A Phase IIIb, Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Patients From Birth to 12 Months of Age With Hemophilia A Without Inhibitors
Phase: PHASE3
Conditions: Severe Hemophilia A
Sponsor: Hoffmann-La Roche

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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.
Emicizumab—F. Hoffmann-La Roche Ltd
Protocol MO41787, Version 3
PROTOCOL
TITLE:
A PHASE IIIb, MULTICENTER, OPEN-LABEL,
SINGLE-ARM STUDY TO EVALUATE THE
EFFICACY, SAFETY, PHARMACOKINETICS,
AND PHARMACODYNAMICS OF
SUBCUTANEOUS EMICIZUMAB IN PATIENTS
FROM BIRTH TO 12 MONTHS OF AGE WITH
HEMOPHILIA A WITHOUT INHIBITORS
PROTOCOL NUMBER:
MO41787
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001733-12
IND NUMBER:
122954
NCT NUMBER:
NCT04431726
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE :
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
08-Aug-2021 09:05:27

Emicizumab—F. Hoffmann-La Roche Ltd
2/Protocol MO41787, Version 3
PROTOCOL HISTORY
Protocol
Version
Date Final
3
See electronic date stamp on title page.
2
28 March 2021
1
29 May 2020

Emicizumab—F. Hoffmann-La Roche Ltd
3/Protocol MO41787, Version 3
PROTOCOL AMENDMENT, VERSION 3:  
RATIONALE 
Protocol MO41787 has primarily been amended to update the schedule of activities 
(SOA) of the 7-year Long-Term Follow-Up (LTFU) period including the continuation of 
the data collection of the Bleed Medication Questionnaire data using the electronic 
handheld device (eBMQ), and the process of study drug dispensation clinic visits. The 
other changes include clarifications on the acceptable time window for the emicizumab 
injections; clarification on the derivation of the patient’s age for the timing of the interim 
data review; clarification on the reporting of vitamin K in the eCRF, clarification on the 
inclusion criterion about adequate liver function, clarification on the possibility to collect 
the patient’s body temperature temporally and clarification on the MRI assessment 
during the LTFU. Changes to the protocol in the order they appear in the document, 
along with a rationale for each change, are summarized below:

It has been clarified that during the 7-year LFTU period, the BMQ data will be 
collected using an electronic handheld device given to parents/caregivers instead of 
a paper BMQ.  The goal is to reduce the study burdens on parents/caregivers and 
site personnel in terms of BMQ data collection management with a unique process 
of BMQ data collection for the entire study duration (Sections 3.1, 4.3.2, 4.4., 4.5.2, 
4.5.8.1, 4.5.8.2, 5.3.5.3 and Appendix 1 Tables 13).

Language has been updated to clarify the derivation of the patient’s age for the 
timing of the interim data review (Sections 3.1, 6.9.1 and 9.5).  

Language has been updated in the inclusion criteria (Section 4.1.1) to clarify the 
adequate hepatic function requirement for patients with benign neonatal 
hyperbilirubinemia and breastfed with milk.  In the absence of any liver disease, the 
observation of high total bilirubin in newborns breastfed with milk may be 
physiologic and not pathologic; the condition of benign neonatal hyperbilirubinemia 
should not prevent milk breastfed newborns from participating in the study.

Language has been updated in the exclusion criteria (Section 4.1.2) to clarify that 
the prior use of investigational or commercial emicizumab is not permitted.

Language has been updated to clarify the process where the Medical Monitor is 
consulted by the Investigator for advice and to answer questions related to 
emicizumab administration, emicizumab up-titration and the use of other therapies 
during the study. The Investigator remains the decision-maker on medical decisions 
for patients on the study and the role of the Medical Monitor is to advise 
Investigators to ensure compliance with the protocol and to provide medical 
expertise for trial oversight and safety concern (Sections 4.3.1, 4.3.2, 4.4.2, and 
5.1.2.1).

Language has been updated in Section 4.3.2 to clarify the dosing schedule for 
a missed loading dose during the study:
–
If the scheduled dose (3mg/kg loading dose at Week 2, 3 or 4; 3 mg/kg QW
up-titrated doses; 1.5 mg/kg QW during the 7-year LTFU period) is missed, 
emicizumab should be administered as soon as possible within a window of 

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4/Protocol MO41787, Version 3
3 days from the scheduled dosing date. If more than 3 days have passed, the 
missed dose should be skipped, and the next dose of emicizumab should be 
taken at the next scheduled time resuming the original dosing schedule.
–
If the scheduled dose (6.0 mg/kg Q4W during the 7-year LTFU period) is 
missed, emicizumab should be administered as soon as possible within 
a window of 14 days from the scheduled dosing date.  If more than 14 days 
have elapsed, the missed dose should be skipped and the next dose of 
emicizumab should be taken at the next scheduled time resuming the original 
dosing schedule.

Language has been updated to simplify the process of study drug dispensation 
during the 7-year LFTU period to reduce the study burden on parents/caregivers.  
The study drug dispensation remains every 12 weeks from Week 53 where either 
parents/caregivers can pick-up emicizumab at study site or home shipment can be 
arranged.  The decision is dependent on parents/caregivers preference and will be 
organized by site personnel (Sections 4.3.2, 4.5.3, and Appendix 1 Tables 2 and 4). 

It has been clarified that the receipt of vitamin K should be reported on the 
Concomitant Medications eCRF independently of the date of administration
(Section 4.5.2 and Appendix 1 Table 1).

It has been clarified that the patient’s body temperature can also be collected 
temporally (Section 4.5.4 and Appendix 1 Tables 13).

It has been clarified that the use of gadgets to facilitate the child’s cooperation in 
staying still during the MRI assessment is encouraged, and that when needed the 
MRI assessment could be performed, over two visits around the scheduled date of 
the clinic visit on Years 5 and 8 respectively (Section 4.5.6 and Appendix 1 Table 2).

It has been clarified that the name of the form to be used by the investigators to 
correct/delete eBMQ entries once verified with the parents/caregivers is named
Data Clarification Request Form (Section 4.5.8.1).

The definition of bleed type for the data analysis has been clarified for alignment 
with the other HAVEN studies of the HEMLIBRA program (Section 4.5.8.2).
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.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ......................................... 11
PROTOCOL SYNOPSIS ................................................................................... 12
1.
BACKGROUND .......................................................................................... 20
1.1
Background on Hemophilia A in Infants................................. 20
1.2
Background on Emicizumab.................................................. 22
1.2.1
Molecule and Preclinical Data ............................................... 22
1.2.2
Clinical Experience ................................................................ 23
1.3
Study Rationale and BenefitRisk Assessment..................... 24
2.
OBJECTIVES AND ENDPOINTS ............................................................... 26
2.1
Efficacy Objective .................................................................. 26
2.2
Safety Objective .................................................................... 26
2.3
Pharmacokinetic Objective .................................................... 27
2.4
Biomarker Objective .............................................................. 27
2.5
Immunogenicity Objective...................................................... 27
3.
STUDY DESIGN......................................................................................... 28
3.1
Description of the Study......................................................... 28
3.2
End of Study and Length of Study......................................... 30
3.3
Rationale for Study Design.................................................... 31
3.3.1
Rationale for Emicizumab Dose and Schedule...................... 31
3.3.2
Rationale for Patient Population ............................................ 31
3.3.3
Rationale for Pharmacokinetic Assessments......................... 33
3.3.4
Rationale for Immunogenicity Assessments.......................... 33
3.3.5
Rationale for Biomarker Assessments................................... 33
3.3.6
Rationale for Joint Health Assessments ................................ 34
4.
MATERIALS AND METHODS .................................................................... 35
4.1
Patients.................................................................................. 35
4.1.1
Inclusion Criteria.................................................................... 35
4.1.2
Exclusion Criteria................................................................... 36
4.2
Method of Treatment Assignment and Blinding..................... 37

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4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 37
4.3.1
Study Treatment Formulation and Packaging........................ 37
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 38
4.3.3
Investigational Medicinal Product Handling 
Accountability ........................................................................ 42
4.3.4
Continued Access to Emicizumab ......................................... 43
4.4
Concomitant Therapy and Prohibited Therapy ...................... 43
4.4.1
Permitted Therapy................................................................. 44
4.4.2
Prohibited Therapy ................................................................ 45
4.5
Study Assessments ............................................................... 45
4.5.1
Informed Consent Forms and Screening Log........................ 45
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 46
4.5.3
Physical Examinations........................................................... 46
4.5.4
Vital Signs.............................................................................. 47
4.5.5
Cranial Ultrasound................................................................. 48
4.5.6
Magnetic Resonance Imaging of Joints................................. 48
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 48
4.5.7.1
Testing for Anti-FVIII Antibodies............................................ 50
4.5.7.2
Testing Following the Use of Bypassing Agents.................... 50
4.5.8
Clinical Outcome Assessments ............................................. 51
4.5.8.1
Electronic Bleed and Medication Questionnaire .................... 51
4.5.8.2
Bleed Definitions.................................................................... 52
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 53
4.6.1
Study Treatment Discontinuation........................................... 53
4.6.2
Patient Discontinuation from the Study.................................. 54
4.6.3
Study Discontinuation............................................................ 54
4.6.4
Site Discontinuation............................................................... 55
5.
ASSESSMENT OF SAFETY....................................................................... 55
5.1
Safety Plan ............................................................................ 55

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5.1.1
Risks Associated with Emicizumab ....................................... 55
5.1.1.1
Injection-Site Reactions......................................................... 55
5.1.1.2
Hypersensitivity Reaction, Anaphylaxis, and 
Anaphylactoid Reaction......................................................... 55
5.1.1.3
Hypercoagulation and Thromboembolic Events .................... 56
5.1.1.4
Thrombotic Microangiopathy ................................................. 57
5.1.1.5
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
in the Setting of Emicizumab ................................................. 57
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 57
5.1.2.1
Dose Modifications ................................................................ 57
5.2
Safety Parameters and Definitions ........................................ 59
5.2.1
Adverse Events ..................................................................... 59
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 60
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 61
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 61
5.3.1
Adverse Event Reporting Period ........................................... 61
5.3.2
Eliciting Adverse Event Information....................................... 62
5.3.3
Assessment of Severity of Adverse Events ........................... 62
5.3.4
Assessment of Causality of Adverse Events ......................... 62
5.3.5
Procedures for Recording Adverse Events............................ 63
5.3.5.1
Injection-Site Reactions......................................................... 63
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 63
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 63
5.3.5.4
Persistent or Recurrent Adverse Events................................ 64
5.3.5.5
Abnormal Laboratory Values ................................................. 64
5.3.5.6
Abnormal Vital Sign Values ................................................... 65
5.3.5.7
Abnormal Liver Function Tests.............................................. 66
5.3.5.8
Deaths ................................................................................... 66
5.3.5.9
Preexisting Medical Conditions.............................................. 67

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5.3.5.10
Lack of Efficacy or Worsening of Hemophilia ........................ 67
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 67
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 68
5.3.5.13
Observer-Reported Outcome Data........................................ 70
5.3.5.14
Safety Biomarker Data........................................................... 70
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 70
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 71
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 71
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 71
5.4.2.2
Events That Occur after Study Drug Initiation........................ 71
5.5
Follow-Up of Patients after Adverse Events .......................... 72
5.5.1
Investigator Follow-Up........................................................... 72
5.5.2
Sponsor Follow-Up ................................................................ 72
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 72
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 73
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 73
6.1
Determination of Sample Size ............................................... 73
6.2
Summaries of Conduct of Study............................................ 73
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 74
6.4
Efficacy Analyses .................................................................. 74
6.4.1
Efficacy Endpoint................................................................... 74
6.5
Safety Analyses..................................................................... 75
6.6
Pharmacokinetic Analyses..................................................... 75
6.7
Biomarker Analyses............................................................... 75
6.8
Immunogenicity Analyses...................................................... 75
6.8.1
Anti-Emicizumab Antibodies.................................................. 75
6.8.2
Anti-Factor VIII Antibodies..................................................... 76

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6.9
Interim Analysis ..................................................................... 76
6.9.1
Planned Interim Analysis ....................................................... 76
7.
DATA COLLECTION AND MANAGEMENT ............................................... 76
7.1
Data Quality Assurance......................................................... 76
7.2
Electronic Case Report Forms............................................... 77
7.3
Electronic Observer-Reported Outcome Data ....................... 77
7.4
Source Data Documentation.................................................. 78
7.5
Use of Computerized Systems .............................................. 78
7.6
Retention of Records............................................................. 78
8.
ETHICAL CONSIDERATIONS.................................................................... 79
8.1
Compliance with Laws and Regulations ................................ 79
8.2
Informed Consent.................................................................. 79
8.3
Institutional Review Board or Ethics Committee.................... 80
8.4
Confidentiality........................................................................ 81
8.5
Financial Disclosure .............................................................. 82
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 82
9.1
Study Documentation ............................................................ 82
9.2
Protocol Deviations................................................................ 82
9.3
Management of Study Quality ............................................... 82
9.4
Site Inspections ..................................................................... 82
9.5
Administrative Structure......................................................... 83
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 83
9.7
Protocol Amendments ........................................................... 84
10. REFERENCES ........................................................................................... 85
LIST OF TABLES
Table 1
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 58
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 62

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LIST OF FIGURES
Figure 1
Study Schema............................................................................. 30
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 90
Appendix 2
Hemophilia Joint Health Score.................................................. 100
Appendix 3
Clinical Criteria for Diagnosing Anaphylaxis.............................. 102
Appendix 4
Anaphylaxis Precautions........................................................... 103
Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of 
Laboratory Abnormalities and Adverse Events ......................... 104
Appendix 6
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients Treated with Emicizumab............................................ 108

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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IIIb, MULTICENTER, OPEN-LABEL,
SINGLE-ARM STUDY TO EVALUATE THE
EFFICACY, SAFETY, PHARMACOKINETICS, AND
PHARMACODYNAMICS OF SUBCUTANEOUS
EMICIZUMAB IN PATIENTS FROM BIRTH TO
12 MONTHS OF AGE WITH HEMOPHILIA A
WITHOUT INHIBITORS
PROTOCOL NUMBER:
MO41787
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001733-12
IND NUMBER:
122954
NCT NUMBER:
NCT04431726
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche 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 of 
the signed form to your local study monitor.

Emicizumab—F. Hoffmann-La Roche Ltd
12/Protocol MO41787, Version 3
PROTOCOL SYNOPSIS
TITLE:
A PHASE IIIb, MULTICENTER, OPEN-LABEL, SINGLE-ARM 
STUDY TO EVALUATE THE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF 
SUBCUTANEOUS EMICIZUMAB IN PATIENTS FROM BIRTH TO 
12 MONTHS OF AGE WITH HEMOPHILIA A WITHOUT 
INHIBITORS
PROTOCOL NUMBER:
MO41787
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-001733-12
IND NUMBER:
122954
NCT NUMBER:
NCT04431726
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase IIIb
INDICATION:
Severe hemophilia A
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Study MO41787 will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of 
emicizumab administered at 3 mg/kg every 2 weeks (Q2W) for a period of 52 weeks in 
previously untreated patients (PUPs) and minimally treated patients (MTPs) at study enrollment 
from birth to 12 months of age with severe hemophilia A (intrinsic FVIII level 1%) without 
FVIII inhibitors.  After 1 year of treatment, patients will continue to receive emicizumab 
(1.5 mg/kg once a week [QW], 3 mg/kg Q2W, or 6 mg/kg every 4 weeks [Q4W]) over a 7-year
long-term follow-up (LTFU) period, which will evaluate long-term safety of emicizumab and 
describe the natural history of these patients, including the preservation of joint health over time.  
Study MO41787 is a descriptive study with no formal hypothesis testing.  Specific objectives 
and corresponding endpoints for the study are outlined below.
Efficacy Objective
The efficacy objective for this study is to evaluate the efficacy of emicizumab on the basis of the 
following endpoints:

Number of treated bleeds over time (i.e., treated bleed rate)

Number of all bleeds over time (i.e., all bleed rate)

Number of treated spontaneous bleeds over time (i.e., treated spontaneous bleed rate)

Number of treated joint bleeds over time (i.e., treated joint bleed rate)

Joint health, as assessed through use of the Hemophilia Joint Health Score (HJHS) and 
magnetic resonance imaging (MRI) score of specific joints at specified timepoints only 
during the 7-year LTFU period
Safety Objective
The safety objective for this study is to evaluate the safety of emicizumab on the basis of the 
following endpoints:

Incidence and severity of adverse events, with severity determined according to World 
Health Organization (WHO) Toxicity Grading Scale

Incidence of thromboembolic events

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
Incidence of thrombotic microangiopathy (TMA)

Change from baseline in physical examination findings 

Change from baseline in vital signs

Incidence of laboratory abnormalities

Incidence and severity of injection-site reactions

Incidence of adverse events leading to study drug discontinuation

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the emicizumab PK profile 
on the basis of the following endpoint:

Plasma trough concentrations (Ctrough) of emicizumab prior to study drug administration at 
the following timepoints:
–
Q2W during Weeks 19
–
Q4W during Weeks 1353
Additional PK samples will be obtained from patients who require up-titration (only if up-titration 
occurs during the first year of emicizumab treatment).
Additional PK samples will be obtained in case of clinical suspicion of anti-drug antibody (ADA) 
development during the 7-year LTFU period.
Biomarker Objective
The biomarker objective for this study is to investigate the effect of emicizumab on 
pharmacodynamic (PD) parameters, including aPTT, thrombin generation (TG), and reported 
FVIII activity, as well as FIX antigen and FX antigen (emicizumab substrates) levels prior to 
study drug administration at the following timepoints:

Q2W during Weeks 19

Q4W during Weeks 1353
Additional biomarker samples will be obtained in patients who require up-titration (only if 
up-titration occurs during the first year of emicizumab treatment).
Additional biomarker samples will be obtained in case of clinical suspicion of ADA development 
during the 7-year LTFU period.
Biomarkers related to bone and joint health will be assessed at specified timepoints only during 
the 7-year LTFU period.
Immunogenicity Objective
The immunogenicity objective for this study is to evaluate the immune response to treatment on 
the basis of the following endpoints:

Incidence and significance of anti-emicizumab antibodies

Incidence of de novo development of FVIII inhibitors
Additional ADA samples will be obtained from patients who require up-titration (only if 
up-titration occurs during the first year of emicizumab treatment).
Additional ADA samples will be obtained in case of clinical suspicion of ADA development 
during the 7-year LTFU period.
Study Design
Description of Study
Study MO41787 is a Phase IIIb, multicenter, open-label, single-arm study of emicizumab in 
PUPs and MTPs at study enrollment from birth to 12 months of age with severe hemophilia A 
(intrinsic FVIII level 1%) without FVIII inhibitors.  The study is designed to evaluate the 
efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at 

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3 mg/kg Q2W for 52 weeks.  After 1 year of treatment, patients will continue to receive 
emicizumab (1.5 mg/kg QW, 3 mg/kg Q2W or 6 mg/kg Q4W) over a 7-year LTFU period under 
this study frame.  Study MO41787 is a descriptive study with no formal hypothesis testing.
Approximately 50 patients from birth to 12 months of age and weighing 3 kg at time of 
informed consent will be recruited.  A minimum of 20 patients from birth to 3 months of age 
and a maximum of 30 patients from 3 months to 12 months of age will be enrolled.  Once the 
30 patients from 3 months to 12 months of age have been recruited, no additional patients in
this age group will be enrolled.  The recruitment of patients from birth to 3 months of age will 
remain open until 20 patients in this age group are enrolled.
Initially, all patients will receive four loading doses of 3 mg/kg emicizumab SC QW for 4 weeks 
followed by the maintenance dosing regimen 3 mg/kg SC Q2W for a total of 52 weeks.  Starting 
from Week 17 of treatment with emicizumab, individual patients may have their dose up-titrated 
to 3 mg/kg SC QW if they experience suboptimal bleeding control.  At the Week 53 clinic visit 
following consultation with the treating physician, parents/caregivers may elect for their child to 
continue with the maintenance 3-mg/kg SC Q2W dosing regimen or to switch to the 
maintenance 1.5-mg/kg SC QW or 6-mg/kg SC Q4W dosing regimen for the subsequent 7-year 
LTFU period.  During the study, patients will be treated with emicizumab until unacceptable 
toxicity, discontinuation from the study due to any cause, or other criteria specified in the 
protocol, whichever occurs first.  Patients who discontinue study treatment prior to the end of 
the study (with the exception when the reason for discontinuation is the patient switching to 
commercial emicizumab product) will return to the clinic for a safety follow-up visit, 24 weeks 
after the final dose of study drug.
Safety assessments will include physical examinations, vital signs, and safety laboratory 
assessments (serum chemistry and hematology) performed as specified in the schedule of 
activities.  Adverse events will be recorded on an ongoing basis as they occur during the study.  
All patients in this study will undergo PK assessments.  Blood samples will also be collected to 
assess the PD properties of emicizumab (i.e., aPTT, TG, reported FVIII activity), to assess FIX 
and FX antigen levels, to assess immunogenicity (i.e., anti-emicizumab antibodies and 
anti-FVIII antibodies), as well as to assess bone and joint biomarkers.
During the study, individual bleeds will be recorded by the parents/caregivers as the bleeds 
occur using a Bleed and Medication Questionnaire (BMQ).  Breakthrough bleeds will be treated 
with FVIII at the lowest dose expected to achieve hemostasis.  When a bleed occurs, 
parents/caregivers will be required to report bleed information details (e.g., date and time, 
location, and reason) and medication details including the reason for the use of FVIII 
(e.g., treatment for bleed, prior to surgery or short-term prophylaxis prior to activity), agent, date, 
time, and dose on the BMQ.  During the entire study duration, information on bleeds, 
hemophilia medications for bleeds, and emicizumab doses will be collected using an electronic 
BMQ (eBMQ) on an electronic handheld device given to parents/caregivers.
The primary analysis will be performed when the last patient has completed 52 weeks in the 
study, is lost to follow-up, or has withdrawn from study treatment, whichever occurs first.  An 
interim analysis to review safety, efficacy, pharmacokinetics, pharmacodynamics, and 
immunogencity data will be performed when the 10th patient from birth to 3 months of age at 
the time of informed consent has completed 24 weeks in the study, is lost to follow-up, or has 
withdrawn from study treatment, whichever occurs first.  All patients will be included at the 
time of the interim analysis irrespective of their age and time in the study.  The interim analysis 
will be performed by the Sponsor’s study team. An Internal Monitoring Committee (IMC) and 
Scientific Overview Committee (SOC) (as needed) will review the interim analysis reports 
generated by the Sponsor’s study team.
The 7-year LTFU period will evaluate long-term safety of emicizumab and describe the natural 
history of this population including the preservation of joint health over time.  Joint health will be 
assessed through the use of MRI of knees, ankles and elbows, the HJHS, bone and joint 
biomarkers complemented with physical examination of the joints.  
Number of Patients
Approximately 50 patients from birth to 12 months of age and weighing 3 kg at time of 
informed consent will be enrolled with a minimum of 20 patients from birth to 3 months of age 
and a maximum of 30 patients from 3 months to 12 months of age.  Once the 30 patients 
from 3 months to 12 months of age have been recruited, no additional patients in this age 

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group will be enrolled.  The recruitment of patients from birth to 3 months of age will remain 
open until 20 patients in this age group have been enrolled.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent obtained from parent or legally authorized representative (latest 
approved version by Ethics Committee [EC]/Institutional Review Board [IRB]) prior to any 
study-specific assessments or procedures being performed

Age from birth to 12 months at time of informed consent

Body weight 3 kg at time of informed consent
Patients with a lower body weight can be enrolled after they have reached a body 
weight of 3 kg.
Premature babies (gestational age 38 weeks) may be enrolled as long as they have 
reached a body weight of 3 kg.  For premature babies, the corrected gestational age 
should be reported.

Mandatory receipt of vitamin K prophylaxis according to local standard practice

Diagnosis of severe congenital hemophilia A (intrinsic FVIII level 1%)

A negative test for FVIII inhibitor (i.e., 0.6 Bethesda units [BU]/mL) locally assessed during 
the 2-week screening period for all patients

No history of documented FVIII inhibitor (i.e., 0.6 BU/mL), FVIII drug-elimination half-life 
6 hours, or FVIII recovery 66%

PUPs or MTPs (i.e., up to 5 days of exposure with hemophilia-related treatments such as 
plasma-derived FVIII, recombinant FVIII, fresh frozen plasma, cryoprecipitate, or whole 
blood products)

Documentation of the details of the hemophilia-related treatments received since birth

Documentation of the details of the bleeding episodes since birth

For patients from birth to 3 months of age at the time of study entry:  no evidence of active 
intracranial hemorrhage (ICH), as confirmed by a negative cranial ultrasound at screening 
irrespective of delivery mode

Adequate hematologic function, defined as platelet count 100,000/L 
(100109cells/L) and hemoglobin 8 g/dL (4.97 mmol/L) at screening

Adequate hepatic function, defined as total bilirubin 1.5 the age-specific upper limit of 
normal (ULN) (excluding patients with Gilbert syndrome and patients with benign neonatal 
hyperbilirubinemia because of breastfeeding) and both AST and ALT3 the age-specific 
ULN at screening

Adequate renal function, defined as a serum creatinine 1.5the age-specific ULN
Note:  When the serum creatinine is 1.5ULN, creatinine clearance by Schwartz 
estimation must be 70 mL/min/1.73 m2.

For parents/caregivers:  willingness and ability to comply with the study protocol 
requirements, scheduled visits, treatment plans, laboratory tests, completion of applicable 
questionnaires, and other study procedures
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than severe hemophilia A

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study

Receipt of any of the following:
–
Prior use of emicizumab prophylaxis including investigational or commercial 
emicizumab

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–
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 drug-elimination half-lives of last drug administration
–
A nonhemophilia-related investigational drug within the last 30 days or 
5 drug-elimination half-lives, whichever is shorter
–
An investigational drug concurrently

Current active severe bleed, such as ICH

Planned surgery (excluding minor procedures, e.g., circumcision, CVAD placement) during 
the study

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA, such as thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome) 
in the investigator's judgment

Previous or current treatment for thromboembolic disease (with the exception of previous 
catheter-associated thrombosis in patients for whom anti-thrombotic treatment is not 
currently ongoing) or signs of thromboembolic disease

Any hereditary or acquired maternal condition that may predispose the patient to thrombotic 
events (e.g., inherited thrombophilias antiphospholipid syndrome)

Other diseases (e.g., certain autoimmune diseases) that may increase risk of bleeding or 
thrombosis

Known infection with HIV, hepatitis B virus, or hepatitis C virus

Serious infection requiring antibiotics or antiviral treatments within 14 days prior to
screening

Concurrent disease, treatment, abnormality in clinical laboratory tests, vital signs 
measurements, or physical examination findings that could interfere with the conduct of the 
study or that would, in the opinion of the investigator or Sponsor, preclude the patient’s safe 
participation in and completion of the study or interpretation of the study results 

Unwillingness of the parent or caregiver to allow receipt of blood or blood products, or any 
standard-of-care treatment for a life-threatening condition

Any other medical, social, or other condition that may prevent adequate compliance with the 
study protocol in the opinion of the investigator
End of Study
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., last patient, last visit), as demonstrated by any one of the following:  completed 
the last visit of the LTFU period, completed the end of study safety follow-up visit 24 weeks after 
discontinuing emicizumab, switched to commercial emicizumab product, withdrew consent, or 
was lost to follow-up.
Length of Study
The length of the entire study from screening of the first patient to the last patient completing the 
LTFU period will be approximately 10 years. 
Investigational Medicinal Products
Test Product (Investigational Drug)
Patients treated with emicizumab will receive a loading dose of 3 mg/kg SC QW for the first 
4 weeks (on Day 1 of each week) followed by a maintenance dose of 3 mg/kg SC Q2W at 
Week 5 (on Day 1 of each 2-week period).  Patients will receive prophylactic emicizumab during 
their participation in the study for 52 weeks.  After the first 52 weeks of treatment with 
emicizumab, switching to other dosing regimens (1.5 mg/kg SC QW or 6 mg/kg SC Q4W) will 
be permitted for the 7year LTFU period.

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Statistical Methods
Primary Analysis
No formal hypothesis testing is planned for the study.  All the analyses will be descriptive.  No 
adjustment for multiplicity of endpoints will be considered.  Further details will be provided in the 
Statistical Analysis Plan.
Determination of Sample Size  
The sample size for this study is based on recruitment feasibility and clinical considerations 
rather than on statistical considerations, taking into account the limited number of pediatric 
patients from birth to 12 months of age, especially patients younger than 3 months with 
hemophilia A without inhibitors available for participation in clinical studies and in an effort to 
collect sufficient data to assess the efficacy, safety, pharmacokinetics, and pharmacodynamics 
of emicizumab in this population.
During the study, a re-assessment of the initially specified sample size based on enrollment 
consideration may be performed.
Interim Analyses
An interim data review will occur when the 10th patient aged 3 months at the time of informed 
consent has completed 24 weeks in the study, is lost to follow-up, or has withdrawn from 
study treatment, whichever occurs first, with the aim of having an early look at the totality of 
the data (particularly safety) in the youngest population.  All patients will be included at the time 
of the interim analysis irrespective of their age and time in the study. The interim analysis will 
be performed by the Sponsor’s study team.  The evaluation of the interim data review will be 
performed on the safety and efficacy endpoints as well as on the pharmacokinetics, 
pharmacodynamics, and immunogenicity results.  The IMC and SOC (as needed) will review 
the interim analysis reports generated by the Sponsor’s study team.
Additional interim analyses may be conducted at an intermediate timepoint during the LTFU 
period between the primary analysis and the end of the study.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
annualized bleed rate
ADA
anti-drug antibody
aPCC
activated prothrombin complex concentrate
BMQ
Bleed and Medication Questionnaire
BU
Bethesda units
CDC
Centers for Disease Control and Prevention
Ctrough
trough concentration
CVAD
central venous access device
EC
Ethics Committee
eBMQ
electronic Bleed and Medication Questionnaire
eCRF
electronic Case Report Form
EDC
electronic data capture
eObsRO
electronic observer-reported outcome
FDA
Food and Drug Administration
FII
factor II
FIX
factor IX
FVII
factor VII
FVIII
factor VIII
FX
factor X
HCP
health care provider
HIPAA
Health Insurance Portability and Accountability Act
HJHS
Hemophilia Joint Health Score
HTC
Hemophilia Treatment Center
IA
interim analysis
ICH
intracranial hemorrhage
IFU
Instructions for Use
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IPSG
International Prophylaxis Study Group
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LTFU
long-term follow-up
MRI
magnetic resonance imaging
MTP
minimally treated patient
ObsRO
observer-reported outcome
PD
pharmacodynamic
PK
pharmacokinetic
pop-PK
population-pharmacokinetic

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Abbreviation
Definition
PUP
previously untreated patient
Q2W
every 2 weeks
Q4W
every 4 weeks
QV
quarterly visit
QW
once a week
rFVIIa
recombinant activated factor VII
SOC
Scientific Overview Committee
TG
thrombin generation
TMA
thrombotic microangiopathy
UDC
Universal Data Collection
ULN
upper limit of normal
WFH
World Federation of Hemophilia

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1.
BACKGROUND
1.1
BACKGROUND ON HEMOPHILIA A IN INFANTS
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 F8 gene mutation within 
the Xq28 region of the X chromosome.  It occurs almost exclusively in males with 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 future mother who is a carrier will have a 50% chance to receive 
a mutated F8 gene; thus, hemophilia A could be transmitted to one-half of the boy
infants, and one-half of girl infants will be carriers.
Diagnosis of hemophilia A in newborns and infants is prompted by known maternal 
carrier status, positive family history, or the occurrence of bleeds. Accurate knowledge 
regarding maternal carrier status and the ability to elicit a family history of hemophilia are
crucial to identify affected individuals before and at birth and to propose an optimal 
management of the disease. Diagnosis following a bleed occurs in 30%40% of the 
cases in infants: Patients bleeding remains the single most common manifestation 
leading to the diagnosis of hemophilia (Kulkarni et al. 2009, 2017; Kenet et al. 2010).
Precise laboratory assessment, including adapted coagulation assays for small blood 
volumes and age-related reference ranges of hemostatic tests, at onset of a bleed is 
crucial to ensure the proper and meaningful interpretation of disease diagnosis for the 
future management of the affected newborns and infants (Andrew et al. 1992; Monagle 
et al. 2006, 2010; Ignjatovic et al. 2015).
A comprehensive surveillance study from the Centers for Disease Control and 
Prevention (CDC) Universal Data Collection (UDC) project analyzed prospective data 
collected in 580 children with hemophilia from 0 to 2 years of age who were followed in 
Hemophilia Treatment Centers (HTCs) (Kulkarni et al. 2009, 2017). The study showed 
that 75% of infants were diagnosed early in the first month of life: Of the 580 children,
64.7% of infants had a family history or mothers who were known carriers, 33%
presented with bleed during the first 2 years of life, and more than 80% of children 
experienced at least one bleed.
Bleeds in newborns commonly result from the mode of delivery (vacuum extraction or 
forceps) that can potentially lead to an intracranial hemorrhage (ICH). ICH is 
a life-threatening condition in children with hemophilia A. Several studies were 
published with a uniform consensus that around 3%4% of boys with hemophilia born in 
countries with a good standard of obstetric care have had ICH diagnosed during the 
neonatal period (Ljung et al. 1994; Klinge et al. 1999; Revel-Vilk et al. 2004). Prenatal 

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referral of pregnant women who are known or potential carriers to HTCs often results in 
avoidance of the use of instrument-assisted deliveries so that the newborns are more 
likely to be delivered by cesarean section (Andersson et al. 2019).  Another common
bleed in newborns occurs as a result of complications related to circumcision.
Subsequently, the other types of bleeds experienced during the first 2 years of life are 
related to other iatrogenic procedures (heel punctures, venipunctures, intramuscular 
injections) and are caused by ambulation with frequent falls during the toddler years,
resulting in soft tissue/intramuscular hematomas, head trauma, joint hemorrhages, and 
other oral and nasal bleeds (Kenet et al. 2010).  
At birth, routine vitamin K injection is recommended in all newborns for the coagulant 
activity of factor II (FII), factor VII (FVII), factor IX (FIX) and factor X (FX) and Proteins C 
and S. In newborns with hemophilia A, the administration of prophylactic vitamin K is 
important to avoid early- and late-onset vitamin K deficiency bleedings, including ICH 
(Doneray et al. 2007; Kulkarni et al. 2009). Therapeutic options for the treatment and 
prevention of bleeds in newborns and infants rely upon proper use of IV replacement 
therapy with recombinant FVIII or plasma-derived FVIII concentrates administered on 
demand or prophylactically and repeated hemostatic evaluations of a patient’s status, 
while dealing with underlying etiological causes.  Newborns are more likely to receive 
prophylaxis at birth if they are born to carrier mothers or if they have a family history of 
hemophilia.  In the UDC surveillance study, nearly 10% of newborns with severe 
hemophilia received factor concentrate within 24 hours of birth; more than one-half of 
these were given prophylactic administration to prevent bleeds (Kulkarni et al. 2009).  
In children, the current standard of care is primary prophylaxis with regular FVIII 
infusions (starting from the first joint bleed onward or earlier), focusing on joint 
preservation with optimally, no bleeds and the prevention of long-term consequences 
such as joint damage (Valentino et al. 2012).  Because of difficulties in venous access in 
newborns and infants, replacement therapy often necessitates the placement of central 
venous access devices (CVADs). However, long-term CVAD use requires considerable 
commitment from caregivers and parents, and serious complications can occur, 
including thrombosis, bleeding, mechanical dysfunction, and most commonly, infection
(Valentino et al. 2004).  
Although the primary indication for routine prophylaxis in hemophilia is to prevent joint 
damage and to decrease the frequency of joint and other hemorrhages (Manco-Johnson 
et al. 2007), the high rate of ICH observed in the UDC surveillance study and other 
cohort studies provides a compelling argument for the initiation of early prophylaxis to 
prevent a first occurrence of ICH (Kulkarni et al. 2017; Haque et al. 2019). Beyond the 
neonatal period, infants may present with an ICH as the first manifestation of their 
bleeding disorder (Kenet et al. 2018).  Other life-threatening bleeds include 
nasopharyngeal and tongue/oral hematomas with airway compression as a result of 
neck dissection (Hoots 2007; Riley et al. 2012). ICH is one of the most dreaded 
complications of hemophilia and is associated with a high rate of morbidity and mortality

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(Abbondanzo et al. 1988; Yoffe and Buchanan 1988; Nowak-Göttl et al. 2015). Head 
trauma, as an underlying etiology of ICH, was reported in 38%67% of cases of 
hemophilia in all pediatric ages (Witmer et al. 2007).  A 10-year French study in 
106 patients of all ages, including 32 patients aged less than 24 months, showed 8.1% 
and 17.9% prevalence of ICH in patients aged 01 month and 124 months, 
respectively, among all cases of ICH (Stieltjes et al. 2005).  Clinical data showed a high 
risk of significant and long-term neurological consequences from ICH, including seizure 
disorder, intellectual and behavioral problems, paralysis, or other motor problems
(Kulkarni et al. 2017). The optimal management of ICH depends on immediate 
recognition and prompt and intensive replacement therapy, for which prophylaxis is 
highly appropriate, given that these patients are at increased risk of ICH recurrence
(Haque et al. 2019).  
The administration of prophylactic factor concentrate at birth is recommended because it 
is highly efficacious to prevent bleeds, but the risks of FVIII inhibitor development from 
early factor exposure of newborns and infants remain (Buchanan et al. 1999; 
Rivard et al. 2005; Kulkarni et al. 2006; Chalmers et al. 2007). The development of FVIII 
inhibitors represents a challenging and costly complication of treatment (Soucie et al. 
2010).  Clinicians monitor inhibitor development in all newborns and infants with 
hemophilia who regularly receive factor concentrate because FVIII inhibitors are also 
associated with increased mortality and morbidity in patients who experience an ICH 
(Haque et al. 2019).  
In summary, this underlines that newborn and infant patients with hemophilia A 
constitute a vulnerable population with high unmet medical need.
1.2
BACKGROUND ON EMICIZUMAB
1.2.1
Molecule and Preclinical Data
Emicizumab (also known as ACE910, RO5534262, and HEMLIBRA®) is a recombinant, 
humanized, bispecific, IgG4 monoclonal antibody that binds with moderate affinity to 
activated FIX and 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, the SC 
administration of emicizumab removes the need for venous access.  Finally, because of 
the pharmacokinetic (PK) and pharmacodynamic (PD) properties of this antibody, use of 
emicizumab enables a dosing interval of once a week (QW; 1.5 mg/kg), every 2 weeks 
(Q2W; 3.0 mg/kg), or every 4 weeks (Q4W; 6.0 mg/kg).
In vivo pharmacology experiments in cynomolgus monkeys were conducted in 
a hemophilia A model in which 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
of emicizumab under spontaneous or local trauma-induced bleeding conditions.  

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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 (recombinant activated FVII [rFVIIa] or activated 
prothrombin complex concentrate [aPCC]).  Thrombus formation with emicizumab did 
not markedly exceed formation observed with rFVIIa, aPCC, or FVIII.
A subgroup of the cynomolgus monkeys treated with repeat doses of emicizumab 
showed the formation of anti-emicizumab antibodies (which is expected with humanized 
monoclonal antibodies) in a few animals also showing antibodies with neutralizing 
potential.  Aspects of acute as well as repeat-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 QW) and a 4-week IV dose toxicity study 
(at doses up to 100 mg/kg QW).  No toxicologically relevant changes attributable to SC 
or IV administration of emicizumab were observed; the no-observed-adverse-effect level 
was the highest tested dose in each toxicity study.  In these experiments, 
normocoagulative monkeys with normal FVIII activity were exposed to repeat doses and 
showed no prothrombotic effects in any organs or tissues even at supratherapeutic 
levels of emicizumab.  This nonclinical model provides a more extreme condition than 
prophylaxis treatment of patients with non-severe disease whose residual FVIII activities 
are far below 100%.  
Refer to the RO5534262 (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 three 
completed Phase I studies (ACE001JP, JP29574, and YP39308); one completed 
Phase I/II study (ACE002JP) and its extension in patients with hemophilia A; six ongoing 
Phase III studies in adults and adolescent patients with hemophilia A (with inhibitors 
BH29884 and MO39129, without inhibitors BH30071 and BO41423 [of note, BO41423 
also evaluates pediatric patients less than 12 years old], and with or without inhibitors 
BO39182 and YP39309); two Phase III studies in pediatric patients less than 12 years of 
age (with inhibitors BH29992, ongoing; and without inhibitors JO39881, completed).
Based on the Phase III program, emicizumab received approval in many countries, 
including the United States. Emicizumab is indicated for routine prophylaxis to prevent 
bleeding or to reduce the frequency of bleeding episodes in adults and children with 
hemophilia A (congenital FVIII deficiency), with or without FVIII inhibitors, and can be 
used in all age groups.  In the European Union (E.U.), emicizumab is indicated for 
routine prophylaxis of bleeding episodes in all ages of patients with hemophilia A treated

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with FVIII inhibitors and in the severe phenotype in patients, without FVIII inhibitors.
Refer to the emicizumab U.S. Prescribing Information and E.U. Summary of Product 
Characteristics for full details on approved indications.
Refer to the RO5534262 (Emicizumab) Investigator's Brochure for details on clinical 
studies.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Emicizumab is approved for use in pediatric patients with hemophilia A, although limited 
clinical data have been obtained in patients younger than 2 years of age, and particularly 
in infants.  Real-world data on the prophylactic use of emicizumab in infant patients has 
started to emerge.  A recent single-center study prospectively followed children with 
hemophilia A showed that the emicizumab use was safe and efficacious in young 
children, including infants (with the youngest patient 2 months of age at the time of 
initiation of emicizumab treatment) (Barg et al. 2019).  Another multicenter observational 
study enrolled 12 patients with or without FVIII inhibitors who were 2 years of age and 
the youngest of whom was a non-inhibitor patient 0.16 years of age.  Overall, 
emicizumab was shown to be efficacious and safe in this pediatric population, including 
in the surgical setting (McCary et al. 2020).  However, there remains limited data on the 
use of emicizumab in newborns and infants in the setting of a controlled clinical trial.
The pediatric study BH29992 demonstrated that emicizumab provided clinically 
meaningful efficacy and a favorable safety profile in 88 patients with hemophilia A with 
FVIII inhibitors from 1 to 12 years of age (at the time of enrollment 8 patients were 2 
years of age, with the youngest being 14 months of age) receiving QW, Q2W, or Q4W 
emicizumab regimens; the annualized rate of treated bleeds in the primary cohort was 
0.3 (95% CI, 0.17-0.50) with 77% of patients having zero treated bleeds (Young et al. 
2019).  Of note, the number of patients less than 2 years of age (N=8) was limited in 
Study BH29992, as the prevalence of patients treated with FVIII inhibitors is rare in this 
age group.  The observed emicizumab PK profiles in patients less than 12 years of age 
were consistent with those observed in patients more than 12 years of age in 
Studies BH29884 and BH30071 (Oldenburg et al. 2017; Mahlangu et al. 2018).  
Recently a small pediatric study (JO39881) of 13 patients from 4 months to 12 years of 
age (3 of them were 2 years of age) at the time of enrollment with severe hemophilia A 
without FVIII inhibitors showed that Q2W and Q4W emicizumab exposure was within the 
variability observed in the preceding adult/adolescent and pediatric studies confirming 
the appropriateness of the emicizumab use in children with hemophilia A without FVIII 
inhibitors (Pipe et al. 2019). This study showed substantial efficacy and favourable 
safety of emicizumab in this pediatric population (Shima et al. 2019).
Given the limited clinical data of emicizumab use in infants, an initial population-PK
(pop-PK) model was developed using the data derived from clinical studies conducted 
with emicizumab, wherein potential baseline covariate effects, including, but not limited 
to, body size and age, were assessed (Retout et al. 2020).  A modified pop-PK model 

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that also used an explicit age-based maturation function of clearance comparable to the 
model that predicted the pharmacokinetics of another monoclonal antibody, palivizumab, 
in infants (Robbie et al. 2012) was also developed (Retout et al. 2019).  Using 
a comprehensive model-based extrapolation approach, including initial and modified 
pop-PK, physiologically based PK and exposure-response analyses, up to 20-30% lower
emicizumab exposure is predicted in patients less than 1 year of age patients compared 
to the older ones. The efficacy is however expected to be maintained as this exposure 
level remains at the plateau of the exposure-response relationship, even in newborn 
patients (Jonsson et al. 2019; Retout et al. 2019). The model showed no evidence of 
any dependence of the exposure response across the patients enrolled in these studies
(i.e., 1 year of age).  Although neonates and young infants have quantitatively lower 
levels of vitamin K dependent coagulation factors including emicizumab targets (FIX and 
FX) compared with those in adults, many anticoagulant factors are also reduced at this 
age, resulting in a hemostatic system that remains balanced (Andrew et al. 1987;
Revel-Vilk et al. 2012). Therefore, a similar exposure response relationship was 
assumed for infants aged less than 1 year of age (as observed with FVIII coagulation 
factors).  Altogether, despite the absence of data in patients less than 1 year of age, PK 
simulations and pharmacological rationale suggest that a different dose for infant 
patients less than 1 year of age is not warranted.  Using the identical emicizumab dosing 
strategy as the other pivotal Phase III studies of emicizumab, the objective of 
Study MO41787 will be to provide clinical evidence of the efficacy, safety, and tolerability 
of emicizumab in newborn and infant patients 12 months of age (see Section 5.1 for 
the safety plan).
Current approaches to prophylaxis initiation are such that infants are likely not on 
prophylactic therapy until the end of the first year of life or later.  This is pragmatic in that 
spontaneous bleeding is less common, and regular IV access for prophylaxis is 
challenging (Weyand et al. 2019).  Yet, infants remain at risk for significant bleeding with 
trauma, including ICH. In this context, emicizumab may have a role to play, and if 
initiated soon after birth, could potentially fill this important treatment gap.
Study MO41787 aims to confirm the benefitrisk profile of the efficacy and safety of 
emicizumab in patients from birth to 12 months of age observed in the pediatric 
population enrolled in Studies BH29992 and JO39881.  Study MO41787 aims to provide 
supportive clinical evidence that early initiation of prophylactic treatment with SC 
emicizumab in newborns and infants with hemophilia A, ideally near birth prior to their 
first bleed, is beneficial and safe in this high-unmet medical need pediatric population.  
Importantly, Study MO41787 provides a unique opportunity to describe the natural 
history of patients with hemophilia A who initiate early prophylaxis soon after birth. As 
such, Study MO41787 will also contain a long-term follow-up (LTFU) period of 7 years to 
continue the collection of long-term clinical data (including, but not limited to, safety and 
joint health outcomes) in patients with hemophilia A from birth to early childhood who are
treated with prophylactic emicizumab.

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2.
OBJECTIVES AND ENDPOINTS
Study MO41787 will evaluate the efficacy, safety, pharmacokinetics, and 
pharmacodynamics of emicizumab administered at 3 mg/kg Q2W for a period of 
52 weeks in previously untreated patients (PUPs) and minimally treated patients (MTPs)
at study enrollment from birth to 12 months of age with severe hemophilia A (intrinsic 
FVIII level 1%) without FVIII inhibitors. After 1 year of treatment, patients will continue 
to receive emicizumab (1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg Q4W) over a 7-year
LTFU period, which will evaluate long-term safety of emicizumab and describe the 
natural history of these patients, including the preservation of joint health over time. 
Study MO41787 is a descriptive study with no formal hypothesis testing. Specific 
objectives and corresponding endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVE
The efficacy objective for this study is to evaluate the efficacy of emicizumab on the 
basis of the following endpoints:

Number of treated bleeds over time (i.e., treated bleed rate)

Number of all bleeds over time (i.e., all bleed rate)

Number of treated spontaneous bleeds over time (i.e., treated spontaneous bleed 
rate)

Number of treated joint bleeds over time (i.e., treated joint bleed rate)

Joint health, as assessed through use of the Hemophilia Joint Health Score (HJHS) 
and magnetic resonance imaging (MRI) score of specific joints at specified 
timepoints only during the 7-year LTFU period
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of emicizumab on the basis of 
the following endpoints:

Incidence and severity of adverse events, with severity determined according to 
WHO Toxicity Grading Scale (see Appendix 5)

Incidence of thromboembolic events

Incidence of thrombotic microangiopathy (TMA)

Change from baseline in physical examination findings 

Change from baseline in vital signs

Incidence of laboratory abnormalities

Incidence and severity of injection-site reactions

Incidence of adverse events leading to study drug discontinuation

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events

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2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the emicizumab PK profile on the basis
of the following endpoint:

Plasma trough concentrations (Ctrough) of emicizumab prior to study drug 
administration at the following timepoints:
–
Q2W during Weeks 19
–
Q4W during Weeks 1353
Additional PK samples will be obtained from patients who require up-titration (only if 
up-titration occurs during the first year of emicizumab treatment).
Additional PK samples will be obtained in case of clinical suspicion of anti-drug antibody 
(ADA) development during the 7-year LTFU period.
2.4
BIOMARKER OBJECTIVE
The biomarker objective for this study is to investigate the effect of emicizumab on PD
parameters, including aPTT, thrombin generation (TG), and reported FVIII activity, as 
well as FIX antigen and FX antigen (emicizumab substrates) levels prior to study drug 
administration at the following timepoints:

Q2W during Weeks 19

Q4W during Weeks 1353
Additional biomarker samples will be obtained in patients who require up-titration (only if 
up-titration occurs during the first year of emicizumab treatment).
Additional biomarker samples will be obtained in case of clinical suspicion of ADA 
development during the 7-year LTFU period.
Biomarkers related to bone and joint health will be assessed at specified timepoints only 
during the 7-year LTFU period.
2.5
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is to evaluate the immune response to 
treatment on the basis of the following endpoints:

Incidence and significance of anti-emicizumab antibodies

Incidence of de novo development of FVIII inhibitors
Additional ADA samples will be obtained from patients who require up-titration (only if 
up-titration occurs during the first year of emicizumab treatment).
Additional anti-drug antibody (ADA) samples will be obtained in case of clinical suspicion 
of ADA development during the 7-year LTFU period.

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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study MO41787 is a Phase IIIb, multicenter, open-label, single-arm study of emicizumab 
in PUPs and MTPs at study enrollment from birth to 12 months of age with severe 
hemophilia A (intrinsic FVIII level 1%) without FVIII inhibitors. The study is designed to 
evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab
administered at 3 mg/kg Q2W for 52 weeks. After 1 year of treatment, patients will 
continue to receive emicizumab (1.5 mg/kg QW, 3 mg/kg Q2W or 6 mg/kg Q4W) over 
a 7-year LTFU period under this study frame. Study MO41787 is a descriptive study 
with no formal hypothesis testing.
Approximately 50 patients from birth to 12 months of age and weighing 3 kg at time of 
informed consent will be recruited. A minimum of 20 patients from birth to 3 months of 
age and a maximum of 30 patients from 3 months to 12 months of age will be 
enrolled.  Once the 30 patients from 3 months to 12 months of age have been 
recruited, no additional patients in this age group will be enrolled. The recruitment of 
patients from birth to 3 months of age will remain open until 20 patients in this age 
group are enrolled.
Initially, all patients will receive four loading doses of 3 mg/kg emicizumab SC QW for 
4 weeks followed by the maintenance dosing regimen 3 mg/kg SC Q2W for a total of 
52 weeks. Starting from Week 17 of treatment with emicizumab, individual patients may 
have their dose up-titrated to 3 mg/kg SC QW if they experience suboptimal bleeding 
control (see Section 4.3.2).  At the Week 53 clinic visit following consultation with the 
treating physician, parents/caregivers may elect for their child to continue with the 
maintenance 3-mg/kg SC Q2W dosing regimen or to switch to the maintenance
1.5-mg/kg SC QW or 6-mg/kg SC Q4W dosing regimen for the subsequent 7-year LTFU 
period. During the study, patients will be treated with emicizumab until unacceptable 
toxicity, discontinuation from the study due to any cause, or other criteria specified in the 
protocol, whichever occurs first. Patients who discontinue study treatment prior to the
end of the study (with the exception when the reason for discontinuation is the patient 
switching to commercial emicizumab product) will return to the clinic for a safety 
follow-up visit, 24 weeks after the final dose of study drug.
Safety assessments will include physical examinations, vital signs, and safety laboratory 
assessments (serum chemistry and hematology) performed as specified in the schedule 
of activities (see Appendix 1 for the details of the respective assessments performed 
during the first 52 weeks of treatment and the LTFU period).  Adverse events will be 
recorded on an ongoing basis as they occur during the study.  All patients in this study 
will undergo PK assessments.  Blood samples will also be collected to assess the PD 
properties of emicizumab (i.e., aPTT, TG, reported FVIII activity), to assess FIX and FX
antigen levels, to assess immunogenicity (i.e., anti-emicizumab antibodies and anti-FVIII
antibodies), as well as to assess bone and joint biomarkers (see Appendix 1 for the 

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details of the respective assessments performed during the first 52 weeks of treatment 
and the LTFU period).
During the study, individual bleeds will be recorded by the parents/caregivers as the 
bleeds occur using a Bleed and Medication Questionnaire (BMQ).  Breakthrough bleeds 
will be treated with FVIII at the lowest dose expected to achieve hemostasis. When 
a bleed occurs, parents/caregivers will be required to report bleed information details 
(e.g., date and time, location, and reason) and medication details including the reason 
for the use of FVIII (e.g., treatment for bleed, prior to surgery or short-term prophylaxis 
prior to activity), agent, date, time, and dose on the BMQ. During the entire study
duration, information on bleeds, hemophilia medications for bleeds, and emicizumab 
doses will be collected using an electronic BMQ (eBMQ) on an electronic handheld 
device given to parents/caregivers.
The primary analysis will be performed when the last patient has completed 52 weeks in 
the study, is lost to follow-up, or has withdrawn from study treatment, whichever occurs 
first. An interim analysis to review safety, efficacy, pharmacokinetics, 
pharmacodynamics, and immunogenicity data will be performed when the 10th patient
from birth to 3 months of age at the time of informed consent has completed 24 weeks 
in the study, is lost to follow-up, or has withdrawn from study treatment, whichever 
occurs first. All patients will be included at the time of the interim analysis irrespective of 
their age and time in the study. The interim analysis will be performed by the Sponsor’s
study team. An Internal Monitoring Committee (IMC) and Scientific Overview Committee 
(SOC) (as needed) will review the interim analysis reports generated by the Sponsor’s
study team. See Sections 6.9 and 9.5 for details on the IMC/SOC roles and 
responsibilities.
The 7-year LTFU period will evaluate long-term safety of emicizumab and describe the 
natural history of this population including the preservation of joint health over time. 
Joint health will be assessed through the use of MRI of knees, ankles and elbows, the 
HJHS, bone and joint biomarkers complemented with physical examination of the joints.
See Appendix 1 for the details of the assessments performed during the LTFU period.
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.

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Figure 1
Study Schema
FVIII factor VIII; MTP minimally treated patient; PUP previously untreated patient;
QW once a week; Q2W every 2 weeks; Q4W every 4 weeks.
Note:  Patients who discontinue study treatment prior to end of study (with the exception when 
the reason for discontinuation is the patient switching to commercial emicizumab product) will
return to the clinic for a safety follow-up visit 24 weeks after the final dose of study drug.
a The primary analysis will be performed when the last patient has completed 52 weeks in the 
study, is lost to follow-up, or has withdrawn from study treatment, whichever occurs first.
b Interim analysis will be performed when the 10th patient from birth to 3 months of age at the 
time of informed consent has completed 24 weeks in the study, is lost to follow-up, or has 
withdrawn from study treatment, whichever occurs first. The analysis will include all patients 
enrolled at the time of the interim analysis irrespective of their age and time in the study.
3.2
END OF STUDY AND LENGTH OF STUDY
After 52 weeks in the study, all patients who continue to derive clinical benefit will 
continue receiving prophylactic emicizumab as part of this study in the 7-year LTFU 
period or switch to commercial emicizumab product. For an individual patient, the length 
of the study will be 8 years.
The length of the entire study from screening of the first patient to the last patient 
completing the LTFU period will be approximately 10 years. 
Patients who discontinue study treatment prior to end of study (with the exception where 
the reason for discontinuation is the patient switching to commercial emicizumab 
product) will return to the clinic for a safety follow-up visit, 24 weeks after the final dose 
of study drug.
The end of this study is defined as the date when the last remaining patient has
completed the last visit (i.e., last patient, last visit), as demonstrated by any one of the 
following:

Completed the last visit of the LTFU period

Completed the end of study safety follow-up visit 24 weeks after discontinuing 
emicizumab

Switched to commercial emicizumab product

Withdrew consent 

Was lost to follow-up

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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Emicizumab Dose and Schedule
The three maintenance dosing regimens of SC emicizumab QW (1.5 mg/kg), Q2W 
(3 mg/kg), and Q4W (6 mg/kg) have shown equivalent average steady-state exposure, 
demonstrated consistent efficacy and safety, and are approved in several countries for 
the treatment of hemophilia A, with or without FVIII inhibitors, in adult and pediatric 
patients, including newborn and older children.
Despite the conduct of pivotal Phase III studies in pediatric patients, with and without 
FVIII inhibitors, receiving the three dosing regimens, limited clinical data have been 
collected in pediatric patients younger than 2 years of age (see Section 1.3).  This study 
aims to provide clinical evidence of the safety, tolerability and efficacy of emicizumab in 
the youngest group of patients. In this study, the treatment period until the primary 
analysis will be 52 weeks, which is similar to the length of treatment in prior pediatric 
Phase III studies investigating emicizumab. During the first year of treatment, all 
patients will receive the maintenance dosing regimen of emicizumab 3 mg/kg SC Q2W.
Taking into consideration frequency of injection and simplicity of the maintenance dosing 
regimen (which is the same as the loading doses), the Q2W regimen was selected 
because the maintenance dose is identical to the loading dose (3 mg/kg). The choice for 
Q2W dosing regimen is also consensually supported by treating pediatricians who have 
reported an empirical preference for a lower frequency of injections with limited volume 
injected with this regimen while treating young patients in their practice (no published 
data). At the Week 53 clinic visit, following consultation with the treating physician, 
parents/caregivers may elect to have their child continue treatment with emicizumab
Q2W regimen or to switch to QW or Q4W regimen for the 7-year LTFU period.
3.3.2
Rationale for Patient Population
Hemophilia A is a congenital disease in which the lack of FVIII function since birth 
results in severe bleeding diathesis throughout patients’ lives. Restoring FVIII function 
and thereby adequate hemostasis is the ultimate goal of management, independent of 
age. Hemostasis is a dynamic process that starts in utero. Physiologic concentrations 
of coagulation factors gradually increase with time, with levels lower in premature infants 
compared with full-term neonates and healthy children (Andrew et al. 1987, 1988, 1992; 
Monagle at el. 2006, 2010; Ignjatovic et al. 2015; Nowak-Göttl et al. 2017).  Neonates 
display physiologically reduced levels of vitamin Kdependent coagulation factors,
including FII, FVII, FIX, and FX that are approximately 50% of adult values, while the 
levels of FVIII, FV, and FXIII correlate well with adult boundaries (Kenet al. 2010, 2018;
Favaloro and Lippi 2017). Coagulation factors in newborns and adults are qualitatively 
similar in their molecular weights and degree of glycosylation (Hassan et al. 1990).  The 
coagulation cascade is almost mature at birth, with well-balanced hemostasis and 
thrombosis, and is fully mature at 6 months of age (Andrew et al. 1987; Revel-Vilk et al. 
2012). Notably, FVIII activity at birth is equivalent to adult activity level and remains 
stable from the newborn period onward (Kuhle et al. 2003).  Consequently, dosing 

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strategies are similar for adult and for pediatric patients with hemophilia A, including 
infants (Mahlangu et al. 2014, Young et al. 2015). Emicizumab mimics FVIII activity and 
binds to the same qualitatively identical FIX and FX and therefore should be efficacious 
in newborns and infants with hemophilia A, as in the pediatric population in 
Studies BH29992 and JO39881. Studying this very young pediatric population with 
emicizumab early in life in Study MO41787 is designed to provide supportive clinical 
evidence, that prophylactic emicizumab is safe and efficacious during infancy when the 
physiologic developmental hemostatic maturation is occurring.
A comprehensive surveillance study from the CDC UDC project of 580 children with 
hemophilia from 0 to 2 years of age followed in HTCs, showed that 75% of infants were 
diagnosed in the first month of life; 10% of infants were born prematurely with a range 
from 28 to 36 weeks of gestation; 64% of all term and preterm infants received vitamin K 
at birth (Kulkarni et al. 2009, 2017). Thus in Study MO41787, infants from birth to 
12 months of age, including premature babies (gestational age 38 weeks; as long as 
they have reached a body weight of 3 kg at time of informed consent) will be eligible to 
enroll to benefit from prophylactic treatment with emicizumab as early as possible (i.e., 
at birth or diagnosis); all patients are expected to have received vitamin K prophylaxis 
according to local standard practice.
A significant proportion of potentially preventable complications of hemophilia A occur in 
early childhood, including bleeds, falls, complications of treatment associated with CVAD 
use, and FVIII inhibitor formation that may have a lifelong impact. While joint disease is 
a hallmark of hemophilia in the older age groups, bleeds due to circumcision, ICH due to 
delivery or head trauma, and soft tissue or oral or nasal bleeds, are more likely to occur 
in early childhood (see Section 1.1).  
 
 
.
In Study MO41787, the early initiation of prophylaxis with emicizumab between birth and 
1 year of age, and before the first exposure of FVIII (PUPs) or a limited number of FVIII 
doses (MTPs), will likely delay or minimize the early exposure of infants to FVIII, and 
consequently suspend or limit potential development of FVIII inhibitors.
In Study MO41787, FVIII replacement therapy will remain a treatment option to manage 
breakthrough bleeds and surgical procedures. Patients will be tested for anti-FVIII 
antibodies (FVIII inhibitors) when exposed to FVIII (see Section 4.5.7.1).  If a patient
develops FVIII inhibitors while on study, the patient will be permitted to continue to 
receive emicizumab on study, as emicizumab is effective irrespective of the presence or 
absence of FVIII inhibitors.  However, the patient will be required to discontinue 
participation in the study should immune tolerance induction be initiated. While the 
diagnosis of hemophilia A is being made at an early age, bleeds still predominate as the 

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diagnostic trigger in newborns (see Section 1.1).  Early initiation of prophylactic 
emicizumab at birth or diagnosis will potentially reduce the occurrence of ICH and
associated long-term clinical sequelae. In Study MO41787, newborn and infant patients 
with evidence of active ICH will not be eligible to enroll.
3.3.3
Rationale for Pharmacokinetic Assessments
PK assessments in this study will help confirm that plasma concentrations in newborns
and infants are consistent within the ranges of concentrations predicted by 
population-PK modeling and are effective and safe as in previous emicizumab Phase III 
studies. For consistency, the PK sampling in this study will show similarity with the 
pediatric study BH29992 evaluating emicizumab in patients younger than 12 years of 
age, with less sampling considering the limits of blood volume drawn in these very young 
patients. In this study, plasma samples will be collected Q2W until Week 9 and 
subsequently at less frequent intervals Q4W until Week 53 in order to document the 
emicizumab exposure in this infant age group, where very limited PK data have been 
collected yet. Additionally, influence of various demographic (e.g., body weight) or 
clinical factors (e.g., ADA) on exposure in individual patients may be investigated.  
Therefore, samples for measurement of emicizumab concentrations in plasma will be 
collected at designated timepoints.
3.3.4
Rationale for Immunogenicity Assessments
Monitoring of immune response is important for biologics as development of ADAs may 
affect the safety and/or efficacy of emicizumab.  Samples for measurement of ADAs will 
therefore be collected at regular timepoints during the first 52 weeks of study. 
Subsequently during the 7-year LTFU, samples for ADAs will be collected only in case of 
clinical suspicion for ADA development (see Appendix 1).  In case of ADA positivity, 
further investigations will be conducted to assess their neutralizing potential, either 
through visual inspections of the PK and PD profiles and/or, if available, by means of
testing on a neutralizing antibody assay.
De-novo development of anti-FVIII antibodies in patients with emicizumab will be 
monitored during the study. During screening, one plasma sample for anti-FVIII 
antibodies will be mandated for MTPs only.  Subsequently, all patients will be tested for 
anti-FVIII antibodies following exposure to FVIII as detailed in Section 4.5.7.1.
Non-neutralizing FVIII antibody development may be explored if sample volume permits.
3.3.5
Rationale for Biomarker Assessments
Samples to assess biomarkers to measure the PD effect of emicizumab on hemostasis 
will be collected at the same time as PK samples (see Appendix 1). These will assess 
evidence of biologic activity of emicizumab in patients from birth to 12 months of age at 
study enrollment with severe hemophilia A (intrinsic FVIII level 1%) without FVIII 
inhibitors. The PD biomarkers include aPTT, TG, and reported FVIII activity. These 
assays have shown in previous Phase I/II and III studies to exhibit a dose-response

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relationship to emicizumab concentration in patients with hemophilia A more than 1 year 
of age (for more information, refer to the RO5534262 [Emicizumab] Investigator's 
Brochure).
TG assays will be performed using a FXIa-triggering reagent, which is consistent with 
what has been used in previous emicizumab clinical studies. Emicizumab PD activity
will also be measured using a chromogenic FVIII activity assay containing human 
coagulation factors.
Plasma concentrations of coagulation factors in the neonate differ from those of adults 
and older children (Kenet et al. 2019).  This includes concentrations of FIX and FX, the 
binding targets of emicizumab, which are known to be quantitatively lower in neonates
versus in adults (Andrew et al. 1987; Attard et al. 2013). FIX and FX concentrations will 
be monitored over time during emicizumab treatment. Additional coagulation-related 
biomarkers may be explored if sample volume permits.
During the 7-year LTFU period only and on an annual basis, serum and plasma will be 
collected for the assessment of bone and joint biomarkers, which may include, but will 
not be limited to, procollagen type 1 amino-terminal propeptide, C-terminal telopeptide of 
collagen 1, osteoprotegerin, and soluble RANK-L.  Samples for the analysis of bone and 
joint biomarkers will be collected under fasting conditions if blood volume drawn permits
(see Appendix 1).
3.3.6
Rationale for Joint Health Assessments
Prophylaxis replacement therapy prior to the onset of joint bleed is aimed at a reducing 
or eliminating hemarthrosis and thus joint damage in patients with hemophilia (Fischer 
et al. 2008). The Joint Outcome Study, evaluating prophylactic versus episodic 
treatment, has demonstrated improved outcomes with prevention of joint damage and 
decrease of the frequency of joint bleeds for boys receiving prophylaxis (Manco-Johnson
et al. 2007).  However, it has also been observed that joint deterioration could be 
observed in patients despite good bleed management, suggesting that joint 
abnormalities may be observed in the absence of clinically evident joint bleeds. MRI is 
considered as the reference standard to assess early joint changes in hemophilia 
(Foppen et al. 2020). It is an optimal tool for assessment of musculoskeletal outcomes 
in boys with hemophilia treated with prophylaxis because of its capacity to detect early 
soft tissue and osteochondral abnormalities in joints into which bleeding has occurred 
(Kraft et al. 2012; Puetz et al. 2018).
This study provides an opportunity to describe the natural history of a cohort of infants 
with hemophilia A who initiated prophylaxis early in infancy. Importantly, this study will 
evaluate the preservation of joint health (pristine joints at birth) over time in patients who 
initiated emicizumab prophylaxis prior to 1 year of age. The 7-year LTFU will assess 
health of joints using the MRI score of bilateral knees, ankles and elbows on an annual 
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joint biomarkers complemented with physical examination of the joints.  Of note, only
patients 4 years of age at the time of the assessment will undergo HJHS, and bone 
and joint biomarker evaluation; only patients 5 years of age at the time of the 
assessment will undergo MRI.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 50 patients from birth to 12 months of age and weighing 3 kg at time of 
informed consent will be enrolled with a minimum of 20 patients from birth to 3 months 
of age and a maximum of 30 patients from 3 months to 12 months of age. Once the 
30 patients from 3 months to 12 months of age have been recruited, no additional 
patients in this age group will be enrolled. The recruitment of patients from birth to 
3 months of age will remain open until 20 patients in this age group have been 
enrolled.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent obtained from parent or legally authorized representative 
(latest approved version by Ethics Committee [EC]/Institutional Review Board [IRB]) 
prior to any study-specific assessments or procedures being performed

Age from birth to 12 months at time of informed consent

Body weight 3 kg at time of informed consent
–
Patients with a lower body weight can be enrolled after they have reached 
a body weight of 3 kg.
–
Premature babies (gestational age 38 weeks) may be enrolled as long as they 
have reached a body weight of 3 kg. For premature babies, the corrected 
gestational age should be reported.

Mandatory receipt of vitamin K prophylaxis according to local standard practice

Diagnosis of severe congenital hemophilia A (intrinsic FVIII level 1%)

A negative test for FVIII inhibitor (i.e., 0.6 Bethesda units [BU]/mL) locally 
assessed during the 2-week screening period for all patients

No history of documented FVIII inhibitor (i.e., 0.6 BU/mL), FVIII drug-elimination 
half-life 6 hours, or FVIII recovery 66%

PUPs or MTPs (i.e., up to 5 days of exposure with hemophilia-related treatments,
such as plasma-derived FVIII, recombinant FVIII, fresh frozen plasma, 
cryoprecipitate, or whole blood products)

Documentation of the details of the hemophilia-related treatments received since 
birth

Documentation of the details of the bleeding episodes since birth

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
For patients from birth to 3 months of age at the time of study entry: no evidence 
of active ICH, as confirmed by a negative cranial ultrasound at screening
irrespective of delivery mode

Adequate hematologic function, defined as platelet count 100,000/L 
(100109cells/L) and hemoglobin 8 g/dL (4.97 mmol/L) at screening

Adequate hepatic function, defined as total bilirubin 1.5the age-specific upper 
limit of normal (ULN) (excluding patients with Gilbert syndrome and patients with 
benign neonatal hyperbilirubinemia because of breastfeeding) and both AST and 
ALT3the age-specific ULN at screening

Adequate renal function, defined as a serum creatinine 1.5the age-specific ULN
Note:  When the serum creatinine is 1.5ULN, creatinine clearance by
Schwartz estimation must be 70 mL/min/1.73 m2.

For parents/caregivers: willingness and ability to comply with the study protocol 
requirements, scheduled visits, treatment plans, laboratory tests, completion of 
applicable questionnaires, and other study procedures
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 severe hemophilia A

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use 
during the study

Receipt of any of the following:
–
Prior use of emicizumab prophylaxis including investigational or commercial 
emicizumab
–
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 drug-elimination half-lives of last drug administration
–
A nonhemophilia-related investigational drug within the last 30 days or 
5 drug-elimination half-lives, whichever is shorter
–
An investigational drug concurrently

Current active severe bleed, such as ICH

Planned surgery (excluding minor procedures, e.g., circumcision, CVAD placement) 
during the study

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Patients who are at high risk for TMA (e.g., have a previous medical or family history 
of TMA, such as thrombotic thrombocytopenic purpura, atypical hemolytic uremic 
syndrome) in the investigator's judgment

Previous or current treatment for thromboembolic disease (with the exception of 
previous catheter-associated thrombosis in patients for whom anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease

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
Any hereditary or acquired maternal condition that may predispose the patient to 
thrombotic events (e.g., inherited thrombophilias antiphospholipid syndrome)

Other diseases (e.g., certain autoimmune diseases) that may increase risk of 
bleeding or thrombosis

Known infection with HIV, hepatitis B virus, or hepatitis C virus

Serious infection requiring antibiotics or antiviral treatments within 14 days prior to 
screening

Concurrent disease, treatment, abnormality in clinical laboratory tests, vital signs 
measurements, or physical examination findings that could interfere with the 
conduct of the study or that would, in the opinion of the investigator or Sponsor, 
preclude the patient’s safe participation in and completion of the study or 
interpretation of the study results 

Unwillingness of the parent or caregiver to allow receipt of blood or blood products, 
or any standard-of-care treatment for a life-threatening condition

Any other medical, social, or other condition that may prevent adequate compliance 
with the study protocol in the opinion of the investigator
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is a single-arm, openlabel study.  After initial written informed has been obtained
from parent or caregiver, all screening procedures and assessments have been 
completed, and eligibility has been established for a patient, the study site will obtain the 
patient's identification number from an interactive voice or web-based response system 
(IxRS). The time between screening and enrollment of eligible patients should be 
2 weeks; otherwise, patients must be re-screened to determine if they continue to meet 
the inclusion and exclusion criteria.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is emicizumab.
4.3.1
Study Treatment Formulation and Packaging
Emicizumab will be supplied by the Sponsor as a sterile liquid for SC injection; it 
contains no preservatives and requires storage at 2°C8°C (do not freeze and protect 
from light).  Single-use vials contain 30 or 150 mg (nominal) of emicizumab at pH 6.0.  
The drug product is formulated in 150 mmol/L arginine, 0.5 mg/mL poloxamer 188, and 
20 mmol/L histidine-aspartic acid buffer (pH 6.0).  Because emicizumab is administered 
according to a weight-based dosing regimen, two vial strengths will be supplied for this 
study differing from each other only in emicizumab concentration:  nominal vial strength 
150 mg (150 mg/mL, 1.0 mL); nominal vial strength 30 mg (30 mg/mL, 1.0 mL). The 
less-concentrated formulation will enable safe SC weight-based volume dosing of very 
small children with sufficient precision. The excipient composition and primary
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of emicizumab, refer to the RO5534262 (Emicizumab) Investigator's Brochure. Details 
on the devices to be used for withdrawal of study drug from the vial and SC injection are 
provided in the “Instructions for Use” (IFU) document.
In order to minimize the number of injections for pediatric patients in certain high-weight 
categories if applicable, the administration per single injection of up to 2 mL of drug 
product solution may be permitted.  This will require combining emicizumab drug product 
solution from more than one vial of a given concentration (i.e., vial pooling) into a single 
syringe using a new transfer needle for each vial.  The detailed procedure for vial 
pooling is described in the IFU document.  Vials of emicizumab with different 
concentrations must not be combined.
4.3.2
Study Treatment Dosage, Administration, and Compliance
Patients treated with emicizumab will receive a loading dose of 3 mg/kg SC QW for the 
first 4 weeks (on Day 1 of each week) followed by a maintenance dose of 3 mg/kg SC 
Q2W at Week 5 (on Day 1 of each 2-week period). Patients will receive prophylactic 
emicizumab during their participation in the study for 52 weeks. After the first 52 weeks
of treatment with emicizumab, switching to other dosing regimens (1.5 mg/kg SC QW or 
6 mg/kg SC Q4W) will be permitted for the 7-year LTFU period.  During the study, 
patients will be treated with emicizumab until unacceptable toxicity, discontinuation from 
the study due to any cause, or other criteria specified in the protocol, whichever occurs 
first.  
During the first year of treatment, the study drug will be dispensed at the scheduled 
clinic visits (see Appendix 1 Table 1).
During the 7-year LTFU period, the study drug dispensation will occur every 12 weeks
(quarterly) from Week 53 until the end of the 7-year LTFU. Within each year of the 
7-year LTFU period, there will be quarterly visits (QV) for drug dispensation (QV1, 
QV2, QV3 and QV4):

At QV1 and QV3 (non-study site visits), the patient’s body weight assessed by 
patient’s local general practitioner or local nurse will determine via IxRS the 
strength and number of vials for the administration of emicizumab for the next 
12 weeks. The corresponding vials will then be shipped to patient’s home by the 
site. For convenience, the parents/caregivers may come to the study site for the 
study drug to be picked-up directly at the study site (see Appendix 1 Table 4). The 
details for weight assessment are included in Section 4.5.3.

At QV2 and QV4 (study drug dispensation clinic visits), the assessment of the 
patient’s body weight will determine via IxRS the strength and number of vials of 
study drug to be given to the parents/caregivers for the administration of 
emicizumab for the next 12 weeks (see Appendix 1 Table 4).
During the study, individual patients may have their dose up-titrated if they experience
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2 qualifying bleeds within a 12-week interval may have the opportunity to have their 
maintenance emicizumab dose increased to 3 mg/kg QW starting at Week 17.  The 
Medical Monitor is available to the investigator for consultation and to answer 
questions related to up-titration.  Qualifying bleeds are defined as spontaneous and 
clinically significant, physician verified (e.g., with diagnostic imaging, clinical 
examination, photograph), and occurring while on prophylactic emicizumab at steady
state on the maintenance dose (after Week 5).  Should patients meet protocol-defined 
criteria for up-titration, the investigator may contact the Medical Monitor regarding advice 
for possible up-titration, which will take place as follows (see Appendix 1):  

From Week 17 to Week 41 (included) upon up-titration to the new maintenance 
dose of 3 mg/kg QW, the patient’s schedule of activities will reset to Week 1 where
the next five clinic visits must take place at the site and the subsequent clinic visits 
will follow the reset schedule of activities until one year of treatment (actually after 
52 weeks); subsequently the clinic visits will follow the regular schedule of activities 
of the 7-year LTFU.
Example of up-titration during Week 40: the first up-titrated dose will be given at 
Week 41 at 3 mg/kg, the subsequent 3 mg/kg doses will be administered QW. 
The reset schedule of activities will continue until 53 weeks only; subsequently 
the clinic visits will follow the schedule of activities of the 7-year LTFU.

In case of up-titration between Week 42 and Week 53, the patient’s schedule of 
activities will reset to Week 1 where the next five clinic visits must take place at the 
site and the subsequent clinic visits will follow the reset schedule of activities for 
a duration of 12 weeks only; subsequently the clinic visits will follow the regular 
schedule of activities of the 7-year LTFU.
Example of up-titration during Week 52: the first up-titrated dose will be given at 
Week 53 at 3 mg/kg, the subsequent 3 mg/kg doses will be administered QW. 
The reset schedule of activities will continue until 65 weeks only; subsequently 
the clinic visits will follow the schedule of activities of the 7-year LTFU.

If up-titration takes place after Week 53, the schedule of activities will not be altered. 
The clinic visits will follow the regular schedule of activities of the 7-year LTFU.

Once up-titration is initiated, the patient will stay on the maintenance dose of 
3 mg/kg QW until the end of the study: in case the patient missed a scheduled dose
(3 mg/kg QW), emicizumab should be administered as soon as possible within 
a window of 3 days from the scheduled dosing date.  If more than 3 days have 
passed, the missed dose should be skipped, and the next dose of emicizumab should 
be taken at the next scheduled time resuming the original dosing schedule (3 mg/kg 
QW).
Any cases of overdose, medication error, drug abuse, or drug misuse of study drug will 
be determined from emicizumab data entered into the electronic handheld device (see 
Section 5.3.5.12 for details).

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If a patient has a systemic hypersensitivity reaction or severe adverse reaction that may 
be attributable to emicizumab, subsequent doses should be held. The situation may be
discussed with the Medical Monitor and advice sought before dosing is resumed.  Should 
unanticipated events occur during the study that require treatment with multiple daily 
administrations of FVIII concentrates for multiple days, such as non-elective surgery or 
severe/life-threatening bleeds, the investigator should contact the Medical Monitor 
immediately to discuss such cases and the management of future emicizumab doses.  
Any other request for emicizumab dose adjustment may require discussion of the clinical 
case with the Medical Monitor.
Study site healthcare providers (HCPs) will be trained on how to properly prepare the 
study drug and administer the correct calculated dose subcutaneously as described in 
the IFU document.  Parents/caregivers will in turn be trained by an HCP on study drug
preparation and administration at the recommended sites of injection as detailed in the 
IFU document.  The HCP is to inform the parents/caregivers of the volumetric dose to be 
administered and dosing frequency.  Note that during the course of the study, should the 
patient’s body weight change to affect the dose (e.g.,10%), the new volumetric dose to 
be administered must be communicated to the parents/caregivers.
Emicizumab will be administered to patients as an SC injection in the home setting after 
a period of in-clinic administration and training.  The first five study drug administrations 
must be performed in a monitored setting such as an infusion center, clinic, or hospital, 
with a 60-minute observation period following each of the first three doses.  For patients 
with a history of a clinically significant hypersensitivity reaction, additional precautions as 
described in Section 5.1.1.2 should be considered.  The fourth and fifth scheduled study 
drug administrations must also be performed in a monitored setting, and
parents/caregivers will be trained and have the opportunity to ask any questions of the 
HCP before the scheduled start of home administration.  Each site will have the 
discretion to provide additional training if deemed appropriate.  If, despite additional 
training, the investigator determines that the parents/caregivers are unable to inject 
emicizumab correctly, then arrangements may be made to identify a trained caregiver or 
HCP to administer the SC injections. 
Parents/caregivers will be provided with the clinic contact information, to use in case 
they have questions related to administration between clinic visits.
Medication administration errors during training will be recorded and competence of the 
parents/caregivers to administer emicizumab at home will be documented on the 
electronic Case Report Form (eCRF). If necessary, parents/caregivers or their HCP 
may choose to continue administration of study drug in the clinic.  Compliance in the 
home setting is to be monitored by recording emicizumab administration on an electronic
handheld device during the entire study duration and by recording collected used and 
unused vials during each study drug dispensation clinic visit.

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Emicizumab should be administered on the scheduled dosing day.  On days when 
trough plasma PK, PD, and ADA samples are to be collected, patients will be dosed 
after those samples are drawn. 
In case the patient missed a scheduled loading dose (3 mg/kg) at Weeks 2 or 3, 
emicizumab should be administered as soon as possible within a window of 3 days from 
the scheduled dosing date.  If more than 3 days have passed, the missed loading dose 
should be skipped, and the next loading dose of emicizumab should be taken at the next 
scheduled time resuming the original dosing schedule (3 mg/kg QW) until Week 4. If 
the Week 4 loading dose is missed, emicizumab should be administered as soon as 
possible within a window of 3 days from the scheduled Week 4 dosing date. If more 
than 3 days have passed, the missed Week 4 loading dose should be skipped, and the 
next dose of emicizumab should be the Week 5 maintenance dose.
For patients receiving emicizumab 3 mg/kg Q2W from Week 5 (first maintenance dose) 
during the first 52 weeks of the study and patients receiving emicizumab 3 mg/kg Q2W 
during the 7-year LTFU period, if parents/caregivers forget or cannot administer study 
treatment on the scheduled dosing day, study drug should be administered as soon as 
possible within a window of 7 days from the scheduled dosing date.  If more than 7 days 
have elapsed, the missed dose should be skipped and the parents/caregivers should 
administer the subsequent dose at the next scheduled time with the study treatment 
dosing resumed in accordance with the original dosing schedule (3 mg/kg Q2W).
For patients receiving emicizumab 1.5 mg/kg QW during the 7-year LTFU period, if 
parents/caregivers forget or cannot administer study treatment on the scheduled dosing 
day, study drug should be administered as soon as possible within a window of 3 days 
from the scheduled dosing date.  If more than 3 days have elapsed, the missed dose 
should be skipped and the parents/caregivers should administer the subsequent dose at 
the next scheduled time with the study treatment dosing resumed in accordance with 
the original dosing schedule (1.5 mg/kg QW).
For patients receiving emicizumab 6 mg/kg Q4W during the 7-year LTFU period, if 
parents/caregivers forget or cannot administer study treatment on the scheduled dosing 
day, study drug should be administered as soon as possible within a window of 14 days 
from the scheduled dosing date.  If more than 14 days have elapsed, the missed dose 
should be skipped and the parents/caregivers should administer the subsequent dose at 
the next scheduled time with the study treatment dosing resumed in accordance with 
the original dosing schedule (6 mg/kg Q4W).
The parents/caregivers should not administer two doses on the same day to make up for 
a missed dose.
During the first 52 weeks of study, the emicizumab doses administered to patients will be 
documented by the parents/caregivers on the handheld electronic observer-reported 

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outcome (eObsRO) device using the eBMQ, both during patient’s clinic visits and when
the patient is outside the clinic. Similarly during the 7-year LTFU period, the QW, Q2W 
or Q4W emicizumab doses will be documented by the parents/caregivers on the 
hand-held eObsRO device using the eBMQ, both when the patient is outside the clinic 
and during patient’s clinic visits.
Parents/caregivers will be provided with alert cards, which they will be requested to carry 
at all times.  These will include guidance on how to recognize signs and symptoms of 
thromboembolic events or allergic, anaphylactic, and anaphylactoid reactions and how to 
obtain emergency care.  In addition, alert cards are designed to notify non-study HCPs
that emicizumab will interfere with certain coagulation laboratory tests (see the
RO5534262 [Emicizumab] Investigator's Brochure for more information) and the 
investigator should be contacted for assistance in interpreting the test results.
Guidelines for treatment interruption or discontinuation are provided in Section 4.6.1.
4.3.3
Investigational Medicinal Product Handling Accountability
Emicizumab, the only IMP in this study, is required for completion of this study and will 
be provided by the Sponsor.  The study site (i.e., investigator or other authorized 
personnel [e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the 
site, IMP inventory at the site, IMP use by each patient, and disposition or return of 
unused IMP, thus enabling reconciliation of all IMP received, and for ensuring that 
patients are provided with doses specified by the protocol.  
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff.
Only patients enrolled in the study may receive IMPs, only authorized staff may supply 
IMPs, and only parents/caregivers and authorized staff may administer IMPs.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the study drug accountability log.
Refer to the pharmacy manual and/or the emicizumab IB and IFU document for 
information on IMP handling, including preparation and storage, and accountability. 
4.3.4
Continued Access to Emicizumab
The Sponsor will offer continued access to Roche IMP (emicizumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (emicizumab) 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 Roche IMP 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 Roche IMP (emicizumab) after completing the 
study if any of the following conditions are met:

The Roche IMP 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 wouldn't 
otherwise create a financial hardship for the patient).

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for hemophilia A.

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
hemophilia A.

Provision of the Roche IMP 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 website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive emicizumab as part of a potential future extension 
study.
4.4
CONCOMITANT THERAPY AND PROHIBITED THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
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from 4 weeks prior to enrollment to the study completion or safety follow-up visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
During treatment with emicizumab, other medicinal products for SC administration 
should preferably be injected at different anatomical sites than the sites of emicizumab 
administration.
All hemophilia-related treatments (e.g., FVIII) administered to patients since birth before 
enrolling in the study should be documented on eCRF. During the study, 
hemophilia-related treatments administered to patients will have to be reported by 
parents/caregivers through the eBMQ on the electronic handheld device.
4.4.1
Permitted Therapy 
Patients will be permitted to use the following concomitant drugs and therapies during 
the study:

Intermittent doses or short-term FVIII prophylaxis (e.g., around the time of surgery 
or procedure)
However, concomitant routine prophylaxis with FVIII (including low-dose FVIII
or ITI) is not permissible during the study. 

For the treatment of breakthrough bleeds, FVIII 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 FVIII doses used prior to the study.
The exact dose and schedule of FVIII should be discussed between the 
investigator and the parents/caregivers at the beginning and throughout the 
study.  Repeat dosing of FVIII should be performed only under medical 
supervision and consideration should be given to verifying bleeds prior to 
repeated dosing.

Antifibrinolytics intended to control bleeds

Local anesthetic cream for emicizumab SC administration

Vaccinations should be administered following national immunization schedules.  As 
per the World Federation Hemophilia (WFH) recommendations for vaccinations 
(WFH 2012), patients with hemophilia should be vaccinated.  Thus, vaccinations 
should be administered according to the WFH recommendations and local HTC
practice and ideally during a period when the bleeding status of the child is well 
controlled and stable.  Vaccinations should not be administered on the same day as 
an emicizumab administration but ideally at a timepoint between two emicizumab 
administrations (48 hours after emicizumab administration).  Children who receive 
vaccinations must be carefully followed for any adverse reactions in the subsequent 
days following vaccine administration.

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
Drugs and therapies to treat adverse events and use of topical antiseptic 
treatments, anesthetic medications, eye drops, and so forth that are not considered 
to result in systemic exposure

Drugs to treat an existing medical condition ongoing at study entry that does not 
violate the eligibility criteria
The use of bypassing agents is unexpected in patients with hemophilia A without 
inhibitors.  In the interest of completeness, Appendix 6 includes dosing and monitoring 
guidance for the use of bypassing agents for patients in this study, in case such 
unforeseen circumstances occur. Use of bypassing agents as concomitant prophylactic 
treatment, including for short-term prophylaxis, is not permitted.
As per Section 4.1.2, patients who are at high risk for TMA (e.g., have a previous 
medical or family history of TMA) in the investigator’s judgment are excluded from
participating in the study. Caution should be used when treating patients in the study 
who are receiving concomitant medication known to be a risk factor for the development 
of TMA (e.g. ciclosporin, quinine, and tacrolimus).
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 unless otherwise specified:

Use of 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 CVAD])
However, drugs intended to control bleeding episodes or used in the context of 
surgeries or injuries (e.g., concussion) to prevent deterioration are allowed.

Elective surgery during the emicizumab loading phase (prior to Week 5) (excluding 
minor procedures such as CVAD placement or removal as well as emergency 
surgeries)

Use of other investigational drugs
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 may be consulted for advice about any changes in the benefitrisk assessment
and whether the patient should continue in the study.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent must be obtained from parent or legally authorized 
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procedures (including screening evaluations).  Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the 
study site.
All screening evaluations must be completed 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, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, procedures, medical allergies, 
history of prior anaphylaxis, or known thrombophilia since birth will be recorded on the 
General Medical History and Baseline Conditions eCRF.  All bleeds (date and time, type, 
location, and reason) experienced since birth and before enrolling in the study on Day 1 
should be documented on the eCRF at baseline.
Any medication (e.g., vitamin K, prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) administered to patient in 
addition to protocol-mandated treatment from 4 weeks prior to enrollment through the 
study completion or safety follow-up visit should be reported on the Concomitant 
Medications eCRF. The receipt of vitamin K should be reported on the Concomitant 
Medications eCRF independently of the date of administration. All hemophilia-related 
treatments (e.g., FVIII, including date and time of administration, type of medication, 
dose, and purpose) administered to patients since birth and before enrolling in the study 
on Day 1 should be documented on the eCRF at baseline. During the entire study
duration, hemophilia-related treatments administered to patients will be reported by 
parents/caregivers only through the eBMQ on the electronic handheld device.
At baseline, information about nutrition received by patient, breast-feeding or formula 
(name and type) or other, will be documented on eCRF.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race and 
ethnicity are standard data points in clinical trials conducted by Roche, collected as part 
of the demographics, as there is potential that diseases might affect racial groups 
differently.
4.5.3
Physical Examinations
A complete physical examination should include, but not necessarily be limited to, the 
evaluation of head, eyes, ears, nose, and throat and include the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  
Additional targeted physical examinations of joints for bleeds, skin for bruises, 
hematomas, injection-site reactions, and lipodystrophies should be conducted as noted 
in the schedule of activities (see Appendix 1) and as clinically indicated. Any 

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abnormality identified during screening should be recorded on the General Medical 
History and Baseline Conditions eCRF. New or worsened abnormalities from screening 
should be recorded as adverse events.
Height/length and weight should be recorded before study treatment administration.  
Frequency of these assessments should be performed as noted in the schedule of 
activities (see Appendix 1) but may also be obtained any time as unscheduled 
assessments as judged by the investigator. 
During the first year of treatment, the patient’s body weight should be assessed in the 
clinic and recorded on the eCRF when emicizumab is dispensed (See Appendix 1
Table 1). During the 7-year LTFU period, the patient’s body weight should be assessed 
every 12 weeks (quarterly) from Week 53 until the end of the 7-year LTFU. Within 
each year of the 7-year LTFU period, there will be four QV for drug dispensation (QV1, 
QV2, QV3 and QV4):

At QV1 and QV3 (non-study site visits) the patient’s body weight will be assessed 
by patient’s local General Practitioner or local Nurse. The weight value will be 
provided by phone to the site personnel who will check its consistency with the 
patient’s previous weight records before recording it on the eCRF. The weight will 
be used to determine via IxRS the strength and number of vials for the 
administration of emicizumab for the next 12 weeks. The corresponding vials will 
then be shipped to patient’s home by the site. For convenience, the 
parents/caregivers may prefer to come to the study site for the study drug to be 
picked-up directly in the study site, in this case the patient’s body weight will be 
assessed in the clinic (see Appendix 1 Table 4.

At QV2 and QV4 (study drug dispensation clinic visits), a complete physical 
examination will be performed. The patient’s body weight will also be assessed and 
recorded on the eCRF. The weight will be used to determine via IxRS the strength 
and number of vials of study drug to be given to the parents/caregivers for the 
administration of emicizumab for the next 12 weeks (see Appendix 1 Table 4).
The HJHS (see Appendix 2) will be assessed annually as part of physical examination 
during the 7-year LTFU period only in patients 4 years of age at the time of the 
assessment (see Appendix 1).
4.5.4
Vital Signs
Vital signs will include measurements of pulse, respiratory rate, temperature (oral, rectal, 
axillary, temporal, or tympanic), systolic and diastolic blood pressure using age-adapted 
measurements when possible should be recorded before study treatment administration.  
Frequency of vital sign assessments should be performed as noted in the schedule of 
activities (see Appendix 1) but may also be obtained any time as unscheduled 
assessments as judged by the investigator.

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4.5.5
Cranial Ultrasound
Patients from birth to 3 months of age must not demonstrate evidence of active ICH at 
the time of study entry. A cranial ultrasound will be performed at screening and must be 
negative to fulfil the bleed-related eligibility criteria.
4.5.6
Magnetic Resonance Imaging of Joints
MRI has been shown to be the most preferable imaging technique for joint abnormalities 
in young patients with hemophilia (Manco-Johnson et al. 2007).  The MRI will focus on 
knees, ankles, and elbows, because these are the most susceptible to hemophilic 
arthropathy. In this study, bilateral MRI without contrast of knees, ankles and elbows will 
be performed during the 7-year LTFU period only in patients 5 years of age at the time 
of the assessment with no requirement for sedation; two MRI timepoints, one around 
5 years of age and another in the last year of the LTFU (see Appendix 1). Of note, MRI
scan is a mandatory assessment of the study during the LTFU period. If necessary, the 
use of gadgets (e.g., movie goggles if available in the radiology department) to facilitate 
the child’s cooperation in staying still during the MRI assessment is encouraged. If it 
remains necessary, the use of sedation/anesthesia will be at the discretion of the 
investigator per strict local institutional guidelines and practice in performing MRI in 
young children. The priority joints for MRI assessment will be the knees and ankles, 
while every effort should be made to also assess elbows. Preferably, all six joints will 
be assessed during the same MRI assessment visit. However if it is not possible, the 
MRI assessment could be performed over two visits around the scheduled date of the 
clinic visit on Years 5 and 8, respectively (see Appendix 1). MRI scans will be centrally 
reviewed by two independent radiologists where each of the bilateral elbows, ankles and 
knees will be scored using the additive MRI scale for hemophilic arthropathy of the 
International Prophylaxis Study Group (IPSG) (Lundin et al. 2012); disagreement in MRI 
scores between reviewers should be resolved in a consensus meeting. The IPSG MRI 
scale for hemophilic arthropathy quantifies the presence of soft tissue changes 
(effusion/hemarthrosis, synovial hypertrophy, and hemosiderin deposition) and 
osteochondral changes (surface erosions, subchondral cysts, and cartilage 
degradation). MRI evaluation of joints has been shown to provide relevant information 
about association of MRI findings with bleeding, development, and progression of 
arthropathy in a long-term perspective study (Foppen et al. 2020).
Further details about the MRI review process as well as the roles and responsibilities of 
the independent radiologists will be provided in a separate radiology charter.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Laboratory assessments will be performed as indicated on the schedule of activities
(see Appendix 1).  On days of study drug administration, laboratory samples should be 
drawn before the administration of study treatment.  Deviations from the schedule of 
activities of2 days are acceptable; however, pre-dose PK and biomarker sample 
collections and study treatment administration should coincide.

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Samples for the following laboratory tests will be sent to the study site's local laboratory
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
absolute differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width

Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN, creatinine, 
calcium, phosphate, magnesium, total and direct bilirubin, albumin, ALP, ALT, AST, 
and LDH
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for centralized analysis:

Plasma samples for PK analysis

Plasma samples for biomarker assessments: aPTT, TG, reported FVIII activity, FIX
and FX antigens (emicizumab substrates)
Other coagulation-related biomarkers may also be considered for exploration
only when the blood volume drawn permits.

Plasma samples for immunogenicity assessment (anti-emicizumab antibodies and 
anti-FVIII antibodies; see Section 4.5.7.1 for details)

Plasma and serum samples for bone and joint biomarker assessment (only during 
the 7-year LTFU period)
Assessments that require blood draws should be monitored closely to ensure that 
institutional mandates regarding total sample blood volumes are followed. In situations 
where no institutional guidance is available, the following limits should be used and have 
been included in the design of the sampling program:  No more than 1% of the total 
blood volume should be taken at one time and no more than 3% of the total blood 
volume should be taken over a 30-day period (total blood volume is defined as 
8090 mL/kg [European Commission 2008]).  Thus, blood sampling timepoints and 
volumes will follow the EC guideline on Ethical Considerations for Clinical Trials on 
Medicinal Products Conducted with the Paediatric Population (European Commission 
2008).  In situations where the total volume of blood drawn might exceed the limits 
stated above, clinical (safety) laboratory assessments should be prioritized.  Any 
remaining permitted blood volume should be collected for PK and immunogenicity 
samples, followed by PD biomarker sample.  Refer to the laboratory manual for detailed 
weight-based blood sampling guidelines.
For sampling procedures, storage conditions, and shipment instructions, see the sample 
handling manual.
Data arising from sample analysis, will be subject to the confidentiality standards 
described in Section 8.4.

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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7.1
Testing for Anti-FVIII Antibodies
During screening, one plasma sample for anti-FVIII antibodies (centralized analysis) will 
be mandated for MTPs only. Subsequently for all patients while during their participation 
in the study, after any 3 exposure days to FVIII or a block of FVIII exposure days (e.g.,
a block is defined as a minimum of two consecutive doses of FVIII) administered for 
treatment of a bleed, a surgical procedure, or other (e.g., preventative doses before 
activity), one plasma sample for anti-FVIII antibodies (for centralized analysis) will be 
collected 14 days after the final dose of FVIII administered.  If this occurs during the first 
52 weeks of treatment, the blood sampling will be timed with the next scheduled clinic 
visit.  During the 7-year LTFU period, the blood sampling will be performed where 
applicable (see Appendix 1).  In case of clinical suspicion for development of anti-FVIII 
antibodies, a plasma sample will also be collected if blood volume drawn permits.
4.5.7.2
Testing Following the Use of Bypassing Agents
In patients who receive bypassing agents, the following local laboratory tests will be 
performed within 24 to 48 hours of initial bypassing agent use, if blood volume drawn 
permits, so the investigator may monitor for potential thromboembolic events and TMA:

Platelet count

Serum creatinine

LDH

Peripheral blood smear analysis to evaluate for schistocytes
If blood volume drawn permits, a plasma sample should also be provided for local
laboratory monitoring of the following:

Prothrombin fragment 12

Fibrinogen

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 and if the results from the local 
reference laboratory can be obtained within a reasonable timeframe to allow for 
decision-making.
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 final 
dose of bypassing agents administered to treat a given bleed.

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If applicable, laboratory results should be recorded on the Local Lab Following 
Treatment with Bypassing Agents eCRF.
4.5.8
Clinical Outcome Assessments
Bleed and medication related observer-reported outcome (ObsRO) data will be collected 
during the entire study duration at home or in the clinic on an eBMQ.
Parent/caregivers should be given the following instructions for completing ObsRO 
instruments at home:

Parents/caregivers should complete the instruments in a quiet area with minimal 
distractions and disruptions.

Parents/caregivers should answer questions to the best of their ability; there are no 
right or wrong answers.

Parents/caregivers should not obtain advice or help from others (e.g., family 
members or friends) when completing the instruments.
During clinic visits, ObsRO instruments should be administered as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for parents/caregivers to complete the instruments.

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.

Parents/caregivers should be instructed to answer questions to the best of their 
ability; there are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request.

Parents/caregivers should not obtain advice or help from others (e.g., family 
members or friends) when completing the instruments.
4.5.8.1
Electronic Bleed and Medication Questionnaire
During the study, to capture the administration of emicizumab, the bleed experienced by 
the patient, and the hemophilia related medication administered to patients, 
parents/caregivers will complete the BMQ on an electronic handheld device that will be 
provided to them on the first day of study enrollment at the site.  The instructions for 
completing the electronic handheld device will be provided by site personnel. The 
device will remain with the parents/caregivers until the end of the 7-year LFTU period.
Parents/caregivers will be asked on a weekly basis to record at home or in the clinic 
(when applicable) whether a bleed has occurred and whether treatment for a bleed or 
treatment to prevent a bleed (e.g., prior to surgery or short-term prophylaxis prior to 
activity) has been given, and when an emicizumab administration was performed

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(possible retrospective reporting for last 7 days): bleed information with date and time, 
type, location, and reason; information on hemophilia-related medication with date and 
time of administration, type of medication, dose, and purpose; information on
emicizumab with the date and time, vial strength, volume injected and number of 
injections. After the eBMQ entries have been saved on the electronic handheld device, 
the data will be transmitted automatically from the device to a centralized vendor 
database.  The data will be available for access by appropriate study personnel. Bleed 
and medication use data entered since a patient’s previous clinic visit will be reviewed 
and discussed for completeness and accuracy by the parents/caregivers and the 
investigator at subsequent clinic visits according to the schedule of activities.  
Investigators will have the ability to review the data, and in agreement with the 
parents/caregivers, to correct/delete or complete entries once verified with the 
parents/caregivers using a Data Clarification Request Form process or through the
vendor web-based portal respectively. Of note, if the electronic data collection system 
becomes unavailable, the site may instruct the parents/caregivers to collect exactly the 
same ObsRO data (bleed data, emicizumab use, hemophilia-related medication use) on 
paper, and once electronic data entry is available, all information will need to be entered 
and submitted electronically by the site using the vendor web-based portal. The
Sponsor will have view- access- only but will perform a review of the bleed and 
medication use data as per the Medical Data Review Plan.
4.5.8.2
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/Factor IX 
subcommittee of the International Society of Thrombosis and Hemostasis, and similar to 
that used in a recent clinical study, will be used in this study (Blanchette et al. 2014; 
Mahlangu et al. 2014) as follows:

An event is considered a treated bleed if coagulation factors are administered to 
treat signs or symptoms of bleeding (e.g., pain, swelling).  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 final
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 administered to treat the bleed 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 the last injection.

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Definition of Bleed Sites
Bleed sites are defined as follows:

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:  defined as bleeds with bleed type “joint bleed” reported on the eBMQ
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 compared with 
baseline

Muscle bleeds (sites per the eBMQ)

Other (sites per the eBMQ)
Definitions of Bleed Types
The assessment of a bleed will be separated into spontaneous bleeds, traumatic bleeds, 
and bleeds related to procedure and surgery.  Both spontaneous bleeds (i.e., the 
occurrence of hemorrhage for which the parents/caregivers cannot identify a reason) 
and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such as trauma, 
“strenuous” activity, or “overuse”) will be recorded.

Spontaneous bleeds:  Bleeds should be classified as spontaneous if the 
parents/caregivers record 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 
parents/caregivers.

Traumatic bleeds:  Bleeds should be classified as traumatic if parents/caregivers 
record a bleed when there is a known or believed reason for the bleed.

Bleeds related to procedure and surgery:  For example, hematomas resulting from 
any surgery or invasive procedure (e.g., tooth extractions, venipuncture, or SC 
study drug administrations), or invasive diagnostic procedures (e.g., lumbar 
puncture, arterial blood gas determination, or endoscopy with biopsy) would  be 
considered a bleed related to procedure/surgery.  Such bleeds are not associated 
with any trauma except procedure and surgery-induced trauma.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

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
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a safety follow-up visit 24 weeks after the final dose of 
study drug (with the exception where the reason for discontinuation is the patient 
switching to commercial emicizumab product) (see Appendix 1 for additional details).
4.6.2
Patient Discontinuation from the Study
Patients will return to the clinic for a safety follow-up visit 24 weeks after the final dose of 
study drug as per the schedule of activities (see Appendix 1).
Parents/caregivers have the right to voluntarily withdraw the patient 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 patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent by parent or legally authorized representative

Study termination or site closure

Adverse event

Unacceptable toxicity with study treatment

Patient’s requirement for immune tolerance induction therapy

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on
the appropriate eCRF.  If parents/caregivers request the patient to be withdrawn from 
the study, this request must be documented in the source documents and signed by the 
investigator. Patients who withdraw from the study will not be replaced.
4.6.3
Study 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.

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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
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 guideline for Good 
Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with emicizumab 
in completed and ongoing studies (see Section 1.3).  The anticipated important safety 
risks for emicizumab are outlined below.  Refer to the RO5534262 (Emicizumab) 
Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities (see Section 4.1.2).  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  
In addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Emicizumab
5.1.1.1
Injection-Site Reactions
Injection-site reactions have been observed in patients with hemophilia A.  These local 
injection-site reactions included erythema, hematoma, rash, discomfort, pain, and 
pruritus and were mostly of mild or moderate intensity.  Further details for observed 
injection-site reactions are available in the RO5534262 (Emicizumab) Investigator’s 
Brochure.  Directions for emicizumab administration should be followed, as outlined in 
Sections 3.1 and 4.3.2.
5.1.1.2
Hypersensitivity Reaction, Anaphylaxis, and 
Anaphylactoid Reaction
Because 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.  

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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.
HCPs administering study drug in the clinic must be trained in the appropriated 
administration procedures; must 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 and Appendix 4).  HCPs should also instruct parents/caregivers 
how to recognize the signs and symptoms of hypersensitivity, anaphylactic, and 
anaphylactoid reactions and to contact an HCP or seek emergency care in case of any 
occurrence.  Patients and caregivers will also receive two alert cards to remind them of 
this information and these instructions should any of these reactions occur.
For patients with a history of clinically significant hypersensitivity reactions, 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.
5.1.1.3
Hypercoagulation and Thromboembolic Events
A total of four thromboembolic events have been observed in 3 patients receiving 
emicizumab in clinical studies.  There was one event of Grade 1 device occlusion 
(non-serious) reported in 1 patient (Study BH29884).  The event resolved and was 
assessed by the investigator as not related to emicizumab.  In addition, 2 patients 
experienced a total of three serious adverse events of thromboembolic event in 
Study BH29884.  One patient developed a cavernous sinus thrombosis after repeated 
use of supratherapeutic doses of aPCC, and the event was considered by the 
investigator to be related to emicizumab and aPCC.  Another patient developed 
extensive skin necrosis on the right shin and local skin necrosis on the left shin due to 
superficial thrombophlebitis after administering aPCC.  Ultrasound showed a superficial 
thrombophlebitis of the right saphenous vein, and the investigator considered the skin 
necrosis due to the thrombophlebitis and was assessed as being related to emicizumab 
and with use of aPCC.  Refer to the RO5534262 (Emicizumab) Investigator's Brochure
for further details.
Thromboembolic events should be reported as a serious adverse event or adverse event
of special interest as described in Sections 5.2.2 and 5.2.3.  HCPs should educate 
parents/caregivers on how to recognize signs and symptoms of potential 
thromboembolism (i.e., dyspnea, chest pain, leg pain, or swelling; or if in the head, 
headache, numbness in the face, eye pain or swelling, or vision impairment) and ensure 
that they understand the importance of seeking appropriate medical attention.  
Parents/caregivers will also receive two alert cards to remind them of this information 
and instructions should thromboembolism be suspected.

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5.1.1.4
Thrombotic Microangiopathy
TMA 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, central nervous system, and so on.
Three cases of TMA were reported in Study BH29884.  All cases were assessed by the 
investigator as being related to study treatment and occurred after recent concomitant 
aPCC use. All three TMAs occurred when on average a cumulative amount of 
100 U/kg/24 hr of aPCC for 24 hours or more was administered during a treatment 
event. This study will be conducted in infant patients without FVIII inhibitors, and
therefore aPCC is not expected to be used for the treatment of breakthrough bleeds.  
For further details on TMAs, refer to the RO5534262 (Emicizumab) Investigator's 
Brochure.
Any TMA event should be reported as an adverse event of special interest and also as 
a serious adverse event, if it meets criteria for such (see Sections 5.2.2 and 5.2.3).
5.1.1.5
Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays in the Setting of 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII activity, 
and FVIII inhibitor measurement using Bethesda assay) are not reliable and do not 
accurately reflect the patient’s underlying hemostatic status while receiving emicizumab 
prophylaxis (see Table 1).  In one-stage assays, emicizumab is associated with 
a supraphysiologically 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, cannot be detected using
a functional test such as Bethesda or Nijmegen-Bethesda assays, which use 
a one-stage clotting-based readout.  Furthermore, 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 RO5534262 
(Emicizumab) Investigator's Brochure for additional details as to which tests can be used 
and how the test results can be interpreted.
Because of the long elimination half-life of emicizumab, these effects on coagulation 
assays may persist for up to 6 months after the final dose of the study drug.
There is a risk of life-threatening bleeding due to unreliable standard coagulation tests 
and inhibitor assays in the setting of emicizumab in the market setting by practitioners, 
particularly for emergency care practitioners.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
See Table 1 for guidelines for management of patients who experience adverse events.

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Table 1
Guidelines for Management of Patients Who Experience 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 during the period immediately following injections.  
Parents/caregivers will be given guidance on reporting injection-site 
reactions when administering study drug at home or after they leave the 
clinic.
Hypersensitivity 
reaction, 
anaphylaxis, and 
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 the 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, site personnel 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.

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Table 1
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Event
Actions to Be Taken
Thrombotic
microangiopathy
Breakthrough bleeds will be treated with FVIII at the lowest dose 
expected to achieve hemostasis (see Sections 3.1 and 4.4.1).
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.  The decision to resume emicizumab after an event of 
TMA is encouraged to be discussed with and advised by the Medical 
Monitor.
Hypercoagulation 
and thromboembolic 
events
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.  The decision to resume emicizumab after 
a thromboembolic event is encouraged to be discussed with and advised 
by the Medical Monitor.
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.
FVIIIfactor VIII; HCPhealthcare provider; TMAthrombotic microangiopathy.
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 International Council for Harmonisation 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) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information)

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 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).  Adverse events of special interest for this study 
are as follows:

Cases of potential study 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 Appendix 3)

Thromboembolic events

Microangiopathic hemolytic anemia or TMA (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 parents/caregivers 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 final study visit.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in 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 has the patient felt since the last clinic visit?"

"Has the patient had any new or changed health problems since the last clinic visit?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO Toxicity Grading Scale (see Appendix 5 ) will be used for assessing adverse 
event severity.  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 consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of 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.  If possible, avoid ambiguous terms such as 
"systemic reaction."  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
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.
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 
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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.
Bleeds considered as serious adverse events should be reported on the appropriate 
adverse event eCRF page regardless of whether the bleed is consistent with patients’ 
pre-study disease state (the bleed will remain recorded as well on the eBMQ).  New, 
non-serious bleeds consistent with patients’ pre-study disease state will not be 
considered adverse events and will not be recorded on the eCRF but will be captured on 
the eBMQ.
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

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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

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., ALP 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.

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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).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) 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 the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
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.
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 solely to progression of hemophilia, "hemophilia progression"
should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.

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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.
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 Hemophilia
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 FVIII 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.  When recording an unanticipated worsening of hemophilia on the 
Adverse Event eCRF, it is important to convey that the underlying condition has changed 
by including applicable descriptors (e.g., "increased clinical severity of hemophilia").  
A clinically significant bleed (i.e., Intracranial, retroperitoneal) does not by itself constitute 
loss of efficacy, unless it is associated with features indicating worsening of the 
underlying hemophilia phenotype.
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., inpatient 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)

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
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.
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
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
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.

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
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.

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.

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
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.
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
Observer-Reported Outcome Data
Adverse event reports will not be derived from ObsRO data by the Sponsor, and safety 
analyses will not be performed using ObsRO data.  Sites are not expected to review the 
ObsRO data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
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 trial.  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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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

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
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 IRB/EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
Contact Information for All Sites
Medical Monitor:
 Ph.D.
Telephone No.:
Mobile Telephone No.:
Emergency Medical Contact:
, M.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to 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 paper Clinical Trial 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 emailing the form using the fax number or 
email 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 final 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.

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In the event that the EDC system is unavailable, the paper Clinical Trial 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 emailing 
the form using the fax number or email 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 serious adverse events that occur 24 weeks after the final dose 
of study drug are provided in Section 5.6.
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 
follow-up, or withdrawal of patient’s consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-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.
5.5.2
Sponsor Follow-Up
For serious adverse events and adverse events of special interest, the Sponsor or 
a designee may follow up by telephone, fax, email, 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 final dose of study drug), 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 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.

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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest 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:
Study Drug
Document
Emicizumab
RO5534262 (Emicizumab) Investigator's Brochure
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 the study. All the analyses will be 
descriptive. No adjustment for multiplicity of endpoints will be considered. Further 
details will be provided in the Statistical Analysis Plan.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on recruitment feasibility and clinical 
considerations rather than on statistical considerations, taking into account the limited 
number of pediatric patients from birth to 12 months of age, especially patients younger 
than 3 months with hemophilia A without inhibitors available for participation in clinical 
studies and in an effort to collect sufficient data to assess the efficacy, safety,
pharmacokinetics, and pharmacodynamics of emicizumab in this population.
During the study, a re-assessment of the initially specified sample size based on 
enrollment consideration may be performed.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients, who enroll, discontinue, or complete the study will be 
summarized. Moreover, 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.

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Variables from the eCRF used to establish how many patients reached the various 
stages of the study, how many patients dropped out, and for what reasons for dropping 
out will be described in the Statistical Analysis Plan.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (e.g., age, sex, weight) will be summarized 
using means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate. Summaries will be presented by 
age groups and overall as appropriate.
6.4
EFFICACY ANALYSES
The efficacy analyses are to evaluate the clinical effect of prophylactic emicizumab on 
the number of bleeds over time (i.e., bleed rate). This will be based on the treated 
population, which corresponds to all patients who received at least one administration of 
emicizumab. Efficacy analyses will be performed for each age group separately, and 
overall, as appropriate.
6.4.1
Efficacy Endpoint
Treated bleeds, all bleeds, treated spontaneous bleeds, and treated joint and muscle 
bleeds will be reported (Section 4.5.8.2). The analysis of bleed rates will be performed 
for each age group separately and overall, as appropriate.  The number of bleeds, sites,
and types of bleeds will be summarized for all patients and listed for each patient 
individually.  The clinical effect of prophylactic emicizumab will be assessed using the 
annualized bleeding rate (ABR) estimated using a negative binomial regression model, 
which accounts for different follow-up times, with the number of bleeds experienced by
patients as a function of the time such that each patient who stays in the study is 
included as an offset in the model. The ABR will be calculated for each patient using the 
following formula:
The mean and median ABRs based on the above formula using the observed numbers 
of bleeds instead of the number resulting from the model will also be calculated.  In the 
case, where the negative binomial model does not converge, the alternative derivations 
of the ABR will be used as the sole method of analysis.
Joint health, as assessed through use of the HJHS and MRI score of specific joints at 
specified timepoints only during the 7-year LTFU period, will be summarized 
descriptively.
ABR
Number of bleeds during the study period
365.25
Total number of days during the study period

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6.5
SAFETY ANALYSES
The safety analyses will be based on treated population, which corresponds to all 
patients who receive at least one administration of emicizumab, and will be performed 
for each age group separately, and overall, as appropriate.  Descriptive summaries will 
be prepared for adverse events (all adverse events, serious adverse events, deaths, 
adverse events of special interest, adverse events leading to study drug discontinuation 
or withdrawal from the study, and injection-site reactions), safety laboratory test results 
(serum chemistry and hematology), ADAs, and vital sign abnormalities.  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, 
including de novo development of FVIII inhibitors, 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
For all patients, pre-dose Ctrough of emicizumab will be presented descriptively, including 
arithmetic and geometric means, median, range, standard deviations, and coefficients of 
variation.
Nonlinear mixed effects modeling may be used to analyze the dose-concentration-time 
data of emicizumab following SC administration. Data may be pooled with data from 
previous Phase I/II and Phase III studies. If performed, these modeling analyses will be 
reported in a dedicated report.
PK analyses will be completed on the PK-evaluable population, defined as all enrolled 
patients who received at least one dose of study drug and have sufficient PK data for 
analysis.
6.7
BIOMARKER ANALYSES
PD biomarkers, including but not limited to aPTT, parameters derived from TG, reported
FVIII activity, and other exploratory markers (FIX and FX antigens) will be presented 
using summary statistics, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation. In addition, bone and joint health 
biomarkers may be explored.
6.8
IMMUNOGENICITY ANALYSES
6.8.1
Anti-Emicizumab Antibodies
The immunogenicity analyses for emicizumab antibodies will include patients with at 
least 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 

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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 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 
may be analyzed and reported descriptively in subgroup analyses.
6.8.2
Anti-Factor VIII Antibodies
The number and proportion of patients who develop anti-FVIII antibodies (FVIII 
inhibitors) (titer 0.6 BU/mL) following study drug administration will be summarized.
6.9
INTERIM ANALYSIS
6.9.1
Planned Interim Analysis
An interim data review will occur when the 10th patient aged 3 months at the time of
informed consent has completed 24 weeks in the study, is lost to follow-up, or has 
withdrawn from study treatment, whichever occurs first, with the aim of having an early 
look at the totality of the data (particularly safety) in the youngest population. All patients 
will be included at the time of the interim analysis irrespective of their age and time in the 
study. The interim analysis will be performed by the Sponsor’s study team. The 
evaluation of the interim data review will be performed on the safety and efficacy 
endpoints as well as on the pharmacokinetics, pharmacodynamics, and immunogenicity 
results. The IMC and SOC (as needed) will review the interim analysis reports 
generated by the Sponsor’s study team (see Section 9.5).
Additional interim analyses may be conducted at an intermediate timepoint during the 
LTFU period between the primary analysis and the end of the study.
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 
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.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.

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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.
eObsRO data will be collected through the use of an electronic device provided by 
a vendor (see Section 7.3 for details).  In the event that the electronic device is 
unavailable, the paper version provided to investigators should be completed, and once 
electronic data entry is available, all information will need to be entered and submitted 
electronically.
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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC OBSERVER-REPORTED OUTCOME DATA
An electronic device will be used to capture ObsRO data.  The device is designed for 
entry of data in a way that is attributable, secure, and accurate, in compliance with U.S. 
Food and Drug Administration (FDA) regulations for electronic records (21 CFR Part 11).  
The data will be transmitted to a centralized database maintained by the electronic 
device vendor.
The electronic data will be available for view access only, via a secure portal provided by 
the vendor.  Only identified and trained users may view the data, and their actions will 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.

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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review 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, observer-reported outcomes, 
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 trial.
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 and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-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 or paper ObsRO data (if applicable), 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 

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the length of time 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 study results have 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 International Council for 
Harmonisation 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 International Council for Harmonisation 
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 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 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 the patient’s parent 
or legally authorized representative the objectives, methods, and potential risks 
associated with each optional procedure.  The parent or legally authorized 
representative 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 parent or legally authorized representative agreement to participate in 

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optional procedures.  Parent or legally authorized representative who decline to 
participate will not provide a separate signature.
The Consent Forms must be signed and dated by the parent or legally authorized 
representative before the patient participates 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 parent 
or legally authorized representative for the patient to participate.  The final revised 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while 
a patient is participating in the study, the parent or legally authorized representative must 
re-consent by signing the most current version of the Consent Forms or the addendum, 
in accordance with applicable laws and IRB/EC policy.  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 parent or 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 parent or legally 
authorized representative 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 parent or 
legally authorized representative 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 parent or 
legally authorized representative, 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 
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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 9.7).
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 
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 parent 
or legally authorized representative, 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.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
parents or legally authorized representatives unless required by law.  The aggregate 
results of any conducted research will be available in accordance with the effective 
Sponsor policy on study data publication (see Section 9.6).
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.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).

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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 (see definition of end of 
study in Section 3.2).
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 
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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan.
9.4
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 

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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 20 sites globally will participate to enroll approximately 50 patients.  
Enrollment will occur through an IxRS.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarkers, ADA, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An IMC and SOC will be in place throughout the duration of the study. The IMC will be
composed of selected internal Sponsor members (clinical pharmacologist, biomarker 
specialist, pediatric medical specialist, safety scientist, and statistician). The SOC will be
composed of external pediatric experts specialized in neonatology, pediatric 
pharmacology and pediatric hematology. The SOC members will be selected on the 
basis that they have no contact with the sites as part of their responsibilities. At the time 
of the interim analysis, the IMC will involve the SOC as needed in the review of the 
safety, efficacy, PK, PD, and immunogenicity data. The interim analysis will occur when 
the 10th patient aged 3 months at the time of informed consent has completed
24 weeks in the study, is lost to follow-up, or has withdrawn from study treatment, 
whichever occurs first; all patients will be included in the interim analysis irrespective of 
their age and time in the study. During the study conduct, the SOC may also be 
consulted by the IMC as needed. The role of the SOC will be to provide objective 
scientific advice to the IMC, including, but not limited to, expertise in data interpretation 
in the use of monoclonal antibodies in neonates and infants. Specific operational 
details, such as IMC/SOC composition, member roles and responsibilities, data review, 
and meeting organization will be detailed in a separate IMC/SOC Charter.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to health care 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 website:

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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials 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 trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials 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 trials 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.
9.7
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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Emicizumab—F. Hoffmann-La Roche Ltd
90/Protocol MO41787, Version 3
Appendix 1
Schedule of Activities
Table 1
Schedule of Activities Up to Week 53
Screening
Emicizumab SC Q2W Treatment 
Early 
Discontinuation 
Safety FU Visit 
before Week 53
Week
NA
1
2
3
4
5
7
9
13
17
21
25
29
33
37
41
45
49
53
Day –14 to –1
1
8
15
22
29
43
57
85
113
141
169
197
225
253
281
309
337
365
Informed consent a
x
Demographics b
x
Medical history and baseline conditions b
x
Cranial ultrasound c
x
Vital signs d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Height/length and weightd
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical examination e
x
x
x
x
x
x
x
Safety laboratory assessmentsf, g, i, q
x
x
x
x
x
x
x
x
x
Plasma PK sample g, h, i, q
x r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for biomarkers g, h, i, q
x r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma ADA sample g, h, i, j, q
x r
x
x
x
x
x
x
Anti-FVIII antibodies assessment h
x k
As clinically indicated l
eBMQ m
At least once a week, when a bleed occurs and/or when a hemophilia medication is administered
eBMQ data reviewn
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications and 
procedures o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Study drug dispensation
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events p
x
Ongoing

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
91/Protocol MO41787, Version 3
Table 1 Schedule of Activities Up to Week 53 (cont.)
ADAanti-drug antibody; eBMQelectronic Bleed and Medication Questionnaire; eCRF electronic Case Report Form; eObsRO electronic 
observer-reported outcome FUfollow-up; FVIIIfactor VIII; PDpharmacodynamic; PKpharmacokinetic; MTPminimally treated patient; 
NAnot applicable; Q2W every 2 weeks, SCsubcutaneous.
Notes:  All patients will receive four loading doses of emicizumab 3 mg/kg SC QW for 4 weeks followed by the maintenance dosing regimen 
3 mg/kg SC Q2W for a total of 52 weeks. All study visits and assessments should be performed within2 days of the scheduled visit, until 
Week 53. If the patient discontinues emicizumab early at Week 53 or before Week 53, a safety follow-up visit should be performed 24 weeks after
the final dose of study drug; deviation of 7 days is acceptable. Except for the eBMQ, all other patient data will be collected during clinic visits.
Individual patients may have their dose up-titrated if they experience suboptimal bleeding control during emicizumab treatment (see Section 4.3.2); 
please refer to Table 3 for details about the up-titration process during the first year of treatment.  On treatment days, all assessments should be 
performed prior to emicizumab dosing, unless otherwise specified.
a Written informed consent must be obtained from parents and legally authorized representative before performing any study-related procedures 
(including screening evaluations, distribution of the electronic handheld device and collection of any data).  An enrollment form will be completed 
after informed consent form is obtained.  If patient fulfills the inclusion and exclusion criteria, the patient should be enrolled in the study on the 
same day when the first dose of emicizumab is administered (Day 1).
b Information will be collected from patient medical records and documented on the eCRF. Medical history, including clinically significant 
diseases, procedures, medical allergies, history of prior anaphylaxis, or known thrombophilia since birth, will be recorded on the General Medical 
History and Baseline Conditions eCRF.  All bleeds (date and time, type, location and reason) experienced since birth and before enrolling in the 
study on Day 1 should be documented at baseline on the eCRF.
c Patients from birth to 3 months of age are required to show no evidence of active intracranial hemorrhage at the time of study entry. A cranial 
ultrasound will be performed at screening and must be negative to fulfil the bleed related eligibility criteria.
d Vital signs include measurements of pulse, respiratory rate, temperature (oral, rectal, axillary, temporal or tympanic), systolic and diastolic blood 
pressure using age-adapted measurements when possible. Vital signs, height/length, and weight should be recorded on the eCRF. If screening 
and Week 1 visits occur on the same date, the vital signs, height/length, and weight should be measured only once. If the screening and Week 1 
visits occur on different dates, vital signs, height/length, and weight should be repeated for both assessments.
e A complete physical examination and targeted physical examination of joints for bleeds and skin for bruises, hematomas, injection-site reactions, 
and lipodystrophies will be performed at screening and subsequent visits, in addition to other organ systems as clinically indicated and/or report 
of new or worsening adverse events.
f
Pre-dose laboratory data (performed locally) includes: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and absolute differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and other cells), mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width; sodium, potassium, glucose, BUN, creatinine, calcium, phosphate, 
magnesium, total and direct bilirubin, albumin, ALP, ALT, AST, and LDH.
g Samples should always be drawn pre-dose.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
92/Protocol MO41787, Version 3
Table 1 Schedule of Activities Up to Week 53 (cont.)
h Samples will be collected only if blood volume drawn permits (based on patient body weight as described in Section 4.5.7).  Refer to the 
laboratory manual for details.
i
When blood is drawn by means of a catheter or CVAD, a discard tube (containing only few drops) must be used prior to collection of samples for 
any laboratory assessment, due to the possibility of contamination by saline or anticoagulants used to flush the device, if blood volume drawn 
permits. Please consult the study laboratory manual for details on sample collection and processing.
j
ADA samples may also be drawn if hypersensitivity event occurs or at any time (unscheduled) in the investigator’s judgment, if blood volume 
drawn permits.
k During screening, a plasma sample for anti-FVIII antibodies will be mandated for MTPs only.
l
For all patients, after any 3 exposure days to FVIII or a block of FVIII exposure days (e.g., a block is defined as a minimum of two consecutive 
doses of FVIII) administered for a treatment of a bleed, a surgical procedure or other (e.g., preventative doses before activity), one plasma 
sample for anti-FVIII antibodies will be collected 14 days after the final dose of FVIII administered. The samples will ideally be timed with the 
next scheduled clinic visit. In case of clinical suspicion for development of anti-FVIII antibodies, a plasma sample will also be collected, if blood 
volume drawn permits.
m eObsRO information collected through the eBMQ for each bleed (date and time, type, location and reason) and hemophilia medication for bleed
(e.g., FVIII, the date and time of administration, type of medication, dose, and purpose) should be reported by the parents/caregivers on an 
electronic handheld device when a bleed occurs, when a hemophilia medication is administered or at least on a weekly basis (retrospective 
reporting for last 7 days).  If the patient discontinues study treatment early prior to or at Week 53, bleed and bleed medication information should 
be provided by the parents/caregivers until the early discontinuation safety follow-up visit (24 weeks after the final dose of study drug).  
Emicizumab doses (date and time, vial strength, volume injected and number of injections) should be recorded by the parents/caregivers in the 
eBMQ starting on Day 1 until the end of study.
n Investigator review of bleed, hemophilia-related medication and emicizumab administration information derived from the electronic handheld 
device.
o Medications (e.g., vitamin K, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
administered to patient in addition to protocol-mandated treatment from 4 weeks prior to enrollment through Week 53 visit should be reported.
The receipt of vitamin K should be reported on the Concomitant Medications eCRF independently of the date of administration. All 
hemophilia medication (e.g., FVIII, including the date and time of administration, type of medication, dose and purpose) administered to patients 
since birth and before enrolling in the study on Day 1 should be documented at baseline. Historical procedures should be recorded on the 
Surgery and Procedure History eCRF.  Procedures occurring on study should be collected on the On-Study Surgery eCRF.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
93/Protocol MO41787, Version 3
Table 1 Schedule of Activities Up to Week 53 (cont.)
p 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. Adverse events will be recorded on an ongoing basis throughout the study.  Injection-site reactions will be 
recorded on a separate form from the Adverse Event eCRF.  After initiation of study drug, all adverse events will be reported until Week 53 or 
until the early discontinuation safety follow-up visit (24 weeks after the last study drug administration).
q In case of up-titration, if blood volume drawn permits, additional assessments including PK, biomarkers, ADA and safety laboratory samples will 
be required, with the schedule of activities reset to Week 1.
r
Samples should be drawn pre-dose on Day 1.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
94/Protocol MO41787, Version 3
Table 2 Schedule of Activities during the 7-Year Long-Term Follow-Up Period a
Emicizumab SC QW, Q2W or Q4W Treatment during 
LTFU
Early Discontinuation Safety FU Visit 
before End of LTFU c
Year
2
3
4
5
6
7
8
Week b
105
157
209
261
313
365
417
Concomitant medications and procedures d
x
x
x
x
x
x
x
x
Vital signs, height/length e
x
x
x
x
x
x
x
x
HJHS f
x
x
x
x
x
Bilateral MRI of knees, ankles, and elbows g
x
x
Plasma and serum sample for bone and joint 
biomarkers h, i, j
x
x
x
x
x
x
x
eBMQ
k
At least once a week, when a bleed occurs and/or when a hemophilia medication is 
administered 
Anti-FVIII antibodies assessment i, j
As clinically indicated l
Plasma ADA sample
In case of clinical suspicion for ADA development m, n
Adverse events o
Ongoing
ADAanti-drug antibody; CVADcentral venous access device; eCRFelectronic Case Report Form; FUfollow-up; FVIIIfactor VIII; 
HJHSHemophilia Joint Health Score; LTFULong-Term Follow-Up; MRImagnetic resonance imaging; eBMQelectronic Bleed and Medication 
Questionnaire; eObsROelectronic observer-reported outcome; QW once a week; Q2W every 2 weeks; Q4W every 4 weeks;
SCsubcutaneous.
Notes:  The QW, Q2W or Q4W emicizumab doses administered during the LTFU period will be collected on the electronic handheld device eBMQ.
In the event a patient discontinues emicizumab early before the end of the LTFU period, an early discontinuation safety follow-up visit should be 
performed 24 weeks after discontinuation of emicizumab; deviation of 7 days is acceptable. All other patient data will be collected during clinic
visits. During the LTFU period, individual patients may have their dose up-titrated if they experience suboptimal bleeding control on emicizumab 
(see Section 4.3.2).

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
95/Protocol MO41787, Version 3
Table 2 Schedule of Activities during the 7-year Long-Term Follow-up Period (cont.)
a See Appendix 1 Table 4 for the details of the study drug dispensation visits during the 7-year LTFU period.
b The clinic visit with all the expected assessments of the visit should be performed within12 weeks (84 days) of the scheduled date.
c A complete physical examination and targeted physical examination of joints for bleeds and skin for bruises, hematomas, injection-site reactions, 
and lipodystrophies will be performed, in addition to other organ systems as clinically indicated and/or report of new or worsening adverse 
events.
d Medications (except coagulation factors) administered to patient should be reported on the Concomitant Medications eCRF. Procedures should 
be collected on the On-Study Surgery eCRF.
e Vital signs include measurements of pulse, respiratory rate, temperature (oral, rectal, axillary, temporal or tympanic), systolic and diastolic blood 
pressure using age-adapted measurements when possible. Vital signs and height/length should be assessed in the clinic and recorded on the 
eCRF. Please refer to Table 4 for the assessment of patient’s body weight.
f
Only in children 4 years of age at the time of the assessment.  HJHS should be collected on the eCRF.
g MRI without contrast, only in children 5 years of age at the time of the assessment with no requirement for sedation. If necessary, the use of 
gadgets (e.g., movie goggles if available in the radiology department) to facilitate the child’s cooperation in staying still during the MRI 
assessment is encouraged.  If necessary, the use of sedation/anesthesia will be at the discretion of the investigator per strict local institutional 
guidelines and practice in performing MRI in young children.  The priority joints will be the knees and ankles, while every effort should be made 
to also assess elbows. Preferably, all six joints will be assessed during the same MRI assessment visit.  However if it is not possible, the MRI 
assessment could be performed over two visits around the scheduled date of the clinic visit on Years 5 and 8, respectively.  Of note, MRI during 
the LTFU is a mandatory assessment of the study.
h Samples to be collected after fasting overnight.  Samples should be drawn pre-dose if applicable and blood volume drawn permits.
i
Samples will only be collected if blood volume drawn permits (based on patient body weight as described in Section 4.5.7).  Refer to the 
laboratory manual for details.
j
When blood is drawn by means of a catheter or CVAD, a discard tube (containing only few drops) must be used prior to collection of samples for 
any laboratory assessment, due to the possibility of contamination by saline or anticoagulants used to flush the device, if blood volume drawn 
permits.  Please consult the study laboratory manual for details on sample collection and processing.
k eObsRO information collected at least once a week on the electronic handheld device through the eBMQ for each bleed (date and time, type, 
location and reason), hemophilia related medication (e.g., FVIII; date and time of administration, type of medication, dose, and purpose) and the 
emicizumab doses (date and time, vial strength, volume injected and number of injections) administered Q2W, QW or Q4W will be reviewed with 
the Investigator during the clinic visits of the LTFU period, when parents/caregivers visit the site for the supply of study drug or intermittently at 
earlier timepoints if the patient, parents/caregivers have clinic visits. .
l
In case of clinical suspicion for development of anti-FVIII antibodies, a plasma sample will be collected within 14 days after the final dose of FVIII 
administered, if blood volume drawn permits.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
96/Protocol MO41787, Version 3
Table 2 Schedule of Activities during the 7-year Long-Term Follow-up Period (cont.)
m PK and biomarkers samples should also be drawn, if blood volume drawn permits.
n ADA samples may also be drawn if hypersensitivity event occurs or at any time (unscheduled) in the investigator's judgment, provided the blood 
volume drawn permits.
o Adverse events will be collected on an ongoing basis until the end of the LTFU period or until early discontinuation safety follow-up visit 
(24 weeks after last study drug administration).  After this period, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to study drug treatment (see Section 5.6).

Emicizumab—F. Hoffmann-La Roche Ltd
97/Protocol MO41787, Version 3
Table 3 Schedule of Activities in Case Up-Titration between Week 42 and Week 53
Emicizumab SC 3 mg/kg QW Treatment
Week Xweek of initiation of up-titration, weeks 
X
X+1
X+2
X+3
X+4
X+6
X+8
X+12
Vital signs a
x
x
x
x
x
x
x
x
Height/length and weight a
x
x
x
x
x
x
x
x
Complete physical examination b
x
Safety laboratory assessments c, d, f
x
x
Plasma PK sample d, e, f
x
x
x
x
x
x
Plasma sample for biomarkers d, e, f
x
x
x
x
x
x
Plasma ADA sample d, e, f, g
x
x
Anti-FVIII antibodies assessment h, e
As clinically indicated j
Concomitant medications and procedures i
x
x
x
x
x
x
x
x
Adverse events k
Ongoing
ADAanti-drug antibody; eCRFelectronic Case Report Form; eObsRO electronic observer-reported outcome; FVIIIfactor VIII; 
PDpharmacodynamic; PK pharmacokinetic; QW once a week, SCsubcutaneous.
Notes:  Study visits and assessments of Table 3 should be performed within2 days of the scheduled visit, until 12 weeks after the week of 
initiation of up-titration.  If the patient discontinues emicizumab early at 12 weeks after the week of initiation of up-titration or before 12 weeks 
after the week of initiation of up-titration, a safety follow-up visit should be performed 24 weeks after the final dose of study drug; deviation 
of 7 days is acceptable.  On treatment days, all assessments should be performed prior to emicizumab dosing, unless otherwise specified.
eObsRO information collected through the eBMQ for each bleed (date and time, type, location and reason), hemophilia related medication 
(e.g., FVIII, the date and time of administration, type of medication, dose, and purpose) and the emicizumab doses (date and time, vial strength, 
volume injected and number of injections) should be reported for the entire study duration by the parents/caregivers on an electronic handheld 
device when a bleed occurs, when a hemophilia medication is administered,  when emicizumab is administered or at least once a week
(retrospective reporting for last 7 days).  .
a Vital signs include measurements of pulse, respiratory rate, temperature (oral, rectal, axillary, temporal or tympanic), systolic and diastolic blood 
pressure using age-adapted measurements when possible.  Vital signs, height/length, and weight should be recorded on the eCRF.
b A complete physical examination and targeted physical examination of joints for bleeds and skin for bruises, hematomas, injection-site reactions, 
and lipodystrophies will be performed, in addition to other organ systems as clinically indicated and/or report of new or worsening adverse 
events.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
98/Protocol MO41787, Version 3
Table 3 Schedule of Activities in Case Up-Titration between Week 42 and Week 53 (cont.)
c Pre-dose laboratory data (performed locally) includes: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and absolute differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and other cells), mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width; sodium, potassium, glucose, BUN, creatinine, calcium, phosphate, 
magnesium, total and direct bilirubin, albumin, ALP, ALT, AST, and LDH.
d Samples should always be drawn pre-dose.
e Samples will be collected only if blood volume drawn permits (based on patient body weight as described in Section 4.5.7).  Refer to the 
laboratory manual for details.
f
When blood is drawn by means of a catheter or CVAD, a discard tube (containing only few drops) must be used prior to collection of samples for 
any laboratory assessment, due to the possibility of contamination by saline or anticoagulants used to flush the device, if blood volume drawn 
permits. Please consult the study laboratory manual for details on sample collection and processing.
g ADA samples may also be drawn if hypersensitivity event occurs or at any time (unscheduled) in the investigator’s judgment, if blood volume 
drawn permits.
h For all patients, after any 3 exposure days to FVIII or a block of FVIII exposure days (e.g., a block is defined as a minimum of two consecutive 
doses of FVIII) administered for a treatment of a bleed, a surgical procedure or other (e.g., preventative doses before activity), one plasma 
sample for anti-FVIII antibodies will be collected 14 days after the final dose of FVIII administered.  The samples will ideally be timed with the 
next scheduled clinic visit.  In case of clinical suspicion for development of anti-FVIII antibodies, a plasma sample will also be collected, if blood 
volume drawn permits.
i
Medications (e.g., vitamin K, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
administered to patient should be reported. Procedures occurring on study should be collected on the On-Study Surgery eCRF.
j
In case of clinical suspicion for development of anti-FVIII antibodies, a plasma sample will be collected within 14 days after the final dose of FVIII 
administered, if blood volume drawn permits.
k Adverse events will be recorded on an ongoing basis throughout the study.  Injection-site reactions will be recorded on a separate form from the 
Adverse Event eCRF.

Appendix 1:  Schedule of Activities (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
99/Protocol MO41787, Version 3
Table 4
Study Drug Dispensation during the 7-Year Long-Term Follow-Up Period
Study Drug Dispensation during each Year of LTFU
Quarterly visit (QV) for study drug dispensation
QV1
QV2
QV3
QV4 a
Study drug dispensation in the clinic c
x
x
Study drug shipped to patient’s home b
x
x
Locally: weight assessed by general practitioner or 
nurse b
x
x
In clinic: weight and complete physical examination c
x
x
QV Quarterly visit; LTFU Long-Term Follow-Up.
Notes:  From Week 53 until the end of the LTFU, the study drug dispensation will occur every 12 weeks (quarterly).  The quarterly study drug 
dispensation visits (QV1, QV2, QV3, and QV4 should be performed within 1 week of the scheduled date.
a The QV4 study drug dispensation clinic visit should coincide with the clinic visit where the assessments are to be performed (see Appendix 1,
Table 2).
b During the study drug dispensation visits QV1 and QV3, the patient's weight will be assessed by local general practitioner or local nurse.  
The weight value will be provided by phone to the site personnel who will check its consistency with the patient’s previous weight records 
before entering it on the eCRF.  The weight will determine via IxRS the strength and number of vials for the administration of emicizumab for 
the next 12 weeks.  The corresponding vials will then be shipped to patient’s home by the site.  For convenience, the parents/caregivers may 
prefer to come to the study site for the study drug to be picked-up directly in the study site; in this case, the patient’s body weight will be 
assessed in the clinic.
c
A complete physical examination will be performed during the study drug dispensation clinic visits at QV2 and QV4, where the patient’s 
body weight will also be assessed and recorded on the eCRF.  The weight will be used to determine via IxRS the strength and number of vials 
of study drug to be given to the parents/caregivers for the administration of emicizumab for the next 12 weeks.

Emicizumab—F. Hoffmann-La Roche Ltd
100/Protocol MO41787, Version 3
Appendix 2
Hemophilia Joint Health Score

Appendix 2:  Hemophilia Joint Health Score (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
101/Protocol MO41787, Version 3

Emicizumab—F. Hoffmann-La Roche Ltd
102/Protocol MO41787, Version 3
Appendix 3
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 1.  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 pressure 2
_________________________
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 of age, less than (70 mmHg[2age]) from 1 to 10 years of age, and less than 
90 mmHg from 11 to 17 years of age.

Emicizumab—F. Hoffmann-La Roche Ltd
103/Protocol MO41787, Version 3
Appendix 4
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, the following 
procedures should be performed:
1.
Stop the study treatment.
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.

Emicizumab—F. Hoffmann-La Roche Ltd
104/Protocol MO41787, Version 3
Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities
and Adverse Events
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
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
75,00099,999/mm3
50,00074,999/mm3
20,00049,999/mm3
20,000/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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
Amylase
1.11.5ULN
1.62.0ULN
2.15.0ULN
5.0ULN

Appendix 5:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
105/Protocol MO41787, Version 3
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
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
CHEMISTRIES (cont.)
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

Appendix 5:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
106/Protocol MO41787, Version 3
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
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

Appendix 5:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
107/Protocol MO41787, Version 3
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
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
OTHER PARAMETERS (cont.)
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
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
ADLactivities of daily living; FEV1forced expiratory volume in 1 second; GGT gamma-glutamyl transferase; ULNupper limit of normal.

Emicizumab—F. Hoffmann-La Roche Ltd
108/Protocol MO41787, Version 3
Appendix 6
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients Treated with Emicizumab
The use of bypassing agents is not expected in patients with hemophilia A without 
inhibitors.  For completeness, this appendix includes guidelines provided for treatment of 
breakthrough bleeds in patients with inhibitors.  Careful consideration of the risks and 
potential benefits is advised when combining emicizumab, factor VIII (FVIII), and 
bypassing agent. 
Drugs intended to control bleeds, including bypassing agents, 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 recombinant activated factor VII 
(rFVIIa [e.g., consideration of using no more than 90 g/kg of rFVIIa as an initial dose]).
Use of activated prothrombin complex concentrate (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 U/kg of aPCC to be administered as an initial dose.
Other bypassing agents (e.g., Byclot®) should be avoided.  In cases in which 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®).
The exact dose and schedule of bypassing agents should be discussed with 
parents/caregivers of patients at the beginning and throughout the study.  Repeated 
dosing of rFVIIa, aPCC, or other bypassing agents should be performed only under 
medical supervision, which includes laboratory monitoring by additional local and central 
laboratory assessments, and consideration should be given to verifying bleeds prior to 
repeated dosing.
Caution should be taken if anti-fibrinolytic agents are used in conjunction with rFVIIa in 
patients receiving emicizumab.  The use of anti-fibrinolytic agents in conjunction with 
aPCC or Byclot® is prohibited.  
MONITORING
In the event of a bleed treated with bypassing agents, the following local laboratory tests 
will be performed within 2448 hours of initial bypassing agent use so the investigator 

Appendix 6:  Guidelines for Dosing and Monitoring Bypassing Agents for Patients Treated 
with Emicizumab (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
109/Protocol MO41787, Version 3
may monitor for potential thromboembolic events and thrombotic microangiopathy:  
platelet count, serum creatinine, LDH, and peripheral blood smear analysis to evaluate 
for schistocytes.  A plasma sample should also be provided for local 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 and if the results from the local reference 
laboratory can be obtained within a reasonable timeframe to allow for decision making.  
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 final
dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory 
results should be recorded on the Unscheduled Visit electronic Case Report Forms.