitis 
superficial and cavernous sinus thrombosis). In Study MO391291, 1 patient 
experienced a serious adverse event of acute myocardial infarction. Details of the
serious adverse events are described below.
The first patient from Study BH29884 experienced a right knee hemarthrosis and 
self-administered 200 units/kg/day of aPCC for 2 consecutive days.  The patient was 
hospitalized after a diagnosis (by MRI) of Grade 3 cavernous sinus thrombosis. No 
anticoagulation was administered; treatment with emicizumab was withheld. The 
patient was discharged after symptoms improved with supportive care. A follow-up 
MRI was normal with no evidence of thrombus, and the event was considered resolved. 
Treatment with emicizumab was restarted. The investigator assessed the event as being 
related to emicizumab and aPCC. 
The second patient from Study BH29884 experienced a spontaneous right knee 
hemarthrosis and self-administered 100 units/kg/day aPCC for 2 consecutive days. The 
patient placed ice over his right shin for several hours to treat pain. Extensive skin 
necrosis of the right shin and locally limited skin necrosis of the left shin subsequently 
developed. The patient was hospitalized and an ultrasound indicated superficial 
thrombosis of the right saphenous vein (no evidence of deep vein or arterial thrombosis). 
The patient was treated with supportive care and his condition improved. Emicizumab 
was permanently discontinued. The investigator assessed the skin necrosis as due to 
the thromboembolic event and related it to emicizumab and aPCC. Both skin necrosis 
(Grade 3) and thrombophlebitis superficial (Grade 2) were reported as recovering. 
The third patient, enrolled in Study MO39129, presented with chest pain, sweating and 
pallor and was diagnosed with ST-elevation myocardial infarction on Day 235 of the 
study. ECG showed ST elevation, right bundle branch block, and inferior Q waves. 
Troponin was 0.46 ng/ml (reference range: 0.04 ng/ml). Coronarography 
demonstrated stenosis of the right coronary artery due to thrombotic subocclusion. 
Treatment included stent, unfractionated heparin, clopidogrel, and aspirin. The event 
resolved after 5 days and treatment with emicizumab was maintained. 


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Hypercoagulation and thromboembolic events should be reported as Serious Adverse 
Events or Adverse Events of Special Interest as described in Sections 5.2.2 and 5.2.3, 
respectively.  HCPs should educate patients/caregivers to recognize signs and 
symptoms of potential thromboembolism (i.e., dyspnea, chest pain, leg pain or swelling, 
etc.) and ensure that they understand the importance of seeking appropriate medical 
attention.  Patients/caregivers will also receive two alert cards to remind them of this 
information and these instructions should thromboembolism be suspected.
5.1.2.4
Thrombotic Microangiopathy
Thrombotic microangiopathy is used to describe a group of disorders with clinical 
features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage 
that can include the kidneys, gastrointestinal system, or central nervous system, etc.  As 
of May 2019, 3 cases of TMA were observed in a Phase III clinical study involving 
patients with hemophilia A with inhibitors while receiving emicizumab.  The first patient 
self-administered 2 doses of aPCC 94 units/kg in 2 days to treat his left knee 
hemarthrosis.  The next day, he started experiencing icterus and severe back pain and 
the patient self-administered 2 doses of rFVIIa 85 g/kg and 2 doses of aPCC 94 
units/kg.  Then the patient presented with thrombocytopenia, hyperbilirubinemia, and 
acute renal failure with schistocytes on peripheral blood smears.  The patient was 
diagnosed with aHUS and treated with plasmapheresis, hemodialysis, and supportive 
care and his condition improved and resolved after 15 days.  The patient discontinued 
treatment with emicizumab.  The second patient self-administered 5 doses of aPCC 74 
units/kg over 3 consecutive days before the serious adverse event onset.  The patient 
had abdominal pain and emesis, acute renal failure, thrombocytopenia, elevated LDH, 
and a low haptoglobin with schistocytes on peripheral blood smears.  The patient was 
diagnosed with aHUS and recovered without plasmapheresis or hemodialysis after 9 
days.  The patient restarted treatment with emicizumab approximately 10 days after 
resolution of the serious adverse event.
The third patient presented at the hospital complaining of rectal bleeding, postural 
dizziness, and exertional dyspnea.  Of note, the patient declined receipt of blood and 
blood products throughout his hospital course.  Multiple doses of rFVIIa were 
administered and various interventions (hemostatic powder application, absorbable 
hemostat packing, and embolization of rectal arteries) were used in an attempt to control 
bleeding.  Despite these measures, the patient continued to have rectal hemorrhage.  
The patient’s bypassing agent treatment was then changed to aPCC and temporary 
cessation of bleeding was achieved.  Subsequently, the patient developed an serious 
adverse event of thrombotic microangiopathy following concomitant bypassing agent 
treatment.  Emicizumab prophylaxis and aPCC were discontinued and therapeutic 
plasma exchange with albumin was provided.  Three days later, investigators assessed 
the patient’s thrombotic microangiopathy to be improving based on laboratory 
assessments (LDH and platelet count).  However, the patient experienced recurrent 
rectal hemorrhage.  Surgery and arterial embolization were no longer deemed to be 


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feasible and the patient was placed on comfort care before passing away the same day.  
The investigator assessed the patient death as related to the serious adverse event of 
rectal hemorrhage and unrelated to emicizumab, and the thrombotic microangiopathy as 
related to emicizumab and aPCC. For more details please refer to Investigator 
Brochure.
TMA events should be reported as serious adverse events or adverse events of special 
interest, see Sections 5.2.2 and 5.2.3, respectively. 
5.1.2.5
Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays Associated with 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII activity,
and FVIII inhibitor measurement by Bethesda assay) are not reliable and do not 
accurately reflect the patient’s underlying hemostatic status while receiving emicizumab 
prophylaxis (see Section 5.1.4). Due to the long t1/2 of emicizumab, these effects on 
coagulation assays may persist for up to 6 months after the last dose.
Practitioners, especially emergency care practitioners, should note that life-threatening 
bleeding caused by unreliable standard coagulation tests and inhibitor assays poses a 
risk for patients receiving emicizumab treatment.
Emicizumab’s mechanism of action and resulting interference was clearly demonstrated 
in a wide variety of coagulation laboratory tests approved for in vitro diagnostic use.  
Clinical trials also demonstrated the effects of emicizumab on laboratory tests.  
However, as of May 2019, no instances of under-treatment of bleeding events due to 
unreliable standard coagulation tests and inhibitor assays during and after emicizumab 
treatment were observed.


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5.1.3
Management of Specific Adverse Events
Table 1
Guidelines for Management of Specific Adverse Events
Event
Actions to Be Taken
Injection-Site Reaction

Injection-site reactions should be treated as clinically indicated.

Emicizumab should not be injected into areas where the skin is red, 
bruised, tender, or hard or into areas where there are moles or scars.  

In the clinic setting, patients will be monitored for signs of injection-site 
reactions in the period immediately following injections.  Patients will 
be given guidance on reporting injection-site reactions when 
administering drug at home or after they leave the clinic.
Hypersensitivity Reaction, 
Anaphylaxis, 
Anaphylactoid Reaction

Suspected cases should be fully evaluated and treated as clinically 
indicated.

Medicinal products for the treatment of hypersensitivity reactions (e.g., 
epinephrine, antihistamines, and glucocorticoids) and resuscitation 
equipment must be available for immediate use during the initial 
administrations in the infusion center, clinic, or hospital.

If a patient has symptoms of anaphylaxis or severe hypersensitivity, 
administration of study drug must be immediately stopped and 
treatment of the reaction be initiated. 

The investigator should contact the Medical Monitor to assess if the 
clinical benefit clearly outweighs the risk to determine if and when the 
patient should resume taking emicizumab and discuss the patient’s 
continued study participation.  If patient continues in the study, the 
next two scheduled doses must be in a monitored setting with at least 
a 60-minute observation period and resuscitation treatment 
immediately available.  After each of these two doses in the clinic, the 
site will call the patient 24 hours after each dose to assess status of 
the patient. 

Investigators may order any pertinent laboratory tests, including an 
unscheduled anti-drug antibody, in the event any of these reactions 
occur.
Hypercoagulation and 
Thromboembolic Events

Please see Section 4.5.5 for guidance on required laboratory 
monitoring in the event of use of bypassing agents.

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with thromboembolic events and immediately begin work-up 
and treatment, as per local guidelines.  

If a patient has a thromboembolic event, further administration of study 
drug should be interrupted.  Decision to resume emicizumab after a 
thromboembolic event must be discussed with and approved by the 
Medical Monitor. 
Thrombotic 
microangiopathy

Please see Section 4.5.5 for guidance on required laboratory 
monitoring in the event of use of bypassing agents. 

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with TMA and immediately begin work-up and treatment, as 
per local guidelines.  

If a patient has a TMA event, further administration of study drug 
should be interrupted.  Decision to resume emicizumab after an event 
of TMA must be discussed with and approved by the Medical Monitor.  


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Table 1
Guidelines for Management of Specific Adverse Events (cont.)
Event
Actions to Be Taken
Coagulation Disorder and 
Risk of Bleeding

HCPs should be vigilant for abnormal or unusual bleeding 
tendencies.  Coagulation tests or other work-up may be indicated if 
judged to be appropriate by the investigator.  If bleeding is observed, 
appropriate action as per local guidelines must be taken immediately.
HCPhealthcare provider; TMAthrombotic microangiopathy.
5.1.4
Interpretation of Coagulation Assays for Patients Receiving 
Emicizumab
Emicizumab interacts with standard laboratory assays used in the management of 
patients with hemophilia A.  In one-stage assays, emicizumab is associated with a 
supra-physiologically short time to clot formation and thus normalization of aPTT at 
subtherapeutic levels and an overestimation of true FVIII activity.  Emicizumab is not 
recognized or neutralized by FVIII inhibitors, and therefore FVIII inhibitors cannot be 
detected in patients receiving emicizumab by a functional test such as Bethesda or 
Nijmegen-Bethesda assays, which use a one-stage clotting-based readout.  Emicizumab 
activity cannot be detected by chromogenic assays using purified bovine coagulation 
proteins and can only be detected using an assay composed of human proteins.  See 
the RO5543262 (Emicizumab) Investigator's Brochure for additional details on which 
tests can be used and how the test results can be interpreted.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more 
severe form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of
an adverse event (e.g., rated as mild, moderate, or severe, or according to the World 
Health Organization [WHO] toxicity grading scale; see Section 5.3.3); the event itself 
may be of relatively minor medical significance (such as severe headache without any 
further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  These may include suspected or confirmed 
cases.  Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected.

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
(see Sampson’s Criteria in Appendix 3 and Appendix 4) 

Thromboembolic events

Microangiopathic hemolytic anemia or thrombotic microangiopathy (e.g., thrombotic 
thrombocytopenic purpura, hemolytic uremic syndrome)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).


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After initiation of study drug, all adverse events will be reported until the patient 
completes his or her last study visit.  After this period, the investigator should report any 
serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 3) will be used for assessing adverse 
event severity (WHO 2003).  Table 2 will be used for assessing severity for adverse 
events that are not specifically listed in the WHO toxicity grading scale.
Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2). 
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)


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
Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection-Site Reactions
Local adverse events that occur within 24 hours after study drug administration and are 
judged to be related to study drug injection should be captured as an “injection-site 
reaction” on the Adverse Event eCRF.  Associated signs and symptoms (e.g., 
injection-site erythema or injection-site rash) should be recorded on the dedicated 
Injection-Site Reaction eCRF.  If a patient experiences both a local and systemic 
reaction to the same administration of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF.  Only for local injection-site reactions should the 
dedicated Injection-Site Reaction eCRF be used to capture the individual 
signs/symptoms. 
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, other than injection-site reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF.  If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event of 
special interest the occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice in the absence of cholestasis or other cause of hyperbilirubinemia
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of hemophilia A.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of hemophilia A, "hemophilia A progression" 
should be recorded on the Adverse Event eCRF.  
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic Bleeds
Medical occurrences or symptoms of deterioration that are anticipated as part of 
hemophilia should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in terms of severity (e.g., increased number of doses of 
bypassing agents to stop bleeds with emicizumab, in the absence of neutralizing 
anti-emicizumab antibodies, compared with before study entry), frequency of bleeds, or 
nature of hemophilia at any time during the study.  Should any of these occur (according 
to the investigator’s clinical assessment), they should be documented as an adverse 
event on the Adverse Event eCRF, conveying that the underlying condition has changed 
by including applicable descriptors (e.g., "increased clinical severity of hemophilia").
Events that are clearly consistent with the anticipated pattern of the underlying disease 
and do not indicate an unexpected worsening in severity or frequency should not be 
recorded as adverse events.  These data will be reflected in efficacy assessment data 
only.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during 
the study when elective surgery became necessary because of the 
expected normal progression of the disease
The patient has not experienced an adverse event


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse could 
involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
emicizumab, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes
In addition, all special situations associated with emicizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.


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As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC).


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for all sites 
Medical Monitor
 M.D., M.A.S. (primary)
Telephone No.:
Medical Monitor
 M.D. (secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form with use of the fax number or e-mail address 
provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 24 weeks after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and e-mailing the form with 
use of the fax number or e-mail address provided to investigators.  Once the EDC 
system is available, all information will need to be entered and submitted via the EDC 
system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and e-mailing the form with 
use of the fax number or e-mail address provided to investigators.  Pregnancy should 
not be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
drug and counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Although embryo-fetal development studies are not available, condom use will not be 
required in male patients enrolled in the study because the margin between the minimal 
anticipated biological effect level (MABEL) plasma concentration (7 ng/mL) and the 
estimated maternal Cmax (at both 1.5 and 3 mg/kg QW dosing regimens) is greater than 
10-fold (Banholzer et al. 2012).  At this time, very little emicizumab is thought to transfer 
into semen, and there are no known reproductive risks to female partners of male 
patients treated with emicizumab, so contraception use by male patients is not required 
for participation in the study.  Therefore, no proactive collection of pregnancy information 
for female partners of male patients treated with emicizumab will be required.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 


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follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
24 weeks after the last dose of study drug or rollover to an extension study), if the event 
is believed to be related to prior study drug treatment.   
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and e-mailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form with use of the fax 
number or e-mail address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events (see Section 5.2.2) and 
adverse events of special interest (see Section 5.2.3) against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRBs, ECs, and applicable health authorities based on applicable 
legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO5534262 (Emicizumab) Investigator's Brochure


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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
No formal hypothesis testing is planned for this study.  All analyses will be descriptive.  
The 6 run-in patients will be analyzed separately from the expansion cohort.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size of 6 patients for the PK run-in cohort is considered appropriate to 
assess pharmacokinetics and safety to allow for an informed decision to open the 
subsequent expansion cohort with 40 additional patients.
The overall sample size of 40 patients in the expansion cohort is based primarily on 
clinical considerations taking into account the limited number of patients with 
hemophilia A. A sample size of 40 patients is expected to provide statistically robust 
point estimates with meaningfully narrow confidence intervals.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, etc.) will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  
6.4
EFFICACY ANALYSES
The efficacy objective is to evaluate the clinical effect of 6 mg/kg emicizumab Q4W 
based on the number of bleeds over time.  
6.4.1
Efficacy Endpoints
The key efficacy objective is to characterize the efficacy of 6 mg/kg emicizumab Q4W 
based on the number of bleeds over time for patients in the expansion cohort.


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The analyses will be performed using a negative binomial regression model, which 
accounts for different follow-up times, with the patient’s number of bleeds as a function 
of the time that each patient stays in the study included as an offset in the model. 
The number of bleeds will be also annualized (Annualized Bleeding RateABR) for 
each patient using the following formula: 
In case the negative binomial model does not converge the above formula will be used 
as the sole method of analysis.
The clinical effect of prophylactic emicizumab on the number of bleeds, joint bleeds, 
target joint bleeds, spontaneous bleeds and all bleeds (i.e., those treated and untreated 
with coagulation factors) over time will be evaluated (see Section 2.2.1).
The number of bleeds, sites of bleeds, and types of bleeds will be summarized for all 
patients and listed for each patient individually.  Several exploratory analyses will be 
conducted to characterize the type, location, duration, frequency, and pattern of bleeds.  
For continuous endpoints, descriptive statistics will be calculated and categorical 
endpoints will be characterized through frequency tables. 
The primary final analysis will be performed 24 weeks after the last enrolled patient 
started treatment or has withdrawn prematurely, whichever occurs first.  
A detailed description of the statistical methods that will be used for the efficacy 
analyses will be provided in the Statistical Analysis Plan.
6.4.2
Patient-Reported Outcomes
Scale scores for the Haemo-QoL-SF and the Haem-A-QoL will be calculated for each 
assessment, with change scores being examined for the assessments over the course 
of 24 weeks.  These will be summarized descriptively.  
The proportion of patients preferring emicizumab after 17 weeks of treatment will be 
presented along with the reasons for that choice.  Summary statistics of the number of 
days away from school and days hospitalized will be presented.
6.5
SAFETY ANALYSES
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including 
complete blood count with differential and platelet counts), ECGs, vital signs, ADAs, and 
de novo anti-FVIII inhibitors.


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To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate 
thesaurus level, and toxicity grade.  
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading 
scale (WHO 2003).
6.6
PHARMACOKINETIC ANALYSES
PK Run-In Cohort
PK parameters of emicizumab will be estimated using non-compartmental methods after 
the first and the sixth injection and include:

Tmax: Time to maximum observed plasma concentration

Cmax: Maximum observed plasma concentration

AUC: Area under the plasma concentrationtime curve over a dosing interval 

AUC0-inf: Area under the plasma concentrationtime curve between time zero 
(predose) extrapolated to infinity (only for the first injection)

t½: Apparent terminal half-life

CL/F and CLss/F: Apparent Clearance
Concentration data and calculated PK parameters for emicizumab will be presented in 
individual listings, summary tables (including descriptive statistics: mean, geometric 
means, medians, ranges, standard deviations, and coefficients of variation) and graphs 
(including concentration versus time plots on linear and semi-logarithmic scales) as 
appropriate.
Expansion Cohort
For all patients, predose (trough) plasma concentrations of emicizumab will be 
presented descriptively, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various
covariates, such as age, gender, and body weight, on these parameters will be 
investigated graphically.  Secondary PK parameters, such as area under the curve, will 
be derived from individual post-hoc predictions.  Data may be pooled with data from 
previous Phase I/II studies and completed Phase III studies.  These analyses will be 
reported in a dedicated report.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include patients with at least one predose and one 
postdose ADA assessment.
The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up periods will be summarized.  Patients are 
considered to be ADA positive if they are ADA negative at baseline but develop an ADA 
response following study drug administration (treatment-induced ADA response), or if 
they are ADA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater (i.e., 0.60 titer units) than the titer of the baseline sample 
(treatment-enhanced ADA response).  Patients are considered to be ADA negative if 
they are ADA negative at baseline and all post-baseline samples are negative, or if they 
are ADA positive at baseline but do not have any post-baseline samples with a titer that 
is at least 4-fold greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses.
6.8
EXPLORATORY ANALYSES
PD parameters (e.g., aPTT, parameters derived from thrombin generation, FVIII activity) 
will be presented using summary statistics, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation.
6.9
INTERIM ANALYSIS
6.9.1
Planned Interim Analysis 
An analysis of pharmacokinetics and safety will occur when the first 6 patients have 
been on treatment for 6 weeks. On the basis of the results for pharmacokinetics and 
safety (e.g., lower limit of 95% CI of the predicted mean PK profile, no severe 
unexpected safety findings), the study will proceed with the expansion cohort.
This analysis will be conducted by a Roche internal group of representatives from 
Clinical Pharmacology, Clinical Science, Clinical Safety and Statistics; no formal IMC will 
be set up.
6.9.2
Optional Interim Analysis 
Additional interim data reviews may be performed at various timepoints to support 
regulatory submissions.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 


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discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically with use of electronic devices.  The 
electronic device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with FDA regulations for electronic records (21 Code of Federal 
Regulations, Part 11).  The data will be transmitted electronically in real-time to a 
centralized database at the vendor of the electronic handheld devices.  The data from 
the electronic devices are available for view access only via secure access to a Web 
portal provided by the vendor.  The Sponsor will have view access only.  Regular data 
transfers will occur from the centralized database at the vendor to the database at the 
Sponsor.  The Sponsor will receive all data entered by patients on the electronic 
handheld devices and all relevant study documentation.
Once the study is complete, the data, audit trail, and study and system documentation 
will be archived.  The investigator will receive patient data for the site in both human-
and machine-readable formats on an archival-quality compact disc that must be kept 
with the study records as source data.  Acknowledgement of receipt of the compact disc 
is required.  In addition, the Sponsor will receive all data in a machine-readable format 
on a compact disc.


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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, electronic handheld device 
records, evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies of transcriptions that are certified after verification as 
being accurate and complete, microfiche, photographic negatives, microfilm or magnetic 
media, X-rays, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 15 years after completion or discontinuation of the study, or for the length of time 


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required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
reported or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.


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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 


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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 


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policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This global study will enroll 46 patients.
For the PK run-in only sites will be selected that have proven via feasibility that they can 
comply with the extensive PK/PD sampling requirements and the schedule of 
assessments without any deviations. 
Drug assignment will be performed by an IxRS, which will also manage emicizumab 
inventory for all sites globally.
PROs will be captured on an electronic handheld device provided by a third-party vendor 
for all patients globally.
Central laboratories will be used for a subset of laboratory assessments specified in 
Section 4.5.5. 
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 


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availability of the respective clinical study report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Assessments
PK RUN-IN COHORT
Screening
Treatment Period
From Week 25 
to Study 
Completion
Study Completion 
or Early 
Termination a
Safety 
F/U Visit
Week
—
—
1
2
3
4
5
9
13
17
21
25
Day b –28 to –1 –7 to –1
1
8
15
22
29
57
85
113
141
169
Informed consent  c 
x
Inclusion/exclusion criteria
x
Demographics and medical 
history d 
x
Physical examination 
including height and 
weight e 
x
x f
x f
x f
x f
x f
x f
x f
x f
Q12W f
x f
x
Vital signs g
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Concomitant medications h
x
x
x
x
x
x
x
x
Q12W
x
x
Adverse events i
Ongoing
12-lead ECG j
x
x k
x
x l
x
Hematology m
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Blood chemistry  n
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Pregnancy test  o
x
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Emicizumab 
administration p
x
x
x
x
x
x
x
Q4W
PK, PD, and ADA
See Appendix 2


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
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PK RUN-IN COHORT
Screening
Treatment Period
From Week 25 
to Study 
Completion
Study Completion 
or Early 
Termination a
Safety 
F/U Visit
Week
—
—
1
2
3
4
5
9
13
17
21
25
Day b –28 to –1 –7 to –1
1
8
15
22
29
57
85
113
141
169
Bleed/medication 
questionnaire q
Weekly and on days of bleeds
x
x
Bleed/medication review r
x
x
x
x
x
x
x
Q4W
x
x
Following treatment with 
bypassing agents s
Monitoring for thromboembolic events and thrombotic microangiopathy. s
FVIII or BPA administration 
during investigational site 
attendance (e.g., 
hospitalization or site visit) t
After Week 25, blood sample collection for 
analysis of hemostatic status
ADAanti-drug ant body; BPAbypassing agent; eCRFelectronic Case Report Form; EQ-5D-5LEuropean Quality of Life 5-Dimension, 5-Level questionnaire;
F/Ufollow-up; HRQoLhealth-related quality of life; PDpharmacodynamic; PKpharmacokinetic; PROpatient-reported outcome; Q4W every 4 weeks; Q12W every 
12 weeks.
a
Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has completed the 
24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the study, the completion 
assessments displayed in the schedule of assessments are similar with the Week 25 visit.
b
In order to characterize pharmacokinetics, it is mandatory for assessments to be performed on the exact visit day until Week 25; no deviation from visit day is acceptable 
until Week 25, deviations of 2 days are acceptable thereafter until safety follow-up visit.  Safety follow-up visit should be performed 24 weeks after discontinuation of 
emicizumab, deviation of 7 days is acceptable.  The safety follow-up visit will not be performed for patients who transfer to an extension study or to commercial 
emicizumab.
c
Obtain written informed consent (or patient written assent and parent written informed consent if patient is an adolescent) before performing any study related procedures.  
If patient fulfils the inclusion criteria, the patient should be enrolled in the study on the same day when the first dose of emicizumab is administered (Day 1).


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
97/Protocol BO39182, Version 5
d
Collected from patient’s medical record and documented in the eCRF.
e
Height assessment at Day 1 only for adults and weight assessments Q4W for all patients.
f
Height assessments for adolescents at Day 1 and ideally at all drug administration and PK sampling visits when the patients will be at the investigational site but at least every 
12 weeks (repeated assessments).
g
Body temperature (oral, tympanic, or axillary), blood pressure, pulse rate, respiratory rate.
h
Concomitant medication (e.g., extra pain medication to treat bleeds) will be recorded at the time of the visits, excluding treatments for bleeds, which will be collected in the bleeding 
questionnaire.
i
Adverse events are collected on an ongoing basis throughout the study.  Injection-site reactions will be collected on a separate form from the adverse event form.  After informed 
consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be reported.
j
If screening ECG is abnormal, repeat at Week 1.  ECGs will also be performed:  once during Weeks 48 after starting emicizumab or dose escalation (up-titration); once 24 weeks 
after starting emicizumab or dose escalation (up-titration); and at study completion/early termination.  
k
Once during Weeks 48 after starting emicizumab.
l
For any dose increase (i.e., 3 mg/kg QW), an ECG should be obtained after 48 weeks and 24 weeks after dose up-titration, as well as at study completion/ early termination. 
m
Predose (hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other cells], mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and RBC distribution width), performed locally.  Laboratory assessments 
completed at the screening visit do not have to be repeated at Week 1 if the period between Screening and Week 1 is 5 days or less and there has been no change in health status 
as assessed by the investigator.  If patients undergo up-titration of their dose after 24 weeks on emicizumab, an additional blood draw for safety laboratory assessments should be 
performed within the first 4 weeks after up-titration.
n
Predose (sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine aminotransferase, aspartate 
aminotransferase, and alkaline phosphatase), performed locally.  Laboratory assessments completed at the screening visit do not have to be repeated at Week 1 if the period 
between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the investigator.  If patients undergo up-titration of their dose 
after 24 weeks on emicizumab, an additional blood draw for safety laboratory assessments should be performed within the first 4 weeks after up-titration.
o
Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening and up to 7 days prior to enrollment (Day 7 to Day 1).  If 
applicable, during the study, urine pregnancy tests will be performed at the scheduled visits.
p
6 mg/kg Q4W emicizumab.
q
Bleed information (start date and time, reason, type, location, and associated symptoms of each bleed) and medication for bleeds (breakthrough bleeds) should be reported by the 
patient via an electronic handheld device when a bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days). If the patient discontinues study treatment, 
bleed and bleed medication data should be provided by the patient until the safety follow-up visit (24 weeks after last study drug administration).  Emicizumab doses should be 
recorded by the patient in the bleed/medication questionnaire starting from Day 1. 
r
Investigator review of bleed information. 


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
98/Protocol BO39182, Version 5
s
Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic microangiopathy for platelet count, 
serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent use. A plasma sample should also be provided for local (one aliquot) and central (a second 
aliquot) laboratory monitoring of f brinogen, prothrombin fragment 12, and D-dimer.  If prothrombin fragment 12 test cannot be done at the site, the sample should be sent to the 
local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 
2448 hours following the last dose of bypassing agents.  If applicable, laboratory results should be recorded on the Following Treatments with Bypassing Agents eCRF.
t 
For patients who receive FVIII or bypassing agents during hospitalization (e.g., because of surgery, treatment for severe bleeds, etc.) or on the day of an unscheduled visit at the 
investigational site, additional blood samples will be collected:  plasma samples for PK analysis, plasma for exploratory PD biomarker assessments (FVIII activity [using a human 
chromogenic test] and thrombin generation assay). For patients who receive FVIII, FVIII activity will be also measured using bovine chromogenic test.  The blood sampling should be 
performed within 30 minutes to 24 hours after FVIII or bypassing agent administration on days of hospitalization or attendance at the investigational site.  In case patient receives 
multiple administrations of coagulation factors, blood sampling should be performed after each administration.  If multiple administrations occur on the same day, only one blood 
sample should be drawn per day.


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
99/Protocol BO39182, Version 5
Expansion Cohort
Screening
Treatment Period
From 
Week 25 to 
Study 
Completion
Study 
Completion or 
Early 
Termination a
Safety 
Follow-
Up Visit
Week
—
—
1
2
3
4
5
9
13
17
21
25
Day b –28 to –1 
–7 to –1
1
8
15
22
29
57
85
113
141
169
Informed consent c
x
Inclusion/exclusion criteria
x
Demographics and medical 
history d
x
Physical examination 
including height and 
weight  e
x
x f
x f
x f
x f
x f
x f
x f
x f
Q12W f
x f
x
Vital signs g
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Concomitant medications h
x
x
x
x
x
x
x
x
Q12W
x
x
Adverse events i
Ongoing
12-lead ECG j
x
x k
x
x l
x
Hematology m
x
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Blood chemistry n
x
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Pregnancy test o
x
x
x
x
x
x
x
x
x
x
x
x
Q12W
x
x


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
100/Protocol BO39182, Version 5
Expansion Cohort
Screening
Treatment Period
From 
Week 25 to 
Study 
Completion
Study 
Completion or 
Early 
Termination a
Safety 
Follow-
Up Visit
Week
—
—
1
2
3
4
5
9
13
17
21
25
Day b –28 to –1 
–7 to –1
1
8
15
22
29
57
85
113
141
169
PRO (HRQoL) p
x
x
x
Q12W
x
Days missed from 
school/work q
x
x
x
Q12W
x
PRO (Preference)
x r
Health status (EQ-5D-5L) s
x
x
x
Q12W
x
Emicizumab 
administration t
x
x
x
x
x
x
x
x
x
x
Q4W
PK, PD, ADA
See Appendix 2
Bleed/medication 
questionnaire u
Weekly and on days of bleed
x
x
Bleed/medication review v
x
x
x
x
x
x
x
Q4W
x
x
Following treatments with 
bypassing agents w
Monitoring for thromboembolic events and thrombotic microangiopathy w


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
101/Protocol BO39182, Version 5
Expansion Cohort
Screening
Treatment Period
From 
Week 25 to 
Study 
Completion
Study 
Completion or 
Early 
Termination a
Safety 
Follow-
Up Visit
Week
—
—
1
2
3
4
5
9
13
17
21
25
Day b –28 to –1 
–7 to –1
1
8
15
22
29
57
85
113
141
169
FVIII or BPA administration 
during investigational site 
attendance (e.g., 
hospitalization or site visit) 
x
After Week 25, blood sample 
collection for analysis of hemostatic 
status
ADAanti-drug antibody; BPAbypassing agent; eCRFelectronic Case Report Form; EQ-5D-5LEuropean Quality of Life 5-Dimension, 5-Level questionnaire; ETearly 
termination; F/Ufollow-up; FIXfactor IX; FVIIIfactor VIII; FXfactor X; FXIIIfactor XIII; HRQoLhealth-related quality of life; PDpharmacodynamic; PKpharmacokinetic; 
PROpatient-reported outcome; Q4W every 4 weeks; Q12W every 12 weeks.
a
Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has completed the 24-week safety 
follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the study, the completion assessments displayed in the
schedule of assessments are similar with the Week 25 visit.
b
Assessments can deviate from planned schedule by 2 days until safety follow-up visit. Safety follow-up visit should be performed 24 weeks after discontinuation of emicizumab; 
deviation of +7 days is acceptable. Safety follow- up visit will not be performed for patients who transfer to an extension study or to commercial emicizumab.
c
Obtain written informed consent (or patient written assent and legal representative written informed consent if patient is an adolescent) before performing any study related 
procedures. If a patient fulfills the inclusion criteria, the patient should be enrolled in the study on the same day when the first dose of emicizumab is administered (Day 1).
d
Collected from patient’s medical record and documented in the eCRF.
e
Height assessment at Day 1 only for adults and weight assessments Q4W for all patients.
f
Height assessments for adolescents at Day 1 and ideally at all drug administration and PK sampling visits that the patients will be at the investigational site, but at least every 12 
weeks (repeated assessments).
g
Body temperature (oral, tympanic, or axillary), blood pressure, pulse rate, respiratory rate.


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
102/Protocol BO39182, Version 5
h
Concomitant medication (e.g., extra pain medication to treat bleeds) will be recorded at the time of the visits, excluding treatments for bleeds, which will be collected in the bleeding 
questionnaire starting from Day 1. FVIII taken in the week prior to starting emicizumab (week prior to Day 1) will also be collected on the Concomitant Medication eCRF page for 
patients without inhibitors to FVIII who will continue their prior FVIII prophylaxis during the first week of the study.
i
Adverse events are collected on an ongoing basis throughout the study.  Injection-site reactions will be collected on a separate form from the adverse event form.  After informed 
consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be reported.
j
If screening ECG is abnormal, repeat at Week 1. ECGs will also be performed:  once during Weeks 48 after starting emicizumab or dose escalation (up-titration); once 24 weeks 
after starting emicizumab or dose escalation (up-titration); and at study completion/early termination.
k
Once during Weeks 48 after starting emicizumab.
l
For any dose increase (i.e., 3 mg/kg QW), an ECG should be obtained after 48 weeks and 24 weeks after dose up-titration, as well as at study completion/ early termination.
m
Predose:  (hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other cells], 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and RBC distribution width), performed locally. Laboratory assessments 
completed at the Screening visit do not have to be repeated at Week 1 if the period between screening and Week 1 is 5 days or less and there has been no change in health status 
as assessed by the investigator. If patients undergo up-titration of their dose after 24 weeks on emicizumab, an additional blood draw for safety laboratory assessments should be 
performed within the first 4 weeks after up-titration.
n
Predose (e.g., sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine aminotransferase, aspartate 
aminotransferase, and alkaline phosphatase), performed locally.  Laboratory assessments completed at the Screening visit do not have to be repeated at Week 1, if the period 
between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the investigator.  If patients undergo up-titration of their dose 
after 24 weeks on emicizumab, an additional blood draw for safety laboratory assessments should be performed within the first 4 weeks after up-titration.
o
Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening and up to 7 days prior to enrollment (Day7 to Day 1).  
If applicable, during the study, urine pregnancy tests will be performed at the scheduled visits.
p
Day 1 assessment predose (baseline), followed by assessments at Week 13 predose and Week 25 predose by Haem-A-QoL (age 18 years) and Haemo-QoL-Short Form (ages 
1217 years).
q
Day 1 assessment predose (baseline), followed by assessments at Week 13 predose and Week 25 predose.
r
Predose.
s
Day 1 assessment predose (baseline), followed by assessments at Week 13 predose and Week 25 predose by EQ-5D-5L questionnaire.
t
3 mg/kg QW emicizumab loading dose for 4 weeks, followed by 6 mg/kg Q4W emicizumab maintenance dose.


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
103/Protocol BO39182, Version 5
u
Bleed information (start date and time, reason, type, location, and associated symptoms of each bleed) and medication for bleeds (breakthrough bleeds) should be reported by the 
patient via an electronic, handheld device when a bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days). If the patient discontinues study treatment, 
bleed and bleed medication data should be provided by the patient until the safety follow-up visit (24 weeks after last study drug administration). Emicizumab doses should be 
recorded by the patient in the bleed/medication questionnaire starting from Day 1. 
v
Investigator review of bleed information.
w
Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic microangiopathy for platelet count, 
serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent use. A plasma sample should also be provided for local (one aliquot) and central (a second
aliquot) laboratory monitoring of f brinogen, prothrombin fragment 12, and D-dimer.  If prothrombin fragment 12 test cannot be done at the site, the sample should be sent to the 
local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 
2448 hours following the last dose of bypassing agents.  In the case that such local laboratory tests are performed, laboratory results should be recorded on the Following 
Treatments with Bypassing Agents eCRF.
x 
For patients who receive FVIII or bypassing agents during hospitalization (e.g., because of surgery, treatment for severe bleeds, etc.) or on the day of an unscheduled visit at the 
investigational site, additional blood samples will be collected:  plasma samples for PK analysis, plasma for exploratory PD biomarker assessments (FVIII activity [using a human 
chromogenic test] and thrombin generation assay). For patients who receive FVIII, FVIII activity will be also measured using bovine chromogenic test.  The blood sampling should 
be performed within 30 minutes to 24 hours after FVIII or bypassing agent administration on days of hospitalization or attendance at the investigational site.  In case patient receives 
multiple administrations of coagulation factors, blood sampling should be performed after each administration.  If multiple administrations occur on the same day, only one blood 
sample should be drawn per day.


Emicizumab—F. Hoffmann-La Roche Ltd
104/Protocol BO39182, Version 5
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples
PK RUN-IN
Screen
-ing
Treatment Period
From 
Week 25 
to Study 
Com-
pletion
Study 
Com-
pletion 
or ET a
Safety 
F/U visit
Week
1
2
3
4
5
6
7
8
9
10 to 
12b
13
14 to 
16b
17
18 to 
20b
21
22
23
24
25
Day
-28 to 
-1 days
1
3
5
8
11 15 18
22
25
29
36
43
50 57
85
113
141 148 155 162
169
Emicizumab PK b
x
x c,d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Emicizumab ADAd
x
x
x
x
x
x
x
Q12W
x
x
Emicizumab 
biomarker set 1 e
x
x
x
x
x f
x
x f
x
x f
x
x
x
Q12W
x
x
Emicizumab 
biomarker set 2 g
xc
x
x
x
x
x
x
x
x
Anti-FVIII 
ant bodies h, i
x
x
x
x
x
Q12W
x
x
Following 
treatments with 
bypassing agents 
Monitoring for thromboembolic events and thrombotic microangiopathy j


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
105/Protocol BO39182, Version 5
PK RUN-IN
Screen-
ing
Treatment Period
From 
Week 25 
to Study 
Com-
pletion
Study 
Com-
pletion 
or ET a
Safety 
F/U visit
Week
1
2
3
4
5
6
7
8
9
10 to 
12b
13
14 to 
16b
17
18 to 
20b
21
22
23
24
25
Day
-28 to 
-1 days
1
3
5
8
11 15 18
22
25
29
36
43
50 57
85
113
141 148 155 162
169
FVIII or BPA 
administration 
during 
investigational site 
attendance (e.g., 
hospitalization or 
site visit) k
After Week 25, blood 
sample collection for 
analysis of hemostatic 
status
ADAanti-drug antibody; BPAbypassing agent; ETearly termination; F/Ufollow-up; FIXfactor IX; FVIIIfactor VIII; FXfactor X; FXIIIFactor XIII; 
PDpharmacodynamic; PKpharmacokinetic; Q4W every 4 weeks; Q12W every 12 weeks.
Note:  Blood samples should always be drawn predose (if taken on days of emicizumab administration); consult the Sample Handling Manual for details.  PD 
biomarker tests will include, but are not limited to those listed here.  In order to characterize pharmacokinetics, it is mandatory that assessments are being 
performed on the exact visit day until Week 25; no deviation from visit day is acceptable until Week 25.  Deviations from the schedule of assessments of 2 days 
are acceptable after Week 25.
a
Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has 
completed the 24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the 
study, the completion assessments displayed in the schedule of assessments are similar with the Week 25 visit.


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
106/Protocol BO39182, Version 5
b
During the first 8 weeks, PK sampling will occur at the following timepoints:  Week 1 (predose Day 1; 8 hours post-injection on Day 1; then Day 3, Day 5), 
Week 2 (Day 8, Day 11), Week 3 (Day 15, Day 18), Week 4 (Day 22), Week 5 (Day 29 predose), Week 6 (Day 36), Week 7 (Day 43), and Week 8 (Day 50).  
A reduced PK sampling schedule will follow to characterize repeated Q4W SC administration from Week 9 to Week 25.  From Week 9 to Week 21, patient will 
have PK blood samples taken at Week 9 (Day 57), Week 13 (Day 85), Week 17 (Day 113), and Week 21 (Day 141).  From Week 9 to Week 21, additionally the 
patient will return once between two emicizumab administrations for a blood sample to be drawn for PK analysis; patients can decide whether this sampling will 
be 1, 2, or 3 weeks after the latest injection.  An individual patient may choose each of the specific intervals (1, 2, or 3 weeks after to the latest injection) at least 
once.  After the sixth injection at Week 21, PK sampling frequency will be increased to characterize steady-state pharmacokinetics, with samples collected at 
Week 22 (Day 148), Week 23 (Day 155), and Week 24 (Day 162). Another sample will be taken at Week 25 (Day 169) followed by PK assessments every 
12 weeks until study completion.
c
8 hours postdose on Day 1.
d
Emicizumab ADA blood samples may also be drawn to if hypersensitivity event occur or on an unscheduled basis (at the clinical judgment of the investigator) at 
any time.
e
Set 1Standard aPTT, modified aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, FVIII antigen (baseline only), D-dimer, prothrombin 
fragment 1.2, vWF antigen (timepoints of Week 1 Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit), fibrinogen (timepoints of Week 1 
Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit), and FXIII activity (baseline only).
f
PD assessments occurring once between two Q4W emicizumab administrations to be done on the same day the PK sample is taken (see footnote above). 
g
Set 2FVIII activity, D dimer, prothrombin fragment 1.2, standard aPTT, modified aPTT, and PT.
h
A sample for inhibitor testing (anti-FVIII antibodies) must be obtained during screening, within 4 weeks prior to enrollment (i.e., before initiation of Week 1, Day 1 
assessments).  The results must be available before enrollment, and local testing will not replace the central laboratory inhibitor testing performed at Week1. 
i
Starting at Week 1, this and all subsequent anti-FVIII antibodies will be measured at a central laboratory.  Anti-FVIII antibodies will be tested by a central 
laboratory at Week 1, Week 25, every 12 weeks thereafter, at the completion visit, and safety follow-up visit for all patients.  Testing at Week 9 (Day 57) and 
Week 17 (Day 113) for non-inhibitor patients only.


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
107/Protocol BO39182, Version 5
j
Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic 
microangiopathy for platelet count, serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent use. A plasma sample should also 
be provided for local (one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 12, and D-dimer.  If prothrombin 
fragment 12 test cannot be done at the site, the sample should be sent to the local reference laboratory, if available. For patients who require multiple doses 
of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 2448 hours following the last dose of bypassing agents.  
In the case that such local laboratory tests are performed, laboratory results should be recorded on the Following Treatments with Bypassing Agents eCRF.
k
For patients who receive FVIII or bypassing agents during hospitalization (e.g., because of surgery, treatment for severe bleeds, etc.) or on the day of an unscheduled visit at the 
investigational site, additional blood samples will be collected:  plasma samples for PK analysis, plasma for exploratory PD biomarker assessments (FVIII activity [using a human 
chromogenic test] and thrombin generation assay). For patients who receive FVIII, FVIII activity will be also measured using bovine chromogenic test.  The blood sampling should 
be performed within 30 minutes to 24 hours after FVIII or bypassing agent administration on days of hospitalization or attendance at the investigational site.  In case patient 
receives multiple administrations of coagulation factors, blood sampling should be performed after each administration.  If multiple administrations occur on the same day, only one 
blood sample should be drawn per day.


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
108/Protocol BO39182, Version 5
EXPANSION COHORT
Screen
-ing
Treatment Period
From 
Week 25 to 
Study 
Completion
Study 
Completion or 
Early 
Termination a
Safety F/U 
Visit
Week
1
2
3
4
5
9
13
17
21
25
Day
-28 to 
-1 days
1
8
15
22
29
57
85
113
141
169
Emicizumab PK
x
x
x
x
x
x
x
x
x
x
Q12W
x
x
Emicizumab 
ADA b
x
x
x
x
x
x
x
Q12W
x
x
Emicizumab 
biomarker set 3
(EDTA) c
x
x
x
x
Q12W
Emicizumab 
biomarker set 1d
x
x
x
x
x
x
x
x
x
x
Q12W e
x
x
Anti-FVIII 
antibodies f, g
x
x
x
x
x
Q12W
x
x
Following 
treatments with 
bypassing 
agents
Monitoring for thromboembolic events and thrombotic microangiopathy. h


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
109/Protocol BO39182, Version 5
EXPANSION COHORT
Week
1
2
3
4
5
9
13
17
21
25
Day
-28 to 
-1 days
1
8
15
22
29
57
85
113
141
169
FVIII or BPA 
administration 
during 
investigational 
site attendance 
(e.g., 
hospitalization or 
site visit) i
After Week 25, blood sample collection 
for analysis of hemostatic status
ADAanti-drug antibody; F/Ufollow-up; FIX factor IX; FVIIIfactor VIII; FX factor X; FXIIIFactor XIII; PKpharmacokinetic; 
Q12W every 12 weeks.
Note:  Blood samples should always be drawn predose (if taken on days of emicizumab administration); consult the Sample Handling 
Manual for details.  PD biomarker tests will include, but are not limited to, those listed here.  In order to characterize pharmacokinetics, it is 
mandatory that assessments are being performed within 2 days of the scheduled visits.  
a Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR 
patient has completed the 24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study 
completion occurs after 24 weeks in the study, the completion assessments displayed in the schedule of assessments are similar with the 
Week 25 visit.
b Emicizumab ADA blood samples may also be drawn if hypersensitivity event occurs or on an unscheduled basis (at the clinical judgment 
of the investigator) at any time.
c Set 3Exploratory biomarker assay of emicizumab concentration that requires EDTA rather than citrate plasma.


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
110/Protocol BO39182, Version 5
d Set 1Standard aPTT, modified aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, D-dimer, prothrombin fragment 
1.2 vWF antigen (timepoints of Week 1 Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit), and fibrinogen 
(timepoints of Week 1 Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit). 
e FIX antigen and FX antigen will not be analyzed after Week 24, while all other biomarkers from Set 1 sample will be analyzed after Week 
24. 
f
A sample inhibitor testing (anti-FVIII antibodies) must be obtained within 8 weeks prior to enrollment, (i.e., before initiation of Week 1, 
Day 1 assessments).  The results must be available before enrollment, and local testing will not replace the central laboratory inhibitor 
testing performed at Week 1. 
g Starting at Week 1, this and all subsequent anti-FVIII antibodies will be measured at a central laboratory.  Anti-FVIII antibodies will be 
tested by a central laboratory at Week 1, Week 25, every 12 weeks thereafter, at the completion visit, and safety follow-up visit for all 
patients.  Testing at Week 9 (Day 57) and Week 17 (Day 113) is for non-inhibitor patients only.
h Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and 
thrombotic microangiopathy for platelet count, serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent 
use. A plasma sample should also be provided for local (one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, 
prothrombin fragment 12, and D-dimer.  If prothrombin fragment 12 test cannot be done at the site, the sample should be sent to the 
local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory monitoring should be 
performed every 2448 hours thereafter until 2448 hours following the last dose of bypassing agents.  In the case that such local 
laboratory tests are performed, laboratory results should be recorded on the Following Treatments with Bypassing Agents eCRF.
i
For patients who receive FVIII or bypassing agents during hospitalization (e.g., because of surgery, treatment for severe bleeds, etc.) or 
on the day of an unscheduled visit at the investigational site, additional blood samples will be collected:  plasma samples for PK analysis, 
plasma for exploratory PD biomarker assessments (FVIII activity [using a human chromogenic test] and thrombin generation assay). For 
patients who receive FVIII, FVIII activity will be also measured using bovine chromogenic test.  The blood sampling should be performed 
within 30 minutes to 24 hours after FVIII or bypassing agent administration on days of hospitalization or attendance at the investigational 
site.  In case patient receives multiple administrations of coagulation factors, blood sampling should be performed after each 
administration.  If multiple administrations occur on the same day, only one blood sample should be drawn per day.


Emicizumab—F. Hoffmann-La Roche Ltd
111/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events
HEMATOLOGY
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
7500099999/mm3
5000074999/mm3
2000049999/mm3
20000/mm3
Prothrombin time (PT)
1.011.25 ULN
1.261.5 ULN
1.513.0 ULN
3 ULN
Activated partial thromboplastin
(APPT)
1.011.66 ULN
1.672.33 ULN
2.343 ULN
3 ULN
Fibrinogen
0.750.99 LLN
0.500.74 LLN
0.250.49 LLN
0.25 x LLN
Fibrin split product
2040 mcg/mL
4150 mcg/mL
5160 mcg/mL
60 mcg/mL
Methemoglobin
59.9%
10.014.9%
15.019.9%
20 %
LIVER ENZYMES
AST (SGOT)
1.252.5 ULN
2.65 ULN
5.110 ULN
10 ULN
ALT (SGPT)
1.252.5 ULN
2.65 ULN
5.110 ULN
10 ULN
GGT
1.252.5 ULN
2.65 ULN
5.110 ULN
10 ULN
Alkaline phosphatase
1.252.5 ULN
2.65 ULN
5.110 ULN
10 ULN


Emicizumab—F. Hoffmann-La Roche Ltd
112/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
LIVER ENZYMES continued
Amylase
1.11.5 ULN
1.62.0 ULN
2.15.0 ULN
5.0 ULN
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
< 116 or mental status 
changes or seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
> 165 mEq/L or mental status
changes or seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or intensive
replacement Rx required or
hospitalization required.
2.0 mEq/L
or paresis or ileus or life-
threatening arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L
or life-threatening arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental status
changes or coma
Hyperglycemia (note if fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or ketoacidosis
or seizures
Hypocalcemia (corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or life-threatening
arrhythmia or tetany


Emicizumab—F. Hoffmann-La Roche Ltd
113/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
CHEMISTRIES continued
Hypercalcemia (correct for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL life-threatening
arrhythmia
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or 
life-threatening arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or
replacement Rx required
1.01.4 mg/dL intensive Rx 
or hospitalization required
1.0 mg/dL or life-threatening
arrhythmia
Hyperbilirubinemia
1.11.5 ULN
1.62.5 ULN
2.65 ULN
5 ULN
BUN
1.252.5 ULN
2.65 ULN
5.110 ULN
10 ULN
Creatinine
1.11.5 ULN
1.63.0 ULN
3.16 ULN
6 ULN or required dialysis
URINALYSIS
Proteinuria
1 or 0.3% or 3g/L
or 200 mg1 g loss/day
23 or 0.31.0% or
310 g/L
12 g loss/day
4 or 1.0% or 10 g/L
23.5 g loss/day
nephrotic syndrome or 
3.5 g loss/day
Hematuria
microscopic only
gross, no clots
gross clots
obstructive or required
transfusion


Emicizumab—F. Hoffmann-La Roche Ltd
114/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
CARDIAC DYSFUNCTION
Cardiac Rhythm
asymptomatic, transient
signs, no Rx required
recurrent/persistent; no Rx 
required
requires treatment
Hypertension
transient increase. 20 
mmHg; no Rx required
recurrent, chronic, increase 
20 mmHg, Rx required
requires acute Rx; no
hospitalization
requires hospitalization
Hypotension
transient orthostatic
hypotension, no Rx
symptoms correctable with 
oral fluids Rx
requires IV fluids; no
hospitalization required
requires hospitalization
Pericarditis
minimal effusion
mild/moderate
asymptomatic effusion, no
Rx
symptomatic effusion; pain; 
EKG changes
tamponade;
pericardiocentesis or surgery
required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
12 units transfused
massive blood loss;
3 units transfused
RESPIRATORY
Cough
transient; no Rx
treatment-associated cough
local Rx
uncontrolled
Bronchospasm, Acute
transient; no Rx
< 70%79% FEV1
(or peak flow)
requires Rx normalizes with
bronchodilator; FEV1
50%69%
(or peak Flow)
no normalization with
bronchodilator;
FEV1 25%49%
(or peak flow retractions)
cyanosis: FEV1
25%
(or peak flow) or intubated


Emicizumab—F. Hoffmann-La Roche Ltd
115/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
GASTROINTESTINAL
Stomatitis
mild discomfort; no limits 
on activity
some limits on
eating/drinking
eating/talking very limited
requires IV fluids
Nausea
mild discomfort; maintains 
reasonable intake
moderate discomfort; intake 
decreased significantly; 
some activity limited
severe discomfort; no
significant intake; activities 
limited
minimal fluid intake
Vomiting
transient emesis
occasional/moderate
vomiting
orthostatic hypotension or 
IV fluids required
hypotensive shock or 
hospitalization required for IV 
fluid therapy
Constipation
mild
moderate
severe
distensions w/vomiting
Diarrhea
transient 34 loose
stools/day
5 7 loose stools/day
orthostatic hypotension or
7 loose stools/day or
required IV fluids
hypotensive shock or 
hospitalization for IV fluid 
therapy required
NEURO AND NEUROMUSCULAR
Neuro-cerebellar
slight incoordination
dysdiadochokinesis
intention tremor, dysmetria, 
slurred speech; nystagmus
locomotor ataxia
incapacitated
Mood
mild anxiety or depression
moderate anxiety or
depression and therapy 
required
severe anxiety or
depression or mania;
needs assistance
acute psychosis;
incapacitated, requires
hospitalization


Emicizumab—F. Hoffmann-La Roche Ltd
116/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
NEURO AND NEUROMUSCULAR continued
Neuro control (ADLactivities of
daily living)
mild difficulty
concentrating; no Rx; mild
confusion/agitation; ADL 
unaffected
moderate
confusion/agitation some 
limitation of ADL; minimal 
Rx
severe confusion/agitation
needs assistance for ADL;
therapy required
toxic psychosis;
hospitalization
Muscle strength
subjective weakness
no objective 
symptoms/signs
mild objective
signs/symptoms no 
decrease in function
objective weakness
function limited
paralysis
OTHER PARAMETERS
Fever: oral, 12 hours
37.738.5C or
99.9101.3F
38.639.5C or
101.4103.1F
39.640.5C or
103.2104.9F
40.5C or
104.9F
Headache
mild, no Rx therapy
transient, moderate; Rx
required
severe; responds to initial 
narcotic therapy
intractable; required repeated 
narcotic therapy
Fatigue
no decrease in ADL
normal activity decreased 
2550%
normal activity decreased
50% can’t work
unable to care for self
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria;
angioedema
anaphylaxis


Emicizumab—F. Hoffmann-La Roche Ltd
117/Protocol BO39182, Version 5
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events (cont.)
OTHER PARAMETERS continued
Local Reaction
tenderness or erythema
induration 10 cm or
phlebitis or inflammation
induration ≥10 cm or
ulceration
necrosis
Mucocutaneous
erythema; pruritus
diffuse, maculopapular rash, 
dry desquamation
vesiculation, moist
desquamation, or
ulceration
exfoliative dermatitis, mucous
membrane involvement or
erythema, multiforme or
suspected Stevens- Johnson 
or necrosis requiring surgery


Emicizumab—F. Hoffmann-La Roche Ltd
118/Protocol BO39182, Version 5
Appendix 4
Clinical Criteria for Diagnosing Anaphylaxis
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network.  Anaphylaxis is highly 
likely when any one of the following three criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips, 
tongue/uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia, syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours):

Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease in systolic blood pressure2

Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline
_____________________________________
1
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006;117:391–7.
2
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg [2 x age]) from 1 to 10 years, and less than 90 mmHg from 
11 to 17 years.


Emicizumab—F. Hoffmann-La Roche Ltd
119/Protocol BO39182, Version 5
Appendix 5
Haemo-QoL-SF (United States/English)


Emicizumab—F. Hoffmann-La Roche Ltd
120/Protocol BO39182, Version 5
Appendix 5
Haemo-QoL-SF (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
121/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English)


Emicizumab—F. Hoffmann-La Roche Ltd
122/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
123/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
124/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
125/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
126/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
127/Protocol BO39182, Version 5
Appendix 6
Haem-A-QoL (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
128/Protocol BO39182, Version 5
Appendix 7
EQ-5D-5L (United Kingdom/English)


Emicizumab—F. Hoffmann-La Roche Ltd
129/Protocol BO39182, Version 5
Appendix 7
EQ-5D-5L (United Kingdom/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
130/Protocol BO39182, Version 5
Appendix 8
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.

SAP_001.pdf: 
 
 
Official Title:  
 
A MULTICENTER, OPEN-LABEL, PHASE III STUDY TO 
EVALUATE THE EFFICACY, SAFETY, PHARMACOKINETICS, 
AND PHARMACODYNAMICS OF EMICIZUMAB GIVEN EVERY 4 
WEEKS (Q4W) IN PATIENTS WITH HEMOPHILIA A 
NCT Number: 
NCT03020160 
Document Date: 
STATISTICAL ANALYSIS PLAN 
Version 1: 20 June 2017 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
*Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan. The specific details of 
the legal/regulatory entity within the relevant country are provided within the clinical trial agreement 
with the Investigator/Institution and the Clinical Trial Application with the Competent Authority. 
 
EmicizumabF. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO39182 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A MULTICENTER, OPEN-LABEL, PHASE III STUDY TO 
EVALUATE THE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS 
OF EMICIZUMAB GIVEN EVERY 4 WEEKS (Q4W) IN 
PATIENTS WITH HEMOPHILIA A 
PROTOCOL NUMBER: 
BO39182 
STUDY DRUG: 
Emicizumab (RO5534262) 
VERSION NUMBER: 
1 
IND NUMBER: 
122954 
EUDRACT NUMBER: 
2016-001094-33 
SPONSOR: 
F. Hoffmann-La Roche Ltd and  
Chugai Pharmaceutical Co. Ltd.* 
PLAN PREPARED BY: 
 
DATE FINAL: 
See electronic date stamp below. 
Name
Reason for Signing
Date and Time
(UTC)
20-Jun-2017 16:41:58
Company Signatory (Clinical)


Emicizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan BO39182 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Collection of Patient-Reported Data ........................................ 7 
2.2.1 
Collection of Bleed and Medication Data ................................. 7 
2.2.2 
Collection of Health-Related Quality-of-Life Data .................... 8 
2.3 
Objectives and Endpoints ........................................................ 8 
2.3.1 
Efficacy Period for All Endpoints .............................................. 8 
2.3.2 
Bleed-Related Efficacy Objectives and Endpoints ................... 9 
2.3.2.1 
Treated Bleed .......................................................................... 9 
2.3.2.2 
All Bleeds ................................................................................. 9 
2.3.2.3 
Treated Spontaneous Bleeds ................................................ 10 
2.3.2.4 
Treated Joint Bleeds .............................................................. 10 
2.3.2.5 
Treated Target Joint Bleeds .................................................. 10 
2.3.3 
Health-Related Quality-of-Life (HRQoL) 
Endpoints ............................................................................... 10 
2.3.4 
Pharmacokinetic Endpoints ................................................... 11 
2.3.5 
Safety Endpoints ................................................................... 11 
2.3.6 
Biomarker Endpoints ............................................................. 11 
2.4 
Determination of Sample Size ............................................... 12 
2.5 
Analysis Timing ..................................................................... 12 
3. 
STUDY CONDUCT ..................................................................................... 12 
3.1 
Data Monitoring ..................................................................... 13 
4. 
STATISTICAL METHODS .......................................................................... 13 
4.1 
Output Layouts ...................................................................... 13 
4.2 
Analysis Populations ............................................................. 14 
4.2.1 
Treated Patient Population .................................................... 14 
4.2.2 
All Patient Population ............................................................ 14 
4.2.3 
Pharmacokinetic-Evaluable Population ................................. 14 
4.2.4 
Up-Titrated/Down-Titrated Population ................................... 14 
4.3 
Analysis of Study Conduct ..................................................... 14 


Emicizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan BO39182 
4.4 
Demographics and Baseline Characteristics ......................... 14 
4.5 
Efficacy Analysis .................................................................... 14 
4.5.1 
Bleed Rate Endpoints ............................................................ 14 
4.5.2 
Health-Related Quality-of-Life (HRQoL) Endpoint ................. 15 
4.5.3 
Subgroup Analyses ............................................................... 15 
4.6 
Pharmacokinetic Analyses ..................................................... 16 
4.6.1 
PK Run-In Cohort .................................................................. 16 
4.6.2 
Expansion Cohort .................................................................. 16 
4.7 
Safety Analyses ..................................................................... 17 
4.7.1 
Exposure to Study Medication ............................................... 17 
4.7.2 
Adverse Events ..................................................................... 17 
4.7.3 
Laboratory Data ..................................................................... 17 
4.7.4 
Vital Signs .............................................................................. 17 
4.7.5 
Electrocardiogram ................................................................. 18 
4.8 
Exploratory Biomarker Analyses ............................................ 18 
4.9 
Missing Data .......................................................................... 18 
4.10 
Interim Analyses .................................................................... 18 
4.10.1 
PK Run-In Analysis ................................................................ 18 
4.10.2 
Additional Interim Analysis ..................................................... 18 
5. 
REFERENCES ........................................................................................... 19 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema for Study BO39182 ............................................... 6 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 21 
Appendix 2 
Schedule of Assessments ........................................................... 30 


Emicizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan BO39182 
1. 
BACKGROUND 
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; 
Franchini and Mannucci 2013). 
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the 
Xq28 region of the X chromosome.  It occurs almost exclusively in men having one 
defective copy of the relevant gene on their X chromosome.  The absence or functional 
deficiency of FVIII leads to a lifelong bleeding tendency.  Common clinical symptoms of 
hemophilia A include easy bruising prolonged bleeding after trauma or surgery; 
spontaneous bleeding into joints, muscles, or soft tissues; and intracranial hemorrhage. 
Recombinant FVIII (rFVIII) concentrates have been the standard-of-care treatment 
options for patients with hemophilia A (Kingdon and Lundblad 2002) since the 1990s.  
Prophylactic FVIII replacement therapy is recognized to be superior to episodic 
treatment of symptomatic bleeds for several decades (Khawaji et al. 2012) and has been 
adopted by national and international organizations as the desired treatment approach.  
Existing prophylactic regimens, however, commonly use infusion therapy requiring 
administrations 3 times a week, every other day, or even daily, depending on the 
patient’s needs (Shapiro 2013).  Combined with the fact that the regimen requires 
intravenous (IV) administration, the need for high frequency administration negatively 
impacts patient compliance as both the disease and the treatment tend to affect the 
health-related quality-of-life (HRQoL). 
In addition up to 30% of patients with hemophilia A develop inhibitors against FVIII, 
thereby, requiring treatment with bypassing agents, which have a suboptimal hemostatic 
effect and require more frequent administrations. 
The development of effective prophylactic treatment options with decreased 
immunogenicity and reduced treatment burden is thus a high, unmet medical need in the 
population of patients with hemophilia A.   
Emicizumab (also known as ACE910 and RO5534262) is a humanized monoclonal 
modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure 
produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. 
Emicizumab bridges activated factor IX (FIXa) and factor X (FX) to restore the function 
of missing activated factor VIII (FVIIIa) that is needed for effective hemostasis.  In 
patients with hemophilia A, hemostasis can be restored irrespectively of the presence of 
FVIII inhibitors because emicizumab shares no sequence homology with FVIII.  In 
addition, emicizumab offers the possibility of subcutaneous (SC) administration, 
removing the need for venous access.  Finally, because of the pharmacokinetic (PK) 


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properties of this antibody, markedly extending the dosing interval to once weekly or 
even less frequently, this novel compound has the potential to dramatically change the 
treatment of patients with hemophilia A with or without FVIII inhibitors who are in need of 
effective, safe, and convenient prophylactic therapy. 
Currently available experience with emicizumab in humans includes data from one 
Phase I study (ACE001JP) and its ongoing extension, a Phase I/II study (ACE002JP).  
Details of the results of this study are presented in Section 1.2 of the protocol and 
published in Shima et al. (2016; see also Uchida et al. 2016).  Based on the Phase I/II 
data, a clinical development program in adult and pediatric patients with hemophilia A 
(both with and without FVIII inhibitors) has been initiated.  Four Phase III studies are 
currently ongoing and are aimed at evaluating the efficacy and safety of emicizumab at 
various doses and in different populations.  The studies are Study BH29884, which 
evaluates 1.5 mg/kg weekly (QW) dose in the adult and adolescent population with FVIII 
inhibitors; Study BH29992, which evaluates 1.5 mg/kg QW in pediatric patients with 
inhibitors; Study BH30071, which evaluates a 1.5 mg/kg QW and 3 mg/kg every 2 weeks 
(Q2W) dose in the non-inhibitor population; and Study BO39182, which evaluates 
6 mg/kg every 4 weeks (Q4W) in a mixed (inhibitor and non-inhibitor) population.  
2. 
STUDY DESIGN 
Study BO39182 is a multicenter, open-label, single-arm, Phase III clinical study that will 
enroll patients aged 12 years or older with severe hemophilia A, irrespective of their 
inhibitor status.  The study consists of a PK run-in cohort and an expansion cohort 
(see Figure 1) and will investigate a Q4W dosing regimen that would provide patients 
with a treatment option that requires less frequent dosing while providing an exposure 
similar to 1.5 mg/kg QW and 3 mg/kg Q2W emicizumab regimens that are also currently 
under investigation.  
The PK run-in cohort plans to enroll 6 patients, previously on episodic treatment, to 
receive 6 mg/kg Q4W subcutaneously.  This cohort will provide substantial knowledge 
on the pharmacokinetics (e.g., linearity and SC absorption) and will inform about 
preliminary safety and efficacy, prior to opening of the expansion cohort.  Given that the 
main objective in this cohort is to investigate the pharmacokinetics of emicizumab after 
single and multiple administrations of 6 mg/kg Q4W, patients in this cohort will not 
receive any loading dose.  
An interim analysis will be carried out on the PK run-in cohort after all the patients have 
been followed for at least 6 weeks.  This analysis will constitute characterization of the 
PK profile (to assess whether the mean PK profile is as predicted [i.e., ≥ lower limit of 
95% CI of the predicted mean PK profile]) and assessment of safety to inform the 
decision on whether or not to open the expansion cohort.   


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This analysis will be conducted by a Roche internal group of representatives from 
Clinical Pharmacology, Clinical Science, Clinical Safety and Statistics; no formal Internal 
Monitoring Committee (IMC) will be set up. 
The expansion cohort will enroll 40 patients previously receiving either episodic or 
prophylactic hemophilia A treatment.  Patients in this cohort will receive a loading dose 
of 3 mg/kg QW × 4 subcutaneously followed by a maintenance dose of 6 mg/kg Q4W.  
Study objectives other than PK (i.e., efficacy and safety) will primarily be evaluated 
based on this cohort.   
Figure 1 Study Schema for Study BO39182 
PK run-in cohort:  6 patients
(previous episodic)
6 mg/kg Q4W for at least 24 weeks
Expansion cohort:  ~ 40 patients
Loading dose:  3 mg/kg QW x 4 followed by a 
maintenance dose of 6 mg/kg Q4W for at least 
24 weeks
PK/Safety 
Analysesa
PK/PD 
Efficacy & 
Safety 
Analyses
 
PD = pharmacodynamic; PK = pharmacokinetic; Q4W = every 4 weeks; QW = every week. 
a Analysis will occur when last patient enrolled in the PK run-in cohort has been in the study for 
6 weeks. 
 
The primary efficacy analysis will be conducted after all enrolled patients complete the 
24-week treatment period, are lost to follow-up, or have withdrawn.  The primary 
analysis will only consist of descriptive analyses of the objectives with no formal 
hypothesis testing. 


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An interim analysis for Study BO39182 may be conducted to support regulatory 
submissions and an interim clinical study report (CSR) may be written. 
After 24 weeks of prophylactic treatment with emicizumab, all patients will be provided 
with the option to up-titrate their dose to 3 mg/kg QW, if they meet protocol-defined 
criteria of suboptimal response (see Section 4.3.2.1 of the protocol).  Thereafter, the 
patient may choose to down-titrate to 6 mg/kg Q4W, 3 mg/kg Q2W, or 1.5 mg/kg QW; 
subsequent up-titration would again be allowed if protocol-defined criteria were met.  
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1.   
2.2 
COLLECTION OF PATIENT-REPORTED DATA 
2.2.1 
Collection of Bleed and Medication Data 
Bleed and medication data are collected through a bleed and medication questionnaire 
(BMQ), which was developed by the Sponsor given that no standard questionnaire for 
collection of this data was available.  The BMQ was developed as a patient-reported 
measure of bleeding episodes (including cause, type, location, and symptoms of bleeds) 
and hemophilia-related medication use.  This questionnaire was initially used in the 
non-interventional study (NIS; BH29768), patients with inhibitors study (BH29884), and 
later in the studies for pediatric patients (Study BH29992) and the non-inhibitor patients 
(Study BH30071).   
To capture bleed data, emicizumab use, and other hemophilia medication use during 
study treatment, patients will complete the BMQ on a handheld device that will be 
provided to them during the Week 1 visit at the study site.  This device will remain with 
the patient for the duration of the study to enter bleed and medication data weekly at a 
minimum.  In case a patient did not experience any bleeds or administer any treatments 
for a week, the patient is asked to log into the device and fill in the questionnaire to 
confirm this.  These weekly entries, in addition to the bleeds and medication entries can 
also be used to assess compliance.  Of note, the patient is able to enter bleeds and 
medications for the past 8 days, including the day the entries are made.  This 
retrospective data entry window was considered acceptable in terms of recall bias and 
was added in order to optimize the completeness of data collection. 
Patients who withdraw from emicizumab treatment will continue to record bleeds and 
hemophilia medication administration until they complete the safety follow-up visit.  
The patient is able to edit and delete bleeds and medications for 24 hours after they are 
entered.  Furthermore, the investigator and patient are instructed to review the data 
together at every clinic visit.  If the patient has been unable to enter data for any reason, 
the investigator is able to do so using a data clarification request (Data Change Request 
[DCR]; not subject to the previous 8-day data entry window).  Note, the symptoms of 
joint and muscle bleeds are not collected in this case because the patient may not be 


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able to reliably remember them.  In addition, the investigator is able to request a change 
be made to the vendor’s database by submitting a DCR. 
Furthermore, the Sponsor’s data manager and Medical Monitor review the patient 
entered data for clear inconsistencies against data collected on the electronic Case 
Report Form (eCRF) or to identify obvious data points to be clarified (e.g., missing entry 
of the weekly emicizumab injection).  These requests are sent to the investigator, who 
reviews them with the patient and may enter the data via the site data entry system or 
request a change to be made in the vendor’s database via a DCR, if necessary. 
2.2.2 
Collection of Health-Related Quality-of-Life Data 
The Haem-A-QoL, Haemo-QoL-SF, and European Quality of Life-5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaires; data regarding days away from school/work; and patient 
preference questionnaire at Study Week 17 that asks which treatment they would prefer 
to continue to receive after having been treated with IV FVIII or bypassing agents 
(episodic or prophylactic) prior to study entry and SC emicizumab during the study, are 
filled in by the patients using a separate electronic, handheld device that is different from 
the BMQ device.  While the BMQ device is kept by the patient, the HRQoL questionnaire 
device is kept at the site and is available to the patient at the scheduled visits according 
to the schedule of assessments (see Appendix 2).   
2.3 
OBJECTIVES AND ENDPOINTS 
2.3.1 
Efficacy Period for All Endpoints 
The start of the efficacy period for each individual patient is defined as the date of first 
emicizumab administration.  
The end of the efficacy period is defined as the date of the clinical cutoff or the date of 
withdrawal from the initial study period (i.e., treatment phase according to eCRF-Subject 
Disposition page), whichever is earlier.  For patients whose dose is up-titrated, the 
efficacy period ends a day prior to the first day on the up-titrated dose.   
The efficacy period on a given up-titrated/down-titrated dose starts with the first day on 
this dose and ends on the date of the clinical cutoff or the date of withdrawal or date 
preceding the next up-titration/down-titration.  Bleeds on the up-titrated/down-titrated 
dose are analyzed separately (see Section 4.1).   
Bleed rate is defined as the number of bleeds over the efficacy period.  A bleed is 
counted in the primary analysis if it was treated with coagulation factors and fulfills the 
adapted International Society on Thrombosis and Haemostasis (ISTH; 
Blanchette et al. 2014) criteria, as described in Section 4.5.8 of the protocol.  More 
specifically, the rules outlined in the sections below are applied. 


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2.3.2 
Bleed-Related Efficacy Objectives and Endpoints  
The key efficacy objective is to characterize the efficacy of 6 mg/kg emicizumab Q4W 
based on the number of bleeds over time for patients in the expansion cohort. 
The bleed-related efficacy objectives are as follows: 
• 
To evaluate the efficacy of prophylactic emicizumab in maintaining adequate control 
of bleeding based on treated bleeds over time 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of joint 
bleeds over time 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of target 
joint bleeds over time (target joints are defined as joints with ≥ 3 bleeds occurring in 
the same joint over the last 24 weeks prior to study entry; see Section 2.3.2.5) 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of all 
bleeds (i.e., those treated and untreated with coagulation factors) over time 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of 
spontaneous bleeds over time (spontaneous bleed rate) 
 
2.3.2.1 
Treated Bleed 
A bleed is considered to be a “treated bleed” if it is directly followed (i.e., there is not an 
intervening bleed) by at least one hemophilia medication reported to be a “treatment for 
bleed” as specified in the BMQ, irrespective of the time between the treatment and the 
preceding bleed.  A bleed and the first treatment thereafter and before a new bleed 
starts, are considered to be pairs (i.e., one treatment belongs to one bleed only), with the 
following exception:  if multiple bleeds occur on the same calendar day, the subsequent 
treatment is considered to apply for each of these multiple bleeds. 
Bleeds due to surgery/procedure are not included in the analysis.  Only treatments that 
were recorded as “treatment for bleed” are included in the determination of a treated 
bleed.  Note that a bleed can be treated with more than one treatment.  
72-Hour Rule: 
Two bleeds of the same type (e.g., “joint,” “muscle,” or “other”) and at the same 
anatomical location are counted as one bleed if the second bleed occurs within 
72 hours from the last treatment for the first bleed.  The last treatment is defined as the 
last treatment associated with the bleed before a new bleed occurs, either in the same or 
in a different location.   
2.3.2.2 
All Bleeds 
In addition to treated bleeds, “all bleeds” will be analyzed as an additional endpoint.  This 
definition comprises both treated and non-treated bleeds.  In this definition, all bleeds 
are included, irrespective of treatment with coagulation factors, with the following 
exception:  bleeds due to surgery/procedure are excluded from analysissimilar as in 
the analysis of treated bleeds.   


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The endpoint of “all bleeds” fulfills the adapted ISTH criteria, as described in the protocol 
and the 72-hour rule, in particular.  This applies to the “all bleeds” definition as well.  As 
“all bleeds” comprises treated and non-treated bleeds, the 72-hour rule will be 
implemented separately for the treated and non-treated bleeds.     
For treated bleeds, the 72-hour rule is implemented exactly as defined for the “treated 
bleeds” endpoint (see Section 2.3.2.1).   
For non-treated bleeds, the 72-hour rule is implemented by calculating a treatment-free 
period of 72 hours from the bleed itself.  That is, a non-treated bleed is counted as a new 
bleed if it occurs more than 72 hours after the first sign of the preceding non-treated 
bleed or after the last treatment for a bleed.    
2.3.2.3 
Treated Spontaneous Bleeds 
In the analysis of spontaneous bleeds, only treated bleeds that fulfill the 72-hour rule are 
included. 
Bleeds are classified as “spontaneous” if there is no other known contributing factor such 
as trauma or procedure/surgery.  
2.3.2.4 
Treated Joint Bleeds 
In the analysis of joint bleeds, only treated bleeds that fulfill the 72-hour rule are included.  
Bleeds due to procedure/surgery are again excluded.  
Joint bleeds are defined as bleeds where the bleed type is “joint” as reported in the BMQ 
and is reported with at least one of the following symptoms:  increasing swelling or 
warmth of the skin over the joint and/or increasing pain, decreased range of motion, or 
difficulty in using the joint compared with baseline. 
2.3.2.5 
Treated Target Joint Bleeds 
Target joints are joints into which repeated bleeds occur (i.e., ≥ 3 bleeds into the same 
joint over the last 24 weeks prior to study entry).  The target joints prior to study entry are 
identified through the eCRF.  The bleeds in target joints during the efficacy period are 
defined by first selecting the bleeds that fulfill the definition of a treated joint bleed and 
then counting how many of these occurred in a target joint as defined prior to study entry.  
The locations to be taken into account are shoulder, elbow, wrist, fingers/thumb, hip, 
knee, ankle, sole/heel, and toes.  Left and right sides of the same joint type are 
considered to be separate joints.  
2.3.3 
Health-Related Quality-of-Life (HRQoL) Endpoints  
The EQ-5D-5L index utility score using the U.K. value set and visual analog scale (VAS) 
will be evaluated. 
Because different measures, Haem-A-QoL and Haemo-QoL-SF, are used for the adult 
and adolescent patients, respectively, all calculations and analyses will be conducted 


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separately for these two measures.  For either questionnaire, descriptive analyses 
including summaries and 95% CIs of change from baseline for each individual subscale 
and the overall score will be performed.  
Proportion of patients preferring emicizumab after 17 weeks of treatment will be 
presented along with ranked reasons for that choice.   
Summary statistics of the number of days away from school/work and days hospitalized 
will be presented.  Number of days of missed daycare/school and days hospitalized will 
be analyzed using descriptive statistics and 95% CIs. 
2.3.4 
Pharmacokinetic Endpoints 
The PK endpoint for this study is the exposure (Ctrough) of emicizumab prior to drug 
administration at the following timepoints: 
PK Run-In Cohort 
• 
Week 1 (predose Day 1; 8 hours post-injection on Day 1; then Day 3, Day 5); 
Week 2 (Day 8, Day 11); Week 3 (Day 15, Day 18); Week 4 (Day 22); Week 5 
(Day 29 predose); Week 6 (Day 36); Week 7 (Day 43); and Week 8 (Day 50)   
• 
Week 9 (Day 57); Week 13 (Day 85); Week 17 (Day 113); and Week 21 (Day 141) 
and additionally, once between two emicizumab administrations occurring between 
Week 9 and Week 21 
• 
Week 22 (Day 148); Week 23 (Day 155); Week 24 (Day 162); and Week 25 
(Day 169) 
• 
Every 12 weeks, thereafter, while on emicizumab, until the end of the study. 
 
Expansion Cohort 
• 
Every week during Weeks 1−4 on emicizumab 
• 
Every 4 weeks during Weeks 5−25 on emicizumab 
• 
Every 12 weeks, thereafter, while on emicizumab, until the end of the study. 
 
2.3.5 
Safety Endpoints 
Safety parameters to be measured include exposure, adverse events (including serious 
adverse events, adverse events of special interest, adverse events leading to drug 
discontinuation, and deaths), clinical laboratory results (hematology, chemistry, and 
anti-emicizumab antibodies), vital signs, ECG, concomitant medication use, and 
incidence of de novo development of FVIII inhibitors (in the non-inhibitor population). 
2.3.6 
Biomarker Endpoints 
Biomarker endpoints include standard aPTT, modified aPTT, PT and prothrombin time 
international normalized ratio, D-Dimer, peak height thrombin generation, FIX antigen, 
FXIII activity, FVIII inhibitor titer, FVIII activity, fibrinogen, and pro-thrombin fragment 1.2 
vWF antigen. 


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2.4 
DETERMINATION OF SAMPLE SIZE 
The sample size of 6 patients for the PK run-in cohort is considered appropriate to 
assess pharmacokinetics and safety to allow for an informed decision to open the 
subsequent expansion cohort with 40 additional patients.  One additional patient was 
recruited in the run-in cohort to ensure that the predefined number of patients (6) 
complete 6-weeks treatment for required PK data in order to enable a decision for 
opening the expansion cohort, in case of withdrawal. 
The overall sample size of 40 patients in the expansion cohort is based primarily on 
clinical considerations taking into account the limited number of patients with 
hemophilia A.  It is expected that a sample size of 40 patients would, nonetheless, 
provide statistically robust point estimates with meaningfully narrow CIs. 
2.5 
ANALYSIS TIMING 
Analysis on the PK run-in cohort will be conducted 6 weeks after the first 6 patients have 
completed 6 weeks in the study.  This analysis will focus on pharmacokinetics and safety 
to inform on the opening of the expansion cohort.   
The primary analysis will take place at the earliest time when all enrolled patients in the 
expansion cohort complete 24 weeks in the study or have withdrawn.  These analyses 
will be carried out separately for patients in the expansion cohort and the PK run-in 
cohort.  
The final analysis will occur at the end of the study as defined in the protocol.  Additional 
updates may be performed between the primary and final analyses, as requested by 
Health Authorities or deemed necessary by the Sponsor. 
Additional analyses for Study BO39182 may be conducted to support regulatory 
submissions. 
3. 
STUDY CONDUCT 
Study BO39182 is a single-arm study implemented in two parts.  The first part enrolled 
6 patients to receive 6 mg/kg Q4W of SC emicizumab and will provide pharmacokinetic 
and safety information for opening of the expansion cohort.  An additional seventh 
patient was enrolled to ensure sufficient patients (6) to complete 6 weeks of treatment 
for required PK data to make the decision for opening the expansion cohort, in case of a 
patient withdrawal.  Since patients in the run-in cohort do not receive a loading dose and 
therefore reach steady state concentrations later, their bleeding may not be fully 
controlled by emicizumab; this cohort is restricted to patients who were previously on 
episodic treatment. 
Forty patients will be enrolled in the expansion cohort to receive prophylactic 
emicizumab at 3 mg/kg QW loading dose for 4 weeks, followed by 6 mg/kg Q4W.  


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Patients with either prior episodic or prophylactic treatment regimen are eligible for the 
expansion cohort.  
After 24 weeks in the study, all patients are eligible to up-titrate to 3 mg/kg QW with 
approval from the Medical Monitor if they fulfill the protocol requirements for up-titration 
(see Section 4.3.2.1 of the protocol).  Subsequently, up-titrated patients may decide to 
down-titrate to 6 mg/kg Q4W, 3 mg/kg Q2W, or 1.5 mg/kg QW.  This process of up- and 
down-titration may repeat more than once.  
3.1 
DATA MONITORING 
After 6 enrolled patients in the PK run-in cohort have each completed 6 weeks in the 
study, an analysis will be performed to evaluate PK and preliminary efficacy and safety 
of prophylactic emicizumab administered subcutaneously at 6 mg/kg/Q4W.  This 
analysis will include data collected from all patients at the time.  An internal Roche group 
will be constituted to evaluate whether or not to open the expansion cohort given the 
available data.  There will not be an independent Data Monitoring Committee (iDMC) or 
a formal IMC for this study. 
4. 
STATISTICAL METHODS 
4.1 
OUTPUT LAYOUTS 
While the efficacy and safety objectives will primarily be evaluated on the expansion 
cohort, the same will also be evaluated on the PK run-in cohort at the time of the clinical 
cutoff to complement the data from the expansion cohort, as applicable.  The two key 
output layouts will therefore be:   
• 
PK Run-In Cohort:  Includes data from patients enrolled in the PK run-in cohort.  
This cohort receives 6 mg/kg Q4W without any loading dose. 
• 
Expansion Cohort:  Includes data from the planned 40 patients who receive 
3 mg/kg QW loading dose for 4 weeks followed by 6 mg/kg Q4W. 
 
The output results will be presented in separate tables as below: 
Parameter 
Run-In Cohort 
Total 
 
Parameter 
Expansion Cohort 
Total 
 
The data under the new, up-titrated or down-titrated dose is analyzed and reported 
separately.  Additional summaries will be produced for key safety and exposure on all 
data (i.e., data before and after up-titration). 


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4.2 
ANALYSIS POPULATIONS 
4.2.1 
Treated Patient Population 
This population includes all enrolled patients who received at least one dose of 
emicizumab.  This will be the primary efficacy and safety analysis population separately 
for PK run-in and expansion cohorts as described above.  
4.2.2 
All Patient Population 
This population includes all patients enrolled into the study.   
4.2.3 
Pharmacokinetic-Evaluable Population 
This population includes all patients who have received at least one dose of emicizumab 
and have at least one post-dose emicizumab concentration result. 
4.2.4 
Up-Titrated/Down-Titrated Population 
This population includes patients whose dose was changed at least once during the 
study.  
4.3 
ANALYSIS OF STUDY CONDUCT 
The flow of patients through the study will be displayed in a “CONSORT” diagram.  A 
clear account of all patients who entered the study, were enrolled, and completed the 
study will be displayed.  In addition, reasons for premature discontinuation from study 
treatment and reasons for withdrawing from the study will be described. 
Major protocol deviations will be summarized.  
Observation time and duration of follow-up, as well as adherence to schedule of 
assessments and compliance with data entry into the electronic, handheld device will 
also be evaluated. 
4.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
Demographic data (e.g., age, race/ethnicity, height, weight) and baseline disease 
characteristics (e.g., inhibitor status, previous hemophilia treatment, number of target 
joints) will be summarized for all patients. 
4.5 
EFFICACY ANALYSIS 
Efficacy objectives in this study will be assessed descriptively without any formal 
hypothesis testing.  
4.5.1 
Bleed Rate Endpoints 
The number of bleeds will be analyzed using the negative binomial regression model 
with efficacy period as an offset in the model to account for the difference in follow-up 
times.  Annualized Bleeding Rate (ABR) will be estimated from the model and presented 
with 95% CI.   


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In addition to the model based approach, individual patient ABR will also be calculated 
based on the formula: 
ABR = ൬Number of bleeds the during efficacy period
Number of days during the efficacy period ൰ × 365.25  
 
Should the negative binomial not converge, then only the formula-based ABR will be 
presented.  
All bleeds will be characterized descriptively, including the type, location, and cause of 
bleed (surgery/procedure, traumatic, spontaneous).  Bleed rates for spontaneous and 
traumatic bleeds will also be calculated. 
The number of bleeds, types, and locations of bleed will be summarized for all patients 
and listed for each patient individually.  Exploratory analyses will be conducted to 
characterize the type, location, frequency, and pattern of bleeds. 
4.5.2 
Health-Related Quality-of-Life (HRQoL) Endpoint 
The Health Utilities Index (HUI) score and VAS score at each assessment and change 
from baseline will be calculated from the EQ-5D-5L.  In addition, the number of patients 
who report a clinically meaningful change from baseline to Week 24 on the HUI and VAS 
will be reported.  A meaningful change in the VAS is 7 points and for the HUI it is 
0.7 points (Walters et al. 2005; Pickard et al. 2007). 
The Haem-A-QoL, and Haemo-QoL-SF will be analyzed descriptively for each individual 
subscale and in overall score.  Summaries of change from baseline will be provided with 
95% CIs.  In addition, the proportion of patients reporting a clinically meaningful change 
from baseline to Week 24 on the physical health and total scores will be reported.  A 
meaningful change on the physical health scale is 10 points and for the total score it is 
7 points (Wyrwich et al. 2015).  
The proportion of patients preferring either emicizumab or previous hemophilia treatment 
regimen will be calculated and presented with 95% CIs based on the patient preference 
questionnaire.  The proportion of patients selecting each reason for their preference and 
the top three preferred reasons affecting the patient preference will also be summarized. 
The number of days away from school/work and days hospitalized will be analyzed using 
descriptive statistics and 95% CIs. 
4.5.3 
Subgroup Analyses 
Additional descriptive summaries of both treated bleeds and all bleeds will be computed 
for various subgroups of the study.  The summaries will include subgroup ABR and its 
95% CIs.  The main pre-specified subgroups are as follows:   
• 
Age: < 18, ≥ 18 
• 
Age: < 65, ≥ 65 


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• 
Race: Asian, Black or African American, White, Other 
• 
Hemophilia severity: mild, moderate, severe 
• 
Number of target joints at study entry: no target joint, any target joint 
• 
FVIII Inhibitor status: with FVIII inhibitor, without FVIII inhibitors 
• 
Previous treatment regimen: prior episodic, prior prophylactic 
• 
Number of bleeds in the 24 weeks prior to entry: < 9, ≥ 9 for patients being on prior 
episodic treatment 
 
Note that due to the likely small sample sizes, subgroup analyses will be highly 
susceptible to variability and should therefore be interpreted with caution.  
Additional region- and/or country-specific analyses may be performed to support 
regulatory submissions as needed. 
4.6 
PHARMACOKINETIC ANALYSES 
4.6.1 
PK Run-In Cohort 
PK parameters of emicizumab will be estimated using non-compartmental methods after 
the first and the sixth injection and include: 
• 
Tmax: Time to maximum observed plasma concentration 
• 
Cmax: Maximum observed plasma concentration 
• 
AUCτ: Area under the plasma concentration-time curve over a dosing interval 
• 
AUC0-inf: Area under the plasma concentration-time curve between time zero 
(predose) extrapolated to infinity (only for the first injection) 
• 
t½: Apparent terminal half-life 
• 
CL/F and CLss/F: Apparent Clearance  
 
Concentration data and calculated PK parameters for emicizumab will be presented in 
individual listings, summary tables (including descriptive statistics: mean, geometric 
means, medians, ranges, standard deviations, and coefficients of variation) and graphs 
(including concentration versus time plots on linear and semi-logarithmic scales) as 
appropriate. 
4.6.2 
Expansion Cohort 
For all patients, predose (trough) plasma concentrations of emicizumab will be 
presented descriptively at each timepoint by dose group, including arithmetic and 
geometric means, median, range, standard deviations, and coefficients of variation. 
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance (CL/F) and volume of distribution (V/F), will be estimated, and the influence of 
various covariates, such as age, gender, and body weight, on these parameters will be 


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investigated.  Secondary PK parameters, such as area under the curve, will be derived 
from individual post-hoc predictions.  Data may be pooled with data from other 
emicizumab studies and completed Phase III studies.  These analyses will be reported in 
a dedicated report. 
4.7 
SAFETY ANALYSES 
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry and hematology, including complete blood count with 
differential and platelet counts), ECGs, vital signs, anti-drug antibodies (ADAs), and 
de novo anti-FVIII inhibitors. 
4.7.1 
Exposure to Study Medication 
Information on study drug administration will be summarized by duration and cumulative 
dose.  In addition, treatment exposure will be summarized, including delays and 
interruptions.  The number of patients whose dose was up-titrated will be summarized.  
A similar summary will be generated for patients who down-titrate back to 6 mg/kg Q4W, 
1.5 mg/kg/QW, or 3 mg/kg Q2W.   
Patient withdrawals from study treatment will be reported as listings and summary tables. 
4.7.2 
Adverse Events 
Adverse events will be summarized and presented by System Organ Class mapped 
term, appropriate thesaurus level, and toxicity grade (WHO Criteria).  All adverse events 
will be coded using the current version of MedDRA at time of database closure.  The 
total number and percentage of patients with at least one adverse event and total 
number of adverse events will be summarized.  Separate adverse event summaries for 
serious adverse events, adverse events of special interest, severity, relatedness, and 
discontinuation/modification will be provided.  
4.7.3 
Laboratory Data 
For clinical laboratory data that were collected from local laboratories, summary statistics 
will be presented in International System of Units (SI).  Laboratory data not collected in 
SI units will be converted to SI units as applicable.  In addition, shift tables describing 
changes from baseline will be presented using the WHO toxicity grading scale. 
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or clinical pharmacology and pharmacokinetics will be summarized using standard 
language/terminology (Shankar et al. 2014). 
4.7.4 
Vital Signs 
Vital signs will be summarized using mean change from baseline tables over time.  
Measurements consist of heart and respiratory rate, temperature, and systolic and 
diastolic blood pressure.  


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18/Statistical Analysis Plan BO39182 
4.7.5 
Electrocardiogram 
ECG results and corresponding changes from baseline will be summarized by cohort 
and visit for QT, RR, HR, QTcB, QTcF, PR and QRS and T- and U-wave morphology.    
4.8 
EXPLORATORY BIOMARKER ANALYSES 
PD parameters (e.g., aPTT, PT, FVIII activity, thrombin generation, FIX:Ag, FX:Ag) will 
be presented using summary statistics, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation. 
All other exploratory biomarkers will be analyzed and reported descriptively.  
4.9 
MISSING DATA 
On the electronic, handheld device, it is not possible to leave questions unanswered or 
to enter partial data.  Therefore, the data for bleed-related endpoints coming from the 
electronic, handheld device are complete. 
In the site data entry system (Gather), it is possible to leave the time of a treatment or a 
bleed blank because the patient might not be able to reliably remember these.   
4.10 
INTERIM ANALYSES 
4.10.1 
PK Run-In Analysis 
An analysis of the PK run-in cohort data will be performed after the sixth patient has 
been on treatment for 6 weeks, to support the decision to open the expansion cohort.  
This analysis will constitute characterization of the PK profile (to assess whether the 
mean PK profile is as predicted [i.e., ≥ lower limit of 95% CI of the predicted mean PK 
profile]) and assessment of safety to inform the decision on whether or not to open the 
expansion cohort.  This analysis will be carried out internally and there will be no formal 
IMC.   
4.10.2 
Additional Interim Analysis 
Additional interim analyses may be performed to support regulatory submissions.  The 
results of these analyses will be documented in interim CSRs and would include patients 
from both the run-in and expansion cohorts.  


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5. 
REFERENCES 
Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from 
the SSC of the ISTH. J Thromb Haemost 2014;12:19359. 
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for 
use of central venous access devices in haemophilia. Haemophilia 
2004;10:62948. 
Franchini M and Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:17984. 
Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with 
haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: 
results from the Pro-FEIBA study. Haemophilia 2013;19:73643. 
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult 
patients with severe haemophilia: a beneficial effect on orthopaedic outcome and 
quality of life. Eur J Haematol 2012;88(4):32935. 
Kingdon HS, Lundblad RL. An adventure in biotechnology: the development of 
haemophilia A therapeuticsfrom whole-blood transfusion to recombinant DNA to 
gene therapy. Biotechnol Appl Biochem 2002;35:1418. 
Mannucci PM, Tuddenham EG. The hemophiliasfrom royal genes to gene therapy. N 
Engl J Med 2001;344:17739. 
Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health Qual Life Outcomes 2007;5:70. 
Schrijvers LH, Uitslager N, Schuurmans MJ, et al. Barriers and motivators of adherence 
to prophylactic treatment in haemophilia: a systematic review. Haemophilia 
2013;19:35561. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and 
tactical recommendations. AAPS J 2014;16:65873.  
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Am Soc 
Hematol Educ Program 2013;2013:3743.  
Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized 
bispecific antibody in hemophilia a. N. Engl J Med 2016;374:204453.NEJM paper 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working 
Group on Behalf of the World Federation of Hemophilia. Guidelines for the 
management of hemophilia. Haemophilia 2013;19:e147. 
Thornburg CD. Prophylactic factor infusions for patients with hemophilia: challenges with 
treatment adherence. J Coagul Disord 2010;2:1. 


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Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a 
novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016:1−38. 
Walters SJ, Brazier JE. Comparison of the minimally important difference for two health 
state utility measures: EQ-5D and SF-6D. Qual Life Res 2005;14:1523−32.  
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of 
life change using the Haem-A-QoL. Haemophilia. 2015:21:578−84.  
 


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Appendix 1  
Protocol Synopsis 
TITLE: 
A MULTICENTER, OPEN-LABEL, PHASE III STUDY TO 
EVALUATE THE EFFICACY, SAFETY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF EMICIZUMAB GIVEN EVERY 
4 WEEKS (Q4W) IN PATIENTS WITH HEMOPHILIA A 
PROTOCOL NUMBER: 
BO39182 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2016-001094-33 
IND NUMBER: 
122954 
TEST PRODUCT: 
Emicizumab (RO5534262) 
PHASE: 
Phase III 
INDICATION: 
Hemophilia A 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Chugai Pharmaceutical Co. Ltd. 
 
Objectives and Endpoints 
Pharmacokinetic Run-In Phase Objectives 
The objectives of the pharmacokinetic run-in are as follows: 
• 
To investigate the pharmacokinetics of emicizumab after single and multiple (every 4 weeks 
[Q4W]) subcutaneous (SC) administration of 6 mg/kg 
• 
To assess the safety and tolerability of emicizumab after Q4W SC administration of 6 mg/kg  
• 
To explore the prophylactic effect of emicizumab in maintaining adequate control of 
bleeding 
• 
To investigate the effect of emicizumab on pharmacodynamic (PD) markers including (but 
not limited to) aPTT, thrombin generation, and factor VIII (FVIII) activity 
 
Expansion Phase 
Efficacy Objectives 
The efficacy objectives are as follows: 
• 
To evaluate the efficacy of prophylactic emicizumab in maintaining adequate control of 
bleeding 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of joint bleeds 
over time 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of target joint 
bleeds over time (target joints are defined as joints with ≥ 3 bleeds occurring in the same 
joint over the last 24 weeks prior to study entry) 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of all bleeds (i.e., 
those treated and untreated with coagulation factors) over time 
• 
To evaluate the clinical effect of prophylactic emicizumab on the number of spontaneous 
bleeds over time (spontaneous bleed rate) 


Appendix 1  
Protocol Synopsis (cont.)  
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22/Statistical Analysis Plan BO39182 
• 
To evaluate the health-related quality of life (HRQoL) of patients according to Haem-A-QoL 
(≥ 18y) or Haemo-QoL_SF (ages 12−17) scores after 24 weeks  
• 
To evaluate the health status of patients according to EuroQoL Five-Dimension-Five Levels 
Questionnaire (EQ-5D-5L) scores after 24 weeks  
• 
To assess preference for emicizumab regimen compared with previous regimen used  
• 
To assess the number of days away from school/work 
• 
To assess the number of days hospitalized 
 
Safety Objectives 
The safety objectives of this study are to evaluate the overall safety of emicizumab given Q4W 
in patients with hemophilia A based on the following endpoints: 
• 
The incidence and severity of adverse events 
• 
The incidence and severity of thromboembolic events 
• 
Changes in physical examination findings and vital signs 
• 
Incidence of laboratory abnormalities 
• 
Incidence and severity of injection-site reactions 
• 
Incidence of adverse events leading to drug discontinuation 
• 
Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 
• 
Incidence of thrombotic microangiopathy 
• 
The incidence and clinical significance of anti-emicizumab antibodies 
• 
The incidence of de novo development of FVIII inhibitors (non-inhibitor population) 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective of this study is as follows: 
• 
To characterize the pharmacokinetics of multiple Q4W SC doses of 6 mg/kg emicizumab  
 
Exploratory Pharmacodynamic Biomarker Objective 
The exploratory PD biomarker objective is as follows: 
• 
To investigate the effect of Q4W doses of emicizumab on PD parameters, including but not 
limited to aPTT, thrombin generation and FVIII activity at timepoints throughout the study 
 
Study Design 
Description of Study 
Study BO39182 is a multicenter, open-label, non-randomized study designed to investigate the 
efficacy, pharmacokinetics, safety, and pharmacodynamics of emicizumab (6 mg/kg) 
administered in a Q4W dosing regimen.  Patients with hemophilia A with or without inhibitors 
against FVIII will be enrolled.  The study consists of two parts:  a PK run-in part followed by an 
expansion part.     
PK Run-In-Part 
In the PK run-in part, a full PK profile will be measured in the first 6 enrolled patients during the 
first 4 weeks to characterize the pharmacokinetics of a single SC dose of 6 mg/kg emicizumab 
in patients with hemophilia A.  After the first and second emicizumab administration, an intense 
PK sampling will occur.  A reduced PK sampling schedule will be used to characterize repeated 
Q4W SC administration from Week 9 to Week 21.  After the sixth injection at Week 21, PK 
sampling frequency will be increased to characterize steady-state pharmacokinetics (see 
protocol).   


Appendix 1  
Protocol Synopsis (cont.)  
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23/Statistical Analysis Plan BO39182 
An analysis of the data collected when all 6 patients in the PK run-in cohort have been followed 
for at least 6 weeks will be performed to assess whether the mean PK profile is as predicted 
(i.e., ≥ lower limit of 95% CI of the predicted mean PK profile) after repeated 6 mg/kg SC 
administration Q4W.  In addition to PK, safety will be assessed in order to establish whether the 
expansion cohort can be opened.  This analysis will be conducted by a Roche internal group of 
representatives from Clinical Pharmacology, Clinical Science, Clinical Safety, and Statistics; no 
formal Internal Monitoring Committee (IMC) will be set up. 
Expansion Part 
An expansion phase will be conducted to further investigate the efficacy, pharmacokinetics, 
safety, and pharmacodynamics in a cohort of 40 patients.  These patients will start with loading 
doses of 3 mg/kg QW × 4, followed by a maintenance dose of 6 mg/kg Q4W for at least 
24 weeks overall.  These patients will undergo PK sampling to investigate trough concentrations 
(Ctrough) and samples (predose) will be drawn as per the schedule of assessments (see protocol). 
The primary analysis (descriptive analyses of the study objectives) will be conducted either after 
the last enrolled patient completes the 24-week treatment period, is lost to follow-up, or has 
withdrawn, whichever occurs first.   
During the study, individual bleeds will be captured as they occur while HRQoL, health status, 
patients’ preference and days of school or work missed will be assessed as outlined in the 
schedule of assessments in protocol.  Patients (or their legally authorized representative) will be 
asked on a weekly basis to record via their electronic, handheld device whether a bleed has 
occurred and whether treatment for a bleed or treatment to prevent a bleed has been given. 
Physical examinations, vital signs, ECG, and laboratory assessments will be performed as 
detailed in the schedule of assessments (see protocol) and will be the same for all patients 
receiving emicizumab, regardless of whether they are enrolled in the PK run-in cohort or the 
expansion cohort.  Adverse events will be captured on an ongoing basis, as they occur during 
the study. 
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have already 
occurred).  There is clinical experience in the ongoing Phase I/II clinical studies with the 
treatment of over 60 breakthrough bleeds in patients receiving emicizumab with either FVIII or 
bypassing agents.  FVIII, aPCC, or recombinant activated factor VII (rFVIIa) do not interfere with 
emicizumab PK assessments and no safety signals have been observed when breakthrough 
bleeds were treated with standard-of-care regimens during Phase I/II studies.  However, in the 
ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with 
FVIII inhibitors), 2 events of TMA and 2 thromboembolic events were observed in patients 
who concomitantly used repeated doses of aPCC for the treatment of breakthrough bleeds.  
Therefore, it is recommended that breakthrough bleeds in the inhibitor population are treated 
with rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should be 
avoided or limited.  
Therefore, a washout period of 72 hours prior to the first emicizumab dose in this study is 
required for patients receiving prior aPCC or Byclot.  Also a washout period of 72 hours for 
patients who were previously receiving ITI is required prior to the first emicizumab 
administration.  Patients may require dosing with FVIII or for the treatment of potential 
breakthrough bleeds (see protocol), especially for the time period until steady-state 
concentrations of emicizumab have been reached. 
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation) will be collected as 
per the schedule of assessments and always coupled with a PK assessment for days where PK 
and PD samples are to be drawn.  As values for many tests are normalized by even low plasma 
concentrations of emicizumab, a variety of assay formats (one-stage, chromogenic) and 
modifications (pre-dilution of patient plasma) will be investigated for assessment of PD 
response at higher emicizumab plasma concentrations.  It is not expected that these biomarkers 
will be used to guide the selection of patients to be treated with emicizumab.  However, these 
biomarkers may be used to identify a future assay for the monitoring of emicizumab activity.  In 
addition, factor IX (FIX) and factor X (FX) antigen levels will be monitored. 


Appendix 1  
Protocol Synopsis (cont.)  
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24/Statistical Analysis Plan BO39182 
Biomarkers related to thromboembolism (e.g., D-dimer, prothrombin fragment 1.2) and 
immunologic biomarkers (i.e., anti-emicizumab antibodies and anti-FVIII antibodies) will be 
measured as per the schedule of assessments (see protocol).  
Breakthrough bleeds will be treated with appropriate coagulation products with either FVIII 
(non-inhibitor patients) or rFVIIa (inhibitor patients) at the lowest expected dose to achieve 
hemostasis and captured as they occur.  When a bleed has occurred, patients (or their legally 
authorized representative) will be required to report bleed information, including site of bleed, 
type of bleed, time of each individual bleed (day, start time), symptoms of bleed, and treatment 
for bleed (e.g., other than emicizumab in case of breakthrough bleeds).  The reason for the use 
of coagulation products (e.g., FVIII or rFVIIa) will be documented (e.g., bleeding, preventative 
dose before activity).  Thorough documentation of the treatments for bleeds will be requested, 
including agent, start time, dose, route of administration, and number of infusions needed to 
treat the bleed.  For patients with inhibitors against FVIII who experience a breakthrough 
bleed that requires treatment with bypassing agents, local and central laboratory assessments 
are required to monitor the risk for thromboembolic events or TMA as per the schedule of 
assessments.  
All patients, irrespective of the cohort assigned, who continue to derive clinical benefit will be 
given the opportunity to continue receiving prophylactic emicizumab either within this study or 
as part of a future extension study according to Roche policy on post-study drug access.  After 
24 weeks on prophylactic emicizumab, all patients will be able to continue on their 6 mg/kg 
Q4W maintenance dose or may be provided the option to increase their dose to 3 mg/kg QW if 
they meet protocol-defined criteria of suboptimal response.  Suboptimal response is defined as 
follows:  
• 
≥ 2 qualifying bleeds within 24 weeks while on prophylactic emicizumab 
 
Qualifying bleeds are defined as spontaneous, verified by investigator (e.g., by imaging or 
physical examination), and occurring while on prophylactic emicizumab at steady state (after 
the Week 5 visit for expansion cohort/after Week 17 visit for PK run-in cohort).  These 
patients must receive approval from the Medical Monitor to increase their dose to 3 mg/kg QW. 
Patients who discontinue emicizumab will be followed for 24 weeks after the last emicizumab 
dose. 
Number of Patients 
Approximately 46 patients with congenital hemophilia A previously treated with either FVIII or 
bypassing agents will be enrolled in the study (6 patients in the PK run-in phase and 40 patients 
in the expansion phase).  
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (consent/assent will be taken as appropriate) 
• 
Aged ≥ 12 years 
• 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the patient-reported outcome (PRO) questionnaires 
and bleed diaries through the use of an electronic device  
• 
Body weight ≥ 40 kg at screening  
• 
Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors  
• 
Patients using rFVIIa or willing to switch to rFVIIa as primary bypassing agent for the 
treatment of breakthrough bleeds 
• 
FVIII inhibitor test during screening with titer results available prior to first 
administration of study drug 


Appendix 1  
Protocol Synopsis (cont.)  
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25/Statistical Analysis Plan BO39182 
• 
Patients without FVIII inhibitors (< 0.6 BU/mL) who completed successful ITI must have 
done so at least 5 years before screening and must have no evidence of inhibitor 
recurrence (permanent or temporary) indicated by detection of an inhibitor > 0.6 BU/mL 
since ITI 
• 
For patients to be enrolled into PK run-in cohort: 
Current episodic treatment (FVIII or bypassing agents) at the time of entry into this 
study and documentation of details of episodic treatment for at least 24 weeks prior to 
entry into this study 
• 
For patients to be enrolled into the expansion cohort: 
Documentation of details of prophylactic or episodic treatment (FVIII or bypassing 
agents) and the number of bleeding episodes for at least 24 weeks prior to entry into 
this study 
For patients on an episodic regimen, ≥ 5 bleeds in the prior 24 weeks, regardless of 
inhibitor status 
• 
Adequate hematologic function, defined as a platelet count ≥ 100,000/µL and hemoglobin 
≥ 8 g/dL (4.97 mmol/L) at the time of screening 
• 
Adequate hepatic function, defined as total bilirubin ≤ 1.5 × age-adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT ≤ 3 × age-adapted ULN 
at the time of screening, and no clinical signs or known laboratory/radiographic evidence 
consistent with cirrhosis  
• 
Adequate renal function, defined as serum creatinine ≤ 2.5 × age-adapted ULN and 
creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula  
• 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use highly effective contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 5 elimination 
half-lives (24 weeks) after the last dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 1 year of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus) 
Examples of highly effective contraceptive methods with a failure rate of < 1% per year 
include proper use of combined oral or injected hormonal contraceptives, bilateral 
tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods such as a 
condom and a cervical cap) may be combined to achieve a failure rate of < 1% per 
year.  Barrier methods must always be supplemented with the use of a non-lipid-based 
spermicide 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods for contraception. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Inherited or acquired bleeding disorder other than hemophilia A 
• 
Ongoing or planned ITI therapy; patients in whom ITI has failed will be eligible with a 
72-hour washout period prior to the first emicizumab administration. 
• 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 


Appendix 1  
Protocol Synopsis (cont.)  
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26/Statistical Analysis Plan BO39182 
• 
Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment 
• 
Previous (within the last 12 months) or current treatment for thromboembolic disease (with 
the exception of previous catheter-associated thrombosis for which anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease 
• 
Other conditions (e.g., certain autoimmune diseases) that may currently increase the risk of 
bleeding or thrombosis 
• 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
• 
Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study  
• 
Known HIV infection with CD4 counts < 200 cells/µL 
HIV infection with CD4 counts ≥ 200 cell/µL permitted 
• 
Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy 
• 
Concomitant disease, condition, significant abnormality on screening evaluations or 
laboratory tests, or treatment that could interfere with the conduct of the study, or that would, 
in the opinion of the investigator/co-investigator, pose an additional unacceptable risk in 
administering study drug to the patient   
• 
Receipt of any of the following: 
Emicizumab in a prior investigational study 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
A non−hemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
Any other investigational drug currently being administered or planned to be 
administered  
• 
Inability to comply with the study protocol in the opinion of the investigator 
• 
Pregnancy or lactation or intention to become pregnant during the study 
• 
Women with a positive serum pregnancy test result within 7 days prior to initiation of study 
drug 
 
End of Study 
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (last patient last visit [LPLV]), as defined by any of the following criteria: 
• 
Completion of at least 24 weeks of emicizumab treatment and either transfer to a separate 
extension study to receive further emicizumab as per Roche Global Policy on Continued 
Access to Investigational Medicinal Products  
OR 
• 
Completion of the end-of-study safety follow-up visit 24 weeks after discontinuing 
emicizumab 
OR 
• 
Withdrawal of consent  
OR 
• 
Lost to follow-up 
 


Appendix 1  
Protocol Synopsis (cont.)  
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27/Statistical Analysis Plan BO39182 
Length of Study 
The length of the study for an individual patient will be:  
• 
Screening period up to 4 weeks 
• 
Treatment and observation period at least 24 weeks  
• 
Safety follow-up visit 24 weeks after discontinuing emicizumab unless patient transfers to a 
separate emicizumab extension study  
 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 20 months. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The emicizumab regimen being tested is 3 mg/kg QW for 4 weeks followed by 6 mg/kg Q4W 
subcutaneously for 24 weeks.  All patients with suboptimal control may have the option to 
increase the dose to 3 mg/kg QW after 24 weeks, with approval from the Medical Monitor 
Non-Investigational Medicinal Products 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening to the study completion/discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF page.  
Concomitant use of the following drugs and therapies will be permitted: 
• 
For patients in the expansion cohort who are on FVIII prophylaxis, they may continue their 
regular FVIII prophylaxis until the second emicizumab loading dose in order to avoid bleeds 
before adequate emicizumab level is reached.  Concomitant routine FVIII prophylaxis is not 
otherwise permissible during the study. 
• 
Drugs intended to control bleeds, including FVIII concentrates (non-inhibitor patients) or 
rFVIIa (inhibitor patients), should be used at the lowest dose expected to achieve 
hemostasis.  Given that circulating emicizumab may increase patients’ coagulation 
potential, the doses required to achieve hemostasis may be lower than the FVIII or 
bypassing agent doses used prior to starting the study. 
Caution should be taken for patients who are using rFVIIa (e.g., consideration of using 
no more than 90 µg/kg rFVIIa as an initial dose). 
In the event that aPCC is the only available bypassing agent, the lowest dose expected to 
achieve hemostasis should be prescribed with no more than 50 units/kg of aPCC to be 
administered as an initial dose.  For patients receiving aPCC prior to study entry, a 
washout period of 72 hours prior to first emicizumab dosing is required. 
Other bypassing agents (e.g., Byclot) should be avoided.  In cases where such agents are 
the only available bypassing agent, the lowest dose expected to achieve hemostasis should 
be prescribed, with no more than the lowest dose described in the prescribing information 
to be administered as an initial dose (e.g., no more than 60 µg/kg of Byclot).  For 
patients receiving Byclot prior to study entry, a washout period of 72 hours prior to 
first emicizumab dosing is required. 
Exact dose and schedule of FVIII or bypassing agents should be discussed with patients at 
the beginning and throughout the study.  Repeated dosing of FVIII, rFVIIa, aPCC, or 
other bypassing agents should be performed only under medical supervision and 
consideration should be given to verifying bleeds prior to repeated dosing.  For rFVIIa, 
aPCC, and other bypassing agents, laboratory monitoring by additional local and central 
laboratory assessments should be performed as per the schedule of assessments. 
• 
Drugs and therapies to treat adverse events and use of topical antiseptics, anesthetics, eye 
drops, etc., that are not considered to result in systemic exposure 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
28/Statistical Analysis Plan BO39182 
• 
Drugs to treat an existing medical condition ongoing at study entry that do not violate the 
eligibility criteria (e.g., anti-retroviral therapy for HIV infections) 
 
Statistical Methods 
Primary Analysis 
The efficacy objective is to evaluate the clinical effect of 6 mg/kg emicizumab Q4W based on 
the number of bleeds over time.  
The analyses will be performed using a negative binomial regression model, which accounts for 
different follow-up times, with the patient’s number of bleeds as a function of the time that each 
patient stays in the study included as an offset in the model.   
The number of bleeds will be also annualized (Annualized Bleeding RateABR) for each 
patient using the following formula:  
 
In case the negative binomial model does not converge the above formula will be used as the 
sole method of analysis. 
The clinical effect of prophylactic emicizumab on the number of bleeds, joint bleeds, target 
joint bleeds, spontaneous bleeds and all bleeds (i.e., those treated and untreated with 
coagulation factors) over time will be evaluated. 
The number of bleeds, sites of bleeds, and types of bleeds will be summarized for all patients 
and listed for each patient individually.  Several exploratory analyses will be conducted to 
characterize the type, location, duration, frequency, and pattern of bleeds.  For continuous 
endpoints, descriptive statistics will be calculated and categorical endpoints will be 
characterized through frequency tables.  
The primary final analysis will be performed 24 weeks after the last enrolled patient started 
treatment or has withdrawn prematurely, whichever occurs first.   
Safety Analyses 
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including complete 
blood count with differential and platelet counts), ECGs, vital signs, anti-drug antibodies (ADAs), 
and de novo anti-FVIII inhibitors. 
To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate thesaurus level, 
and toxicity grade.   
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading scale. 
Pharmacokinetic Analyses 
PK Run-In Cohort 
PK parameters of emicizumab will be estimated using non-compartmental methods after the 
first and the sixth injections and include: 
• 
Tmax: Time to maximum observed plasma concentration 
• 
Cmax: Maximum observed plasma concentration 
• 
AUCτ: Area under the plasma concentration-time curve over a dosing interval  
• 
AUC0-inf: Area under the plasma concentration-time curve between time zero (predose) 
extrapolated to infinity (only for the first injection) 
• 
t½: Apparent terminal half-life 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
29/Statistical Analysis Plan BO39182 
• 
CL/F and CLss/F: Apparent Clearance 
 
Concentration data and calculated PK parameters for emicizumab will be presented in individual 
listings, summary tables (including descriptive statistics: mean, geometric means, medians, 
ranges, standard deviations, and coefficients of variation) and graphs (including concentration 
versus time plots on linear and semi-logarithmic scales) as appropriate.   
Expansion Cohort 
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be presented 
descriptively, including arithmetic and geometric means, median, range, standard deviations, 
and coefficients of variation. 
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
gender, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as area under the curve, will be derived from individual post-hoc predictions.  
Data may be pooled with data from previous Phase I/II studies and completed Phase III studies.  
These analyses will be reported in a dedicated report. 
Immunogenicity Analyses 
The immunogenicity analyses will include patients with at least one predose and one postdose 
ADA assessment. 
The numbers and proportions of ADA-positive patients and ADA-negative patients during both 
the treatment and follow-up periods will be summarized.  Patients are considered to be ADA 
positive if they are ADA negative at baseline but develop an ADA response following study drug 
administration (treatment-induced ADA response), or if they are ADA positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) 
than the titer of the baseline sample (treatment-enhanced ADA response).  Patients are 
considered to be ADA negative if they are ADA negative at baseline and all post-baseline 
samples are negative, or if they are ADA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints will be 
analyzed and reported descriptively via subgroup analyses. 
Exploratory Analyses 
PD parameters (e.g., aPTT, parameters derived from thrombin generation, FVIII activity) will be 
presented using summary statistics, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation. 
Determination of Sample Size 
The sample size of 6 patients for the PK run-in cohort is considered appropriate to assess 
pharmacokinetics and safety to allow for an informed decision to open the subsequent 
expansion cohort with 40 additional patients. 
The overall sample size of 40 patients in the expansion cohort is based primarily on clinical 
considerations taking into account the limited number of patients with hemophilia A.  
Planned Interim Analysis 
An analysis of pharmacokinetics and safety will occur when the first 6 patients have been on 
treatment for 6 weeks.  On the basis of the results for pharmacokinetics and safety (e.g., 
≥ lower limit of 95% CI of the predicted mean PK profile, no severe unexpected safety findings), 
the study will proceed with the expansion cohort. 
This analysis will be conducted by a Roche internal group of representatives from Clinical 
Pharmacology, Clinical Science, Clinical Safety and Statistics; no formal IMC will be set up. 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
30/Statistical Analysis Plan BO39182 
Appendix 2  
Schedule of Assessments 
PK RUN-IN COHORT 
 
Screening 
Treatment Period 
From Week 25 
to Study 
Completion 
Study Completion 
or Early 
Termination 
a 
Safety 
F/U Visit
Week 
— 
— 
1 
2 
3  
4 
5 
9 
13 
17 
21 
25 
 
 
 
Day 
b –28 to –1  –7 to –1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
Informed consent
  c  
x 
 
 
Inclusion/exclusion criteria 
x 
 
 
Demographics and medical 
history
 d  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
including height and 
weight
e  
x
 
 
x 
f 
 
x 
f 
 
x 
f 
x 
f 
x 
f 
x 
f 
x 
f 
x 
f 
Q12W 
f 
x 
f 
x 
Vital signs
 g 
 
x
 
 
x
x
x
x
x
x
x
x 
x
Q12W
x
x
Concomitant medications
h 
 
 
x
x
x
x
x
x
x 
x
Q12W
x
x
Adverse events 
i 
 
 
Ongoing 
12-lead ECG 
 j 
 
x 
 
x k
 
x
x 
l
x
Hematology 
 m 
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Blood chemistry
  n 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Pregnancy test
  o 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab 
administration
p  
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Q4W 
 
 
PK, PD, and ADA 
See protocol 
Bleed /medication 
questionnaire
 q 
 
 
Weekly and on days of bleeds 
x 
x 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
31/Statistical Analysis Plan BO39182 
PK RUN-IN COHORT 
 
Screening 
Treatment Period 
From Week 25 
to Study 
Completion 
Study Completion 
or Early 
Termination 
a 
Safety 
F/U Visit 
Week 
— 
— 
1 
2 
3  
4 
5 
9 
13 
17 
21 
25 
 
 
 
Day 
b –28 to –1  –7 to –1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
Bleed/medication review 
r 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Q4W 
x 
x 
Following treatment with 
bypassing agents s 
 
 
Monitoring for thromboembolic events and thrombotic microangiopathy. s 
ADA = anti-drug antibody; eCRF = electronic Case Report Form; EQ-5D-5L = European Quality of Life-5 Dimensions-5 Levels; F/U = follow-up; HRQoL = health-related quality 
of life; PD = pharmacodynamic; PK = pharmacokinetic; PRO = patient-reported outcome; Q4W = every 4 weeks; Q12W = every 12 weeks. 
a Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has completed the 
24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the study, the completion 
assessments displayed in the schedule of assessments are similar with the Week 25 visit. 
b In order to characterize pharmacokinetics, it is mandatory assessments be performed on the exact visit day until Week 25; no deviation from visit day is acceptable until 
Week 25, deviations of ± 2 days are acceptable thereafter. 
c Obtain written informed consent (or patient written assent and parent written informed consent if patient is an adolescent) before performing any study related procedures.  
If patient fulfils the inclusion criteria, the patient should be enrolled in the study on the same day when the first dose of emicizumab is administered (Day 1). 
d Collected from patient’s medical record and documented in the eCRF. 
e Height assessment at Day 1 only for adults and weight assessments Q4W for all patients. 
f 
Height assessments for adolescents at Day 1 and ideally at all drug administration and PK sampling visits when the patients will be at the investigational site but at least 
every 12 weeks (repeated assessments). 
g Body temperature (oral or tympanic), blood pressure, pulse rate, respiratory rate. 
h Concomitant medication (e.g., extra pain medication to treat bleeds) will be recorded at the time of the visits, excluding treatments for bleeds, which will be collected in the 
bleeding questionnaire. 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
32/Statistical Analysis Plan BO39182 
 
i 
Adverse events are collected on an ongoing basis throughout the study.  Injection-site reactions will be collected on a separate form from the adverse event form.  After informed 
consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be reported. 
 j If screening ECG is abnormal, repeat at Week 1.  ECGs will also be performed:  once during Weeks 4−8 after starting emicizumab or dose escalation (up-titration); once 
24 weeks after starting emicizumab or dose escalation (up-titration); and at study completion/early termination.   
k Once during Weeks 4−8 after starting emicizumab. 
l 
For any dose increase (i.e., 3 mg/kg QW), an ECG should be obtained after 4 weeks of starting the new dose at the next scheduled clinic visit.  
m Predose (hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other cells], mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and RBC distribution width), performed locally.  Laboratory assessments 
completed at the screening visit do not have to be repeated at Week 1 if the period between Screening and Week 1 is 5 days or less and there has been no change in health status 
as assessed by the investigator. 
n Predose (sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine aminotransferase, aspartate 
aminotransferase, and alkaline phosphatase), performed locally.  Laboratory assessments completed at the screening visit do not have to be repeated at Week 1 if the period 
between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the investigator.   
o Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening and up to 7 days prior to enrollment (Day − 7 to Day − 1).  If 
applicable, during the study, urine pregnancy tests will be performed at the scheduled visits. 
p 6 mg/kg Q4W emicizumab. 
q Bleed information (start date and time, reason, type, location, and associated symptoms of each bleed) and medication for bleeds (breakthrough bleeds) should be reported by the 
patient via an electronic handheld device when a bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days).  If the patient discontinues study treatment, 
bleed and bleed medication data should be provided by the patient until the safety follow-up visit (24 weeks after last study drug administration). 
r 
Investigator review of bleed information.  
s Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic microangiopathy for 
platelet count, serum creatinine, LDH, and schistocytes within 24−48 hours of initial bypassing agent use.  A plasma sample should also be provided for local (one aliquot) 
and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 1+2, and D-dimer.  If prothrombin fragment 1+2 test cannot be done at the site, 
the sample should be sent to the local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory monitoring should be 
performed every 24−48 hours thereafter until 24−48 hours following the last dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory results 
should be recorded on the unscheduled visit eCRFs.  
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan BO39182 
Expansion Cohort 
 
Screening 
Treatment Period 
From 
Week 25 to 
Study 
Completion 
Study 
Completion or 
Early 
Termination
 a 
Safety 
Follow-Up 
Visit 
Week 
— 
— 
1 
2 
3  
4 
5 
9 
13 
17 
21 
25 
 
 
 
Day
 b –28 to –1 –7 to –1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
Informed consent 
 c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
 d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination including 
height and weight
  e 
x
 
 
x 
f 
 
x
 f 
 
x
 f 
x
 f 
x
 f 
x
 f 
x 
f 
x
 f 
Q12W
 f 
x
 f 
x 
Vital signs
 g 
x
 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Concomitant medications 
h 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Adverse events 
i 
 
 
Ongoing 
12-lead ECG
 j 
x 
 
 
 
 
 
x k 
 
 
 
 
x 
x 
l 
x 
 
Hematology
 m 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Blood chemistry
 n 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
34/Statistical Analysis Plan BO39182 
Expansion Cohort 
 
Screening 
Treatment Period 
From 
Week 25 to 
Study 
Completion 
Study 
Completion or 
Early 
Termination
 a 
Safety 
Follow-Up 
Visit 
Week 
— 
— 
1 
2 
3  
4 
5 
9 
13 
17 
21 
25 
 
 
 
Day
 b –28 to –1 –7 to –1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
Pregnancy test
 o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
PRO (HRQoL)
 p 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Q12W 
x 
 
Days missed from 
school/work q 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Q12W 
x 
 
PRO (Preference) 
 
 
 
 
 
 
 
 
 
x 
r 
 
 
 
 
 
Health status (EQ-5D-5L) 
 s 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Q12W 
x 
 
Emicizumab administration
 t 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q4W 
 
 
PK, PD, ADA 
See protocol  
Bleed/medication 
questionnaire
 u 
 
 
Weekly and on days of bleed 
x 
x 
Bleed/medication review 
v 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Q4W 
x 
x 
Following treatments with 
bypassing agents w 
 
 
Monitoring for thromboembolic events and thrombotic microangiopathy w 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
35/Statistical Analysis Plan BO39182 
ADA = anti-drug antibody; eCRF = electronic Case Report Form; EQ-5D-5L = European Quality of Life-5 Dimensions-5 Levels; ET = early termination; F/U = follow-up; FIX = factor IX; 
FVIII = factor VIII; FX = factor X; FXIII = factor XIII; HRQoL = health-related quality of life; PD = pharmacodynamic; PK = pharmacokinetic; PRO = patient-reported outcome; Q4W = every 
4 weeks; Q12W = every 12 weeks. 
a Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has completed the 24-week safety 
follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the study, the completion assessments displayed in the 
schedule of assessments are similar with the Week 25 visit. 
b 
Assessments can deviate from planned schedule by ± 2 days.  
c Obtain written informed consent (or patient written assent and legal representative written informed consent if patient is an adolescent) before performing any study related procedures.  
If patient fulfils the inclusion criteria, the patient should be enrolled in the study on the same day when the first dose of emicizumab is administered (Day 1). 
d Collected from patient’s medical record and documented in the eCRF. 
e Height assessment at Day 1 only for adults and weight assessments Q4W for all patients. 
f 
Height assessments for adolescents at Day 1 and ideally at all drug administration and PK sampling visits that the patients will be at the investigational site, but at least every 12 weeks 
(repeated assessments). 
g Body temperature (oral or tympanic), blood pressure, pulse rate, respiratory rate. 
h Concomitant medication (e.g., extra pain medication to treat bleeds) will be recorded at the time of the visits, excluding treatments for bleeds, which will be collected in the bleeding 
questionnaire starting from Day 1.  FVIII taken  in the week prior to starting emicizumab (week prior to Day 1) will also be collected on the Concomitant Medication eCRF page 
for patients without inhibitors to FVIII who will continue their prior FVIII prophylaxis during the first week of the study. 
i 
Adverse events are collected on an ongoing basis throughout the study.  Injection-site reactions will be collected on a separate form from the adverse event form.  After informed consent 
has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be reported. 
j 
If screening ECG is abnormal, repeat at Week 1.  ECGs will also be performed:  once during Weeks 4−8 after starting emicizumab or dose escalation (up-titration); once 24 weeks 
after starting emicizumab or dose escalation (up-titration); and at study completion/early termination. 
k Once during Weeks 4−8 after starting emicizumab. 
l 
For any dose increase (i.e., 3 mg/kg/wk), an ECG should be obtained after 4 weeks of starting the new dose at the next scheduled clinic visit. 
m Predose:  (hemoglobin, hematocrit, platelet count, RBC count, WBC count, absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other cells], mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and RBC distribution width), performed locally.  Laboratory assessments completed at 
the Screening visit do not have to be repeated at Week 1 if the period between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the 
investigator. 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
36/Statistical Analysis Plan BO39182 
n Predose (e.g., sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine aminotransferase, aspartate 
aminotransferase, and alkaline phosphatase), performed locally.  Laboratory assessments completed at the Screening visit do not have to be repeated at Week 1, if the period between 
Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the investigator. 
o Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening and up to 7 days prior to enrollment (Day − 7 to Day − 1).  If 
applicable, during the study, urine pregnancy tests will be performed at the scheduled visits. 
p Day 1 assessment predose (= baseline), followed by assessments at Week 13 predose and Week 25 predose by Haem-A-QoL (age > 18 years) and Haemo-QoL-Short Form (ages 
12−17 years). 
q Day 1 assessment predose (= baseline), followed by assessments at Week 13 predose and Week 25 predose. 
r 
Predose. 
s Day 1 assessment predose (= baseline), followed by assessments at Week 13 predose and Week 25 predose by EQ-5D-5L questionnaire. 
t 
3 mg/kg Q4W emicizumab loading dose, followed by 6 mg/kg Q4W emicizumab maintenance dose. 
u Bleed information (start date and time, reason, type, location, and associated symptoms of each bleed) and medication for bleeds (breakthrough bleeds) should be reported by the patient 
via an electronic, handheld device when a bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days).  If the patient discontinues study treatment, bleed and 
bleed medication data should be provided by the patient until the safety follow-up visit (24 weeks after last study drug administration). 
v Investigator review of bleed information. 
w Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic microangiopathy for platelet 
count, serum creatinine, LDH, and schistocytes within 24−48 hours of initial bypassing agent use.  A plasma sample should also be provided for local (one aliquot) and central (a 
second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 1+2, and D-dimer.  If prothrombin fragment 1+2 test cannot be done at the site, the sample should be 
sent to the local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 24−48 hours 
thereafter until 24−48 hours following the last dose of bypassing agents administered to treat a given bleed.  In the case that such local laboratory tests are performed, laboratory 
results should be recorded on the unscheduled visit eCRFs. 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
37/Statistical Analysis Plan BO39182 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND BIOMARKER SAMPLES 
PK RUN-IN 
 
Screen
-ing 
Treatment Period 
From 
Week 25 
to Study 
Com-
pletion 
Study 
Com-
pletion 
or ET 
a 
Safety 
F/U visit 
Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 to 
12b 13 
14 to 
16b 
17 
18 to 
20b 
21 
22 
23 
24 
25 
 
 
 
Day 
-28 to  
-1 days 
1 
3 5 
8 11 15 18 22 
25 
29 
36 
43 50 57 
 
85 
 
113 
 
141 148 155 162 169 
 
 
 
Emicizumab PK 
b 
 
x x 
c,d x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
  
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab ADA
d 
 
x 
 
 
 
 
 
 
 
  
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
 
x 
Q12W 
x 
x 
Emicizumab 
biomarker set 1 
e 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
x 
x 
f 
x 
x 
f 
x 
x 
f 
x 
 
x 
 
x 
Q12W 
x 
x 
Emicizumab 
biomarker set 2
g 
 
 
x
c 
x x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-FVIII 
antibodies 
h, i 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
Q12W 
x 
x 
Following 
treatments with 
bypassing agents  
 
Monitoring for thromboembolic events and thrombotic microangiopathy j 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
38/Statistical Analysis Plan BO39182 
 
ADA = anti-drug antibody; ET = early termination; F/U = follow-up; FIX = factor IX; FVIII = factor VIII; FX = factor X; FXIII = Factor XIII; PD = pharmacodynamic; 
PK = pharmacokinetic; Q4W = every 4 weeks; Q12W = every 12 weeks. 
Note:  Blood samples should always be drawn predose (if taken on days of emicizumab administration); consult the Sample Handling Manual for details.  PD 
biomarker tests will include, but are not limited to those listed here.  In order to characterize pharmacokinetics, it is mandatory that assessments are being 
performed on the exact visit day until Week 25; no deviation from visit day is acceptable until Week 25.  Deviations from the schedule of assessments of ± 2 days 
are acceptable after Week 25. 
a Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has completed 
the 24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in the study, the 
completion assessments displayed in the schedule of assessments are similar with the Week 25 visit. 
b During the first 8 weeks, PK sampling will occur at the following timepoints:  Week 1 (predose Day 1; 8 hours post-injection on Day 1; then Day 3, Day 5), Week 2 (Day 8, 
Day 11), Week 3 (Day 15, Day 18), Week 4 (Day 22), Week 5 (Day 29 predose), Week 6 (Day 36), Week 7 (Day 43), and Week 8 (Day 50).  A reduced PK sampling 
schedule will follow to characterize repeated Q4W SC administration from Week 9 to Week 25.  From Week 9 to Week 21, patient will have PK blood samples taken at 
Week 9 (Day 57), Week 13 (Day 85), Week 17 (Day 113), and Week 21 (Day 141).  From Week 9 to Week 21, additionally the patient will return once between two 
emicizumab administrations for a blood sample to be drawn for PK analysis; patients can decide whether this sampling will be 1, 2, or 3 weeks after the latest injection.  
An individual patient may choose each of the specific intervals (1, 2, or 3 weeks after to the latest injection) at least once.  After the sixth injection at Week 21, PK 
sampling frequency will be increased to characterize steady-state pharmacokinetics, with samples collected at Week 22 (Day 148), Week 23 (Day 155), and Week 24 
(Day 162).  Another sample will be taken at Week 25 (Day 169) followed by PK assessments every 12 weeks until study completion. 
c 8 hours postdose on Day 1. 
d Emicizumab ADA blood samples may also be drawn to if hypersensitivity event occur or on an unscheduled basis (at the clinical judgment of the investigator) at any time. 
e Set 1 = Standard aPTT, modified aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, FVIII antigen (baseline only), D-dimer, prothrombin fragment 
1.2, vWF antigen (timepoints of Week 1 Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit), fibrinogen (timepoints of Week 1 Day 1, Week 13, 
Week 25, study completion or ET, safety follow-up visit), and FXIII activity (baseline only). 
f 
PD assessments occurring once between two Q4W emicizumab administrations to be done on the same day the PK sample is taken (see footnote above).  
g Set 2 = FVIII activity, D dimer, prothrombin fragment 1.2, standard aPTT, modified aPTT, and PT.  
h A sample for inhibitor testing (anti-FVIII antibodies) must be obtained during screening, within 4 weeks prior to enrollment (i.e., before initiation of Week 1, Day 1 
assessments).  The results must be available before enrollment, and local testing will not replace the central laboratory inhibitor testing performed at Week1.  
i 
Starting at Week 1, this and all subsequent anti-FVIII antibodies will be measured at a central laboratory.  Anti-FVIII antibodies will be tested by a central laboratory at 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
39/Statistical Analysis Plan BO39182 
Week 1, Week 25, every 12 weeks thereafter, at the completion visit, and safety follow-up visit for all patients.  Testing at Week 9 (Day 57) and Week 17 (Day 113) for 
non-inhibitor patients only. 
j Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic microangiopathy 
for platelet count, serum creatinine, LDH, and schistocytes within 24−48 hours of initial bypassing agent use.  A plasma sample should also be provided for local 
(one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 1+2, and D-dimer.  If prothrombin fragment 1+2 test cannot 
be done at the site, the sample should be sent to the local reference laboratory, if available.  For patients who require multiple doses of bypassing agents, laboratory 
monitoring should be performed every 24−48 hours thereafter until 24−48 hours following the last dose of bypassing agents administered to treat a given bleed.  In 
the case that such local laboratory tests are performed, laboratory results should be recorded on the unscheduled visit eCRFs. 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
40/Statistical Analysis Plan BO39182 
EXPANSION COHORT 
 
Screen
-ing 
Treatment Period 
From 
Week 25 to 
Study 
Completion 
Study 
Completion or 
Early 
Termination a 
Safety F/U 
Visit 
Week 
 
1 
2 
3 
4 
5 
9 
13 
17 
21 
25 
 
 
 
Day 
-28 to  
-1 days 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
 
 
 
Emicizumab PK 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab 
ADA b 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab 
biomarker 
set 3(EDTA) c  
 
 
x 
x 
x 
 
 
 
 
 
x 
Q12W  
 
 
Emicizumab 
biomarker set 1d 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Anti-FVIII 
antibodies e, f 
x 
x 
 
 
 
 
x 
 
x 
 
x 
Q12W 
x 
x 
Following 
treatments with 
bypassing 
agents 
 
Monitoring for thromboembolic events and thrombotic microangiopathy. g 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
41/Statistical Analysis Plan BO39182 
ADA = anti-drug antibody; F/U = follow-up; FIX = factor IX; FVIII = factor VIII; FX = factor X; FXIII = Factor XIII; PK = pharmacokinetic; Q12W = every 
12 weeks. 
Note:  Blood samples should always be drawn predose (if taken on days of emicizumab administration); consult the Sample Handling Manual for details.  PD 
biomarker tests will include but are not limited to those listed here.  In order to characterize pharmacokinetics, it is mandatory that assessments are being 
performed within ± 2 days of the scheduled visits.   
a Study completion visit when either the patient completed 24 weeks’ study duration and transferred to an emicizumab extension study OR patient has 
completed the 24-week safety follow-up visit after emicizumab discontinuation OR patient is lost to follow-up.  If study completion occurs after 24 weeks in 
the study, the completion assessments displayed in the schedule of assessments are similar with the Week 25 visit. 
b Emicizumab ADA blood samples may also be drawn if hypersensitivity event occurs or on an unscheduled basis (at the clinical judgment of the 
investigator) at any time. 
c Set 3 = Exploratory biomarker assay of emicizumab concentration that requires EDTA rather than citrate plasma.  
d Set 1 = Standard aPTT, modified aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, D-dimer, prothrombin fragment 1.2 vWF antigen 
(timepoints of Week 1 Day 1, Week 13, Week 25, study completion or ET, safety follow-up visit), and fibrinogen (timepoints of Week 1 Day 1, 
Week 13, Week 25, study completion or ET, safety follow-up visit).  
e A sample inhibitor testing (anti-FVIII antibodies) must be obtained within 8 weeks prior to enrollment, (i.e., before initiation of Week 1, Day 1 
assessments).  The results must be available before enrollment, and local testing will not replace the central laboratory inhibitor testing performed at 
Week 1.  
f Starting at Week 1, this and all subsequent anti-FVIII antibodies will be measured at a central laboratory.  Anti-FVIII antibodies will be tested by a central 
laboratory at Week 1, Week 25, every 12 weeks thereafter, at the completion visit, and safety follow-up visit for all patients.  Testing at Week 9 (Day 57) 
and Week 17 (Day 113) is for non-inhibitor patients only. 
g Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic 
microangiopathy for platelet count, serum creatinine, LDH, and schistocytes within 24−48 hours of initial bypassing agent use.  A plasma sample 
should also be provided for local (one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 1+2, and 
D-dimer.  If prothrombin fragment 1+2 test cannot be done at the site, the sample should be sent to the local reference laboratory, if available.  For 
patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 24−48 hours thereafter until 24−48 hours 
following the last dose of bypassing agents administered to treat a given bleed.  In the case that such local laboratory tests are performed, laboratory 
results should be recorded on the unscheduled visit eCRFs.