A Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Emicizumab in Patients With Mild or Moderate Hemophilia A Without FVIII Inhibitors
Phase: PHASE3
Conditions: Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor, Moderate Hereditary Factor VIII Deficiency Disease Without Inhibitor, Hemophilia A
Sponsor: Hoffmann-La Roche

 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 BO41423, Version 3 
PROTOCOL 
TITLE: 
A MULTICENTER, OPEN-LABEL STUDY TO 
EVALUATE THE SAFETY, EFFICACY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF EMICIZUMAB IN 
PATIENTS WITH MILD OR MODERATE 
HEMOPHILIA A WITHOUT FVIII INHIBITORS 
PROTOCOL NUMBER: BO41423 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2019-002179-32 
IND NUMBER: 
122954 
NCT NUMBER: 
NCT04158648 
TEST PRODUCT: 
Emicizumab (RO5534262) 
MEDICAL MONITOR: 
, Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL DATE: 
See electronic date stamp below. 
PROTOCOL AMENDMENT APPROVAL 
 
18-Nov-2020 19:19:45
Title
Approver's Name
CMD
Date and Time (UTC)
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Emicizumab—F. Hoffmann-La Roche Ltd 
2/Protocol BO41423, Version 3 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
1 
27 May 2019 
2 
20 December 2019 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
3/Protocol BO41423, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol BO41423 has been amended to make minor changes, to correct errors, and to 
provide clarification.  Changes to the protocol, along with a rationale for each change, 
are summarized below: 
• 
Sections 2.2.2 and 4.5.7.4 now clarify the definition of target joint bleeds.  The 
definition now includes unresolved target joints.  An unresolved target joint is a 
target joint that does not fulfil the criterion of ≤ 2 bleeds into this joint within a 
consecutive 12-month period.  
• 
Wording was corrected for consistency to state that the primary analysis will be 
conducted after 50 patients (not all patients) with moderate hemophilia A have 
completed 52 weeks of emicizumab treatment, are lost to follow-up, or have 
withdrawn, whichever occurs first (Section 3.1). 
• 
Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during IMP transit either by time 
monitoring (shipment arrival date and time) or temperature monitoring 
(Section 4.3.4). 
• 
The CRF page for entry of FVIII prophylaxis treatment in the week prior to 
enrollment was renamed (Section 4.4, Appendix 1).  
• 
The protocol now clarifies that a mobile nurse may administer emicizumab or 
perform other assessments during home visits if necessary (Sections 4.5, 4.5.5, and 
Appendix 1).  
• 
Language has been added to clarify that adverse events associated with special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12). 
• 
Language regarding investigator reporting of pregnancies has been clarified 
(Section 5.4.3.2). 
• 
A sentence describing a secondary efficacy endpoint was removed 
(Section 6.5.2.2).  This sentence was inadvertently carried over from previous 
HAVEN study protocols but does not apply to BO41423.  
• 
Footnote g in Appendix 1 has been clarified to state that the Emipref (patient 
version) and EQ-5D-5L instruments will not be completed by patients < 12 years of 
age. 
• 
Footnote h in Appendix 1 has been clarified to state that the Hemophilia Joint Health 
Score (HJHS) assessment will be performed for patients ≥ 4 years of age. 
• 
Footnote g in Appendix 2 clarifies the timing for the screening sample for anti-FVIII 
antibodies and notes that results must be available before enrollment.  In addition, it 
now states that local testing will not replace the central laboratory inhibitor testing 
performed at Week 1. 
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Emicizumab—F. Hoffmann-La Roche Ltd 
4/Protocol BO41423, Version 3 
• 
The scoring numbers in tables in the Comprehensive Assessment Tool of 
Challenges in Hemophilia (CATCH) questionnaires have been removed 
(Appendices 4−6) because there were discrepancies with the scoring manual.  The 
scoring is incorporated in the programming of the underlying algorithm.   
 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
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Emicizumab—F. Hoffmann-La Roche Ltd 
5/Protocol BO41423, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 12 
PROTOCOL SYNOPSIS ....................................................................................... 13 
1. 
BACKGROUND .............................................................................................. 21 
1.1 
Background on Hemophilia A and Disease 
Severity ..................................................................................... 21 
1.2 
Background on Emicizumab .................................................... 23 
1.2.1 
Molecule and Preclinical Data ................................................. 23 
1.2.2 
Clinical Experience ................................................................... 24 
1.3 
Study Rationale and Benefit-Risk Assessment ....................... 24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................. 26 
2.1 
Safety Objective ....................................................................... 26 
2.2 
Efficacy Objectives ................................................................... 27 
2.2.1 
Primary Efficacy Objective ....................................................... 27 
2.2.2 
Secondary Efficacy Objectives ................................................ 27 
2.3 
Pharmacokinetic Objective ...................................................... 27 
2.4 
Immunogenicity Objective ........................................................ 28 
2.5 
Biomarker Objective ................................................................. 28 
2.6 
Health Status Utility Objective ................................................. 28 
3. 
STUDY DESIGN ............................................................................................. 28 
3.1 
Description of the Study ........................................................... 28 
3.2 
End of Study and Length of Study ........................................... 31 
3.3 
Rationale for Study Design ...................................................... 32 
3.3.1 
Rationale for Emicizumab Dose and Schedule ....................... 32 
3.3.2 
Rationale for Patient Population and Analysis 
Groups ...................................................................................... 32 
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 Patient-Reported Outcome 
Assessments ............................................................................ 34 
3.3.7 
Rationale for Physical Activity Assessment ............................ 35 
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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 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design .................................................................. 37 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling.................................................................................... 38 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................... 38 
4.3.3 
Investigational Medicinal Product Accountability .................... 40 
4.3.4 
Continued Access to Emicizumab ........................................... 40 
4.4 
Concomitant Therapy and Prohibited Therapy ....................... 41 
4.4.1 
Permitted Therapy .................................................................... 42 
4.4.2 
Prohibited Therapy ................................................................... 42 
4.5 
Study Assessments .................................................................. 43 
4.5.1 
Informed Consent Forms and Screening Log ......................... 43 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 44 
4.5.3 
Physical Examinations ............................................................. 44 
4.5.4 
Vital Signs ................................................................................. 44 
4.5.5 
Laboratory, Biomarker, and Other Biological 
Samples .................................................................................... 44 
4.5.6 
Electrocardiograms .................................................................. 47 
4.5.7 
Clinical Outcome Assessments ............................................... 47 
4.5.7.1 
Data Collection Methods for Clinical Outcome 
Assessments ............................................................................ 47 
4.5.7.2 
Description of Clinical Outcome Assessment 
Instruments ............................................................................... 49 
4.5.7.3 
Bleed and Medication Questionnaire....................................... 51 
4.5.7.4 
Bleed Definitions and Reporting .............................................. 51 
4.5.8 
Physical Activity Assessments ................................................. 53 
4.5.9 
Optional Samples for Research Biosample 
Repository................................................................................. 53 
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7/Protocol BO41423, Version 3 
4.5.9.1 
Overview of the Research Biosample Repository................... 53 
4.5.9.2 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 54 
4.5.9.3 
Sample Collection .................................................................... 54 
4.5.9.4 
Confidentiality ........................................................................... 55 
4.5.9.5 
Consent to Participate in the Research 
Biosample Repository .............................................................. 55 
4.5.9.6 
Withdrawal from the Research Biosample 
Repository................................................................................. 56 
4.5.9.7 
Monitoring and Oversight ......................................................... 56 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ......................................................................... 56 
4.6.1 
Study Treatment Discontinuation ............................................ 56 
4.6.2 
Patient Discontinuation from the Study ................................... 57 
4.6.3 
Study Discontinuation .............................................................. 57 
4.6.4 
Site Discontinuation ................................................................. 57 
5. 
ASSESSMENT OF SAFETY.......................................................................... 58 
5.1 
Safety Plan ............................................................................... 58 
5.1.1 
Risks Associated with Emicizumab ......................................... 58 
5.1.1.1 
Injection-Site Reactions ........................................................... 58 
5.1.1.2 
Hypersensitivity Reaction, Anaphylaxis, and 
Anaphylactoid Reaction ........................................................... 58 
5.1.1.3 
Hypercoagulation and Thromboembolic Events ..................... 59 
5.1.1.4 
Thrombotic Microangiopathy.................................................... 59 
5.1.1.5 
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
in the Setting of Emicizumab ................................................... 60 
5.1.2 
Management of Patients Who Experience 
Adverse Events ........................................................................ 61 
5.2 
Safety Parameters and Definitions .......................................... 62 
5.2.1 
Adverse Events ........................................................................ 62 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ......................................................................... 63 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 64 
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Emicizumab—F. Hoffmann-La Roche Ltd 
8/Protocol BO41423, Version 3 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .................................................. 64 
5.3.1 
Adverse Event Reporting Period ............................................. 64 
5.3.2 
Eliciting Adverse Event Information ......................................... 65 
5.3.3 
Assessment of Severity of Adverse Events ............................ 65 
5.3.4 
Assessment of Causality of Adverse Events........................... 65 
5.3.5 
Procedures for Recording Adverse Events ............................. 66 
5.3.5.1 
Injection-Site Reactions ........................................................... 66 
5.3.5.2 
Diagnosis versus Signs and Symptoms .................................. 66 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events ....................................................................................... 66 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................. 67 
5.3.5.5 
Abnormal Laboratory Values ................................................... 67 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 68 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 69 
5.3.5.8 
Deaths ...................................................................................... 69 
5.3.5.9 
Preexisting Medical Conditions................................................ 70 
5.3.5.10 
Lack of Efficacy or Worsening of Hemophilia.......................... 70 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................... 70 
5.3.5.12 
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse............................................................. 71 
5.3.5.13 
Patient-Reported Outcome Data ............................................. 73 
5.3.5.14 
Safety Biomarker Data ............................................................. 73 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ............................................................ 73 
5.4.1 
Emergency Medical Contacts .................................................. 74 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ...................... 74 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ..................... 74 
5.4.2.2 
Events That Occur after Study Drug Initiation ......................... 74 
5.4.3 
Reporting Requirements for Pregnancies ............................... 75 
5.4.3.1 
Pregnancies in Female Patients .............................................. 75 
5.4.3.2 
Pregnancies in Female Partners of Male Patients .................. 75 
5.4.3.3 
Abortions................................................................................... 76 
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Emicizumab—F. Hoffmann-La Roche Ltd 
9/Protocol BO41423, Version 3 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 76 
5.5 
Follow-Up of Patients after Adverse Events ............................ 76 
5.5.1 
Investigator Follow-Up ............................................................. 76 
5.5.2 
Sponsor Follow-Up ................................................................... 76 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period ............................................................ 77 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees ............................................................ 77 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ........................ 77 
6.1 
Determination of Sample Size ................................................. 77 
6.2 
Summaries of Conduct of Study .............................................. 78 
6.3 
Summaries of Demographic and Baseline 
Characteristics .......................................................................... 78 
6.4 
Safety Analyses ........................................................................ 78 
6.5 
Efficacy Analyses ..................................................................... 78 
6.5.1 
Primary Efficacy Endpoint ........................................................ 78 
6.5.2 
Secondary Efficacy Endpoints ................................................. 79 
6.5.2.1 
Bleed Endpoints ....................................................................... 79 
6.5.2.2 
Health-Related Quality-of-Life, Patient 
Preference, Joint Health, Activity, Menstruation 
Heaviness, and Menstruation-Related Quality of 
Life ............................................................................................ 79 
6.6 
Pharmacokinetic Analyses ....................................................... 80 
6.7 
Immunogenicity Analyses ........................................................ 80 
6.7.1 
Anti-Emicizumab Antibodies .................................................... 80 
6.7.2 
Factor VIII Inhibitors ................................................................. 81 
6.8 
Biomarker Analyses ................................................................. 81 
6.9 
Health Status Utility Analyses .................................................. 81 
6.10 
Optional Interim Analyses Reviews ......................................... 81 
7. 
DATA COLLECTION AND MANAGEMENT ................................................. 81 
7.1 
Data Quality Assurance ........................................................... 81 
7.2 
Electronic Case Report Forms ................................................. 82 
7.3 
Electronic Patient-Reported Outcome Data ............................ 82 
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Emicizumab—F. Hoffmann-La Roche Ltd 
10/Protocol BO41423, Version 3 
7.4 
Source Data Documentation .................................................... 82 
7.5 
Use of Computerized Systems ................................................ 83 
7.6 
Retention of Records ............................................................... 83 
8. 
ETHICAL CONSIDERATIONS ...................................................................... 84 
8.1 
Compliance with Laws and Regulations.................................. 84 
8.2 
Informed Consent ..................................................................... 84 
8.3 
Institutional Review Board or Ethics Committee ..................... 85 
8.4 
Confidentiality ........................................................................... 86 
8.5 
Financial Disclosure ................................................................. 86 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ......................................................................................... 87 
9.1 
Study Documentation ............................................................... 87 
9.2 
Protocol Deviations .................................................................. 87 
9.3 
Management of Study Quality ................................................. 87 
9.4 
Administrative Structure ........................................................... 87 
9.5 
Dissemination of Data and Protection of Trade 
Secrets ...................................................................................... 88 
9.6 
Protocol Amendments .............................................................. 89 
10. REFERENCES ............................................................................................... 90 
 
LIST OF TABLES 
Table 1 
Guidelines for Management of Patients Who Experience 
Adverse Events .............................................................................. 61 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ...................... 65 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ................................................................................ 31 
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Emicizumab—F. Hoffmann-La Roche Ltd 
11/Protocol BO41423, Version 3 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities..................................................................... 93 
Appendix 2 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ....................................................................... 98 
Appendix 3 
Hemophilia Joint Health Score .................................................... 100 
Appendix 4 
Comprehensive Assessment Tool of Challenges in 
Hemophilia (CATCH):  Adult ....................................................... 102 
Appendix 5 
Comprehensive Assessment Tool of Challenges in 
Hemophilia (CATCH):  Pediatric.................................................. 113 
Appendix 6 
Comprehensive Assessment Tool of Challenges in 
Hemophilia (CATCH):  Caregiver ................................................ 121 
Appendix 7 
EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) ........ 123 
Appendix 8 
Emicizumab Preference Survey (EmiPref):  Patient ................... 125 
Appendix 9 
Emicizumab Preference Survey (EmiPref):  Caregiver .............. 127 
Appendix 10 Clinical Criteria for Diagnosing Anaphylaxis ............................... 129 
Appendix 11 Anaphylaxis Precautions ............................................................. 130 
Appendix 12 WHO Toxicity Grading Scale for Determining the Severity of 
Laboratory Abnormalities and Adverse Events .......................... 131 
Appendix 13 Menstrual Bleeding Questionnaire .............................................. 136 
Appendix 14 Menstruation Diary ....................................................................... 141 
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Emicizumab—F. Hoffmann-La Roche Ltd 
12/Protocol BO41423, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A MULTICENTER, OPEN-LABEL STUDY TO 
EVALUATE THE SAFETY, EFFICACY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF EMICIZUMAB IN 
PATIENTS WITH MILD OR MODERATE 
HEMOPHILIA A WITHOUT FVIII INHIBITORS 
PROTOCOL NUMBER: BO41423 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2019-002179-32 
IND NUMBER: 
122954 
NCT NUMBER: 
NCT04158648 
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. 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
13/Protocol BO41423, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE 
SAFETY, EFFICACY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF EMICIZUMAB IN PATIENTS WITH 
MILD OR MODERATE HEMOPHILIA A WITHOUT FVIII 
INHIBITORS 
PROTOCOL NUMBER: 
BO41423 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2019-002179-32 
IND NUMBER: 
122954 
NCT NUMBER: 
NCT04158648 
TEST PRODUCT: 
Emicizumab (RO5534262) 
PHASE: 
Phase III 
INDICATION: 
Mild or moderate hemophilia A 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of 
emicizumab in patients of all ages with mild (factor VIII [FVIII] level between > 5% and < 40%) or 
moderate hemophilia A (FVIII level between ≥ 1% and ≤ 5%) without inhibitors against FVIII 
whose bleeding phenotype warrants prophylactic treatment.  Specific objectives and 
corresponding endpoints for the study are outlined below. 
Safety Objective 
The safety objective for this study is to evaluate the safety profile of emicizumab in patients with 
non-severe hemophilia A without inhibitors on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to WHO 
Toxicity Grading Scale 
• 
Incidence of thromboembolic events 
• 
Incidence of thrombotic microangiopathy 
• 
Change from baseline in physical examination findings  
• 
Change from baseline in and vital signs 
• 
Change from baseline in ECG parameters 
• 
Incidence of laboratory abnormalities 
• 
Incidence and severity of injection-site reactions 
• 
Incidence of adverse events leading to drug discontinuation 
• 
Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 
• 
Incidence and significance of anti-emicizumab antibodies 
• 
Incidence of de novo development of FVIII inhibitors 
 
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14/Protocol BO41423, Version 3 
Efficacy Objectives 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of emicizumab on the 
basis of the following endpoint:  
• 
Number of treated bleeds over time (i.e., bleed rate) 
 
Secondary Efficacy Objectives 
The secondary efficacy objective for this study is to evaluate the efficacy of emicizumab on the 
basis of the following endpoints:  
• 
Number of all bleeds (i.e., those treated and untreated with FVIII) over time 
• 
Number of joint bleeds over time 
• 
Number of target joint bleeds over time (target joints are defined as joints with ≥ 3 bleeds 
occurring in the same joint during the last 24 weeks or unresolved target joints)   
An unresolved target joint is defined as a target joint that does not fulfill the 
criterion of ≤ 2 bleeds into this joint within a consecutive 12-month period. 
• 
Number of spontaneous bleeds over time (spontaneous bleed rate) 
• 
Joint health, as assessed through use of the Hemophilia Joint Health Score at specified 
timepoints 
• 
Health-related quality of life (HRQoL), as assessed through use of the Comprehensive 
Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire over time 
• 
Preference for emicizumab compared with previous FVIII regimen, as assessed through 
use of the Emicizumab Preference Survey (EmiPref) at Week 17 
• 
Effect of emicizumab prophylaxis treatment on physical activity compared with physical 
activity at baseline 
• 
Effect of emicizumab prophylaxis treatment on menstruation heaviness and menstruation-
related quality of life in female patients, as assessed through the use of the Menstrual 
Bleeding Questionnaire (MBQ) and the Menstruation Diary (MD) with the Pictorial Blood 
Assessment Chart (PBAC) 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the emicizumab PK profile 
on the basis of the following endpoint:  
• 
Plasma concentration of emicizumab at specified timepoints 
 
Immunogenicity Objective 
The immunogenicity objective for this study is to evaluate the immune response to emicizumab 
on the basis of the following endpoint: 
• 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study 
• 
Number and proportion of patients who develop anti-FVIII inhibitors (titer≥ 0.6 BU/mL) at 
specified timepoints 
 
Biomarker Objective 
The exploratory biomarker objective for this study is to investigate the effect of emicizumab on 
pharmacodynamic (PD) parameters, including but not limited to thrombin generation, FVIII 
activity, FVIII protein, D-dimer, and prothrombin fragment 1 + 2 (PF1 + 2) at regular intervals 
throughout the study and at times of treated bleeds.  Changes over time in biomarkers related 
to bone and joint health may also be explored. 
Health Status Utility Objective  
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with emicizumab on the basis of the following endpoint: 
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Emicizumab—F. Hoffmann-La Roche Ltd 
15/Protocol BO41423, Version 3 
• 
Change from baseline in EuroQol 5-Dimension 5-level Questionnaire (EQ-5D-5L) index 
utility and visual analog scale scores at specified timepoints 
 
Study Design 
Description of Study 
Study BO41423 is a multicenter, open-label, single-arm study designed to evaluate the safety, 
efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in patients with mild or 
moderate hemophilia A without inhibitors against FVIII.  Four loading doses of emicizumab 
3 mg/kg will be administered subcutaneously once a week (QW) for 4 weeks followed by patient 
preference of one of the following maintenance regimens:  1.5 mg/kg QW, 3 mg/kg every 
2 weeks (Q2W), or 6 mg/kg every 4 weeks (Q4W).  The three maintenance dose regimens have 
shown equivalent average steady-state exposure, and demonstrated consistent efficacy and 
safety, and are approved in several countries for the treatment of Hemophilia A with or without 
FVIII inhibitors.  As patients with mild or moderate Hemophilia A have residual FVIII levels of 
≥ 1%, it is of interest to collect safety data over a longer time period.  Therefore, in this study, 
the observation time to primary analyses was extended to approximately 52 weeks compared 
with prior Phase III studies investigating emicizumab. 
Patients (or their legally authorized representative herein referred to as patient[s]) will choose 
the preferred emicizumab maintenance regimen (1.5 mg/kg SC QW, 3 mg/kg SC Q2W, or 
6 mg/kg SC Q4W) after consultation with his or her treating physician.  The chosen regimen 
needs to be maintained throughout the study until completion of at least 52 weeks. 
During the study, individual bleeds will be captured by the patient as the bleeds occur using a 
Bleed and Medication Questionnaire.  Breakthrough bleeds will be treated with FVIII at the 
lowest dose expected to achieve hemostasis.   
Female patients of childbearing potential will be administered two specific patient-reported 
outcome measures related to their menstruation (both questionnaires administered on paper): 
the MBQ will assess the menstrual bleed-related heaviness, pain, irregularity and quality of life; 
the Menstruation Diary (MD) with the PBAC will assess the use of sanitary products for 
menstruation (including the number of products used, the amount of bleeding, the occurrence 
and size of clots, and the number of episodes of heavy bleeding (flooding)). 
HRQoL (CATCH and EmiPref) and health status (EQ-5D-5L) will be assessed as outlined in the 
schedule of activities.  These measures will be captured either on paper questionnaires or on a 
site-based tablet available to patients during clinic visits. 
Safety assessments will include physical examinations, vital signs, ECG, laboratory 
assessments (serum chemistry and hematology including complete blood count with 
differential), anti-drug antibodies (ADAs), and FVIII inhibitors.  Adverse events will be captured 
on an ongoing basis, as they occur during the study. 
Exploratory PD biomarkers (e.g., FVIII activity, thrombin generation) will be collected on a 
regular basis throughout the study and will be coupled with a PK assessment for days where PK 
and PD samples will be drawn. 
Biomarkers related to thromboembolism (e.g., D-dimer, PF1 + 2) and immunologic biomarkers 
(i.e., anti-emicizumab antibodies) will be measured on a regular basis throughout the study.  
Exploratory PD biomarkers and safety biomarkers will be collected within 24 hours but no later 
than 48 hours of a treated bleed. 
After 24 weeks on prophylactic emicizumab, patients with suboptimal bleed control will be 
offered the option to increase their dose to 3 mg/kg QW, with approval from the Medical 
Monitor, if the protocol-defined criteria of suboptimal response is met. 
Interim data reviews may be performed at various timepoints (e.g., for regulatory submissions), 
and the primary analysis for all patients will be conducted after 50 patients with moderate 
hemophilia A have completed 52 weeks of emicizumab treatment, are lost to follow-up, or have 
withdrawn, whichever occurs first.  The primary analysis will occur at the specified time 
regardless if no patients with mild hemophilia A are enrolled; however, enrollment will be left 
open  for patients with mild hemophilia A in order to enroll approximately 20 such patients.  The 
total number of patients in the study might slightly exceed 70 patients depending on the number 
of female patients enrolled.  Ideally, at least 5 female patients will be enrolled.  If these are not 
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recruited within the pool of 70 patients, the enrollment will remain open until they are enrolled or 
until the cutoff date of primary analysis, whichever occurs sooner.  Note that all patients will be 
included in the primary analysis irrespective of their follow-up time.  After the primary analysis, 
patients will continue to receive emicizumab according to the Roche Policy on post study drug 
access until emicizumab is approved and accessible to patients commercially. 
Patients who discontinue study drug prior to end of study will return to the clinic for a safety 
follow-up visit 24 weeks after the last dose of study drug.  Patients who complete or discontinue 
from the study will return to the clinic for a study completion/discontinuation visit. 
Number of Patients 
Approximately 70 patients of all age groups will be enrolled in the study consisting of 
approximately 20 patients with mild and approximately 50 patients with moderate hemophilia A 
without FVIII inhibitors whose phenotype warrants prophylaxis.  The total number of patients in 
the study might slightly exceed 70 patients depending on the number of female patients 
enrolled. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (signed by patient’s legally authorized representative for 
patients who have not attained the age of majority)  
• 
Signed Assent Form when appropriate, as determined by patient's age and individual site 
and country standards 
• 
Willingness and ability to comply with schedules visits, treatment plans, laboratory tests and 
other study procedures 
• 
Diagnosis of mild (FVIII level between > 5% and < 40%) or moderate (FVIII level between 
≥ 1% and ≤ 5%) congenital Hemophilia A without FVIII inhibitors 
• 
Weight ≥ 3 kg 
• 
Need for prophylaxis based on investigator assessment 
• 
A negative test for inhibitor (i.e., < 0.6 BU/mL) within 8 weeks prior to enrollment  
• 
No documented inhibitor (i.e., < 0.6 BU/mL), FVIII half-life < 6 hours, or FVIII recovery < 66% 
in the last 5 years 
Patients who completed successful immune tolerance induction (ITI) at least 5 years 
before screening are eligible, provided they have had no evidence of inhibitor 
recurrence (permanent or temporary) as may be indicated by a detection of an 
inhibitor, FVIII half-life < 6 hours or FVIII recovery < 66% since completing ITI. 
• 
Documentation of the details of prophylactic or episodic FVIII treatment and of number of 
bleeding episodes for at least the last 24 weeks prior to enrollment 
• 
Adequate hematologic function, defined as platelet count ≥ 100,000 cells/µL and 
hemoglobin ≥ 8 g/dL (4.97 mmol/L) at the time of screening 
• 
Adequate hepatic function defined as total bilirubin ≤ 1.5 × age-adapted upper limit of normal 
(ULN) (excluding Gilbert syndrome) and both AST and ALT ≤ 3 × age-adapted ULN at the 
time of screening, and no clinical signs or known laboratory/radiographic evidence 
consistent with cirrhosis 
• 
Adequate renal function, defined as serum creatinine ≤ 2.5 × age-adapted ULN and 
creatinine clearance ≥ 30 mL/min by Cockroft-Gault formula 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception as defined below: 
Women must remain abstinent or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 24 weeks after the final 
dose of study drug.  
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A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.  
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.  
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Inherited or acquired bleeding disorder other than mild (FVIII level between > 5% 
and < 40%) or moderate (FVIII level between ≥ 1% and ≤ 5%) congenital hemophilia A 
• 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 
• 
Previous (within the last 12 months) or current treatment for thromboembolic disease (with 
the exception of previous catheter-associated thrombosis for which anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease 
• 
Other conditions (e.g., certain autoimmune diseases) that may currently increase the risk of 
bleeding or thrombosis 
• 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
• 
Planned surgery during the emicizumab loading dose phase 
Surgeries in patients on emicizumab from Week 5 onwards are allowed. 
• 
Known HIV infection with CD4 counts < 200 cells/µL 
• 
Concomitant disease, condition, significant abnormality on screening evaluation or 
laboratory tests, or treatment that could interfere with the conduct of the study, or that would 
in the opinion of the investigator, pose an additional unacceptable risk in administering 
study drug to the patient 
• 
Receipt of any of the following: 
− 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives 
of last drug administration with the exception of prior emicizumab prophylaxis (prior 
investigational or commercial emicizumab use is not an exclusion criterion) 
− 
A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
− 
Any other investigational drug currently being administered or planned to be 
administered 
• 
Inability to comply with the study protocol in the opinion of the investigator 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.  
 
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End of Study 
The end of this study is defined as the date when the last remaining patient has completed the 
last visit, as defined by the following criteria:  completion of at least 52 weeks of emicizumab 
treatment during the study and either transfers to commercially available emicizumab or 
receives further emicizumab per Roche Global Policy on Continued Access to Investigational 
Medicinal Products OR completion of the end of study safety follow-up visit 24 weeks after 
discontinuing emicizumab OR withdrawal of consent OR lost to follow-up. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 27 months. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The investigational medicinal product for this study is emicizumab.  The emicizumab dosing 
regimen to be tested is emicizumab 3 mg/kg SC QW for 4 weeks followed by a maintenance 
dose of either 1.5 mg/kg SC QW, 3 mg/kg SC Q2W, or 6 mg/kg SC Q4W. 
All patients with suboptimal control of bleeding as defined by the protocol will be offered the 
option to increase their emicizumab maintenance dose to 3 mg/kg QW, with approval from the 
Medical Monitor.  Suboptimal response is defined as follows:  ≥ 2 qualifying bleeds within 
24 weeks while on prophylactic emicizumab. 
Statistical Methods 
Primary Analysis 
The primary analysis will be performed after 50 patients with moderate hemophilia A have either 
completed 52 weeks of emicizumab treatment, are lost to follow-up, or have withdrawn 
prematurely, whichever occurs first.  Data from all patients (including any female patients and 
any patients with mild hemophilia A) will be included in the primary analysis. 
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including complete 
blood count with differential and platelet counts), ECGs, vital signs, ADAs, and de novo FVIII 
inhibitors.  To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate thesaurus level, 
and toxicity grade.  For clinical laboratory data, summary statistics will be presented.  
In addition, shift tables describing changes from baseline will be presented using the WHO 
Toxicity Grading Scale. 
Summaries will be presented overall, by dosing regimen, and, if applicable, by disease severity.  
Further details will be provided in the Statistical Analysis Plan. 
The key efficacy objective is to characterize the efficacy of emicizumab based on the number of 
treated bleeds over time.  The clinical effect of prophylactic emicizumab will be assessed via the 
annualized bleed rate estimated using a negative binomial regression model, which accounts 
for different follow-up times, with the number of bleeds from patients as a function of the time 
such that each patient who stays in the study is included as an offset in the model.  A detailed 
description of the statistical methods and the summaries, if applicable, presented by dosing 
regimen and/or by disease severity for the efficacy analyses will be provided in the Statistical 
Analysis Plan. 
Determination of Sample Size 
The overall sample size of approximately 70 patients (approximately 50 patients with moderate 
disease, approximately 20 patients with mild disease) is based primarily on clinical 
considerations, taking into account the limited number of patients with non-severe hemophilia A.  
This sample size is expected to provide statistically robust point estimates with meaningfully 
narrow CIs in the overall group of enrolled patients, assuming the same efficacy across dosing 
regimens. 
Optional Interim Analyses Reviews 
Interim data reviews may be performed at various timepoints for regulatory submissions. 
 
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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 
CATCH 
Comprehensive Assessment Tool of Challenges in Hemophilia 
DSC 
daily step count 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EmiPref 
Emicizumab Preference Survey 
EQ-5D-5L 
European Quality of Life 5-Dimension, 5-Level Questionnaire 
FDA 
Food and Drug Administration 
FIXa 
activated factor IX 
FVIII 
factor VIII 
FX 
factor X 
HCP 
healthcare provider 
HIPAA 
Health Insurance Portability and Accountability Act 
HJHS 
Hemophilia Joint Health Score 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITI 
immune tolerance induction 
IxRS 
interactive voice or web-based response system 
MBQ 
Menstrual Bleeding Questionnaire 
MD 
Menstruation Diary 
MN 
mobile nursing 
MVPA 
moderate to vigorous physical activity 
PBAC 
Pictorial Blood Assessment Chart 
PD 
pharmacodynamic 
PF1 + 2 
prothrombin fragment 1 + 2 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
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Abbreviation 
Definition 
QW 
once a week 
RBR 
Research Biosample Repository 
rFVIIa 
recombinant activated factor VII 
SAP 
Statistical Analysis Plan 
TMA 
thrombotic microangiopathy 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
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1. 
BACKGROUND
1.1 
BACKGROUND ON HEMOPHILIA A AND DISEASE SEVERITY 
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately
1 in 5000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; Franchini and Mannucci 
2013).
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the 
Xq28 region of the X chromosome.  It occurs almost exclusively in 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 female who is a carrier will have a 50% chance to receive a mutated 
FVIII gene; thus, hemophilia A will be transmitted to half the male infants and half of 
female infants will be carriers.  Females who are carriers of hemophilia A may
experience bleeding symptoms similar to those seen in men with mild hemophilia A, as 
approximately 10% of carriers have a FVIII activity less than 35% (Plug et al. 2006). 
Rarely, women can have more severe bleeding symptoms requiring treatment and may 
develop FVIII inhibitors.  Approximately 30% of patients with hemophilia A do not have a 
family history of the disorder; these cases arise from spontaneous FVIII gene mutations.
The absence or functional deficiency of FVIII leads to a lifelong bleeding tendency. 
Common clinical signs of hemophilia A include easy bruising; prolonged bleeding after 
trauma or surgery; spontaneous bleeding into joints, muscles, or soft tissues; and 
intracranial hemorrhage.  The severity of the disease roughly correlates with the residual 
endogenous level of FVIII activity.
Severity of hemophilia A is largely defined by either clinical bleeding symptoms or 
residual plasma FVIII activity levels.  A widely used classification system is based on 
plasma FVIII activity, with a FVIII level between > 5% and < 40% of normal considered to 
be mild disease, a level between ≥ 1% and ≤ 5% to be moderate disease, and a level
< 1% to be severe disease (White et al. 2001).  Approximately 63% of people with 
hemophilia A have a moderate (19%) or severe (44%) form, leading to frequent bleeding 
events (bleeds) with the sequelae of musculoskeletal complications (e.g., arthropathy), 
local functional deficits, hemorrhagic shock, neurocognitive defects, or even death
(World Federation of Hemophilia 2017).  Although classifications based exclusively on 
residual FVIII levels are often proportionally manifested in clinical presentations of types 
and numbers of bleeding episodes, phenotypic heterogeneity exists such that a subset
of non-severe patients exhibit a severe bleeding phenotype (Di Minno et al. 2013) and 
therefore may require prophylactic treatment.  Indeed, the predictive value of residual 
FVIII levels to define severity of hemophilia has been recently called into question, with 
traditional classification of patients into mild, moderate, and severe categories being
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recognized as inadequate in directing the management of patients with hemophilia. 
A recent International Society on Thrombosis and Haemostasis guidance (Mancuso 
et al. 2018) now recommends development of criteria for “clinically severe hemophilia”
which would inform treatment strategies (e.g., prescribing prophylaxis vs. on-demand 
regimens based on bleeding phenotype instead of on residual clotting factor activity 
alone).  Therefore, no a priori criteria can be defined and the decision which patient 
warrants prophylaxis remains with the treating physician, as it is currently.
Joint bleeding is a hallmark of hemophilia A, mostly involving large synovial joints such 
as the knees, elbows, and ankles (Bolton-Maggs and Pasi 2003).  Repeated 
hemarthrosis causes inflammation and synovial degeneration leading to chronic 
arthropathy, a common and major complication in patients with hemophilia (Raffini and 
Manno 2007).  Whereas patients with mild and moderate disease generally report a 
significantly lower number of joint bleeds compared with those with severe hemophilia, 
there are patients with non-severe disease who present with recurrent articular bleeds. 
Accordingly, hemophilic arthropathy with its associated morbidity is observed in about 
30% of non-severe patients (Soucie et al. 2004; Den Uijl et al.2009, 2011).  A national 
survey from the Netherlands, which included 1066 patients with hemophilia A showed 
that 43% of patients with moderate hemophilia had joint damage, with 32% of cases 
having multiple sites of articular impairment (Soucie et al. 2004; Den Uijl et al.2009, 
2011).  Of 470 patients with mild disease, 11% of patients required orthopedic aids such 
as crutches and walking sticks and 7% of patients reported chronic joint pain.  These 
data suggest that arthropathy, although uncommon, is debilitating for patients with mild 
disease who experience chronic hemarthrosis (Ling et al. 2011).
The body of literature describes a well-recognized group of patients with non-severe 
hemophilia A whose significant bleeding phenotype results in hemophilic complications 
and thus justifies routine prophylactic treatment.  This is illustrated best by a recent 
report on 3,315 patients with non-severe hemophilia A that revealed a 6-month joint 
bleed rate > 0.8 in adults and adolescents with FVIII level of 10% (Soucie et al. 2018). 
Accordingly, in current practice, the decision to initiate prophylaxis in patients with 
non-severe hemophilia A relies on the clinical judgment of the treating physician, based 
on the bleeding phenotype of the patient.
Primary prophylaxis is beneficial for patients with non-severe hemophilia A who present 
with more severe bleeding patterns.  Indeed, prophylactic replacement therapy is used 
by approximately 30% of patients with non-severe hemophilia A (Di Minno et al. 2013; 
Den Uijl et al. 2014).  A recent survey described the treatment and bleeding patterns in 
adult and pediatric patients across centers and registries from Belgium, France, 
Germany, Italy, Spain, Sweden, and the United Kingdom.  Overall, of 342 patients with 
moderate hemophilia A, approximately one third to one half of patients received regular 
prophylaxis without significant difference across age groups (Berntorp et al. 2017). 
Similarly, a recent survey in Australia revealed that 25% of patients with moderate 
hemophilia A receive regular prophylaxis (Mason et al. 2018).  A recent report from the
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UK National Haemophilia Database is consistent with these results and provides a 
unique nationwide view of treatment of patients with moderate hemophilia A.  
Of 864 patients, 273 (31.6%) patients had a significant bleeding phenotype and kept a 
regular treatment diary.  Complete data was available for 154 individuals, of whom 
68.8% used FVIII prophylaxis regularly.  The median annualized bleed rate (ABR) for 
this group was 3 (1.0−7.0), of which 24% of patients experiencing no bleed (Scott 
et al. 2019). 
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, immunoglobulin G4 monoclonal antibody that binds with 
moderate affinity to activated factor IX (FIXa) and factor X (FX), mimicking the co-factor 
function of FVIII.  In patients with hemophilia A, hemostasis can be restored irrespective 
of the presence of FVIII inhibitors, as emicizumab shares no sequence homology with 
FVIII.  In addition, emicizumab offers the possibility of SC administration, removing 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), every 2 weeks (Q2W), or every 4 weeks (Q4W). 
In vivo pharmacology experiments in cynomolgus monkeys were conducted in a 
hemophilia A model where endogenous FVIII levels were neutralized by a FVIII-specific 
monoclonal antibody.  This model mimics essential characteristics of patients with 
hemophilia A and was used to test in vivo pharmacodynamics and efficacy under 
spontaneous or local trauma-induced bleeding conditions.  In summary, emicizumab 
demonstrated the ability to significantly reduce bleeding tendency under both sets of 
conditions. 
Potential prothrombotic risks associated with emicizumab-induced FVIII mimetic activity 
were further explored in an in vivo cynomolgus monkey venous stasis model.  In this 
model, thrombus formation in the presence of emicizumab was compared with that in the 
presence of FVIII or bypassing agents (recombinant activated factor VII [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) with 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 
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was the highest tested dose in each toxicity study.  These in vitro studies are consistent 
with in vivo results of repeat-dose toxicology studies.  In these experiments, 
normo-coagulative monkeys with 100% FVIII activity were exposed to repeat doses and 
showed no prothrombotic effects in any organs or tissues even at supra-therapeutic 
levels of emicizumab (Roche Report Numbers: 1060133, 1060134, 1060140, and 
1060168).  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 RO5543262 (Emicizumab) Investigator's Brochure for additional details on 
nonclinical studies with emicizumab. 
1.2.2 
Clinical Experience 
Currently available experience with emicizumab in humans includes data from three 
completed Phase I studies (ACE001JP, JP29574, and YP39308); one completed 
Phase I/II extension study (ACE002JP) in patients with hemophilia A; and five ongoing 
Phase III studies in adults and adolescent patients with hemophilia A with inhibitors 
(BH29884, MO39182), without inhibitors (BH30071), and with or without inhibitors 
(BO39182 and YP39309); and two ongoing Phase III studies in pediatric patients with 
(BH29992) and without (JO39881) inhibitors. 
Based on the Phase III program, emicizumab gained approval in many countries, 
including the United States and is indicated for routine prophylaxis to prevent bleeding or 
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, the label is restricted to patients with severe 
hemophilia A (FVIII level < 1%).  Refer to U.S. Prescribing Information and Summary of 
Product Characteristics for full details on approved indications. 
Refer to the RO5543262 (Emicizumab) Investigator's Brochure for details on clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
To investigate emicizumab prophylaxis in patients with mild or moderate hemophilia A, 
this study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of 
emicizumab in patients with mild (FVIII level between > 5% and < 40%) or moderate 
hemophilia A (FVIII level between ≥ 1% and ≤ 5%) without inhibitors against FVIII whose 
bleeding phenotype warrants prophylactic treatment. 
In patients who experience multiple spontaneous bleeds (regardless of their specific 
FVIII level), a prophylactic approach is beneficial as it will prevent the occurrence of 
bleeds and their consequences.  Given the clinically meaningful efficacy of emicizumab 
in the prevention of bleeds and the major benefit it offers over available agents, 
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emicizumab is considered an appropriate option in the medical armamentarium for 
individuals with non-severe hemophilia A who require prophylaxis.  
Patients with non-severe hemophilia A experience bleeds because of reduced FVIII 
activity and consequently inefficient formation of the intrinsic tenase complex.  
Physiologically, the coagulation system is in a dynamic balance between a tendency to 
bleed and the tendency to clot, which should provide adequate hemostasis without 
thrombotic events.  In patients with hemophilia, the balance tips towards bleeding, 
whereas in patients with thrombophilia it tips towards thrombosis.  As described above, 
by its very nature, emicizumab is intended for routine prophylaxis for prevention of 
bleeds.  As such, patients with non-severe hemophilia A who will use emicizumab are 
those patients for whom routine prophylaxis is indicated by clinical symptoms.  These 
individuals are suffering from a severe bleeding phenotype, reflecting a coagulation 
balance markedly slanted towards propensity to bleed despite residual FVIII activity. 
Regarding the theoretical risk of thrombotic complications in patients receiving 
emicizumab prophylaxis in addition to constant residual low FVIII activity, the Sponsor 
considered characteristics of the patient population, emicizumab biochemical properties, 
and in vitro and in vivo data, as well as available clinical experience.  Together, these 
data do not point to an increased risk of thrombosis in patients with non-severe 
hemophilia A treated with emicizumab. 
When considering the coagulation potential of the combination of FVIII and emicizumab, 
it is important to account for their different biochemical characteristics.  Although 
emicizumab facilitates the intrinsic tenase reaction, its affinity for FIXa or FX is at least 
10-fold lower than that of FVIIIa.  Additionally, kinetic analysis of FIXa-catalyzed FX 
activation demonstrates that the rate of tenase reaction in the presence of emicizumab is 
1/44 of the reaction rate in the presence of FVIIIa, suggesting that while emicizumab 
mimics FVIIIa, its enzymatic kinetics are not as strong as FVIIIa (Kitazawa et al. 2017).  
These properties of emicizumab safeguard against the risk of a synergistic effect in 
thrombin generation with FVIIIa. 
In line with these characteristics, in vitro data indicate that while emicizumab is highly 
effective in increasing generation of thrombin in the presence of 1 IU/dL or 10 IU/dL of 
FVIII (FVIII levels akin to patients with mild and moderate hemophilia), the level of 
thrombin generation in these conditions is a fraction of the thrombin generated in the 
presence of normal FVIII concentration.  Importantly, at 100 IU/dL FVIII (normal levels), 
emicizumab does not add to the generation of thrombin, beyond the effect of FVIII 
(Roche Report No. 1060118).  Similarly, Nogami et al. (2018) recently reported the 
results of clot waveform analysis demonstrating a decreasing contribution of emicizumab 
in the presence of increasing FVIII.  They further demonstrated that the combination of 
40% FVIII activity with 100 μg/mL emicizumab yields a lower Ad|min1| (an adjustment of 
the minimum transmittance in the clot waveform to 0% in the immediate postcoagulation 
phase, as detailed in Nogami et al. 2018) than 100% FVIII alone.  This illustrates that 
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even in the presence of normal plasma FVIII activity levels, addition of emicizumab is 
unlikely to increase the risk of clotting.  The coagulation potential of the combination of 
FVIII and emicizumab is unlikely to exceed 100% FVIII activity whereas, hypothetically, 
administering excess FVIII may expose a patient to thrombogenic supraphysiologic 
FVIII levels. 
These data are consistent with the mechanistic understanding that FVIII and 
emicizumab compete for the same targets in the coagulation system, and therefore, the 
combination has a limited additive potential.  This is in contrast with the combination of 
emicizumab and bypassing agents, or the combination of FVIII or bypassing agents with 
inhibitors of endogenous regulators of coagulation (e.g., antithrombin) that exert their 
effect at different levels of the coagulation cascade and synergistically enhance the 
coagulation potential (Pasl et al. 2017).  Therefore, the Sponsor believes that 
emicizumab is a safe option for individuals with non-severe hemophilia A whose 
bleeding phenotype warrants prophylaxis and considers the benefit-risk profile of 
emicizumab in patients with mild or moderate hemophilia A in line with the benefit-risk 
profile of emicizumab as established in the Phase III studies undertaken in patients with 
severe hemophilia A or hemophilia A with inhibitors. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics 
of emicizumab in patients of all ages with mild (FVIII level between > 5% and < 40%) or 
moderate hemophilia A (FVIII level between ≥ 1% and ≤ 5%) without inhibitors against 
FVIII whose bleeding phenotype warrants prophylactic treatment.  Specific objectives 
and corresponding endpoints for the study are outlined below. 
2.1 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety profile of emicizumab in 
patients with non-severe hemophilia A without inhibitors on the basis of the following 
endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to 
WHO Toxicity Grading Scale 
• 
Incidence of thromboembolic events 
• 
Incidence of thrombotic microangiopathy (TMA) 
• 
Change from baseline in physical examination findings  
• 
Change from baseline in and vital signs 
• 
Change from baseline in ECG parameters 
• 
Incidence of laboratory abnormalities 
• 
Incidence and severity of injection-site reactions 
• 
Incidence of adverse events leading to drug discontinuation 
• 
Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 
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• 
Incidence and significance of anti-emicizumab antibodies 
• 
Incidence of de novo development of FVIII inhibitors 
 
2.2 
EFFICACY OBJECTIVES 
2.2.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of emicizumab on 
the basis of the following endpoint:  
• 
Number of treated bleeds over time (i.e., bleed rate) 
 
2.2.2 
Secondary Efficacy Objectives 
The secondary efficacy objective for this study is to evaluate the efficacy of emicizumab 
on the basis of the following endpoints:  
• 
Number of all bleeds (i.e., those treated and untreated with FVIII) over time 
• 
Number of joint bleeds over time 
• 
Number of target joint bleeds over time (target joints are defined as joints with 
≥ 3 bleeds occurring in the same joint during the last 24 weeks or unresolved target 
joints) 
An unresolved target joint is defined as a target joint that does not fulfil the 
criterion of ≤ 2 bleeds into this joint within a consecutive 12-month period. 
• 
Number of spontaneous bleeds over time (spontaneous bleed rate) 
• 
Joint health, as assessed through use of the Hemophilia Joint Health Score (HJHS) 
at specified timepoints 
• 
Health-related quality of life (HRQoL), as assessed through use of the 
Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) 
Questionnaire over time 
• 
Preference for emicizumab compared with previous FVIII regimen, as assessed 
through use of the Emicizumab Preference Survey (EmiPref) at Week 17 
• 
Effect of emicizumab prophylaxis treatment on physical activity compared with 
physical activity at baseline 
• 
Effect of emicizumab prophylaxis treatment on menstruation heaviness and 
menstruation-related quality of life in female patients of childbearing potential, as 
assessed through the use of the Menstrual Bleeding Questionnaire (MBQ) and the 
Menstruation Diary (MD) with the Pictorial Blood Assessment Chart (PBAC) over 
time 
 
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 concentration of emicizumab at specified timepoints 
 
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2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to 
emicizumab on the basis of the following endpoint: 
• 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study 
• 
Number and proportion of patients who develop anti-FVIII inhibitors 
(titer≥ 0.6 BU/mL) at specified timepoints 
 
2.5 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to investigate the effect of 
emicizumab on PD parameters, including but not limited to thrombin generation, 
FVIII activity, FVIII protein, D-dimer, and prothrombin fragment 1 + 2 (PF1 + 2) at regular 
intervals throughout the study and at times of treated bleeds.  Changes over time in 
biomarkers related to bone and joint health may also be explored. 
2.6 
HEALTH STATUS UTILITY OBJECTIVE  
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with emicizumab on the basis of the following endpoint: 
• 
Change from baseline in EuroQol 5-Dimension 5-level Questionnaire (EQ-5D-5L) 
index utility and visual analog scale (VAS) scores at specified timepoints 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study BO41423 is a multicenter, open-label, single-arm study designed to evaluate the 
safety, efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in patients 
with mild or moderate hemophilia A without inhibitors against FVIII.  Four loading doses 
of emicizumab 3 mg/kg will be administered subcutaneously QW for 4 weeks followed by 
patient preference of one of the following maintenance regimens:  1.5 mg/kg QW, 
3 mg/kg Q2W, or 6 mg/kg Q4W.  The three maintenance dose regimens have shown 
equivalent average steady-state exposure, and demonstrated consistent efficacy and 
safety, and are approved in several countries for the treatment of Hemophilia A with or 
without FVIII inhibitors.  As patients with mild or moderate Hemophilia A have residual 
FVIII levels of ≥ 1%, it is of interest to collect safety data over a longer time period.  
Therefore, in this study, the observation time to primary analyses was extended to 
approximately 52 weeks compared with prior Phase III studies investigating emicizumab. 
Approximately 70 patients of all age groups will be enrolled, approximately 20 patients 
with mild (FVIII level between > 5% and < 40%) and approximately 50 patients with 
moderate (FVIII level between ≥ 1% and ≤ 5%) hemophilia A, without FVIII inhibitors 
whose phenotype warrants prophylaxis. 
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Patients (or their legally authorized representative herein referred to as patient[s]) will 
choose the preferred emicizumab maintenance regimen (1.5 mg/kg SC QW, 3 mg/kg SC 
Q2W, or 6 mg/kg SC Q4W) after consultation with his or her treating physician.  The 
chosen regimen needs to be maintained throughout the study until completion of at least 
52 weeks. 
During the study, individual bleeds will be captured by the patient as the bleeds occur 
using a Bleed and Medication Questionnaire (BMQ).  Patients will be asked on a weekly 
basis to record 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 
increased activity) has been given.  Breakthrough bleeds will be treated with FVIII at the 
lowest dose expected to achieve hemostasis.  When a bleed has occurred, patients will 
be required to report bleed information details (e.g., site, type, day, time) and medication 
details including reason for the use of FVIII (e.g., treatment of a bleed, preventative dose 
before activity), agent, start time, dose, route of administration, and number of infusions 
needed to treat the bleed via the BMQ. 
HRQoL (CATCH and EmiPref) and health status (EQ-5D-5L) will be assessed as 
outlined in the schedule of activities.  These measures will be captured either on paper 
questionnaires or on a site-based tablet available to patients during clinic visits.  Female 
patients of childbearing potential will be administered two specific patient-reported 
outcome measures related to their menstruation (both questionnaires administered on 
paper): the MBQ will assess the menstrual bleed-related heaviness, pain, irregularity 
and quality of life; the Menstruation Diary (MD) with the PBAC will assess the use of 
sanitary products for menstruation (including the number of products used, the amount 
of bleeding, the occurrence and size of clots, and the number of episodes of heavy 
bleeding (flooding)). 
Safety assessments will include physical examinations, vital signs, ECG, laboratory 
assessments (serum chemistry and hematology including complete blood count with 
differential), anti-drug antibodies (ADAs), and FVIII inhibitors.  Adverse events will be 
captured on an ongoing basis, as they occur during the study. 
Exploratory PD biomarkers (e.g., FVIII activity, thrombin generation) will be collected on 
a regular basis throughout the study and will be coupled with a PK assessment for days 
where PK and PD samples will be drawn.  For pediatric patients, see Section 4.5.5 
regarding blood draw volumes. 
Biomarkers related to thromboembolism (e.g., D-dimer, PF1 + 2) will be measured on a 
regular basis throughout the study.  For pediatric patients, see Section 4.5.5 regarding 
blood draw volumes. 
Exploratory PD biomarkers and safety biomarkers will be collected within 24 hours but 
no later than 48 hours of a treated bleed. 
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After 24 weeks on prophylactic emicizumab, patients with suboptimal bleed control will 
be offered the option to increase their dose to 3 mg/kg QW, with approval from the 
Medical Monitor, if the protocol-defined criteria of suboptimal response is met (see 
Section 4.3.2). 
Interim data reviews may be performed at various timepoints (e.g., for regulatory 
submissions), and the primary analysis for all patients will be conducted after 50 patients 
with moderate hemophilia A have completed 52 weeks of emicizumab treatment, are lost 
to follow-up, or have withdrawn, whichever occurs first.  The primary analysis will occur 
at the specified time regardless if no patients with mild hemophilia A are enrolled; 
however, enrollment will be left open for patients with mild hemophilia A in order to enroll 
approximately 20 such patients.  The total number of patients in the study might slightly 
exceed 70 patients depending on the number of female patients enrolled.  Ideally, at 
least 5 female patients will be enrolled.  If these are not recruited within the pool of 70 
patients, the enrollment will remain open until they are enrolled or until the cutoff date of 
primary analysis, whichever occurs sooner.  Note that all patients will be included in the 
primary analysis irrespective of their follow-up time.  After the primary analysis, patients 
will continue to receive emicizumab according to the Roche Policy on post study drug 
access until emicizumab is approved and accessible to patients commercially. 
Patients who discontinue study drug prior to end of study will return to the clinic for a 
safety follow-up visit, 24 weeks after the last dose of study drug.  Patients who complete 
or discontinue from the study will return to the clinic for a study 
completion/discontinuation visit (see Appendix 1 and Appendix 2). 
Figure 1 presents an overview of the study design.  The schedules of activities are 
provided in Appendix 1 and Appendix 2. 
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• 
Treatment period at least 52 weeks 
• 
For patients who discontinue emicizumab, safety follow-up visit 24 weeks after 
discontinuation of emicizumab 
 
3.3 
RATIONALE FOR STUDY DESIGN 
The Sponsor proposes a single-arm, multicenter, Phase III trial that will enroll patients of 
all ages with mild or moderate hemophilia A.  The study will use approved dosing 
regimens at the choice of the patient following consultation with the treating physician.  
The study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of 
emicizumab in patients with non-severe hemophilia A, as emicizumab has not been 
tested in patients without FVIII inhibitors with residual FVIII levels of ≥ 1%. 
3.3.1 
Rationale for Emicizumab Dose and Schedule 
The three maintenance dose regimens have shown equivalent average steady-state 
exposure, and demonstrated consistent efficacy and safety, and are approved in several 
countries for the treatment of Hemophilia A with or without FVIII inhibitors.  As patients 
with mild or moderate Hemophilia A have residual FVIII levels of ≥ 1%, it is of interest to 
collect safety data over a longer time period.  Therefore, in this study, the observation 
time to primary analyses was extended to approximately 52 weeks compared with prior 
Phase III studies investigating emicizumab. 
Patients in consultation with investigators will be allowed to choose the dosing regimen 
that is most appropriate for them as follows: 
• 
Loading dose of 3 mg/kg SC QW × 4 weeks followed by one of the following: 
– 
Maintenance dose of 1.5 mg/kg SC QW  
– 
Maintenance dose of 3 mg/kg SC Q2W 
– 
Maintenance dose of 6 mg/kg SC Q4W 
 
3.3.2 
Rationale for Patient Population and Analysis Groups 
This study will include patients of all ages with mild or moderate hemophilia A without 
inhibitors against FVIII who warrant FVIII prophylaxis.  As it has been shown that primary 
prophylaxis is beneficial for patients with non-severe hemophilia A who present with 
more severe bleeding patterns and prophylactic replacement therapy is used by 
approximately 30% of patients with non-severe hemophilia A, the efficacy and safety of 
emicizumab prophylaxis in these patients will be evaluated.  The majority of patients 
enrolled will be of moderate severity (approximately 50 patients) as bleeding phenotypes 
that warrant prophylaxis in patients with mild disease are rare.  The cutoff date of the 
primary analysis will be the observation time of 52 weeks after the last patient with 
moderate disease has been enrolled to reduce the risk of significant timeline 
prolongation because of potential difficulties in recruiting patients with mild hemophilia A 
who warrant FVIII prophylaxis.  The primary analysis will occur at the specified time 
regardless if no patients with mild hemophilia A are enrolled; however, enrollment will be 
left open for patients with mild hemophilia A in order to enroll approximately 20 such 
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patients.  Ideally, at least 5 female patients will be enrolled.  If these are not recruited 
within the pool of 70 patients, the enrollment will remain open until they are enrolled or 
until the cutoff date of primary analysis, whichever occurs sooner.  Note that all patients 
will be included in the primary analysis regardless of their follow-up time. 
3.3.3 
Rationale for Pharmacokinetic Assessments 
PK assessments allow for confirming that plasma concentrations are consistent within 
the expected concentration ranges observed in previous emicizumab Phase III studies 
that were effective and safe.  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 
anti-emicizumab antibodies will therefore be collected at regular timepoints.  In case of 
ADA positivity, further investigations will be conducted to assess their neutralizing 
potential, either via visual inspections of the PK and PD profiles or, if available, via 
testing on a neutralizing antibody assay. 
De-novo development of FVIII inhibitors in patients with emicizumab will be monitored 
during the study.  Although the development of de novo FVIII antibodies during 
treatment with emicizumab is unexpected, occurrence of these would impact the 
management of breakthrough bleeds requiring the need of bypassing agents.  
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 at all clinic visits.  These will assess 
evidence of biologic activity and safety of emicizumab in patients with non-severe 
hemophilia A with residual endogenous FVIII levels of ≥ 1%. 
The PD biomarkers include, but are not limited to, coagulation assays such as thrombin 
generation, and FVIII activity assays.  These assays have shown in previous Phase I/III 
studies to exhibit a dose-response relationship to emicizumab concentration (for more 
information, refer to the RO5543262 [Emicizumab] Investigator’s Brochure). 
Two thrombin generation assays will be run, one using FXIa triggering reagent, which is 
more sensitive and has been used in previous emicizumab clinical studies, and one 
using tissue factor as triggering reagent, which is more commonly used and enables 
viewing data in the context of other analyses. 
Endogenous and exogenous FVIII activity will be measured using a chromogenic assay 
containing bovine coagulation factors that is insensitive to emicizumab as well as using a 
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chromogenic assay containing human coagulation factors.  FVIII protein levels will also 
be measured using an immunoassay. 
Serum and plasma will be collected periodically for the assessment of bone and joint 
health-related biomarkers, which may include, but 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 markers need to be 
collected under fasting conditions (see Appendix 1). 
One blood sample will be collected for clinical genotyping and may be used to analyze 
FVIII mutations and potentially other coagulation-related gene polymorphisms. 
3.3.6 
Rationale for Patient-Reported Outcome Assessments 
HRQoL is an important outcome in the care of patients with hemophilia (Brown et al. 
2009), and its measurement in clinical trials quantifies the benefit of treatment from the 
perspective of the patient.  HRQoL in patients with hemophilia is multifaceted and 
affected by disease symptoms (e.g., pain, bleeding), treatment (prophylactic, on 
demand, side effects), limitation on daily functioning, anxiety/depression, etc. 
The newly developed CATCH instrument addresses the need for a content-valid, 
fit-for-purpose, hemophilia-specific, self-reported questionnaire to capture the benefit of 
modern therapies and breakthrough therapies in development (Regnault et al. 2019; see 
Section 4.5.7.2). 
The study will also include a measure, the EmiPref, designed to capture patient 
preference with regard to treatment and will be completed by patients ≥12 years of age.  
Additionally, for patients younger than 18 years of age, the patient’s caregiver will be 
asked to fill out the EmiPref (caregiver version).  For patients < 12 years old, only the 
caregiver will fill out the EmiPref (caregiver version).  Previous studies noted that 
patients have expressed preference for treatments that do not have negative effects 
(e.g., pain that results from infusions), are not time consuming, are not associated with 
high treatment burden, and have a goal of achieving a “normal life” (Cimino et al. 2014).  
Previous Phase III studies documented patient preference for emicizumab compared 
with prior treatment (Mahlangu et al. 2018; Pipe et al. 2019). 
For female patients with bleeding disorders, menorrhagia has shown to adversely affect 
their HRQoL (Shankar et al. 2008).  In order to assess the potential impact of 
emicizumab prophylaxis treatment on menorrhagia, this study will include two PRO 
measures for female patients of childbearing potential, the MBQ and the MD.  The MBQ 
is a validated measure for menorrhagia and is widely used in clinical practice to assess 
impact on menstrual bleed-related heaviness, pain, irregularity, and quality of life 
(Matteson et al. 2015).  The MD will use a PBAC, which has been shown to be a reliable 
method for assessing blood loss (Higham et al. 1990). 
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3.3.7 
Rationale for Physical Activity Assessment 
This study provides an opportunity to evaluate whether physical activity of patients 
treated with emicizumab change during the course of treatment.  Accelerometer-based 
instruments provide a patient-independent, objective-movement count.  Despite the gold 
standard of global activity assessment being the direct measurement of activity-related 
energy expenditure, there is evidence that acceleration measurements from the wrist 
can be used to estimate energy expenditure accurately and relatively precisely 
(Staudenmayer et al. 2015).  Weighing these considerations, an objective assessment 
using an accelerometer that is worn on the wrist will focus on, but is not limited to, 
measuring changes in amount of moderate to vigorous physical activity (MVPA) and 
daily step count (DSC) as reliably derived outcome measures (Staudenmayer et al. 
2015; Kendall et al. 2019). 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 70 patients of all age groups will be enrolled in the study consisting of 
approximately 20 patients with mild and approximately 50 patients with moderate 
hemophilia A without FVIII inhibitors whose phenotype warrants prophylaxis. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form (signed by patient’s legally authorized 
representative for patients who have not attained the age of majority) 
• 
Signed Assent Form when appropriate, as determined by patient's age and 
individual site and country standards 
• 
Willingness and ability to comply with schedules visits, treatment plans, laboratory 
tests and other study procedures 
• 
Diagnosis of mild (FVIII level between > 5% and < 40%) or moderate (FVIII level 
between ≥ 1% and ≤ 5%) congenital Hemophilia A without FVIII inhibitors 
• 
Weight ≥ 3 kg 
• 
Need for prophylaxis based on investigator assessment 
• 
A negative test for inhibitor (i.e., < 0.6 BU/mL) within 8 weeks prior to enrollment  
• 
No documented inhibitor (i.e., < 0.6 BU/mL), FVIII half-life < 6 hours, or FVIII 
recovery < 66% in the last 5 years 
Patients who completed successful immune tolerance induction (ITI) at least 
5 years before screening are eligible, provided they have had no evidence of 
inhibitor recurrence (permanent or temporary) as may be indicated by a 
detection of an inhibitor, FVIII half-life < 6 hours or FVIII recovery < 66% since 
completing ITI (Antun et al. 2015). 
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• 
Documentation of the details of prophylactic or episodic FVIII treatment and of 
number of bleeding episodes for at least the last 24 weeks prior to enrollment 
• 
Adequate hematologic function, defined as platelet count ≥ 100,000 cells/µL and 
hemoglobin ≥ 8 g/dL (4.97 mmol/L) at the time of screening 
• 
Adequate hepatic function defined as total bilirubin ≤ 1.5 × age-adapted upper limit of 
normal (ULN) (excluding Gilbert syndrome) and both AST and ALT 
≤ 3 × age-adapted ULN at the time of screening, and no clinical signs or known 
laboratory/radiographic evidence consistent with cirrhosis 
• 
Adequate renal function, defined as serum creatinine ≤ 2.5 × age-adapted ULN and 
creatinine clearance ≥ 30 mL/min by Cockroft-Gault formula 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception as defined below: 
Women must remain abstinent or use contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 24 weeks 
after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis).  The definition 
of childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.  If required per 
local guidelines or regulations, locally recognized acceptable methods of 
contraception and information about the reliability of abstinence will be described 
in the local Informed Consent Form. 
 
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 mild (FVIII level between > 5% 
and < 40%) or moderate (FVIII level between ≥ 1% and ≤ 5%) congenital 
hemophilia A 
• 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 
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• 
Previous (within the last 12 months) or current treatment for thromboembolic 
disease (with the exception of previous catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic 
disease 
• 
Other conditions (e.g., certain autoimmune diseases) that may currently increase 
the risk of bleeding or thrombosis 
• 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
• 
Planned surgery during the emicizumab loading dose phase 
Surgeries in patients on emicizumab from Week 5 onwards are allowed. 
• 
Known HIV infection with CD4 counts < 200 cells/µL 
• 
Concomitant disease, condition, significant abnormality on screening evaluation or 
laboratory tests, or treatment that could interfere with the conduct of the study, or 
that would in the opinion of the investigator, pose an additional unacceptable risk in 
administering study drug to the patient 
• 
Receipt of any of the following: 
– 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration with the exception of prior emicizumab 
prophylaxis (prior investigational or commercial emicizumab use is not an 
exclusion criterion) 
– 
A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
– 
Any other investigational drug currently being administered or planned to be 
administered 
• 
Inability to comply with the study protocol in the opinion of the investigator 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is a single-arm, open-label study.  After initial written informed consent/assent has 
been obtained, 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) 
and indicate the maintenance treatment regimen chosen.  The time between screening 
and enrollment of eligible patients should be ≤ 4 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. 
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4.3.1 
Study Treatment Formulation, Packaging, and Handling 
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 
on 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) and nominal vial strength 30 mg (30 mg/mL, 1.0 mL).  The 
less concentrated formulation will enable safe SC weight-based volume dosing of small 
children with sufficient precision.  The excipient composition and primary packaging is 
identical for all configurations.  For further information on the formulation and handling of 
emicizumab, refer to the RO5543262 (Emicizumab) Investigator's Brochure. 
To minimize the number of injections for patients in certain weight categories, the 
administration per single injection of up to 2 mL of drug product solution will be 
permitted.  This will require pooling of emicizumab drug product solution from up to two 
1-mL vials into a single syringe using a new transfer needle for each vial.  The detailed 
procedure for vial pooling is described in the Instructions for Use.  It is important to note 
that vials of different emicizumab concentrations must not be combined in the same 
syringe. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.  The emicizumab dosing 
regimen to be tested is emicizumab 3 mg/kg SC QW for 4 weeks followed by a 
maintenance dose of either 1.5 mg/kg SC QW, 3 mg/kg SC Q2W, or 6 mg/kg SC Q4W. 
All patients with suboptimal control of bleeding as defined by the protocol will be offered 
the option to increase their emicizumab maintenance dose to 3 mg/kg QW, with approval 
from the Medical Monitor.  Suboptimal response is defined as follows: 
• 
≥ 2 qualifying bleeds within 24 weeks while on prophylactic emicizumab 
 
A qualifying bleed is defined as spontaneous, verified by investigator (e.g., by imaging or 
physical examination), and occurring while on prophylactic emicizumab at steady state 
(after Week 5).  If the investigator believes that a specific patient warrants dose 
escalation on the basis of a different reason, he or she may discuss the case with the 
Medical Monitor for consideration and potential approval. 
An increase of the emicizumab dose to 3 mg/kg QW can occur at the next scheduled 
emicizumab administration of the initial regimen (i.e., 1 week from the last dose of a QW 
regimen, 2 weeks from the last dose of a Q2W regimen, and 4 weeks from the last dose 
of a Q4W regimen). 
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Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
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). 
Patients will be observed for a minimum of 60 minutes after the first three doses as 
described in Section 3.1. 
Patients (≥ 7 years of age) capable to self-administer study drug will be able to perform 
home administration of emicizumab provided they did not experience prior clinically 
significant hypersensitivity reactions with emicizumab.  For home administration, 
patients/caregivers will be required to complete in-person instructional training, using the 
Instructions for Use document, on how to administer emicizumab as an SC injection.  
Patients/caregivers need to observe at least one SC injection performed by the 
healthcare provider (HCP) and successfully administer at least one SC injection while 
being observed by an HCP prior to starting home administration.  Each site will have the 
discretion to provide additional training if deemed appropriate.  If, despite additional 
training, the investigator determines that the patient/caregiver is unable to inject 
emicizumab correctly, study drug may be administered by a trained home nursing 
professional at the patient’s home or another suitable location. 
Medication administration errors during training will be recorded and competence of the 
patient or caregiver to administer at home will be documented in the electronic Case 
Report Form (eCRF).  If necessary, patients 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 the handheld device and 
recording collected used and unused vials at each visit. 
Patients/caregivers should administer emicizumab on the scheduled dosing days.  
On days when blood is to be collected, patients will receive emicizumab after samples 
are drawn in the clinic.  On the other days, for patients receiving emicizumab 1.5 mg/kg 
QW who miss a scheduled dose, 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.  
For patients receiving emicizumab 3 mg/kg Q2W who miss a scheduled dose, 
emicizumab should be administered as soon as possible within a window of 7 days from 
the scheduled dosing date.  If more than 7 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.  For patients receiving emicizumab 6 mg/kg 
Q4W who missed a dose, emicizumab should be administered as soon as possible but 
no later than 14 days from the scheduled dosing date.  If more than 14 days have 
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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. 
All emicizumab dosing should be clearly documented on the handheld device during 
patient’s visits in clinic and when the patient is out of the clinic. 
Patients will be provided with alert cards that they will be requested to carry at all times.  
These will include guidance on recognizing signs/symptoms of thromboembolic events 
or allergic/anaphylactic/anaphylactoid reactions and how to obtain emergency care.  
In addition, the alert cards are designed to notify non-study HCPs that emicizumab will 
interfere with certain coagulation laboratory tests (see the RO5543262 [Emicizumab] 
Investigator’s Brochure for more information) and the investigator should be contacted 
for assistance in interpreting the test results. 
4.3.3 
Investigational Medicinal Product Accountability 
Emicizumab, the only IMP in this study, is required for completion of this study and will 
be provided by the Sponsor.  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, either by time 
monitoring (shipment arrival date and time) or temperature monitoring, for all IMP 
received and that any discrepancies have been reported and resolved before use of the 
IMP.  The IMP 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. 
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 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
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. 
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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 would not 
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 
 
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 
supplements) used by a patient in addition to protocol-mandated treatment from 4 weeks 
prior to enrollment to the study completion/discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.  Medications taken to treat a bleed (e.g., FVIII) will be reported only via the BMQ, 
except for FVIII taken in the week prior to starting emicizumab by patients who will 
continue their prior FVIII prophylaxis until the second loading dose of emicizumab.  
For these patients only, FVIII treatment taken in the week prior to the first dose of 
emicizumab will be recorded on the Hemophilia History Medication 7 Days Prior to 
Enrollment eCRF page. 
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4.4.1 
Permitted Therapy  
Patients will be permitted to use the following concomitant drugs and therapies during 
the study: 
• 
Regular FVIII prophylaxis may continue until the second emicizumab loading dose 
to avoid bleeds before adequate emicizumab levels are reached.  Concomitant 
routine FVIII prophylaxis is otherwise 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. 
Exact dose and schedule of FVIII should be discussed with patients at the 
beginning and throughout the study.  Repeat dosing of VIII should be performed 
only under medical supervision and consideration should be given to verifying 
bleeds prior to repeated dosing. 
• 
Other drugs intended to control bleeds (e.g., bypassing agents, DDAVP, or 
antifibrinolytics) are permitted.  However the use of aPCC should be avoided unless 
no other treatment options/alternatives are available.  If aPCC is indicated in a 
patient receiving emicizumab prophylaxis, the initial dose should not exceed 50 U/kg 
and laboratory monitoring is recommended (including but not restricted to renal 
monitoring, platelet testing, and evaluation of thrombosis).  If bleeding is not 
controlled with the initial dose of aPCC up to 50 U/kg, additional aPCC doses should 
be administered under medical guidance or supervision with consideration made to 
laboratory monitoring for the diagnosis of TMA or thromboembolism and verification 
of bleeds prior to repeated dosing.  The total aPCC dose should not exceed 100 
U/kg in the first 24-hours of treatment.  Treating physicians must carefully weigh the 
risk of TMA and thromboembolism against the risk of bleeding when considering 
aPCC treatment beyond a maximum of 100 U/kg in the first 24-hours. 
• 
Drugs and therapies to treat adverse events and use of topical antiseptics, 
anesthetics, eye drops, etc. that are not considered to result in systemic exposure 
are permitted. 
• 
Drugs to treat an existing medical condition ongoing at study entry that does not 
violate the eligibility criteria (e.g., anti-retroviral therapy for HIV infections) are 
permitted. 
 
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. 
• 
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 declot a venous access device])  
However, drugs intended to control bleeding episodes or used in the context of 
surgeries or injuries (e.g., concussion) to prevent deterioration are allowed. 
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• 
Systemic immunomodulators (e.g., rituximab, interferon) other than anti-retroviral 
therapy 
• 
Elective surgery during the emicizumab loading phase (prior to Week 5)  
• 
Use of other investigational drug 
 
Use of concomitant prophylactic regimen with FVIII or bypassing agents is prohibited 
during the study. 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1 
and Appendix 2.  All activities should be performed and documented for each patient. 
If a breakthrough bleed occurs outside of a hospital visit and requires treatment, 
collection of a blood sample should occur within 30 minutes−24 hours but no later than 
48 hours after treatment for the bleed has been administered.  In such a case, to avoid 
requiring patients to return to the study site for a blood draw, this sample collection may 
be performed by a mobile nursing (MN) professional at the patient's home or another 
suitable location to improve access and convenience for patients participating in the 
study.  In addition, if a patient or caregiver needs assistance with injecting emicizumab 
correctly, emicizumab may be administered by a MN professional. 
The Sponsor will select a healthcare company that will be responsible for providing MN 
services for participating sites (the MN vendor).  The MN vendor is responsible for 
ensuring that all MN professionals are licensed, qualified, and in good standing, as per 
applicable regulations, and that appropriate background checks have been performed.  
If the investigator at a participating site determines that MN services are appropriate for 
a patient and the patient gives written informed consent to participate in MN visits, the 
MN network will communicate with the patient and the patient's site.  MN visits will be 
scheduled on specified visit days, to allow for relevant assessments to be performed by 
the MN professional.  The schedule of activities (see Appendix 1 and Appendix 2) will 
specify which assessments may be performed by an MN professional.  
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent/assent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent/Assent 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. 
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4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, procedures, use of alcohol and 
drugs of abuse within the past year, and medical allergies will be recorded at baseline.  
In particular, sites should record whether the patient has any history of prior ITI, 
anaphylaxis, or known thrombophilia.  For female patients, fertility status, and 
menstruation and menorrhagia history data will be recorded at baseline.  In addition, all 
medications (including prescription, over-the-counter, and herbal/homeopathic remedies 
and therapies) used by the patient within 4 weeks prior to enrollment will be recorded.  
All bleed information (i.e., start date, cause, type, location) during the 24 weeks prior to 
study entry should be documented. 
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, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.  The HJHS 
(see Appendix 3) will be performed as part of physical examination as per the schedule 
of activities (see Appendix 1) 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
4.5.5 
Laboratory, Biomarker, and Other Biological Samples 
Laboratory assessments will be performed as indicated on the schedule of assessments.  
On days of study drug administration, laboratory samples should be drawn before the 
administration of study drug.  Deviations from the schedule of assessments of ± 2 days 
are acceptable; however, pre-dose PK and PD sample collection and drug 
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, 
LDH, and CPK 
• 
Coagulation tests (aPTT, PT/INR) 
• 
Pregnancy test 
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening and within 7 days prior 
to initiation of study medication, if applicable.  Urine pregnancy tests will be 
performed at specified subsequent visits.  If a urine pregnancy test result is 
positive, it must be confirmed by a serum pregnancy test. 
 
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 immunogenicity assessment (ADA) 
• 
Plasma samples for anti-FVIII antibody measurement (inhibitor titer) 
• 
Plasma samples for PD biomarker assessments (FVIII activity, FVIII protein level, 
thrombin generation, and others as listed in Appendix 2). 
• 
Plasma aliquot for assessment of fibrinogen, D-dimer, and PF1 + 2 
• 
Plasma and serum samples for bone and joint biomarkers 
• 
Blood sample for clinical genotyping 
 
In the event of coagulation factor product treatment for breakthrough bleeds, plasma 
samples should be collected within 30 minutes−24 hours (but no later than 48 hours) of 
initial coagulation factor product  administration and sent to the central laboratory (see 
below) for monitoring of emicizumab pharmacokinetics, fibrinogen, FVIII activity (bovine 
and human coagulation factor chromogenic assays), D-dimer, PF1 + 2, and thrombin 
generation (two triggering agents; see Section 3.3.5). 
A blood sample for clinical genotyping will be collected at pre-dose on Day 1 (see 
Appendix 2).  DNA obtained from blood may be analyzed for FVIII mutations and 
potentially other coagulation-related gene polymorphisms (see Section 3.3.5).  If the 
sample is missed on Day 1, it can be collected at any other scheduled visit.  Only one 
clinical genotyping sample is required per patient.  If the patient gives consent, the 
remainder of the clinical genotyping samples (blood) and their derivatives (DNA) will be 
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stored under the Research Biosample Repository (RBR) policy, otherwise the remainder 
will be destroyed. 
For the pediatric population, 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 Union 2008]).  Thus, blood sampling timepoints and 
volumes follow the Ethics Committee (EC) guideline on Ethical Considerations for 
Clinical Trials on Medicinal Products Conducted with the Pediatric Population (European 
Union 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 samples/safety biomarkers.  Refer to the laboratory manual for 
detailed weight-based blood sampling guidelines. 
In certain instances, blood draws, emicizumab administration, or other assessments may 
be performed by an MN professional (see Section 4.5). 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling Manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research or RBR (see Section 4.5.9), biological samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
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. 
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4.5.6 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following parameters will be obtained (and reported by the 
instrument):  uncorrected QT interval, RR interval, heart rate, QT interval corrected 
through use of Bazett’s formula, QT interval corrected through use of Fridericia's formula 
based on the machine readings of the individual ECG tracings, PR duration and 
QRS interval, and T- and U-wave morphology. 
Any ECG changes that are associated with symptoms or lead to a change in study 
treatment or concomitant treatment, or discontinuation from study treatment must be 
reported as an adverse event on the adverse event eCRF.  The ECG may be repeated if 
investigator deems it appropriate.  During the study, the Sponsor may request copies of 
ECGs to be submitted to the Sponsor or a Central Vendor.  Centralized ECG reading 
and interpretations will not be performed unless safety concerns arise. 
4.5.7 
Clinical Outcome Assessments 
PRO data will be collected through use of the following instruments:  BMQ, CATCH, 
EmiPref, EQ-5D-5L, MBQ, and MD with the PBAC. 
4.5.7.1 
Data Collection Methods for Clinical Outcome Assessments 
The BMQ, CATCH, EmiPref, and EQ-5D-5L will be collected electronically using two 
devices (BMQ collected at home on a handheld device given to the patient/caregiver; the 
other questionnaires collected at site on a tablet).  In addition, for female patients of 
childbearing potential, the MBQ and MD with PBAC will be collected on paper.  These 
instruments will be translated into the local language as appropriate. 
For the BMQ data, the patient will be provided with a handheld device 
(see Section 4.5.7.3).  The handheld device to capture bleed data, emicizumab use, and 
other hemophilia medication use during study treatment via the BMQ will be 
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provided/performed/during the Week 1 visit at the study site and will be used by the 
patient for the duration of the study to enter bleed and medication data weekly at a 
minimum.  Patients who withdraw from emicizumab treatment will continue to record 
bleeds and hemophilia medication administration until they complete the safety follow-up 
visit. For the collection of the CATCH, EQ-5D-5L, and EmiPref, a site-based tablet will 
be used. 
The devices will be pre-programmed to enable the BMQ (see Section 4.5.7.3), CATCH, 
EQ-5D-5L, and EmiPref at each specified timepoint (see Appendix 1).  The electronic 
device and instructions for completing the instruments electronically will be provided by 
the site staff.  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.  The data will be available for access by appropriate study 
personnel.  If the electronic data collection system becomes unavailable, the Sponsor 
may instruct sites to collect PRO data (bleed data, emicizumab use, hemophilia 
medication use, and HRQoL) on paper, and once electronic data entry is available, all 
information will need to be entered and submitted electronically. 
For female patients of childbearing potential, the MBQ will be self-administered on paper 
at the site during the clinic visits on Day 1 and subsequently every 4 weeks.  The MD 
with PBAC will be completed on paper by patients at home.  The MD with PBAC will be 
given to patients on Day 1 and should be completed monthly on days of menstruation.  
The patient should return the completed MD with PBAC to the site personnel during the 
next clinic visit.  All MBQ and MD data will be entered into the study database by site 
personnel.  
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see Appendix 1) and at home when appropriate.  At the clinic, instruments will be 
administered before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. 
Patients should be given the following instructions for completing PRO instruments at 
home: 
• 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
• 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
During clinic visits, PRO instruments should be administered as outlined below: 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
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• 
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 patients to complete the instruments, estimated 
to be 15 minutes at each specified visit. 
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Patients 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. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
  
4.5.7.2 
Description of Clinical Outcome Assessment Instruments 
Comprehensive Assessment Tool of Challenges in Hemophilia 
CATCH is a newly developed, validated instrument to measure the effect of hemophilia 
and its treatment on pediatric (aged 8−17 years) and adult patients (aged ≥ 18 years), 
and caregivers of pediatric patients (Regnault et al. 2019).  The adult and pediatric 
versions of CATCH are composed of seven domains, and the caregiver version of 
CATCH is composed of two domains.  Each domain constitutes a set of specific items 
and overall items that help to assess the overall impact of the disease on a given 
domain.  The current versions of the CATCH can be administered electronically.  The 
instructions for completion are within the body of the questionnaire to allow participants 
to complete it independently. 
The adult version covers concepts including daily activity risk perception and impact 
(48 items), social activity risk perception and impact (22 items), recreational activity risk 
perception and impact (32 items + larger bank of additional items), work impact 
(10 items), preoccupation (10 items), treatment burden (8 items), and pain (5 items) (see 
Appendix 4).  The pediatric version includes concepts of daily activity risk perception and 
impact (38 items), social activity risk perception and impact (16 items), recreational 
activity risk perception and impact (34 items + larger bank of additional items), school 
impact (11 items), preoccupation (3 items), treatment burden (7 items), and pain 
(2 items) (see Appendix 5).  For recreational activities, patients only respond to those 
items that are relevant to them.  On average, the adult and pediatric versions take 
15−20 minutes to complete.  The caregiver version comprises concepts related to 
preoccupation (13 items) and treatment burden (8 items), and takes approximately 
5 minutes to complete (see Appendix 6). 
The items in the CATCH versions are scored on ordinal scales (3−4 points for pediatric 
version, 4−5 points for adults and caregiver versions), with an 11-point numeric rating 
scale for pain.  All CATCH raw scores are obtained by calculating the mean of the item 
scores for all items within the corresponding concept and applying a linear 
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transformation.  The transformed scores range from 0 to 100 scale with higher scores 
indicating higher perceived risk or effect. 
EQ-5D-5L 
The EQ-5D-5L is a validated, self-report, health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (see Appendix 7).  
There are two components to the EQ-5D-5L:  a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a VAS that measures health state.  Published weighting systems allow for 
creation of a single composite score of the patient's health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete and will be completed by patients 12 years of age 
and older.  It will be used in this study for informing pharmacoeconomic evaluations. 
Emicizumab Preference Survey 
Patient preference will be assessed through the EmiPref (see Appendix 8 and 
Appendix 9).  Patients and/or caregivers will be asked to report which treatment regimen 
they would prefer to continue to receive or administer after having been treated with or 
administered IV FVIII prior to study entry and SC emicizumab during the study.  Patients 
and/or caregivers who express a preference will then be asked to identify which reasons 
may have influenced their decision and indicate the top three reasons for this choice.  
This assessment will be performed at Week 17 when patients have gained sufficient 
experience with SC injection of emicizumab, while still reliably recalling their experience 
with prior therapy. 
Menstrual Bleeding Questionnaire and Menstruation Diary  
For females with bleeding disorders, menorrhagia can further diminish their health-
related quality of life (Shankar et al. 2008).  Menorrhagia is defined subjectively as 
excessive or prolonged loss of blood on a regular cyclical basis or objectively as 
menstrual blood loss ≥ 80 mL for the whole period (Higham et al. 1990).  
All female patients of childbearing potential will be asked to complete two PROs, the 
MBQ and MD (See Appendix 13 and Appendix 14). 
• 
The MBQ is a validated measure for menorrhagia and is widely used in research 
and clinical practice to assess impact on the menstrual bleed-related heaviness, 
pain, irregularity, and quality of life (Matteson et al. 2015).  The MBQ is a 20-item 
measure covering four aspects regarding heavy menstrual bleeding:  heaviness 
(8 items), quality of life (8 items), irregularity (1 item), and pain (1 item).  
• 
The MD will use a PBAC, which has shown good correlation with menstrual blood 
loss (Higham et al. 1990).  The PBAC is a chart that records the occurrence and 
size of clots, and the number of episodes of heavy bleeding (flooding), as well as 
depicts the amount of blood loss during a cycle.  When summed, the weighted 
scores for light, moderate, or severe blood loss determine a PBAC score for each 
cycle. 
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4.5.7.3 
Bleed and Medication Questionnaire 
Patients (or their legally authorized representative) will complete a BMQ whenever a 
bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days) via an 
electronic, handheld device.  For each bleed episode, the patient will provide information 
regarding bleed start date and time, reason, type, location, and associated symptoms 
(only collected for muscle and joint bleeds in patients 12 years of age and older).  
Hemophilia medications and reason for treatment (e.g., bleed, surgery, physical activity) 
will also be collected through the use of the BMQ.  If the electronic, handheld device is 
not available, a paper questionnaire might be used.  Investigators will review the bleed 
and bleed medication data as per the schedule of activities (see Appendix 1) and will 
have the option to correct or complete the BMQ in agreement with the patient via a Data 
Request Form process or via a web-based portal, once implemented.  The Sponsor will 
have view-access only but will perform a review of the bleed and bleed medication data 
as per the Medical Data Review Plan. 
4.5.7.4 
Bleed Definitions and Reporting 
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 last 
treatment for the bleed, within which any symptoms of bleeding at the same location 
or injections are ≤ 72 hours apart, are considered the same bleed. 
• 
Any injection to treat the bleed, taken > 72 hours after the preceding injection, is 
considered the first injection to treat a new bleed at the same location. 
• 
Any bleed at a different location is considered a separate bleed regardless of time 
from last injection. 
 
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) or as an unresolved target joint.  An 
unresolved target joint is defined as a target joint that does not fulfil the criterion 
of ≤ 2 bleeds into this joint within a consecutive 12-month period (Blanchette et al. 
2014). 
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• 
Joint bleeds:  defined as bleeds with bleed type “joint bleed” reported via the BMQ 
with at least one of the following symptoms: 
– 
Increasing swelling or warmth of the skin over the joint 
– 
Increasing pain 
– 
Progressive loss of range of motion or difficulty in using the limb as compared 
with baseline 
• 
Muscle bleeds (sites as per the BMQ) 
• 
Other (sites as per the BMQ) 
 
Definitions of Bleed Types 
The assessment of a bleed will be separated into spontaneous bleeds, traumatic bleeds, 
and bleeds related to procedure/surgery.  Both spontaneous bleeds (i.e., the occurrence 
of hemorrhage where neither the patient nor a caregiver can identify a reason) and 
traumatic bleeds (i.e., hemorrhage occurring secondary to an event such as trauma, 
“strenuous” activity, or “overuse”) will be collected. 
• 
Spontaneous bleeds:  Bleeds should be classified as spontaneous if a patient 
records a bleed when there is no known contributing factor such as definite trauma, 
antecedent “strenuous” activity, or “overuse.”  The determination of what constitutes 
“strenuous” or “overuse” will be at the discretion of the patient.  For example, light 
jogging may be considered “non-strenuous,” while sprinting may be considered 
“strenuous,” lifting of weights for a short period of time may be considered 
“moderate use,” while repetitive weightlifting may be considered “overuse.” 
• 
Traumatic bleeds:  Bleeds should be classified as traumatic if a patient records a 
bleed when there is a known or believed reason for the bleed.  For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 
obvious injury, the bleed would be recorded as a traumatic bleed because, although 
no injury occurred, there was antecedent “strenuous” activity.  Bleeds subsequent to 
injuries would certainly be classified as traumatic. 
• 
Bleeds related to procedure/surgery:  For example, hematomas resulting from any 
surgery or invasive procedure (e.g., tooth extractions, venipuncture, or SC drug 
administrations), or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy) would not be considered a 
bleed related to procedure/surgery.  Such bleeds are not associated with any 
trauma except procedure/surgery-induced trauma. 
 
Reporting of Bleed Data 
Patients will complete a BMQ weekly and whenever a bleed occurs via an electronic, 
handheld device.  For each bleeding episode, the patient will provide information on the 
above topics as well as on the medication used to treat the bleed.  Hemophilia 
medications that were taken will also be collected through the BMQ.  If the electronic, 
handheld device is not available, a paper questionnaire might be used.  Investigators will 
review the bleed and bleed medication data as per the schedule of assessments 
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(see Appendix 1) and have the option to correct or complete these in agreement with the 
patient via a Data Request Form process or via a web-based portal, once implemented. 
The Sponsor will have view-access only but will perform a review of the bleed and bleed 
medication data as per the Medical Data Review Plan and have the option to correct or 
complete these in agreement with the patient via a Data Request Form process or via a 
web-based portal, once implemented. 
Reporting of Menstrual Bleed and Menstruation Diary Data 
All female patients of childbearing potential will be asked to complete the following paper 
questionnaire and diary: 
• 
MBQ in the clinic on Day 1 and subsequently every 4 weeks to document the 
menstrual bleed-related heaviness, pain, irregularity, and quality of life during the 
past month (See Appendix 13). 
• 
MD with the PBAC to document at home the use of menstrual products during the 
past month (including the number of products used, the amount of bleeding, the 
occurrence and size of clots, and the number of episodes of heavy bleeding 
(flooding)).  The MD with PBAC will be given to patients on Day 1 and should be 
completed monthly on days of menstruation (See Appendix 14).  The patient should 
return the completed MD with PBAC to the site personnel during the next clinic visit. 
 
All MBQ and MD data will be entered into the study database by site personnel. 
4.5.8 
Physical Activity Assessments 
Patients (≥ 5 years of age) should wear the study device continuously (24 hr/day) every 
day for designated 2-week periods during the study (see Appendix 1) as follows:  
Weeks 1−2, Weeks 12−13, Weeks 24−25, Weeks 36−37, and Weeks 48−49.  Patients 
will be instructed to wear the accelerometer on the wrist for 14 consecutive days.  
Patients will be instructed to charge the device. 
Accelerometry data will be collected passively using the study device and uploaded 
regularly to provide continuous measures of, but not limited to, MVPA and DSC; in 
addition, further analyses may be performed. 
An activity count is a measure of the acceleration that is measured by the device.  
The number of hours the device is worn each day will also be derived from the activity 
counts data. 
4.5.9 
Optional Samples for Research Biosample Repository 
4.5.9.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
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development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
• 
To increase knowledge and understanding of disease biology and drug safety 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.9.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board (IRB) or EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RBR sampling, this section 
of the protocol (Section 4.5.9) will not be applicable at that site. 
4.5.9.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to emicizumab, diseases, or 
drug safety: 
• 
Leftover blood samples and any derivatives thereof (e.g., DNA, RNA, proteins, 
peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.9.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, 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. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.9.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
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4.5.9.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global_rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.9.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
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 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
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Patients will return to the clinic for a safety follow-up visit 24 weeks after the final dose of 
study drug (see Appendix 1 and Appendix 2 for additional details). 
4.6.2 
Patient Discontinuation from the Study 
Patients will return to the clinic for a study completion visit as per the schedule of 
activities (see Appendix 1 and Appendix 2). 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
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 a patient requests 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 
 
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 
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• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Emicizumab is approved for the treatment of hemophilia A including mild and moderate 
disease in several countries; however, the clinical development in patients with mild or 
moderate hemophilia A without FVIII inhibitors is ongoing, as emicizumab was not tested 
in this population before.  The safety plan for patients in this study is on the basis of 
clinical experience with emicizumab in completed and ongoing studies.  The anticipated 
important safety risks for emicizumab are outlined below.  Refer to the RO5543262 
(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.  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 and moderate intensity.  Further details for observed 
injection-site reactions are available in the RO5543262 (Emicizumab) Investigator’s 
Brochure.  Directions for emicizumab administration should be followed, as outlined in 
Section 3.3.1 and Section 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.  
These events should be reported as serious adverse events or adverse events of special 
interest as described in Section 5.4.2. 
HCPs administering study medication 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. 
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2006; see Appendix 10 and Appendix 11).  HCPs should also instruct patients how to 
recognize the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid 
reactions and to contact an HCP or seek emergency care in case of any occurrence.  
Patients/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 previous history of a clinically significant hypersensitivity reaction, 
after each of the first three doses, the site will call the patient 24 hours after each dose to 
assess the status of the patient.  Additional precautions following each of these doses 
may also be considered, including having an extended observation period or IV access 
prior to dosing, etc.  The investigator may include these or other precautions, as deemed 
appropriate. 
5.1.1.3 
Hypercoagulation and Thromboembolic Events 
A total of four thromboembolic events have been observed in 3 patients receiving 
emicizumab.  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 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 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 RO5543262 (Emicizumab) Investigator's Brochure 
for further details. 
Thromboembolic events should be reported as serious adverse events or adverse 
events of special interest as described in Sections 5.2.2 and 5.2.3.  HCPs should 
educate patients 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.  Patients will also receive two alert 
cards to remind them of this information and instructions should thromboembolism be 
suspected. 
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, etc.  
Three cases of TMA were reported in Study BH29884.  All cases were assessed as 
being related to study treatment and occurred after recent concomitant aPCC use.  This 
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study will be conducted in patients without FVIII inhibitors, and aPCC is therefore not 
expected to be used for the treatment of breakthrough bleeds.  For further details on 
TMAs, refer to the RO5543262 (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 by 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 by 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 RO5543262 (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 half-life of emicizumab, these effects on coagulation assays may 
persist for up to 6 months after the last dose. 
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. 
However, as of June 2018, no instances of under-treatment for bleeding events due to 
unreliable standard coagulation tests and inhibitor assays in the setting of emicizumab 
were reported by patients receiving emicizumab prophylaxis in clinical trials. 
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5.1.2 
Management of Patients Who Experience Adverse Events 
See Table 1 for guidelines for management of patients who experience adverse events. 
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.  Patients 
will be given guidance on reporting injection-site reactions when 
administering 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, the site will call 
the patient 24 hours after each dose to assess status of the patient. 
• Investigators may order any pertinent laboratory tests, including an 
unscheduled anti-drug antibody, in the event any of these reactions 
occur. 
 
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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.  Decision to resume emicizumab after an event of TMA 
must be discussed with and approved 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.  Decision to resume emicizumab after a
thromboembolic event must be discussed with and approved 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 ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
•
Any unfavorable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal product,
whether or not considered related to the medicinal product
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• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 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 National 
Cancer Institute Common Terminology Criteria for Adverse Events; 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 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 10) 
• 
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 patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
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After initiation of study drug, all adverse events will be reported until the patient 
completes his or her last study visit. 
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 have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The WHO Toxicity Grading Scale (see Appendix 12) 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 
severe or serious secondary events.  A medically significant secondary adverse event 
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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 BMQ).  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 BMQ. 
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  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
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. 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
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 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, 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. 
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• 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
• 
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. 
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• 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO 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) 
• 
Pregnancies (see Section 5.4.3 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 
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• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites 
Medical Monitor:  
 Ph.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Roche Medical Responsible: 
, M.D. 
Telephone No.: 
 
Mobile Telephone No.: 
 
  
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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 treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 24 weeks after the final dose of study drug.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Although embryo-fetal development studies are not available, condom use will not be 
required in male patients enrolled in the study because the margin between the minimal 
anticipated biological effect level plasma concentration (7 ng/mL) and the estimated 
maternal maximum concentration (for all dosing regimens:  1.5 mg/kg QW, 3 mg/kg 
Q2W, 6 mg/kg Q4W, and up-titrated to 3 mg/kg QW) is greater than 10-fold (Banholzer 
et al. 2012).  At this time, very little emicizumab is thought to transfer into semen, and 
there are no known reproductive risks to female partners of male patients treated with 
emicizumab, so contraception use by male patients is not required for participation in the 
study.  Therefore, no proactive collection of pregnancy information for female partners of 
male patients treated with emicizumab will be required. 
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5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or 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. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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. 
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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. 
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: 
• 
RO5543262 (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 
The primary analysis will be performed after 50 patients with moderate hemophilia A 
have either completed 52 weeks of emicizumab treatment, are lost to follow-up, or have 
withdrawn prematurely, whichever occurs first.  Data from all patients (including any 
female patients and any patients with mild hemophilia A) will be included in the primary 
analysis. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The overall sample size of approximately 70 patients (approximately 50 patients with 
moderate disease, approximately 20 patients with mild disease) is based primarily on 
clinical considerations, taking into account the limited number of patients with 
non-severe hemophilia A.  This sample size is expected to provide statistically robust 
point estimates with meaningfully narrow CIs in the overall group of enrolled patients, at 
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the time of the primary analysis or at earlier timepoints appropriate for regulatory 
submissions (see Section 6.10), assuming the same efficacy across dosing regimens. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, and self-reported 
race/ethnicity) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall (all patients), by dosing regimen, and, if applicable, 
by disease severity.  Menstruation history will be summarized descriptively for female 
patients.  Further details will be provided in the Statistical Analysis Plan (SAP). 
6.4 
SAFETY ANALYSES 
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including 
complete blood count with differential and platelet counts), ECGs, vital signs, ADAs, and 
de novo FVIII inhibitors.  To evaluate the overall safety of emicizumab, the incidence of 
adverse events will be summarized and presented by System Organ Class mapped 
term, appropriate thesaurus level, and toxicity grade.  For clinical laboratory data, 
summary statistics will be presented.  In addition, shift tables describing changes from 
baseline will be presented using the WHO Toxicity Grading Scale. 
Summaries will be presented overall, by dosing regimen, and, if applicable, by disease 
severity.  Further details will be provided in the SAP. 
6.5 
EFFICACY ANALYSES 
6.5.1 
Primary Efficacy Endpoint 
The key efficacy objective is to characterize the efficacy of emicizumab based on the 
number of treated bleeds over time.  The definition of a treated bleed is described in 
Section 4.5.7.3. 
The clinical effect of prophylactic emicizumab will be assessed via the ABR estimated 
using a negative binomial regression model, which accounts for different follow-up times, 
with the number of bleeds from patients as a function of the time such that each patient 
who stays in the study is included as an offset in the model. 
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The number of bleeds resulting from the model will be annualized for each patient using 
the following formula: 
 
 
The mean and median ABR 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. 
A detailed description of the statistical methods and the summaries, if applicable, 
presented by dosing regimen and/or by disease severity for the efficacy analyses will be 
provided in the SAP. 
6.5.2 
Secondary Efficacy Endpoints 
6.5.2.1 
Bleed Endpoints 
The clinical effect of prophylactic emicizumab on the secondary bleed endpoints of all 
bleeds (i.e., those treated and untreated with coagulation factors), joint bleeds, target 
joint bleeds, and spontaneous bleeds (see Section 4.5.7.3 for bleed definitions) will be 
analyzed in the same manner as for the primary analysis. 
The number of bleeds, sites of bleeds, and types of bleeds will be summarized for all 
patients and listed for each patient individually.  Several exploratory analyses will be 
conducted to characterize the type, location, duration, frequency, and pattern of bleeds.  
For continuous endpoints, descriptive statistics will be calculated and categorical 
endpoints will be characterized through frequency tables. 
6.5.2.2 
Health-Related Quality-of-Life, Patient Preference, Joint Health, 
Activity, Menstruation Heaviness, and Menstruation-Related 
Quality of Life 
With regards to the PRO secondary objectives, scores by each domain for the CATCH 
will be computed for each assessment with changes in scores examined for the 
assessments over time, and these will be summarized descriptively.  Patient compliance 
with the CATCH will be summarized at each assessed timepoint. 
For the EmiPref, the proportion of patients/caregivers preferring emicizumab after 
17 weeks of treatment will be presented along with the reasons for that choice.  
Patient/caregivers compliance with the EmiPref will be summarized for Week 17.   
For the activity assessment and HJHS, descriptive analyses will be presented by 
timepoints.  All enrolled subjects who contribute to valid activity data (e.g., at least 8 
days of wearing the device within a 14-day observation period) will be analyzed for 
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activity.  The definition of valid activity data and the handling of missing values will be 
provided in the SAP. 
Relative change from baseline (Weeks 1−2 period) at Weeks 13 (Weeks 12−13 period), 
25 (Weeks 24−25 period), 37 (Weeks 36−37 period), and 49 (Weeks 48−49 period) in 
mean MVPA and DSC will be calculated and summarized.  Subject-level data will also 
be presented at each timepoint. 
MBQ will be summarized descriptively over time, including change from baseline for 
individual subscales (heaviness, quality of life, irregularity, and pain) and total score.  
PBAC scores will be summarized descriptively over time.  If the number of female 
patients of childbearing potential is too low to provide reliable summaries, the data will 
listed and presented in individual patient plots where applicable.  
6.6 
PHARMACOKINETIC ANALYSES 
Pre-dose (trough) plasma concentrations of emicizumab will be presented descriptively, 
including arithmetic and geometric means, median, range, standard deviations, and 
coefficients of variation. 
Nonlinear mixed-effects modeling may also be used to analyze the 
dose-concentration-time data of emicizumab following SC administration and estimate 
population PK parameters.  If conducted, these analyses will be reported in a dedicated 
report. 
6.7 
IMMUNOGENICITY ANALYSES 
6.7.1 
Anti-Emicizumab Antibodies 
The immunogenicity analyses for emicizumab antibodies will include patients with at 
least one pre-dose and one post-dose ADA assessment. 
The numbers and proportions of ADA-positive patients and ADA-negative patients 
during both the treatment and follow-up periods will be summarized.  Patients are 
considered to be ADA positive if they are ADA negative at baseline but develop an ADA 
response following study drug administration (treatment-induced ADA response), or if 
they are ADA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater than the titer of the baseline sample (treatment-enhanced ADA 
response).  Patients are considered to be ADA negative if they are ADA negative at 
baseline and all post-baseline samples are negative, or if they are ADA positive at 
baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
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6.7.2 
Factor VIII Inhibitors 
The number and proportion of patients who develop anti-FVIII inhibitors 
(titer ≥ 0.6 BU/mL) following study drug administration will be summarized. 
6.8 
BIOMARKER ANALYSES 
Change over time in PD parameters (e.g., parameters derived from thrombin generation, 
FVIII activity, and protein levels) will be presented using summary statistics 
(e.g., arithmetic and geometric means, median, range, standard deviations, and 
coefficients of variation).  Bone and joint health (if applicable, presented by HJHS 
categories at baseline) may also be explored in the same manner.  Association of FVIII 
mutations and other coagulation-related gene polymorphisms with safety, efficacy, PK, 
and PD endpoints may be explored and reported descriptively. 
6.9 
HEALTH STATUS UTILITY ANALYSES 
Absolute values and change from baseline in EQ-5D-5L health utility index-based and 
VAS scores at specified timepoints will be summarized descriptively. 
6.10 
OPTIONAL INTERIM ANALYSES REVIEWS 
Interim data reviews may be performed at various timepoints for regulatory submissions.  
The results of each of these analyses will be documented in an interim Clinical Study 
Report. 
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. 
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. 
PRO data will be collected through the use of an electronic device provided by a vendor 
and tablet at the clinic (see Section 7.3 for details).  In the event that the electronic 
device is unavailable, the paper version provided to investigators should be completed, 
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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 PATIENT-REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO 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. 
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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
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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 PRO 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 
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. 
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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 ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form, Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
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to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
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.  
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
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 
(see Section 9.5). 
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, which may include data on genomic variants, 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 9.5). 
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). 
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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. 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This 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 70 patients.  
Enrollment will occur through an IxRS. 
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Emicizumab—F. Hoffmann-La Roche Ltd 
88/Protocol BO41423, Version 3 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.5.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
9.5 
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 healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical 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. 
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Emicizumab—F. Hoffmann-La Roche Ltd 
89/Protocol BO41423, Version 3 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
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Emicizumab—F. Hoffmann-La Roche Ltd 
90/Protocol BO41423, Version 3 
10. 
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Soucie JM, Cianfrini C, Janco RL, et al. Joint range-of-motion limitations among young 
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Staudenmayer J, He S, Hickey A, et al. Methods to estimate aspects of physical activity 
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Emicizumab—F. Hoffmann-La Roche Ltd 
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Appendix 1  
Schedule of Activities 
 
Screening a 
Treatment 
Week >49  
to Study 
Completion 
Safety 
FU b 
Study 
Completion/
Discon. c 
Week 
− 
− 
1 
2 
3 
4 
5 
9 13 17 
21 
25 
29 
33 
37 
41 
45 
49 
Day d 
–28 to 
–1 
–7 to 
–1 
1 
8 
15 22 29 57 85 113 141 169 197 225 253 281 309 337 
 
 
 
Informed consent 
x e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROs, HRQoL (CATCH) g 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Q12W 
 
x 
Patient-reported outcomes 
(EmiPref) g 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Health status (EQ-5D-5L) g 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Q12W 
 
x 
Joint health (HJHS) h 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Q24W 
 
x 
Activity i 
 
 
Weeks 1−2, Weeks 12−13, Weeks 24−25, Weeks 36−37, and Weeks 48−49 
 
 
 
Vital signs j 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
 
x 
Weight  
x 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
 
x 
Height k, l 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Q12W 
 
 
Complete physical 
examination m 
x 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Q12W 
 
x 
ECG, n 
x 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
x 
Q12W 
 
x 
Hematology o 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
 
x 
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Appendix 1: 
Schedule of Activities (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
94/Protocol BO41423, Version 3 
 
Screening a 
Treatment 
Week >49  
to Study 
Completion 
Safety 
FU b 
Study 
Completion/
Discon. c 
Week 
− 
− 
1 
2 
3 
4 
5 
9 13 17 
21 
25 
29 
33 
37 
41 
45 
49 
Day d 
–28 to 
–1 
–7 to 
–1 
1 
8 
15 22 29 57 85 113 141 169 197 225 253 281 309 337 
 
 
 
Chemistry p 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
 
x 
Local coagulation tests 
(aPTT, PT/INR) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Pregnancy test q 
 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab administration r 
 
 
x 
x 
x 
x 
To be administered QW, Q2W, or Q4W depending on regimen 
 
 
Samples for PK, PD, ADA, 
and biomarkers 
See Appendix 2. 
BMQ s 
 
 
QW and on days of bleed 
BMQ review t 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q4W 
x 
x 
MBQ u 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q4W 
x 
x 
MD with PBAC u 
 
 
Monthly 
Monthly 
x 
x 
Concomitant medications  
x v 
x v 
x v 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q4W 
x 
x 
Adverse events w 
x 
x 
Ongoing 
ADA = anti-drug antibody; BMQ = Bleed Medication Questionnaire; CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia; 
Discon. = discontinuation; eCRF = electronic Case Report Form; EmiPref = Emicizumab Preference Survey; EQ-5D-5L = European Quality of Life 
5-Dimension, 5-Level Questionnaire; FU = follow-up; FVIII = factor VIII; HJHS = Hemophilia Joint Health Score; HRQoL = health-related quality of life; 
NA = not applicable; PD = pharmacodynamic; PK = pharmacokinetic; PRO = patient-reported outcome; QW = once a week; Q2W = every 2 weeks; 
Q4W = every 4 weeks; Q12W = every 12 weeks; UV = unplanned visit; MBQ = Menstrual Bleeding Questionnaire; MD = Menstruation Diary; 
PBAC = Pictorial Blood Assessment Chart 
Notes:  All study visits and assessments should be performed within ± 2 days of the scheduled visit, until safety follow-up visit.  Safety follow-up 
visit should be performed 24 weeks after discontinuation of emicizumab; deviation of  ± 7 days is acceptable.  Safety follow-up visit will not be 
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Appendix 1: 
Schedule of Activities (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
95/Protocol BO41423, Version 3 
performed for patients who transfer to commercial emicizumab.  On treatment days, all assessments should be performed prior to emicizumab 
dosing, unless otherwise specified.  On treatment days, all PRO assessments, when applicable, should be performed prior to any study 
intervention.
a  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used;
such tests do not need to be repeated for screening.
b Patients who discontinue study drug will return to the clinic for a safety follow-up visit 24 weeks after their final dose of study drug.
c  Study completion/discontinuation visit occurs when the patient completes 52 weeks of emicizumab treatment in the study and either transfer to 
commercially available emicizumab or receive further emicizumab per Roche Global Policy on Continued Access to Investigational Medicinal 
Products; OR patient has completed the 24-week safety follow-up visit after emicizumab discontinuation; OR patient has withdrawn consent; OR 
patient is lost to follow-up.
d  Assessments can deviate from planned schedule by ± 2 days until safety follow-up visit.  Safety follow-up visit should be performed 24 weeks 
after discontinuation of emicizumab; deviation of + 7 days is acceptable.  Safety follow-up visit will not be performed for patients who transfer to
commercial emicizumab.
e  Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days
before initiation of study treatment.
f  Collected from patient’s medical record and documented in the eCRF.
g  Questionnaire will be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment.  For patients younger than 18 years of age, the patient’s caregiver will also be
asked to fill out the EmiPref (caregiver version).  For patients < 12 years old:  only the caregiver will fill out the EmiPref (caregiver version); the 
EmiPref (patient version) and EQ-5D-5L will not be completed.
h  HJHS will be performed as part of the physical examination for patients ≥ 4 years of age.
i Applicable to patients ≥ 5 years of age.  Accelerometer should be worn on the wrist continuously for 24 hr/day for 14 days at each 2-week period
indicated.
j  Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
k  Height assessment at Day 1 only for adults.
l  Height assessments for adolescents at Day 1 and ideally at all drug administration and PK sampling visits at the investigational site, but at least
Q12W (repeated assessments).
m  Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory,
gastrointestinal, genitourinary, and neurologic systems.
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Appendix 1: 
Schedule of Activities (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
96/Protocol BO41423, Version 3 
n If screening ECG is abnormal, repeat at Week 1.  ECGs will also be performed:  once during Weeks 4−8 and once 24 and 49 weeks after 
starting emicizumab. 
o  Pre-dose:  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 will be performed locally.  Laboratory assessments completed at the screening visit do not have to be repeated at 
Week 1 if the period between screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the 
investigator. 
p  Pre-dose:  sodium, potassium, glucose, BUN, creatinine, calcium, phosphate, magnesium, total and direct bilirubin, albumin, ALP, ALT, AST, 
LDH and CPK will be performed locally.  Laboratory assessments completed at the screening visit do not have to be repeated at Week 1 if the 
period between screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the investigator. 
q  All women of childbearing potential (including those who have had a tubal ligation) will be required to have a negative serum pregnancy test 
result at screening and within 7 days prior to initiation of study medication (Day −7 to Day −1).  If applicable, urine pregnancy tests will be 
performed at the scheduled visits, except for Weeks 2−4.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
If the serum pregnancy test is positive, further administration of emicizumab should be discontinued. 
r Emicizumab may be administered by a mobile nursing professional. 
s Bleed information for each bleed (start date and time, reason, type, location, and associated symptoms (only collected for muscle and joint 
bleeds in patients 12 years of age and older)) and medication for bleeds (breakthrough bleeds) should be reported by the patient via an 
electronic, handheld device when a bleed occurs or at least on a weekly basis (retrospective reporting for last 7 days).  If the patient discontinues 
study treatment, bleed and bleed medication data should be provided by the patient until the safety follow-up visit (24 weeks after final study 
drug administration).  Emicizumab doses should be recorded by the patient in the BMQ starting on Day 1. 
t Investigator review of bleed information. 
u All female patients of childbearing potential will be asked to provide the start and end dates of menstruation that will be recorded on eCRF and to 
complete the MBQ and the MD with PBAC, both on paper.  The MBQ will be self-administered in the clinic on Day 1 and subsequently every 4 
weeks; the MD with PBAC will be completed by patients at home.  The MD with PBAC will be given to patients on Day 1 and should be 
completed monthly on days of menstruation.  The patient should return the completed MD with PBAC to the site personnel during the next clinic 
visit.  The MD with PBAC is a monthly form that will be given in multiple copies to the patients to cover the length of the study.  
v Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 4 weeks prior to enrollment to the study completion/discontinuation visit.  FVIII taken 
during the week prior to starting emicizumab (i.e., week prior to Day 1) will also be collected on the Hemophilia History Medication 7 Days 
Prior to Enrollment eCRF page for patients who will continue their prior FVIII prophylaxis during the first week of the study. 
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Appendix 1: 
Schedule of Activities (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
97/Protocol BO41423, Version 3 
w 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 collected on an ongoing basis throughout the study.  Injection-site reactions will be 
collected on a separate form from the adverse event form.  After initiation of study drug, all adverse events will be reported until 24 weeks after 
the final dose of emicizumab.  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 prior study drug treatment (see Section 5.6). 
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Emicizumab—F. Hoffmann-La Roche Ltd 
98/Protocol BO41423, Version 3 
Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
Assessments 
Screening 
Treatment Period 
Week >49  
to Study 
Completion 
Safety 
FU 
Visit 
Study 
Completion/ 
Discon. a 
Week 
 
1 
2 
3 
4 
5 
9 
13 17 21 25 29 33 37 41 45 49 
Day 
–28 to 
–1 
1 
8 
15 22 29 57 85 113 141 169 197 225 253 281 309 337 
 
 
 
Blood sample for genotyping b, 
c, f 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Emicizumab PK (plasma) b 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Emicizumab ADA (plasma) b, d 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
x 
Q12W 
x 
x 
PD and safety biomarkers 
(plasma) b, e, f 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Anti-FVIII antibodies f 
x g 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Q12W 
x 
x 
Plasma and serum sample for 
bone and joint biomarkers h, f 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Plasma samples following 
treatment with coagulation 
factor product i 
 
Monitoring for procoagulant effect i 
ADA = anti-drug antibody; Discon. = discontinuation; FU = follow-up; FXIa = factor XIa; FVIII = factor VIII; PD = pharmacodynamic; 
PK = pharmacokinetic; Q12W = every 12 weeks; TGA = thrombin generation assay. 
Note:  All study visits and assessments during the treatment period should be performed within ± 2 days of the scheduled date until safety follow-up 
visit.  Safety follow-up visit should be performed 24 weeks after discontinuation of emicizumab; deviation of  ± 7 days is acceptable.  Safety follow-
up visit will not be performed for patients who transfer to commercial emicizumab.  On treatment days, all assessments should be performed prior 
to emicizumab dosing, unless otherwise specified.  On treatment days, all PRO assessments, when applicable, should be performed prior to any 
study intervention, 
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Appendix 2:Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
99/Protocol BO41423, Version 3 
a Study completion/discontinuation visit occurs when the patient completes 52 weeks of emicizumab treatment in the study and either transfers to 
commercially available emicizumab or receives further emicizumab per Roche Global Policy on Continued Access to Investigational Medicinal 
Products; OR patient has completed the 24-week safety follow-up visit after emicizumab discontinuation; OR patient has withdrawn consent; OR 
patient is lost to follow-up.   
b Samples should always be drawn pre-dose.  
c If the sample is missed on Day 1, it can be collected at any other scheduled visit. 
d ADA samples may also be drawn if hypersensitivity event occurred or at any time (unscheduled) in the investigator's judgment. 
e PD markers include FVIII activity (bovine and human coagulation factor chromogenic assays), FVIII protein, and thrombin generation (FXIa- and 
tissue factor triggered TGAs).  Safety markers include, but are not limited to, fibrinogen, D-dimer, and prothrombin fragment 1+2.  
f Samples will only be collected if the permitted blood volumes allow (based on patient body weight as described in Section 4.5.5).  Refer to the 
laboratory manual for details. 
g At screening, the evaluation for anti-FVIII antibodies will be performed locally and documented on eCRF to confirm the negative testing for 
inhibitor as per inclusion criteria.  This sample must be obtained during screening, within 4 weeks prior to enrollment (i.e., before initiation of 
Week 1, Day 1 assessments).  The results must be available before enrollment, and local testing will not replace the central laboratory 
inhibitor testing performed at Week 1. 
h Collect after fasting overnight in patients ≥ 12 years of age. 
i Following treatment with coagulation factor product, sample should be collected for central laboratory monitoring of emicizumab 
pharmacokinetics, fibrinogen, FVIII activity (bovine and human coagulation factor chromogenic assays), D-dimer, prothrombin fragment 1 + 2, 
and thrombin generation (FXIa- and tissue factor-triggered TGAs) within 24 hours (but no later than 48 hours) of initial coagulation factor product 
use.  If a breakthrough bleed occurs outside of a hospital visit and requires treatment, collection of a blood sample should occur within 
30 minutes−24 hours but no later than 48 hours after treatment for the bleed has been administered.  In such a case, to avoid requiring patients 
to return to the study site for a blood draw, this sample collection may be performed by a mobile nursing professional at the patient's home or 
another suitable location to improve access and convenience for patients participating in the study. 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
100/Protocol BO41423, Version 3 
Appendix 3  
Hemophilia Joint Health Score 
 
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Appendix 3: Hemophilia Joint Health Score (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
101/Protocol BO41423, Version 3 
 
 
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Appendix 4: Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH):  
Adult (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
106/Protocol BO41423, Version 3 
Recreational activities: Please indicate whether you do the following activities on 
a regular basis.  
 Fishing 
 Swimming 
 Doing yoga 
 Golfing 
 Playing tennis 
 Woodworking 
 Dancing 
 Hiking 
 Camping 
 Canoeing/Kayaking 
 Riding a stationary bicycle 
 Riding a bicycle 
 Running on a treadmill or elliptical trainer 
 Running outside 
 Hunting 
 Rock climbing 
 Surfing 
 Volleyball 
 Frisbee  
 Soccer 
 Baseball 
 Basketball 
 Squash/racquetball 
 Karate or judo 
 Weight lifting 
 Nordic/cross country skiing 
 Downhill skiing 
 Skateboarding 
 Scuba diving 
 Ice hockey 
 Football 
 Rugby 
 
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Appendix 4: Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH):  
Adult (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
107/Protocol BO41423, Version 3 
Recreational activities: Please indicate whether there are any activities on this list 
you do NOT do because of your hemophilia.  
 Fishing 
 Swimming 
 Doing yoga 
 Golfing 
 Playing tennis 
 Woodworking 
 Dancing 
 Hiking 
 Camping 
 Canoeing/Kayaking 
 Riding a stationary bicycle 
 Riding a bicycle 
 Running on a treadmill or elliptical trainer 
 Running outside 
 Hunting 
 Rock climbing 
 Surfing 
 Volleyball 
 Frisbee 
 Soccer 
 Baseball 
 Basketball 
 Squash/racquetball 
 Karate or judo 
 Weight lifting 
 Nordic/cross country skiing 
 Downhill skiing 
 Skateboarding 
 Scuba diving 
 Ice hockey 
 Football 
 Rugby 
 
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Appendix 5: Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH):  
Pediatric (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
116/Protocol BO41423, Version 3 
 Playing paintball 
 Running outside 
 Hunting 
 Frisbee 
 Kickball 
 Fencing 
 Dodgeball 
 Water polo 
 Wakeboarding 
 Snowboarding 
 Rock climbing 
 Soccer 
 Baseball 
 Basketball 
 Lacrosse 
 Volleyball 
 Squash/racquetball 
 Bouncy houses 
 Jumping on trampolines 
 Nordic/cross country skiing 
 Downhill skiing 
 Gymnastics 
 Karate or Judo 
 Parkour 
 Wrestling 
 Boxing 
 Kickboxing 
 Weightlifting 
 Skateboarding 
 Ice hockey 
 Flag football 
 Tackle football 
 Rugby 
 
Recreational activities: Please check off any activities on this list that you DO NOT 
DO because of your hemophilia.  
 
 Swimming 
 Golfing 
 Ping pong 
 Archery 
 Tennis 
 Dancing 
 Climbing trees 
 Riding a scooter 
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Appendix 5: Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH):  
Pediatric (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
117/Protocol BO41423, Version 3 
 Riding a bicycle 
 Riding horses 
 Ice skating 
 Rollerblading 
 Playing paintball 
 Running outside 
 Hunting 
 Frisbee 
 Kickball 
 Fencing 
 Dodgeball 
 Water polo 
 Wakeboarding 
 Snowboarding 
 Rock climbing 
 Soccer 
 Baseball 
 Basketball 
 Lacrosse 
 Volleyball 
 Squash/racquetball 
 Bouncy houses 
 Jumping on trampolines 
 Nordic/cross country skiing 
 Downhill skiing 
 Gymnastics 
 Karate or Judo 
 Parkour 
 Wrestling 
 Boxing 
 Kickboxing 
 Weightlifting 
 Skateboarding 
 Ice hockey 
 Flag football 
 Tackle football 
 Rugby 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
123/Protocol BO41423, Version 3 
Appendix 7  
EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
 
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Appendix 7: EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
124/Protocol BO41423, Version 3 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
125/Protocol BO41423, Version 3 
Appendix 8  
Emicizumab Preference Survey (EmiPref):  Patient 
 
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Appendix 8: Emicizumab Preference Survey (EmiPref):  Patient (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
126/Protocol BO41423, Version 3 
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Emicizumab—F. Hoffmann-La Roche Ltd 
127/Protocol BO41423, Version 3 
Appendix 9  
Emicizumab Preference Survey (EmiPref):  Caregiver 
 
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Appendix 9: Emicizumab Preference Survey (EmiPref):  Caregiver (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
128/Protocol BO41423, Version 3 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
129/Protocol BO41423, Version 3 
Appendix 10  
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 
• 
Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline   
 
 
_________________________ 
1 Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 
2006;117:391–7. 
2 Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg + [2 x age]) from 1 to 10 years, and less than 90 mmHg from 11 to 
17 years. 
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Emicizumab—F. Hoffmann-La Roche Ltd 
130/Protocol BO41423, Version 3 
Appendix 11  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
131/Protocol BO41423, Version 3 
Appendix 12  
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 
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Appendix 12:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
132/Protocol BO41423, Version 3 
Item 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
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 
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Appendix 12:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
133/Protocol BO41423, Version 3 
Item 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
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 
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 
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Appendix 12:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
134/Protocol BO41423, Version 3 
Item 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
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 
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 
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Appendix 12:  WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse Events (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
135/Protocol BO41423, Version 3 
Item 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
NEURO AND NEUROMUSCULAR (cont.) 
Neuro control 
(ADL = activities of daily 
living) 
mild difficulty concentrating; 
no Rx; mild 
confusion/agitation; ADL 
unaffected 
moderate confusion/agitation 
some limitation of ADL; 
minimal Rx 
severe confusion/agitation 
needs assistance for ADL; 
therapy required 
toxic psychosis; 
hospitalization 
Muscle strength 
subjective weakness 
no objective symptoms/signs 
mild objective 
signs/symptoms no 
decrease in function 
objective weakness function 
limited 
paralysis 
OTHER PARAMETERS 
Fever: oral, > 12 hours 
37.7−38.5°C or  
99.9−101.3°F 
38.6−39.5°C or  
101.4−103.1°F 
39.6−40.5°C or 103.2−104.9°F 
> 40.5°C or 
> 104.9°F 
Headache 
mild, no Rx therapy 
transient, moderate; Rx 
required 
severe; responds to initial 
narcotic therapy 
intractable; required repeated 
narcotic therapy 
Fatigue 
no decrease in ADL 
normal activity decreased 
25−50% 
normal activity decreased 
> 50% can’t work 
unable to care for self 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema 
anaphylaxis 
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 
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Emicizumab—F. Hoffmann-La Roche Ltd 
136/Protocol BO41423, Version 3 
Appendix 13 Menstrual Bleeding Questionnaire 
 
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Appendix 13:  Menstrual Bleeding Questionnaire (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
137/Protocol BO41423, Version 3 
 
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Appendix 13:  Menstrual Bleeding Questionnaire (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
138/Protocol BO41423, Version 3 
 
 
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Appendix 13:  Menstrual Bleeding Questionnaire (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
139/Protocol BO41423, Version 3 
 
 
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Appendix 13:  Menstrual Bleeding Questionnaire (cont.) 
  
Emicizumab—F. Hoffmann-La Roche Ltd 
140/Protocol BO41423, Version 3 
 
 
 
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Emicizumab—F. Hoffmann-La Roche Ltd 
141/Protocol BO41423, Version 3 
Appendix 14 Menstruation Diary 
 
 
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