A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to 
Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic 
Emicizumab Versus No Prophylaxis in Hemophilia A Patients 
NCT Number: 
NCT03315455 
Document Date: 
Protocol Amendment Version 5: 22-April-2023 
 
 
 

PROTOCOL AMENDMENT APPROVAL 
 
 
 
 
 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
Protocol YO39309, Version 5 
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III CLINICAL TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF PROPHYLACTIC EMICIZUMAB VERSUS NO 
PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
PROTOCOL NUMBER: YO39309 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT03315455 
TEST PRODUCT: 
Emicizumab (RO5534262) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

Emicizumab—F. Hoffmann-La Roche Ltd 
2/Protocol YO39309, Version 5 
PROTOCOL HISTORY 
Protocol 
Associated Country Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
5 
See electronic 
date stamp on 
the final page of 
this document 
 
 
 
 
 
China 
5 
10 Feburary 2022 a
4 
19 July 2019 
 
 
 
3 
30 October 2017 
 
 
 
2 
20 March 2017 
 
 
 
1 
1 June 2016 
 
 
 
a
Not distributed to sites o. heath authorities.

 
Emicizumab—F. Hoffmann-La Roche Ltd 
3/Protocol YO39309, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol YO39309 has been primarily amended to extend the study.  The study will end 
3 years after the last Arm D patient completes 1 year treatment and patients still having 
clinical benefit are transferred to a post-trial continued access solution per Roche Global 
Policy on Continued Access to Investigational Medicinal Products (see Sections 3.1 and 
4.3.4).  The study will end earlier, before 3 years after the last Arm D patient completes 
1 year treatment, should the post-trial continued access solution be available earlier (see 
Section 3.2.1).  Changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
Language has been added to clarify that collection of pharmacokinetic 
(PK)/anti-drug antibody (ADA)/Biomarker samples from Arm D patients will stop 
when the patient completes the study or after Week 49, whichever occurs first 
(Section 3.1). 
 
Language has been added to clarify that patients who discontinue treatment prior to 
the end of study will return to the clinic for a safety follow-up visit 24 weeks after the 
final dose of study drug (Section 3.2.1). 
 
The length of study has been extended to 88 months to include a study Extension 
Phase because the study had been extended for 3 years after last Arm D patient 
completes 1 year of treatment and patients still having clinical benefit are transferred 
to a post-trial continued access solution.  This is to allow patients who are still 
benefiting from emicizumab to continue treatment and to collect their safety data 
during the extended treatment (Section 3.2.2 and Appendix 1-B). 
 
Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during Investigational Medicinal 
Product (IMP) transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.3). 
 
Language has been added to clarify that the Bleed/Medication questionnaire 
devices will remain with the patient/caregiver for the duration of the study.  Bleed 
and medication data will not be collected during the study extension phase, but 
emicizumab dosing data will continue to be collected (Section 4.5.7). 
 
Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (Section 5.4.1).  Medical Monitor 
contact information has been replaced with a sentence indicating that this 
information will be provided separately to sites. 
 
Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
4/Protocol YO39309, Version 5 
 
The name of a Roche policy on data sharing has been corrected (Section 9.5). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
5/Protocol YO39309, Version 5 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 24 
1.1 
Background on Hemophilia A .................................................. 24 
1.1.1 
Management ............................................................................ 24 
1.2 
Background on Emicizumab .................................................... 29 
1.2.1 
Molecule and Nonclinical Data ................................................. 29 
1.2.2 
Clinical Experience .................................................................. 30 
1.2.2.1 
Clinical Pharmacology ............................................................. 31 
1.2.2.2 
Efficacy .................................................................................... 31 
1.2.2.3 
Safety ...................................................................................... 33 
1.2.2.4 
Immunogenicity ........................................................................ 34 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 35 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 36 
3. 
STUDY DESIGN ........................................................................... 39 
3.1 
Description of the Study ........................................................... 39 
3.2 
End of Study and Length of Study ........................................... 44 
3.2.1 
End of Study ............................................................................ 44 
3.2.2 
Length of Study ........................................................................ 44 
3.3 
Rationale for Study Design ...................................................... 45 
3.3.1 
Rationale for Emicizumab Dose and Schedule ........................ 46 
3.3.2 
Rationale for Patient Population .............................................. 49 
3.3.3 
Rationale for Control Group ..................................................... 50 
3.3.4 
Rationale for the Primary Efficacy Analysis ............................. 50 
3.3.5 
Rationale for Patient-Reported Outcome Assessments ........... 51 
3.3.6 
Rationale for Biomarker Assessments ..................................... 52 
3.3.7 
Rationale for Pharmacokinetic Sample Schedule .................... 53 
4. 
MATERIALS AND METHODS ...................................................... 53 
4.1 
Patients .................................................................................... 53 
4.1.1 
Inclusion Criteria ...................................................................... 53 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
6/Protocol YO39309, Version 5 
4.1.1.1 
Arms A, B, and C ..................................................................... 53 
4.1.1.2 
Arm D ...................................................................................... 54 
4.1.2 
Exclusion Criteria ..................................................................... 55 
4.1.2.1 
Arms A, B, and C ..................................................................... 55 
4.1.2.2 
Arm D ...................................................................................... 56 
4.2 
Method of Treatment Assignment and Blinding ....................... 57 
4.3 
Study Treatment ...................................................................... 57 
4.3.1 
Formulation, Packaging, and Handling .................................... 58 
4.3.1.1 
Emicizumab ............................................................................. 58 
4.3.2 
Dosage, Dose Adjustment, and Administration........................ 58 
4.3.3 
Investigational Medicinal Product Accountability ..................... 61 
4.3.4 
Post-Trial Access to Emicizumab ............................................ 61 
4.4 
Concomitant and Rescue Therapy .......................................... 62 
4.4.1 
Permitted Therapy ................................................................... 62 
4.4.2 
Prohibited Therapy .................................................................. 63 
4.5 
Study Assessments ................................................................. 64 
4.5.1 
Informed Consent Forms and Screening Log .......................... 64 
4.5.2 
Medical History and Demographic Data .................................. 64 
4.5.3 
Physical Examinations ............................................................. 65 
4.5.4 
Vital Signs ................................................................................ 65 
4.5.5 
Laboratory, Biomarker, and Other Biological Samples ............ 65 
4.5.6 
Electrocardiograms .................................................................. 67 
4.5.7 
Patient-Reported Outcomes .................................................... 67 
4.5.7.1 
Health-Related Quality of Life .................................................. 68 
4.5.7.2 
Health Status ........................................................................... 68 
4.5.7.3 
Adapted Inhib-QoL, Including Aspects of Caregiver Burden .... 68 
4.5.7.4 
Daycare/School Absences and Hospitalizations ...................... 69 
4.5.8 
Definition of a Bleed ................................................................. 69 
4.5.8.1 
Bleed Sites............................................................................... 69 
4.5.8.2 
Bleed Types ............................................................................. 70 
4.6 
Patient, Treatment, Study, and Site Discontinuation ................ 71 
4.6.1 
Patient Discontinuation ............................................................ 71 
4.6.2 
Study Treatment Discontinuation ............................................. 71 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
7/Protocol YO39309, Version 5 
4.6.3 
Study and Site Discontinuation ................................................ 71 
5. 
ASSESSMENT OF SAFETY ......................................................... 72 
5.1 
Safety Plan .............................................................................. 72 
5.1.1 
Patient Selection ...................................................................... 72 
5.1.2 
Risks Associated with Emicizumab .......................................... 72 
5.1.2.1 
Identified Risks ........................................................................ 72 
5.1.2.2 
Potential Risks ......................................................................... 74 
5.1.3 
Management of Patients Who Experience Specific 
Adverse Events ........................................................................ 76 
5.1.4 
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab ............................................................ 77 
5.1.5 
Procedure-Related Risks ......................................................... 78 
5.2 
Safety Parameters and Definitions .......................................... 78 
5.2.1 
Adverse Events ........................................................................ 78 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) ............................................................................ 79 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 80 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 80 
5.3.1 
Adverse Event Reporting Period .............................................. 80 
5.3.2 
Eliciting Adverse Event Information ......................................... 81 
5.3.3 
Assessment of Severity of Adverse Events ............................. 81 
5.3.4 
Assessment of Causality of Adverse Events............................ 81 
5.3.5 
Procedures for Recording Adverse Events .............................. 82 
5.3.5.1 
Injection-Site Reactions ........................................................... 82 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 82 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 83 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 83 
5.3.5.5 
Abnormal Laboratory Values ................................................... 83 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 84 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 85 
5.3.5.8 
Deaths ..................................................................................... 85 
5.3.5.9 
Preexisting Medical Conditions ................................................ 86 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
8/Protocol YO39309, Version 5 
5.3.5.10 
Lack of Efficacy or Worsening of Hemophilic Bleeds ............... 86 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 86 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in 
Drug Administration ................................................................. 87 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 87 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 87 
5.4.1 
Emergency Medical Contacts .................................................. 88 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 88 
5.4.2.1 
Events That Occur prior to Randomization or Study Drug 
Initiation ................................................................................... 88 
5.4.2.2 
Events That Occur after Randomization or Study Drug 
Initiation ................................................................................... 88 
5.4.3 
Reporting Requirements for Pregnancies ................................ 89 
5.4.3.1 
Pregnancies in Female Patients .............................................. 89 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 89 
5.4.3.3 
Abortions.................................................................................. 90 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 90 
5.5 
Follow-Up of Patients after Adverse Events............................. 90 
5.5.1 
Investigator Follow-Up ............................................................. 90 
5.5.2 
Sponsor Follow-Up .................................................................. 90 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 91 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 91 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 91 
6.1 
Determination of Sample Size ................................................. 92 
6.2 
Summaries of Conduct of Study .............................................. 93 
6.3 
Summaries of Treatment Group Comparability ........................ 93 
6.4 
Efficacy Analyses ..................................................................... 93 
6.4.1 
Primary Efficacy Endpoint ........................................................ 93 
6.4.2 
Secondary Efficacy Endpoints ................................................. 95 
6.5 
Safety Analyses ....................................................................... 96 
6.6 
Pharmacokinetic Analyses ....................................................... 97 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
9/Protocol YO39309, Version 5 
6.7 
Exploratory Analyses ............................................................... 97 
6.8 
Interim Analysis ....................................................................... 97 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 97 
7.1 
Data Quality Assurance ........................................................... 97 
7.2 
Electronic Case Report Forms ................................................. 98 
7.3 
Electronic Patient-Reported Outcome Data ............................. 98 
7.4 
Source Data Documentation .................................................... 98 
7.5 
Use of Computerized Systems ................................................ 99 
7.6 
Retention of Records ............................................................... 99 
8. 
ETHICAL CONSIDERATIONS .................................................... 100 
8.1 
Compliance with Laws and Regulations ................................ 100 
8.2 
Informed Consent .................................................................. 100 
8.3 
Institutional Review Board or Ethics Committee .................... 101 
8.4 
Confidentiality ........................................................................ 102 
8.5 
Financial Disclosure ............................................................... 102 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 103 
9.1 
Study Documentation ............................................................ 103 
9.2 
Protocol Deviations ................................................................ 103 
9.3 
Site Inspections ..................................................................... 103 
9.4 
Administrative Structure ......................................................... 103 
9.5 
Publication of Data and Protection of Trade Secrets ............. 103 
9.6 
Protocol Amendments ........................................................... 104 
10. 
REFERENCES............................................................................ 106 
 
LIST OF TABLES 
Table 1 
Status of Clinical Studies for Emicizumab ................................... 30 
Table 2 
Objectives and Corresponding Endpoints ................................... 37 
Table 3 
Mean Reduction (%) of Annualized Bleeding Rates in 
Inhibitor and Non-Inhibitor Patients Enrolled in 
Study ACE001JP/ACE002JP ...................................................... 47 
Table 4 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 76 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
10/Protocol YO39309, Version 5 
Table 5 
Coagulation Test Results Affected and Unaffected by 
Emicizumab ................................................................................ 78 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 81 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 41 
Figure 2 
Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event ............................................................................ 47 
Figure 3 
Simulated Plasma Emicizumab Concentration over Time 
(Q4W Dosing) ............................................................................. 48 
 
LIST OF APPENDICES 
Appendix 1-A Schedule of Assessments ......................................................... 114 
Appendix 1-B Schedule of Assessments - Extension Phase ........................... 121 
Appendix 2-A Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (Arm A, QW) a ........................................... 123 
Appendix 2-B Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (Arm B, Q4W) ........................................... 125 
Appendix 2-C Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (Arm C, at Time of Switch to 
Emicizumab) ............................................................................. 127 
Appendix 2-D Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (Arm D, QW) ............................................. 129 
Appendix 3 
Haem-A-QoL (United States/English) ....................................... 131 
Appendix 4 
Haemo-QoL-SF (United States/English) ................................... 138 
Appendix 5 
EQ-5D-5L (United Kingdom/English) ........................................ 140 
Appendix 6 
Adapted Inhibitor-Specific Quality of Life (Inhib-QoL) with 
Aspects of Caregiver Burden (United States/English) ............... 142 
Appendix 7 
Clinical Criteria for Diagnosing Anaphylaxis.............................. 147 
Appendix 8 
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events ......................................................................... 148 
Appendix 9 
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients on Emicizumab ........................................................... 154 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
11/Protocol YO39309, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III CLINICAL TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF PROPHYLACTIC EMICIZUMAB VERSUS NO 
PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
PROTOCOL NUMBER: YO39309 
VERSION NUMBER: 
5  
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT03315455 
TEST PRODUCT: 
Emicizumab (RO5534262) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor. 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
15/Protocol YO39309, Version 5 
STUDY DESIGN 
DESCRIPTION OF STUDY 
Study YO39309 is a multicenter, open-label, Phase III clinical study with randomized and 
non-randomized arms designed to investigate the efficacy, safety, and pharmacokinetics of 
emicizumab in patients with hemophilia A regardless of factor VIII (FVIII) inhibitor status.  
Seventy patients aged  12 years who received episodic therapy with FVIII or bypassing agents 
prior to study entry and experienced at least 5 bleeds over the prior 24 weeks (annualized 
bleeding rate [ABR]  10) will be randomized in a 2:2:1 ratio to the following regimens: 
 
Arm A:  Emicizumab prophylaxis at 3 mg/kg weekly (QW) subcutaneously for 4 weeks, 
followed by 1.5 mg/kg QW subcutaneously 
 
Arm B:  Emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed by 
6 mg/kg every 4 weeks (Q4W) subcutaneously 
 
Arm C:  No prophylaxis control arm 
 
In addition, 15 pediatric patients with hemophilia A and inhibitors who received episodic therapy 
with bypassing agents prior to study entry will be enrolled to Arm D: 
 
Arm D:  Emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed by 
1.5 mg/kg QW subcutaneously 
 
NUMBER OF PATIENTS 
A total of 70 patients with severe hemophilia A who previously received episodic therapy with 
either FVIII or bypassing agents will be enrolled in Arms A, B, and C. 
A total of 15 pediactric patients with hemophilia A with inhibitors from China mainland who 
previously received episodic therapy with bypassing agents will be enrolled in Arm D. 
TARGET POPULATION 
Inclusion Criteria 
Arms A, B, and C 
Patients in Arms A, B, and C must meet the following criteria for study entry: 
 
Signed Informed Consent Form by the patient or a legal guardian 
 
Able to comply with the study protocol, in the investigator’s judgment 
 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of patient-reported outcome (PRO) 
questionnaires and bleed and medication diary through the use of an electronic device 
 
Aged 12 years or older at the time of informed consent 
 
Body weight  40 kg at the time of screening 
 
Diagnosis of severe congenital hemophilia A (intrinsic FVIII level 1 %) or hemophilia A with 
FVIII inhibitors 
 
Patients without FVIII inhibitors ( 0.6 BU/mL) who completed successful immune tolerance 
induction (ITI) must have done so at least 5 years before screening and have no evidence 
of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor 
 0.6 BU/mL since ITI 
 
Documentation of the details of episodic therapy (FVIII or bypassing agents) and of number 
of bleeding episodes for at least the last 24 weeks 
 
 5 bleeds in the last 24 weeks prior to study entry 
 
Adequate hematologic function, defined as platelet count  100,000/L and hemoglobin 
 8 g/dL (4.97 mmol/L) at the time of screening 
 
Adequate hepatic function, defined as total bilirubin  1.5  the upper limit of normal (ULN) 
(excluding Gilbert’s syndrome) and AST and/or ALT  3  ULN at the time of screening; no 
clinical signs or known laboratory/radiographic evidence consistent with cirrhosis 
 
Adequate renal function, defined as serum creatinine  2.5  ULN and creatinine clearance 
by Cockcroft-Gault formula  30 mL/min 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
16/Protocol YO39309, Version 5 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of   1% per year 
during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last 
dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state ( 1 year of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include proper 
use of combined oral or injected hormonal contraceptives, bilateral tubal ligation, male 
sterilization, hormone-releasing intrauterine devices, and copper intrauterine devices.  
Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical 
cap) may be combined to achieve a failure rate of  1% per year.  Barrier methods 
must always be supplemented with the use of a non-lipid-based spermicide. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
 
Arm D 
Patients in Arm D must meet the following criteria for study entry: 
 
Written informed consent must be obtained from parent/legally acceptable representative 
and an assent from the child when applicable (latest approved version by the Independent 
Ethics Committee [IEC]/Institutional Review Board [IRB]) prior to any of the study-specific 
assessments and procedures being performed. 
 
Children  12 years of age at time of informed consent 
 
Body weight  3 kg at time of informed consent 
 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of applicable PRO questionnaires 
 
Caregivers of all children must have the willingness and ability to comply with all study 
procedures, including the completion of the bleed/medication questionnaire and applicable 
HRQoL questionnaires 
 
Diagnosis of congenital hemophilia A of any severity and documented history of high-titer 
inhibitor (i.e.,  5 BU/mL) 
 
Requires treatment with bypassing agents 
 
Adequate hematologic function, defined as platelet count of  100  109 cells/L and 
hemoglobin  8 g/dL (4.97 mmol/L) at the time of screening 
 
Adequate hepatic function, defined as total bilirubin  1.5  age-adapted ULN (excluding 
Gilbert’s syndrome) and both AST and ALT  3  age-adapted ULN at the time of screening 
 
Adequate renal function:  serum creatinine must be  1.5  ULN for age 
If serum creatinine is  1.5  ULN, creatinine clearance by Bedside Schwartz formula 
must be  70 mL/min/1.73m2. 
 
For female patients who are of childbearing potential, follow the same contraception criteria 
as listed above for Arms A, B, and C. 
 
Exclusion Criteria 
ARMS A, B, and C 
Patients in Arms A, B, and C who meet any of the following criteria will be excluded from 
study entry: 
 
Inherited or acquired bleeding disorder other than hemophilia A 
 
Patients who are at high risk for thrombotic microangiopathy (e.g., have a previous medical 
or family history of thrombotic microangiopathy), in the investigator’s judgment 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
17/Protocol YO39309, Version 5 
 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 
 
Previous (within the past 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 increase risk of bleeding or 
thrombosis 
 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
 
Known HIV infection with CD4 count  200 cells/L within 24 weeks prior to screening.  
Patients with HIV infection who has CD4  200 cells/L and meet all other criteria are 
eligible 
 
Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy 
 
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study, may pose additional risk, or would, in the opinion of the 
investigator, preclude the patient’s safe participation in and completion of the study 
 
Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 
 
Receipt of: 
Emicizumab in a prior investigational study 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
A non-hemophilia-related investigational drug concurrently, within last 30 days or 
5 half-lives, whichever is shorter 
 
Inability to comply with the study protocol in the opinion of the investigator 
 
Pregnant or lactating, or intending to become pregnant during the study 
Women with positive serum pregnancy test result within 7 days prior to initiation of 
study drug. 
 
ARM D 
Patients in Arm D who meet any of the following criteria will be excluded from study entry: 
 
Inherited or acquired bleeding disorder other than hemophilia A 
 
Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment with FVIII 
Patients awaiting initiation of ITI will be eligible. 
Patients in whom ITI has failed will be eligible with a 72-hour washout period prior to 
the first emicizumab administration. 
 
Previous (in the past 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 diseases (i.e., certain autoimmune diseases [e.g., systemic lupus erythematosus], 
cardiovascular disease) that may increase risk of bleeding or thrombosis 
 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
 
Known infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) 
 
Patients who are at high risk for thrombotic microangiopathy (e.g., have a previous medical 
or family history of thrombotic microangiopathy), in the investigator’s judgment 
 
Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrollment or 
planned use during the study 

 
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 
Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 
 
Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood products 
(or any standard-of-care treatment for a life-threatening condition) 
 
Receipt of: 
- 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
- 
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
- 
An investigational drug concurrently 
 
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study or that would, in the opinion of the investigator or Sponsor, 
preclude the patient’s safe participation in and completion of the study or interpretation of 
the study results 
 
Pregnant or lactating, or intending to become pregnant during the study 
Female patients with a positive serum pregnancy test result within 7 days prior to 
initiation of study drug. 
 
END OF STUDY 
The primary analysis will take place at the earliest timepoint when all randomized patients 
(Arms A, B, and C) have either completed 24 weeks of treatment or discontinued from the 
study.   
For Arm D, the primary efficacy analysis will be conducted after the last enrolled patient have 
completed 24 weeks in the study or discontinued from treatment. 
Patients who discontinue stuidy treatment prior to end of study (with the exception where the 
reason of discontinuation is the patient switching to commercial emicizumab p roduct) will 
return to the clinic for a safety follow up visit 24 weeks after the final dose of study drug.  
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (LPLV), as defined by any of the following criteria: 
 
Completion of at least 24 weeks of emicizumab treatment  
 
Completion of safety follow-up visit 24 weeks after discontinuing emicizumab 
 
Completion of the study Extension Phase (3 years after the last Arm D patient completes 
1 year treatment) and patients still having clinical benefit are transferred to a post-trial 
continued access solution per Roche Global Policy on Continued Access to Investigational 
Medicinal Products 
 
Withdrawal of consent 
 
Lost to follow-up 
 
The study will end earlier, before 3 years after the last Arm D patient completes 1 year 
treatment, should the post-trial continued access solution be available earlier.  
LENGTH OF STUDY 
The approximate length of the entire study from screening of the first patient to the end of the 
study (including Arm D and study extension phase) will be approximately 88 months. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal product for this study is emicizumab. 
Each single-use vial contains 30 mg 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, 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 more dilute 30-mg vials are intended for 

 
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1.5-mg/kg maintenance dosing for patients in Arm D with body weight  20 kg and will enable 
safe subcutaneous weight-based dosing of small children with sufficient precision.  It is 
important to note that vials of different emicizumab concentrations must not be combined in the 
same syringe. 
Each patient starting on prophylactic emicizumab will receive 3 mg/kg QW subcutaneously for 
4 weeks as loading doses, followed by 1.5 mg/kg QW (Arm A) or 6 mg/kg Q4W (Arm B) 
subcutaneously, for a total of at least 24 weeks or as long as they continue to derive sufficient 
clinical benefit.  After completion of 24 weeks observation in the study, patients in Arm C could 
switch to receive emicizumab prophylaxis at the Arm B dosing regimen (emicizumab 
prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed by 6 mg/kg Q4W). 
After at least 24 weeks on prophylactic emicizumab, patients in Arms A, B, and C will have the 
opportunity to increase their emicizumab dose to 3 mg/kg QW if they meet the following criteria 
and after consulting with the Medical Monitor: 
 
 2 spontaneous and clinically significant bleeds in the last 24 weeks on emicizumab, both 
of which occur after the end of the loading dose period 
 
At least one of the bleeds must be verified by a physician (e.g., with diagnostic imaging, 
photograph) 
Patients in Arm D will receive 3 mg/kg QW for 4 weeks as loading doses, followed by 1.5 mg/kg 
QW as maintenance during the 24-week treatment period.  Individual patients experiencing 
suboptimal bleeding control on emicizumab may also have their dose up-titrated if they meet the 
same criteria as required for patients in Arm A, B and C and after consulting with the Medical 
Monitor. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
Concomitant use of the following drugs and therapies will be permitted: 
 
Drugs intended to control bleeds, including FVIII products or bypassing agents as standard-
of-care episodic treatment.  Exact dosages will not be specified in the study but rather these 
agents should be administered according to the respective prescribing information or as 
previously used by each individual patient (for information on the formulation, packaging, 
and handling of FVIII or bypassing agents, refer to local prescribing information for the 
agent in question). 
 
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 
 
Drugs to treat an existing medical condition ongoing at study entry that do not  violate the 
eligibility criteria (e.g., anti-retroviral therapy for HIV infections) 
 
Local anesthetic cream for emicizumab SC administration 
 
Vaccinations should be administered following national immunization schedules. As per the 
World Federation of Hemophilia recommendations for vaccinations (World Federation of 
Hemophilia 2012), patients with hemophilia should be vaccinated.  Thus, vaccinations 
should be administered according to the World Federation of Hemophilia recommendations 
and local Hemophilia Treating Center practice and ideally during a period when the 
bleeding status of the child is well controlled and stable. Vaccinations should not be 
administered on the same day as an emicizumab administration but ideally at a timepoint 
between two emicizumab administrations ( 48 hours after emicizumab administration).  
Children who receive vaccinations must be carefully followed for any adverse reactions in 
the subsequent days following vaccine administration. 
STATISTICAL METHODS 
A detailed description of the statistical methods for the primary and secondary efficacy analyses 
will be provided in the statistical analysis plan. 
PRIMARY ANALYSIS 
For the randomized arms (Arms A, B, and C), the primary efficacy analysis will be conducted 
after all randomized patients have completed 24 weeks in the study or the last randomized 
patient yet to complete 24 weeks in the study discontinues study participation, whichever occurs 
first, and using an intent-to-treat principle.  The separate comparison of the number of bleeds 
over time between each of the randomized emicizumab arms and control arm will be performed 

 
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using a negative binomial (NB) regression model, which accounts for different follow-up times, 
with the patient’s number of bleeds as a function of randomization and the time that each 
patient stays in the study included as an offset in the model.  The model also includes the 
number of bleeds ( 9 or  9) in the last 24 weeks prior to study entry as a stratification factor in 
the randomization.  This analytic model estimates the rate ratio, t / c., which quantifies the risk 
of bleeding associated with prophylactic emicizumab (t) in comparison to no prophylaxis (c).  
Statistical significance is controlled at the 2-sided, 0.05 alpha () level.  Of note, hierarchical 
testing is used to account for multiple testing and the first test to be included in the hierarchy is 
the emicizumab 1.5 mg/kg QW maintenance dose versus control.  The second test will be 
6 mg/kg Q4W maintenance dose versus control (or 3 mg/kg Q2W versus control, depending on 
global Study BO39182 data readout).  The description below covers both hypotheses to be 
tested: 
H0 (null hypothesis): Rate Ratio1 versus H1 (alternative hypothesis): Rate Ratio ≠ 1. 
 
The treatment effect therein is based on a contrast statement in the model with use of the SAS 
GENMOD procedure.  Statistical significance at the pre-specified alpha level will be based on a 
Wald testing procedure.  Bleed rates for prophylactic emicizumab and no prophylaxis and the 
rate ratio will be presented and include 95% confidence intervals. 
The number of bleeds can also be annualized for each patient using the following formula:  
ABR  (Number of bleeds during the efficacy period/Total number of days during the efficacy 
period)  365.25.  If the NB model converges, van Elteren test to compare the mean ABR 
between the randomized arms will be provided only as a sensitivity analysis.  However, if the 
convergence of the NB model is not achieved or is questionable, the primary efficacy analysis 
will be based on the van Elteren test of ABR. 
For Arm D, one efficacy objective is to evaluate the clinical effect of prophylactic emicizumab on 
the number of bleeds over time.  This analysis will be performed separately as well as overall as 
appropriate. 
DETERMINATION OF SAMPLE SIZE 
For the randomized arms (Arms A, B, and C), the sample size calculation is based on the 
evaluation of the primary efficacy endpoint, defined as the number of bleeds over time (i.e., 
bleed rate) with emicizumab (treatment group, t) versus no prophylaxis (control group, c), 
which are said to follow a NB distribution.  With consideration of enrollment feasibility, a sample 
size of 70 patients, assuming an allocation ratio of 2:2:1 (28 patients in each randomized 
treatment group and 14 patients in control group), will achieve a power of more than 90% 
assuming a mean ABR of 4 and 18 bleeds (with variances  mean  10) for the emicizumab 
treatment and control arms, respectively, representing an expected 78% reduction in the ABR 
compared with the control arm.  Initial sample size calculations were performed assuming the 
patients from each treatment group are followed up to 0.5 units of time (i.e., 24 weeks). 
However, the above approach to sample size calculation assumes similar follow up for each 
patient.  Because this is unlikely to be seen in the study, power was also estimated by 
simulation to account for different follow-up times among patients.  Conducting simulations on 
the basis of an NB regression model including an offset variable to account for variable 
follow-up times, with all other assumptions remaining the same as previously described, the 
sample size is projected to have greater than 90% power at the 2-sided 0.05 level of 
significance. 
Multiplicity will be accounted for by testing emicizumab QW arm versus no prophylaxis first, and 
upon successful testing, emicizumab Q4W (or Q2W, depending on global Study BO39182 data 
readout) versus no prophylaxis, each at 0.05 level. 
During the study, a re-assessment of the initially specified sample size based on aggregated 
(not by treatment arm) global data to date may be performed.  This may result in an increase in 
sample size, if necessary, to maintain adequate power without affecting the type 1 error rate.  
Study integrity will be upheld, as access to information via aggregated analyses and their 
results will be minimized to limit operational bias. 
The sample size for Arm D is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited number of 
pediatric patients with hemophilia A inhibitors available for participation.  Hence, approximately 

 
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15 children  12  years of age with hemophilia A and FVIII inhibitors who are currently receiving 
treatment with bypassing agents will be enrolled in this study. 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABR 
annualized bleeding rate 
ADA 
anti-drug antibody 
aPCC 
activated prothrombin complex concentrate 
AUC 
area under the plasma concentrationtime curve 
AUC 
area under the plasma concentrationtime curve for a 
dosing interval 
Cmax 
maximum plasma concentration 
CCOD 
clinical cutoff date 
CVAD 
central venous access device 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EQ-5D-5L 
European Quality of Life-5 Dimensions-5 Levels 
FDA 
(U.S.) Food and Drug Administration 
FEIBA 
factor eight inhibitor bypassing activity 
FIX 
factor IX 
FVIII 
factor VIII 
FX 
factor X 
HCP 
healthcare provider 
HRQoL 
health-related quality of life 
ICH 
International Conference for Harmonisation 
IFU 
Instructions For Use 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
Inhib-QoL 
(Adapted) Inhibitor-Specific Quality of Life (with 
Aspects of Caregiver Burden) 
IRB 
Institutional Review Board 
ITI 
immune tolerance induction 
IxRS 
interactive voice or Web Response System 
LPLV 
last patient last visit 
NB 
negative binomial 
NEC 
necrotizing enterocolitis 
PCC 
prothrombin complex concentrate 
PD 
pharmacodynamic 
PK 
pharmacokinetic 

 
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Abbreviation 
Definition 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QoL 
quality of life 
QW 
every week 
rFVIII 
recombinant FVIII 
rFVIIa 
recombinant activated factor VII 
SAP 
Statistical Analysis Plan 
ULN 
upper limit of normal 
VAS 
visual analog scale 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HEMOPHILIA A 
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; Franchini and 
Mannucci 2013). 
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the 
Xq28 region of the X chromosome.  It occurs almost exclusively in males having one 
defective copy of the relevant gene on their X chromosome.  Because an affected man 
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 woman carrier have a 50% chance of receiving a mutated FVIII gene, 
thus hemophilia A will be transmitted to half the male infants and half of the 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 that is 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.  Approximately 68% of people with hemophilia A have 
moderate (25%) or severe (43%) forms, characterized by FVIII activity levels  5% or 
 1%, respectively, leading to frequent bleeding events with the sequelae of 
musculoskeletal complications (e.g., arthropathy), local functional deficits, hemorrhagic 
shock, neurocognitive defects, or even death (World Federation of Hemophilia 2013). 
1.1.1 
Management 
Prophylactic FVIII replacement therapy (i.e., administered on a scheduled basis with the 
intent to prevent bleeds) has been proven to minimize bleeding events and 
complications (Manco-Johnson et al. 2007).  Since the 1990s, recombinant FVIII (rFVIII) 
concentrates have been standard-of-care treatment options for patients with 
hemophilia A in many countries (Kingdon and Lundblad 2002).  Since 2007, rFVIII 
concentrates have been standard-of-care treatment options for patients with 
hemophilia A in China.  In children, the current standard-of-care is primary prophylaxis 
with regular FVIII infusions (starting from the first joint bleed onward or earlier; 
Valentino et al. 2012), focusing on joint preservation with, optimally, no bleeds and the 

 
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prevention of long-term consequences such as joint damage.  The overall goal is to 
enable normal psychosocial development without overprotection (Coppola et al. 2010).  
Early prophylaxis has been shown to lead to better long-term outcomes 
(Kreuz et al. 1999; Manco-Johnson et al. 2007; Gouw et al. 2013).  Adolescents and 
adult patients are more likely to have arthropathy with target joints (Gruppo et al. 2013) 
and the treatment goal of secondary prophylaxis (after the second joint bleed) or tertiary 
prophylaxis (after onset of joint disease) is to enable normal activities of daily life and 
physical exercise, as well as reduce progression of arthropathy and disability 
(Tagliaferri et al. 2008). 
Treatment regimens to achieve optimal prevention of bleeding events vary between 
individuals; some patients tolerate trough FVIII levels of 1%, whereas, others require 
higher nadir FVIII levels to achieve the desired therapeutic outcome 
(Ahnstrom et al. 2004; Collins et al. 2010).  Current prophylactic regimens commonly 
use infusion therapy administered 23 times weekly (Adynovate U.S. Package Insert; 
Kovaltry U.S. Package Insert); other regimens use every other day administration 
(Shapiro 2013). 
Prophylactic FVIII replacement therapy has been recognized as superior to episodic 
therapy of symptomatic bleeds for several decades (Khawaji et al. 2012) and was 
adopted by national and international organizations as the desired treatment approach.  
However, the burden of treatment (Eton et al. 2013, Mair and May 2014) is 
extraordinarily onerous, as adequate prophylaxis requires a lifetime of self-administered 
IV infusion of FVIII 34 times each week.  In addition to the obvious toll on the quality of 
patients’ life (Teal et al. 2014), this burden results in suboptimal care for many who elect 
to avoid routine prophylaxis, despite its medical advantage (Geraghty et al. 2006; 
Lindvall et al. 2006; De Moerloose et al. 2008; Collins et al. 2014; Oldenburg 2015).  
Thus, episodic therapy is a standard-of-care for many patients with hemophilia in 
developed countries, where approximately one-third to one-half of the patients use FVIII 
on-demand and avoid continuous prophylaxis.  For example, a recent analysis revealed 
that, in North America and Europe, only 44.3% of 1238 patients with severe 
hemophilia A are treated with routine FVIII prophylaxis (Oldenburg and 
Brackmann 2014).  Similarly, prophylaxis was routinely offered to adults in only 18 of 
35 European countries surveyed, and in 12 out of those 18 countries, 50% or fewer 
adults received FVIII prophylaxis (O'Mahony et al. 2013).  In addition to treatment 
burden, other reasons including venous access and cost concerns underlie this problem 
(Gringeri et al. 2012), which contributes to hemophilia-associated long-term morbidity. 
Although patients on FVIII prophylaxis experience a low number of bleeds, magnetic 
resonance imaging scans demonstrate progressive arthropathy in up to two-thirds of 
patients who receive an adequate primary prophylaxis regimen.  These changes begin 
within the first decade of life and involve clinically “bleed-free” joints (Kraft et al. 2012; 
Olivieri et al. 2012).  Accordingly, 40% of men in the third decade of life reported the 
presence of a target joint, reduced mobility, or chronic pain (Fischer et al. 2013; 

 
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Noone et al. 2013).  These findings indicate that FVIII prophylaxis delays, but does not 
completely prevent, long-term skeletal morbidity (Oldenburg 2015).  This is in part due to 
the challenges of adherence and in part due to microbleeds associated with low FVIII 
trough levels (Ljung and Gretenkort-Andersson 2015).  Due to the short half-life of FVIII, 
current prophylaxis regimens aim at maintaining FVIII levels at a trough of  1%, which 
restores hemostasis for only part of the time (Valentino et al. 2012).  A study of patients 
with varying severities of hemophilia suggests that protection from joint bleeds occurs 
only at continuous levels over 12% (Den Uijl et al. 2011), and achieving higher FVIII 
activity, though difficult to accomplish with current regimens, has been recognized as a 
goal for optimal care in a position paper from the World Federation of Haemophilia 
(Skinner 2012). 
Routine IV FVIII therapy relies on the venous cannulation skills of patients and their care 
providers (Hacker et al. 2001).  In particular, this issue plagues the care of children with 
hemophilia, in whom central venous access devices (CVADs [i.e., Part-a-Cath]) have 
been used regularly to overcome technical difficulties.  Although CVADs make 
prophylaxis feasible in young children, they are associated with complications, including 
mechanical failure, dehiscence of the skin over the reservoir, infection, and thrombosis 
(Ewenstein et al. 2004).  A recent prospective study reported that 183 lines were 
implanted in 99 patients and that 41% of patients had at least one infectious episode.  
The median time to line removal was 483 days (interquartile range:  1431071; 
Rodriguez et al. 2015).  A Finnish retrospective study similarly reported that 47% of 
106 catheters implanted in 58 patients had to be removed due to a complication 
(Vepsalainen et al. 2015).  In addition, significant health care provider efforts are 
required to manage optimal treatment solutions and to overcome identified issues 
(Schrijvers et al. 2013).  Thus, both the disease and its treatment affect patients’ 
health-related quality of life (HRQoL). 
The development of inhibitory alloantibodies (inhibitors) occurs in approximately 
20%30% of patients with severe hemophilia A and in 3%13% of those with moderate 
or mild disease (Franchini and Mannucci 2013).  In China, the development of inhibitors 
occurs in approximately 9%15% of patients with hemophilia A.  Because inhibitors can 
develop very early during the course of FVIII therapy (within 1050 exposure days), with 
half of all cases occurring before the age of 5 years, pediatric patients represent the 
population at highest risk of developing inhibitors (Kreuz et al. 1995; Wight and 
Paisley 2003; Kempton and White 2009; Hay and DiMichele 2012).  Inhibitors neutralize 
the activity of endogenous FVIII as well as of FVIII administered as replacement therapy. 
For patients who develop inhibitors against FVIII, immune tolerance induction (ITI) may 
help restore a patient’s clinical response to FVIII concentrates.  Permanent eradication 
of FVIII inhibitors is the ultimate goal of ITI, and it is successful in approximately 
60%80% of adults and children with inhibitors (Santagostino et al. 2009; Hay and 
DiMichele 2012).  Most physicians delay the start of ITI for up to 1 year from the time the 
inhibitor is first diagnosed to allow very high titers of inhibitors to fall because a pre-ITI 

 
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inhibitor titer measuring  10 BU/mL is the most powerful predictor of ITI success 
(Mariani and Kroner 1999; DiMichele and Kroner 2002).  Regimens that delay treatment 
until the inhibitor has fallen below 10 BU/mL positively affect both the likelihood of 
success (79%87% success rate) and the time required to achieve tolerance 
(Mauser-Bunschoten et al. 1995; Kroner 1999; Rocino and de Biasi 1999; Smith 
et al. 1999).  Furthermore, the rate of response to ITI does not decline until ITI has been 
delayed beyond 5 years from the time of diagnosis (Brackmann et al. 1996; 
Mauser-Bunschoten et al. 1995; Kroner 1999; DiMichele and Kroner 2002).  However, 
an optimal regimen for ITI remains to be defined (although a recent study suggested 
superior safety outcomes using high-dose regimens administered daily [Hay and 
DiMichele 2012]), and the length of treatment is dictated by individual responses, 
ranging from months to years.  Because uninterrupted and uncomplicated venous 
access is essential in children undergoing ITI, this process is particularly burdensome in 
the pediatric patient population, who require frequent visits to hemophilia centers for 
regular infusion of FVIII concentrate through CVADs. 
Long-term CVAD use requires considerable commitment from caregivers and patients, 
and serious complications can occur, including thrombosis, bleeding, mechanical 
dysfunction, and most commonly, infection.  A prospective study in pediatric 
hemophilia A patients with inhibitors reported that 183 lines were implanted in 
99 patients, with 41% of patients having at least one documented infection.  The median 
time to line removal was 483 days [interquartile range (1431071; Rodriguez 
et al. 2015)].  A Finnish retrospective study similarly reported that 47% of 106 catheters 
implanted in 58 patients had to be removed because of a complication (Vepsalainen 
et al. 2015).  CVAD-related bacteremia and sepsis pose potentially lethal problems for 
patients with hemophilia and result in a substantial proportion of emergency room visits 
for children.  A retrospective study of pediatric emergency department management of 
children with hemophilia showed that of 536 visits from 84 male patients (median age 
4 years), 12% were due to suspected CVAD infection (Ozgonenel et al. 2013).  Indeed, 
infection occurs more frequently in hemophilia patients with inhibitors (Bollard 
et al. 2000; Valentino et al. 2004; van Dijk et al. 2004), with rates being highest among 
patients with inhibitors undergoing ITI, ranging from 50%83% (van den Berg 
et al. 1998).  If ITI is unsuccessful, inhibition of FVIII concentrate treatment may persist 
throughout the patient’s life.  Additionally, the use of ITI treatment is not viewed as a 
viable option for patient management in many countries, owing to its high cost, lack of 
availability of FVIII concentrates, and daily administrations.  These disadvantages are 
compounded in the young pediatric population due to the necessity for central venous 
access and related complications, as well as the psychological stress of this treatment 
on patients and their families. 
For patients with a history of a high-titer (  5 BU/mL) inhibitor who are unable to 
eradicate their inhibitors or are not candidates for ITI, the only hemostatic options 
currently available are prothrombotic coagulation factors that augment other parts of the 

 
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coagulation cascade (i.e., “bypassing agents”).  Bypassing products include factor eight 
inhibitor bypassing activity (FEIBA), an activated prothrombin complex concentrate 
(aPCC; FEIBA will be henceforth referred to as aPCC), and NovoSeven (recombinant 
activated human FVIIa [rFVIIa]; NovoSeven will be henceforth referred to as rFVIIa; 
Srivastava et al. 2013).  Unfortunately, the hemostatic effect of bypassing agents in 
patients with inhibitors is suboptimal, leading to a higher number of bleeds (annualized 
bleeding rate [ABR] of 810 with FEIBA [Leissinger et al. 2011; Antunes et al. 2014] and 
23 bleeds per month with NovoSeven [Konkle et al. 2007] compared with that of FVIII 
concentrates in non-inhibitor patients who achieve a median ABR of approximately 
02 with optimal prophylaxis (Manco-Johnson et al. 2013).  In China, the available 
products are prothrombin complex concentrate (PCC) and rFVIIa; however, due to the 
high cost of the prophylaxis treatment, the majority of the patients with inhibitors can only 
afford on-demand treatment when there are bleeds, thus causing suboptimal bleeding 
control compared to those patients with prophylaxis treatment.  In addition, as opposed 
to the 8- to 12-hour half-life and 15- to 20-minute infusion time of FVIII, NovoSeven has 
a short half-life of only 23 hours, and FEIBA requires 2550 minutes to infuse (with a 
half-life of 47 hours), requiring frequent and extended IV infusions, respectively. 
Investigations into prophylactic therapy in adults and children with bypassing agents 
NovoSeven (Konkle et al. 2007) and FEIBA (Leissinger et al. 2011; Antunes et al. 2014) 
have shown that these products lead to reductions in bleed rates compared with 
episodic treatment with these same products.  However, as detailed above, this efficacy 
is suboptimal and does not approach the level of hemophilia control that can be 
achieved with FVIII concentrates in non-inhibitor patients. 
Despite prophylactic regimens being standard-of-care for hemophilia patients without 
inhibitors in many countries, a large proportion of hemophilia patients with FVIII inhibitors 
currently are treated with episodic regimens, partly because of the treatment burden of 
these prophylaxis regimens.  A survey of hemophilia centers across 14 countries 
suggested that 41% of pediatric hemophilia patients with inhibitors were on ITI alone, 
17% were on both ITI and prophylactic bypassing agents, 16% were on prophylactic 
bypassing agents alone, and 26% were on neither ITI nor prophylactic bypassing agents 
(Carcao et al. 2015). 
Of note, treatment of patients with congenital hemophilia A of any severity with high-titer 
inhibitors is similar, and their endogenous severity, as defined based on FVIII activity at 
diagnosis (mild, moderate, or severe), is no longer prognostic of their clinical phenotype 
and risk of bleeding.  This is because the inhibitor would eventrally neutralize the 
residual endogenous FVIII, resulting in a severe bleeding phenotype in the end. 
Both aPCC/PCC and rFVIIa are administered intravenously, with aPCC/PCC prophylaxis 
requiring every-other-day dosing and rFVIIa requiring daily (or more frequent) dosing.  
For years, the suboptimal bleeding control, the short half-life, and high cost of these 

 
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bypassing agents limit the use of prophylaxis treatment in inhibitor patients.  Despite 
physician’s efforts, joint disease ultimately occur. 
The development of effective prophylactic treatment options with decreased 
immunogenicity and less frequent dosing requirements is important to reduce the time 
and burden associated with frequent IV dosing and the effect of the disease on aspects 
of physical health and other areas of function.  A study assessing the relationship 
between self-reported adherence to prophylaxis and health outcomes (HRQoL and 
bleeding episodes) showed that poorer adherence with prophylaxis was associated with 
a greater number of self-reported bleeding episodes, more days of work or school 
missed among pediatric patients, and lower physical health status scores among 
pediatric patients (Krishnan et al. 2015).  Adherence to prophylaxis by patients with 
hemophilia A, defined as the extent to which a person’s behavior corresponds to agreed 
recommendations by a healthcare provider (WHO 2003), ranges from 44% to 87% 
(Llewellyn et al. 2003; De Moerloose et al. 2008; Ho et al. 2014).  In China, the 
adherence to prophylaxis by patients with hemophilia A is even worse, ranging from 
5% to 15% for patients without FVIII inhibitors, and almost no patients with FVIII 
inhibitors receive prophylactic treatment (Xue et al, 2011; Xuan et al. 2014).  In a Dutch 
study investigating patient behavior affecting adherence to prophylactic treatment, 
patients were asked about their experience with and adherence to administration of 
prophylaxis.  Remarkably, some patients willingly chose non-adherence because they 
did not want to adapt their activities to hemophilia, and they were prepared to accept the 
consequences of their decision.  Patients noted the difficulties of regular prophylaxis due 
to inadequate routine and the complexity of the needed self-management skills including 
planning, management of the treatment of bleeds, forgetfulness, stock management, 
and overruling activities in life (Schrijvers et al. 2015). 
Given the incomplete efficacy and the significant management challenges in adults and 
children with hemophilia, there is a true need for therapeutics that have reliable efficacy, 
a long half-life, low treatment burden, and ease of administration to prevent bleeding in 
and minimize long-term morbidity of individuals with hemophilia A. 
1.2 
BACKGROUND ON EMICIZUMAB 
1.2.1 
Molecule and Nonclinical Data 
Emicizumab (also known as ACE910 and RO5534262) is a recombinant, humanized, 
bispecific, immunoglobulin G4 (IgG4) monoclonal antibody that binds with moderate 
affinity to activated factor IX (FIXa) and factor X (FX), mimicking the co-factor function of 
activated FVIII (FVIIIa).  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 the pharmacokinetic (PK) 
properties of this antibody are expected to enable marked extension of the dosing 
interval to once weekly (QW), every 2 weeks (Q2W), or every 4 weeks (Q4W), this novel 

 
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compound has the potential to dramatically change the treatment of patients with 
hemophilia A with and without FVIII inhibitors who are in need of effective, safe, and low 
addburden prophylactic therapy. 
See the RO5543262 (emicizumab) Investigator's Brochure for additional details on 
nonclinical studies with emicizumab. 
1.2.2 
Clinical Experience 
Clinical data are currently available from 8 studies, which are listed below in Table 1.  
Please refer to Emicizumab’s Investigator’s Brochure for the complete, updated 
information. 
Table 1 
Status of Clinical Studies for Emicizumab 
Study 
Status 
Study ACE001JP:  A Phase I study investigating the tolerability, 
safety, pharmacokinetic, and pharmacodynamic response of 
subcutaneously administered emicizumab in healthy Japanese and 
Caucasian male subjects and in Japanese patients with hemophilia A 
Completed 
Study JP29574:  A site of administration, relative and absolute 
bioavailability study in healthy adult male subjects 
Completed 
Study ACE002JP:  A Phase I/II extension study investigating the 
safety and efficacy of long-term administration of emicizumab on 
bleeding control in a subset of patients with hemophilia A who 
participated in Study ACE001JP 
Completed 
Study BH29884 (HAVEN 1):  A Phase III study investigating the 
efficacy, safety, and pharmacokinetics of emicizumab prophylaxis vs. 
no prophylaxis in patients with hemophilia A with FVIII inhibitors 
Completed 
Study BH29992 (HAVEN 2):  A Phase III study investigating the 
efficacy, safety, and pharmacokinetics of subcutaneous 
administration of emicizumab in pediatric patients with hemophilia A 
with inhibitors 
Completed 
Study BH30071 (HAVEN 3):  A Phase III study investigating the 
efficacy, safety, and pharmacokinetics of emicizumab prophylaxis in 
patients with hemophilia A without inhibitors 
Completed 
Study BO39182 (HAVEN 4):  A Phase III study investigating the 
efficacy, safety, pharmacokinetics and pharmacodynamics of 
emicizumab given every 4 weeks in patients with hemophilia A 
Completed 
Study JO39881 (HOHOEMI):  A Phase III study to evaluate the 
efficacy, safety, and pharmacokinetics of emicizumab given every 
2 weeks and 4 weeks in hemophilia A pediatric patients aged less 
than 12 years without FVIII inhibitors 
Completed 
FVIII  factor VIII. 
 

 
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1.2.2.1 
Clinical Pharmacology 
Pharmacokinetics of emicizumab in hemophilia A patients were accurately described by 
a one-compartment disposition model with first-order absorption and first-order 
elimination.  Emicizumab PK parameters were typical for a monoclonal antibody 
(Keizer et al. 2010).  Emicizumab was well absorbed (absolute bioavailability of 
80.4%93.1% depending on the injection site location) following SC injection, with an 
absorption half-life of approximately 1.6 days.  The volume of distribution at steady state 
following IV injection was 106 mL/kg.  The apparent clearance  and the elimination 
half-life were 0.271 L/day and 26.9 days, respectively.  Emicizumab exhibited linear 
pharmacokinetics, with no indication for target-mediated drug disposition. 
Similar emicizumab exposures were observed in children, adolescents, and adult 
patients.  Inhibitor status or disease severity does not impact emicizumab exposure.  
Furthermore, similar PK profiles following SC injections in abdomen, upper arm, and 
thigh indicated that emicizumab can be interchangeably injected in these three locations. 
In patients with hemophilia A, emicizumab shortened (normalized) aPTT, promoted the 
generation of thrombin, and increased the reported FVIII activity in a chromogenic assay 
containing human coagulation factors in a concentration dependent manner. 
1.2.2.2 
Efficacy 
The efficacy of emicizumab in patients with hemophilia A has been evaluated in one 
Phase I/II study (ACE001JP [Part C]/ACE002JP) and four Phase III studies 
(HAVEN 14).  After administration of emicizumab (0.3, 1, or 3 mg/kg/week QW, SC) to 
patients with hemophilia A in Studies ACE001JP (Part C)/ACE002JP, ABRs for treated 
bleeds were zero or decreased from the pre-dose period, regardless of the presence of 
inhibitors and/or prior use of prophylactic bypassing agents. 
Emicizumab provides statistically significant and clinically meaningful prevention of 
bleeding in patients with hemophilia A.  Results from Phase III clinical studies confirmed 
the adequacy of the selected dosing regimens.  Overall, all three dosing regimens 
(loading doses of 3 mg/kg QW for 4 weeks followed by either 1.5 mg/kg QW, 
3 mg/kg Q2W or 6 mg/kg Q4W) using an equivalent cumulative dose, provided 
meaningful efficacy.  This is supported by the primary analysis of pivotal studies 
BH29884 (clinical cutoff date [CCOD]:  8 September 2017), BH29992 (CCOD:  30 April 
2018), BH30071 (CCOD:  15 September 2017), and BO39182 (CCOD:  15 December 
2017). 
At the primary analysis of Study BH29884, all primary and secondary efficacy endpoints 
related to bleed rates were statistically significant and clinically meaningful.  Patients 
with hemophilia A on emicizumab prophylaxis compared with no prophylaxis showed a 
87% and 80% reduction in rates of treated bleeds and all bleeds (treated and untreated), 
respectively.  In addition, emicizumab improved HRQoL and health status in these 

 
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patients.  Subgroup analyses were consistent with and further supported the clinical 
benefit of emicizumab to patients with hemophilia A. 
The primary analysis results of Study BH29992 demonstrate a clinically meaningful 
effect of emicizumab prophylaxis in the prevention of bleeding events in children with 
hemophilia A with FVIII inhibitors.  In total, 22 treated bleeds were reported in 15 of 
65 participants during a median efficacy period of 58 weeks, while 90.9% (20/22) of 
treated bleeds were traumatic related.  Importantly, the intra-patient analysis based on 
18 patients previously treated with episodic or prophylactic bypassing agent showed a 
clinically meaningful 99% reduction in ABR (treated bleeds) with emicizumab 1.5 mg/kg 
QW treatment. 
Study BH30071 met the primary endpoint of reduction of treated bleed rate and all of the 
bleed-related secondary endpoints.  Emicizumab prophylaxis with the maintenance dose 
of 1.5 mg/kg QW or 3 mg/kg Q2W resulted in a statistically significant and clinically 
meaningful 96% and 97% reduction in rate of treated bleeds, respectively, compared 
with no prophylaxis.  More than 55% of patients in all emicizumab treatment arms 
compared with no patients on no prophylaxis experienced zero treated bleeds and more 
than 90% of patients on emicizumab prophylaxis experienced fewer than four treated 
bleeds compared to approximately 6% of patients on no prophylaxis. 
The primary analysis results of Study BO39182 support a clinically meaningful effect on 
bleed prevention of the emicizumab Q4W dosing regimen.  In this study, the negative 
binomial model analysis of bleed rates showed that emicizumab Q4W prophylaxis 
provided adequate control of bleeds, with patients achieving ABR of 2.4 (95% CI:  1.38 
to 4.28) for treated bleeds.  More than half of the patients (n  23, 56.1%) did not 
experience any treated bleeds while receiving emicizumab prophylaxis.  The primary 
analysis report numerical improvements in HRQoL and health status endpoints. 
Long-term efficacy data are available from Phase III Study BH29884, as well as 
ACE002JP.  In the BH29884 study, where 1.5 mg/kg QW dosing of emicizumab 
prophylaxis was assessed, 82.3% patients have completed  48 weeks follow-up at the 
time of the clinical cutoff date.  The median for the efficacy period is 60.29 weeks 
(range:  0.194.3 weeks, n  113).  The longest duration of emicizumab exposure to date 
is for patients (n  16) in Study ACE002JP whose median exposure time is 3.4 years.  
The prevention of overall bleeding was maintained throughout Study ACE001JP and 
extension Study ACE002JP. 
Long-term efficacy dataare available from Phase III StudBH29884as well as ACE002JP.  
Overall, the benefits of emicizumab prophylaxis were sustained and therapeutic effect 
was maintained over the long term as observed in Studies BH29884 and ACE002JP.  
These long-term effects are expected to be maintained with emicizumab treatment in 
patients with hemophilia A of all ages, regardless of the presence of FVIII inhibitors. 

 
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1.2.2.3 
Safety 
Safety in Healthy Subjects 
Safety data from 108 healthy male subjects (Japanese and Caucasian) demonstrated a 
similar incidence of adverse events between placebo and emicizumab dosing groups, no 
racial differences, or dose-dependent increases in adverse events.  Furthermore, there 
were no significant differences in the incidence of adverse events observed by 
formulation, injection site, or administration route.  There were no serious adverse 
events, adverse events leading to discontinuation, or fatal outcomes in Study JP29574 
or Study ACE001JP (Part A and Part B). 
Safety in Patients with Hemophilia A 
Safety data from 417 emicizumab-treated patients with hemophilia A (enrolled, n  419) 
in Studies ACE001JP (Part C)/ACE002JP (n  18) and Studies BH29884 (n  113), 
BH29992 (n  88), BH30071 (n  152), and BO39182 (n  48) have been pooled.  Safety 
data are presented from patients who received emicizumab prophylaxis in 
Studies ACE001JP (Part C)/ACE002JP, BH29884, BH29992, BH30071, and BO39182.  
Study JO39881 (n  13) is not included in the pooled safety data and is presented 
separately due to immaturity of the data. 
A total of 2838 adverse events were reported in 384 patients (92.1%).  Among the 
417 patients overall, 71 patients (17.0%) experienced a serious adverse event, and 
4 patients (1.0%) experienced a serious adverse event that led to withdrawal from 
treatment.  In total, 142 patients (34.1%) experienced an adverse event assessed by the 
investigator as related to emicizumab. 
Among patients in Study ACE001JP (Part C)/ACE002JP, the majority of the adverse 
events were mild or moderate in intensity, except for two adverse events of severe 
intensity (appendicitis and mesenteric hematoma), which were considered to be serious 
and unrelated to emicizumab.  Similarly, most adverse events in the Phase III Studies 
BH29884, BH29992, BH30071, and BO39182 were of Grade 1 or 2 intensity, except for 
63 adverse events of Grade  3 intensity.  Most of the adverse events were unrelated to 
study drug and only 6 patients (1.4%) reported serious adverse events were related to 
treatment.  Observed adverse events of special interest among patients with 
hemophilia A treated with emicizumab included thrombotic microangiopathy (3 patients 
[  1.0%]) and thromboembolic event (3 patients [  1.0%]).  A total of 113 patients 
(27.1%) experienced a local injection site reactions.  All were mild to moderate in 
intensity and only one leading to discontinuation in a patient in the Phase I study. 
One fatal outcome due to rectal hemorrhage which is unrelated to emicizumab was 
reported in Study BH29884.  No fatal outcomes have occurred in the other studies. 
Study JO39881 in Japanese pediatric patients is ongoing. In this study, 13 patients with 
severe hemophilia A without FVIII inhibitors were enrolled in 2 cohorts (6 patients in the 
Q2W cohort and 7 patients in the Q4W cohort).  As of the data cutoff date 

 
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(14 March 2018), all 13 patients were continuing treatment, and no patients had a dose 
up-titration. 
There were no adverse events that were Grade 3 or higher, serious, led to withdrawal 
from treatment, or resulted in dose modification or interruption.  No injection site 
reactions, thromboembolic events, thrombotic microangiopathy, or systemic 
hypersensitivity reactions were observed.  For all the adverse events, a causal 
relationship with emicizumab was ruled out by investigators. 
Study ML39356 (Expanded Access Program) was designed to provide access to 
emicizumab for patients with hemophilia A with FVIII inhibitors prior to its approval in the 
United States.  The study is now completed; All remaining patients were transferred to 
commercial emicizumab once United States Food and Drug Administration (FDA) 
approval was granted for patients with FVIII inhibitors.  The study collected safety data 
and no significant safety signals were observed. 
MO39129 (STASEY) is an ongoing multi-center, open-label Phase IIIb study in patients 
with hemophilia A with FVIII inhibitors is ongoing with the first official safety assessment 
by the Independent Data Monitoring Committee scheduled to occur in February 2019.  
One serious adverse event of “abscess at sick of Hickman line removal” assessed as 
related to emicizumab by the investigator was observed in this study.  At the time of the 
report, therapy with emicizumab was not altered in response to the abscess at the site of 
the Hickman line removal.  No thromboembolic or thrombotic microangiopathy events 
were observed in the study. 
Please refer to the Emicizumab Investigator's Brochure for a complete summary of 
safety information. 
1.2.2.4 
Immunogenicity 
Of the 108 healthy adult male subjects in Studies ACE001JP (Part A and Part B) and 
JP29574, who received a single SC or IV dose of emicizumab, 6 subjects tested positive 
for plasma anti-drug antibodies (ADAs; non-IgE).  Four of these subjects presented with 
treatment-induced ADA.  In all 4 subjects, emicizumab was eliminated faster, and the 
pharmacodynamic (PD) effect (shortening of aPTT and promotion of thrombin 
generation in FVIII depleted plasma) dissipated earlier than in the subjects who tested 
negative.  No adverse events occurred in these subjects. 
In patients with hemophilia A participating in Studies ACE001JP (Part C)/ACE002JP, 
4 of 18 patients tested positive for ADA.  Three patients presented with 
treatment-induced ADA, and 1 patient presented with treatment-boosted response.  No 
clinically relevant changes in the PK and PD profiles of emicizumab were detected, and 
there were no clear differences in bleeding reduction or the safety of emicizumab 
compared with other patients.  Therefore, none of the ADAs were considered to have 
neutralizing potential. 

 
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The incidence of ADA in the HAVEN clinical trials is 3.5% (14/398).  The rate of ADAs 
with neutralizing potential (based on declining PK) is 0.75% (3/398).  The presence of 
ADAs with neutralizing potential may be associated with loss of efficacy.  The patients 
who tested ADA-positive did not have a safety profile that differed from that of the overall 
population. 
No patients in any of the studies developed de novo FVIII inhibitors, as is expected 
based on the fact that emicizumab does not share sequence or structural homology with 
FVIII. 
See the Emicizumab Investigator's Brochure for additional details on clinical studies with 
emicizumab. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This current study is designed to evaluate the efficacy and safety of emicizumab given 
QW or Q4W SC in adolescent and adult patients with hemophilia A irrespective of FVIII 
inhibitor status  The inclusion of inhibitor and non-inhibitor patients is supported by the 
mode of action of emicizumab and the observation from Phase I/II and Phase III studies 
of similar pharmacokinetics, efficacy, and safety between the inhibitor and non-inhibitor 
populations. 
Because the PK properties of this antibody are expected to enable extended dosing 
intervals of QW, Q2W, or Q4W, 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg Q4W 
regimens have been investigated in Phase III studies.  The dosing regimens investigated 
in this study (3 mg/kg QW  4 followed by 1.5 mg/kg QW or 6 mg/kg Q4W) are being 
investigated to provide an option for patients to receive emicizumab QW or Q4W, while 
delivering the same cumulative dose.  The Q4W regimen of 6 mg/kg has resulted in a 
similar exposure (average steady-state concentration [Cavg,ss]) as the 1.5 mg/kg QW and 
3 mg/kg Q2W regimens despite higher maximum plasma concentration (Cmax) and lower 
trough concentration (Ctrough) levels at steady state (see Section 3.3). 
Safety data from 417 emicizumab treated patients with hemophilia A has demonstrated 
that emicizumab was well tolerated.  Most adverse events were of Grade 1 or 2 intensity, 
and most of the adverse events were unrelated to study drug; only 6 patients reported 
serious adverse events that were related to treatment.  Observed adverse events of 
special interest among patients with hemophilia A treated with emicizumab included 
thrombotic microangiopathy (3 patients [  1.0%]) and thromboembolic event (3 patients 
[  1.0%]); see Section 5.1.2 for details.  A total of 113 patients (27.1%) experienced local 
injection site reactions.  All were mild to moderate in intensity, with only one leading to 
discontinuation of a patient in the Phase I study.  However, in Study BH29884, three 
cases of thrombotic microangiopathy was observed in 3 patients on emicizumab who 
received bypassing agents for the treatment of breakthrough bleeds; and 
three thromboembolic events were observed in 2 patients on emicizuamb who received 

 
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bypassing agents for the treatment of breakthrough bleeds, and one device occlusion in 
one patient assessed by the investigator as being unrelated to emicizumab. 
Five of these 6 patients have fully recovered, while one patient’s thrombotic 
microangiopathy has improved but that patient has died because of severe rectal 
bleeding (see Section 5.1.2.1).  The safety is additionally supported by a no observed 
adverse effect level of up to 30 mg/kg QW in cynomolgus monkeys.  The data from this 
nonclinical study estimate the maximum dose of 3 mg/kg QW used in the Phase I/II 
study was associated with a 10.3-fold and 11.2-fold safety margin based on Cmax and 
area under the plasma concentration time-curve for a dosing interval (AUC), 
respectively, while the dose of 6 mg/kg Q4W investigated in the present study is 
predicted to be associated with corresponding 17.4- and 22.5-fold safety margins, 
respectively. 
In conclusion, the management challenges of adults and children with hemophilia A 
highlight the unmet need for therapeutics that have reliable efficacy, long half-life, and 
reduced treatment burden to prevent bleeding for patients with hemophilia A.  Given this 
significant unmet medical need and the positive benefit-risk assessment, initiation of a 
larger, confirmatory Phase III study is indicated. 
Following conditional approval of emicizumab prophylaxis treatment in pediatric patients 
with hemophilia A with inhibitor in China, and review of data from the ongoing Phase III 
HAVEN 2 study (BH29992), among 10 Asian pediactric patients enrolled out of total 
63 patients, there was no difference in terms of PK, safety or efficacy based on ethnicity 
comparision, thus no difference is expected.  However, this study will open one 
additional non-randomized arm to investigate a QW regimen in Chinese pediatric 
patients to further confirm the assumption. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate (with no formal hypothesis testing for Arm D) the efficacy, safety, 
and pharmacokinetics of prophylactic emicizumab administered at 1.5 mg/kg QW and 
6 mg/kg Q4W compared with no prophylaxis in patients with hemophilia A randomized to 
Arms A, B, and C.  A total of approximately 85 patients are planned:  approximately 
70 patients aged  12 years in Arm A, B, and C, and approximately 15 pediatric patients 
aged  12 years in Arm D (1.5 mg/kg QW).  Specific objectives and corresponding 
endpoints for the study are outlined below (see Table 2). 
 

 
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 
Arm C:  No prophylaxis (control arm) 
 
In addition, 15 pediatric patients with hemophilia A and inhibitors who received episodic 
therapy with bypassing agents prior to study entry will be enrolled to Arm D: 
 
Arm D:  Emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, 
followed by 1.5 mg/kg QW subcutaneously 
 
The endpoints will be analyzed separately for the two randomized emicizumab arms 
(Arms A and B):  1.5 mg/kg QW and 6 mg/kg Q4W, as well as for the additional arm in 
pediatric patients (Arm D):  1.5 mg/kg QW. 
Randomized patients will be stratified according to the number of bleeds the patient 
experienced over the 24 weeks prior to study entry—less than versus greater than or 
equal to 9—to ensure a balance of patients with lower versus higher number of bleeds in 
all arms. 
To ensure a representative variety of patients with hemophilia A enrolled in this study to 
investigate the efficacy and safety profile of emicizumab in both inhibitor and 
non-inhibitor adolescent and adult populations, enrollment of up to 55 non-inhibitor 
patients will be permitted. 
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have 
already occurred).  The primary efficacy analysis, defined as comparing the number of 
bleeds over time for patients randomized to receive prophylactic emicizumab versus no 
prophylaxis will be conducted at the earliest timepoint when all randomized patients 
(Arms A, B, and C) have either completed 24 weeks in the study or discontinued from 
treatment.  For Arm D, the primary efficacy analysis will be conducted after the last 
enrolled patient has completed 24 weeks in the study or discontinued from treatment. 
Therefore, there will be a range of observation periods from 6 to approximately 
12 months, or longer.  Randomized patients will be enrolled globally from China and 
other countries.  At least 60 patients will be enrolled from China. 
Arm D will only enroll patients from mainland China. 
To obtain additional safety and efficacy data on emicizumab, patients who are 
randomized to Arm C (control arm with no prophylaxis) will have the opportunity after 
24 weeks to switch to receive emicizumab prophylaxis at the 6 mg/kg Q4W dosing 
regimen (emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed 
by 6 mg/kg Q4W).  This regimen was chosen to enhance the safety and efficacy data 
obtained on this dosing regimen because there will be less data available on this 
regimen from the global studies than from the 1.5 mg/kg QW regimen. 
After completing at least 24 weeks of treatment with prophylactic emicizumab, patients 
who receive emicizumab prophylaxis (Arms A, B, or C after treatment switch and Arm D) 

 
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confirmation that no bleed or medication use occurred.  In addition, health status 
information will be collected whenever a bleed is reported. 
Throughout the study, biomarkers related to thromboembolism (e.g., D-dimer, 
prothrombin 1  2 fragment) and emicizumab trough concentrations will be collected as 
per the schedule of assessments.  Immunologic biomarkers (i.e., anti-emicizumab 
antibodies and anti-FVIII antibodies) will also be measured (see Appendix 2). 
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation assay) will be 
collected as per the schedule of assessments.  As values for some of these tests are 
normalized by low plasma concentrations of emicizumab, a variety of assay formats (one 
stage, chromogenic) and modifications (pre-dilution of patient plasma) will be 
investigated for assessment of PD response at higher emicizumab plasma 
concentrations.  However, it is not expected that these biomarkers will be used to guide 
dosing or the selection of patients to be treated with emicizumab.  Rather, these 
biomarkers may be used to identify a future assay for the monitoring of emicizumab 
activity.  In addition,factor IX (FIX) and FX antigen levels will be measured. 
Physical examinations, vital signs assessments, ECGs, and laboratory assessments will 
be collected as per the schedule of assessments and will be the same for all patients, 
with the exception that emicizumab PK and ADAs will not be measured in patients in 
Arm C prior to switch to emicizumab treatment.  Adverse events will be captured as they 
occur for the duration of the study. 
All patients who receive emicizumab in the study will undergo PK assessments.  Based 
on clinical experience in the ongoing Phase I/II clinical studies with the treatment of 
over 80 breakthrough bleeds in patients receiving emicizumab with either FVIII or 
bypassing agents, FVIII, aPCC, or rFVIIa do not interfere with emicizumab PK 
assessments and no safety signals have been observed when breakthrough bleeds 
were treated with standard-of-care regimens during Phase I and Phase I/II studies.  
Therefore, no washout period is required prior to first emicizumab dose in this study, with 
the exception of patients who were previously receiving ITI in whom a 72-hour washout 
period is required prior to the first emicizumab administration. 
However, in the ongoing Phase III Study BH29884 (adolescent and adult patients with 
hemophilia A with FVIII inhibitors), three thrombotic microangiopathy and three 
thromboembolic events were observed in 5 patients on emicizumab who concomitantly 
used on average, cumulative doses of  100 units/kg/24 hr for 24 hours of aPCC for the 
treatment of breakthrough bleeds.  There was an additional thromboembolic event, 
which was a device occulation without concomitant aPCC and assessed by the 
investigator as being unrelated to emicizumab (see Section 1.2, Section 1.3, 
Section 5.1.2.1 , and Section 5.1.3).  Although FVIII and aPCC are fundamentally 
different in their potential interaction with emicizumab, investigators should keep in mind 

that circulating emicizumab increases patients’ coagulation potential.  Therefore, it is 
recommended that: 

Breakthrough bleeds should be treated with the lowest FVIII or rFVIIa dose
expected to achieve hemostasis, which may be lower than the patients’ prior dose.
Investigators should review with patients the dose to be used to treat breakthrough
bleeds.

The use of aPCC/PCC or other bypassing agents should be avoided or limited (see
Section 4.4.1).

Investigators and patients should consider objective verification of bleeds.
Also, local laboratory assessments are required to monitor the risk for thromboembolic 
events or thrombotic microangiopathy as per the schedule of assessments (see Section 
4.5.5 and Appendix 1-A). 
Patients might require dosing with FVIII or bypassing agents for the treatment of 
potential breakthrough bleeds, especially for the time period until steady-state 
concentrations of emicizum 
ab have been reached.  The reason for the use of coagulation products will be 
documented (e.g., bleeding, prophylaxis).  The number of infusions needed to treat the 
bleed will be derived from the medication log. 
Of note, a non-interventional study (Study BH29768) has been initiated to document the 
number and types of bleeds and current treatment with episodic or prophylactic 
bypassing agents, as well as collect information on HRQoL, health status, and safety in 
patients with hemophilia A (including children < 12 years of age).  The assessments in 
the non-interventional study will mitigate the risk of inaccurate reporting of bleeds 
that may occur with historical data collection and may provide data collected 
prospectively for over 24 weeks.  Patients who are enrolled in the non-interventional 
Study BH29768 are eligible to enroll in this study, provided they meet the eligibility 
criteria and are able to enroll at a participating site while the study is open for 
enrollment. 
Investigators will contact the Medical Monitor in the event of suspected lack or loss of 
efficacy of emicizumab in order to discuss potential laboratory evaluations 
(e.g., anti-emicizumab antibodies, coagulation tests) to be performed as well as to 
re-evaluate their patient’s benefit-risk of continued treatment. 
Collection of PK/ADA/Biomarker samples from Arm D patients will stop when the patient 
completes the study or after Week 49, whichever occurs first. 
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3.2 
END OF STUDY AND LENGTH OF STUDY 
3.2.1 
End of Study 
The primary analysis will take place at the earliest timepoint when all randomized 
patients (Arms A, B, and C) have either completed at least 24 weeks of treatment or 
discontinued from the study.  For Arm D, the primary efficacy analysis will be conducted 
after the last enrolled patient have completed at least 24 weeks in the study or 
discontinued from treatment. 
Patients who discontinue study treatment prior to end of study (with the exception 
where the reason for discontinuation is the patient switching to commercial emicizumab 
product) will return to the clinic for a safety follow-up visit 24 weeks after the final 
dose of study drug. 
The end of this study is defined as the date when the last remaining patient has 
completed the last visit (LPLV), as defined by any of the following criteria: 
 
Completion of at least 24 weeks of emicizumab treatment 
 
Completion of safety follow-up visit 24 weeks after discontinuing emicizumab 
 
Completion of the study Extension Phase (3  years after the last Arm D patient 
completes 1 year treatment) and patients still having clinical benefit are 
transferred to a post-trial continued access solution per Roche Global Policy on 
Continued Access to Investigational Medicinal Products [see Section 4.3.4])  
 
Withdrawal of consent 
 
Lost to follow-up 
 
The study will end earlier, before 3 years after the last Arm D patient completes 1 year 
treatment, should the post-trial continued access solution be available earlier. 
3.2.2 
Length of Study 
The length of the study for an individual patient will be: 
 
Screening period up to 4 weeks 
 
Treatment and observation period at least 24 weeks 
 
Safety follow-up visit 24 weeks after discontinuing emicizumab  
 
An extension phase in this study for all patients who complete at least 52 weeks of 
treatment with prophylactic emicizumab and still deriving clinical benefit for 3 years 
after last Arm D patient completes 1 year of treatment.  Extension phase may end 
earlier, before 3 years after the last Arm D patient completes 1 year treatment, 
should a post-trial continued access solution be available earlier. 
 
The approximate length of the entire study from screening of the first patient to the end 
of the study (including Arm D and study Extension Phase) will be approximately 
88 months. 

 
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3.3 
RATIONALE FOR STUDY DESIGN 
This is a multicenter, open-label, Phase III clinical study with randomized and 
non-randomized arms.  Patients aged 12 years or older with hemophilia A with or without 
inhibitors against FVIII will be randomized to receive one of the following regimens: 
 
Emicizumab prophylaxis at 3 mg/kg QW for 4 weeks, followed by 1.5 mg/kg QW 
subcutaneously (Arm A) 
 
Emicizumab prophylaxis at 3 mg/kg QW for 4 weeks, followed by 6 mg/kg Q4W 
subcutaneously (Arm B) 
 
No prophylaxis control arm (Arm C) 
 
Patients aged  12 years with hemophilia A with inhibitors against FVIII will be enrolled to 
receive the following regimen: 
 
Emicizumab prophylaxis at 3 mg/kg QW for 4 weeks, followed by 1.5 mg/kg QW 
subcutaneously (Arm D) 
 
This prospective, randomized design (Arms A, B, and C) allows uniform collection of 
bleed data, medication use, and patient-reported outcomes (PROs) through the use of 
patient-validated measurement tools in all groups, enabling analysis of the effect of 
prophylactic emicizumab versus episodic therapy on these important measures.  
Reporting of bleeds by patients to their providers (e.g., doctors, nurses) is not 
standardized and can be incomplete in routine clinical care.  In addition, the recording of 
bleeds by providers in medical records may be inconsistent.  Therefore, testing the 
primary endpoint using a prospective randomized design is superior to comparison to 
historical control in patients who were not on prophylaxis prior to enrollment. 
Given the proven efficacy of prophylaxis, it can be expected that standard-of-care may 
evolve towards more widespread treatment of patients with prophylaxis regimens.  
However, for myriad reasons, currently only about half the patients in developed 
countries and less than 20% patients in China are managed with routine prophylaxis, 
making the episodic approach a commonly used standard care (Richards et al. 2007; 
Xue et al. 2011; Gringeri et al. 2012; Zappa et al. 2012; Jackson et al. 2014; Oldenburg 
and Brackmann 2014; Jackson et al. 2015; Oldenburg 2015).  Thus, for the primary 
efficacy endpoint, patients with no prophylactic therapy will be compared with patients 
treated with prophylactic emicizumab.  This study will only enroll patients who previously 
received episodic therapy; this approach will reduce heterogeneity in the study 
population, which is appropriate since the bleed rates for patients receiving therapy on 
an episodic versus prophylactic basis are significantly different (Valentino et al. 2012; 
Manco-Johnson et al. 2013; Powell et al. 2013; Antunes et al. 2014; 
Mahlangu et al. 2014; Windyga et al. 2014).  To help balance measured and 
unmeasured covariates between the groups with prophylactic emicizumab and the 
control group with no prophylactic therapy, randomized patients will be stratified 
according to the number of bleeds they had over the 24 weeks prior to study entry (less 
than versus greater than or equal to 9 bleeds). 

 
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The primary efficacy analysis to assess the effect of emicizumab on bleed rate reduction 
will be performed at the earliest timepoint when all randomized patients have either 
completed 24 weeks of study treatment or discontinued from the study.  Indeed, a similar 
follow-up period was used in recent studies that investigated the safety and efficacy of 
novel FVIII formulations and in the emicizumab global studies (Mahlangu et al. 2014; 
Kavakli et al. 2015; Konkle et al. 2015).  Further, patients who experience frequent 
bleeds may not find it acceptable to be randomized to their usual episodic therapy for 
longer than 24 weeks prior to receiving emicizumab.  For this reason, individual patients 
in the control arm will be offered the opportunity to switch to emicizumab after 24 weeks 
in the study. 
With available PK, efficacy, and safety data of emicizumab prophylaxis treatment in 
pediatric inhibitor patients, the effect of bleeding control is regardless of age, prior 
treatmet choice, and bleeding history.  Thus, Arm D has been added to enroll pediatric 
patients with no limitation in terms of the minimal age; patients with both prior episodic 
and prophylaxis treatment with bypassing agents are allowed. 
3.3.1 
Rationale for Emicizumab Dose and Schedule 
Emicizumab prophylaxis has been administered subcutaneously in 18 Japanese patients 
with hemophilia A (with and without FVIII inhibitors) in Study ACE001JP and in its 
extension Phase I/II Study ACE002JP.  Three dose groups (of 6 patients each) received 
the following treatment (administration period of 12 weeks): 
 
A loading dose of 1 mg/kg followed by weekly doses of 0.3 mg/kg 
 
A loading dose of 3 mg/kg followed by weekly doses of 1 mg/kg 
 
Weekly doses of 3 mg/kg 
 
Emicizumab was safe and well tolerated in these patients (see Section 1.2.2 and the 
Emicizumab Investigator's Brochure).  The maximum clinical dose of 3 mg/kg/week is 
associated with a 10.3-fold and 11.2-fold safety margin based on Cmax and AUC, 
respectively.  No clear difference in the plasma concentrations of emicizumab was 
observed between adolescents (1218 years) and adult (aged 1958 years) patients. 
A substantial reduction in bleeding events has been observed with prophylactic 
emicizumab treatment, especially at doses  1 mg/kg/week (see Table 3, based on data 
cutoff of 17 April 2015).  ABR decreased in all patients, regardless of age or the 
presence of FVIII inhibitors. 
 

 
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Table 3 
Mean Reduction (%) of Annualized Bleeding Rates in Inhibitor 
and Non-Inhibitor Patients Enrolled in 
Study ACE001JP/ACE002JP 
Emicizumab Dose 
0.3 mg/kg/wk 
1 mg/kg/wk 
3 mg/kg/wk 
ABR reduction 
74.5% 
95.3% 
96.4% 
ABR  annualized bleeding rate; wk  week. 
 
A median ABR of 0 was achieved with weekly maintenance doses of 1 and 3 mg/kg.  
The number of bleeding events decreased with increased emicizumab plasma 
concentrations (see Figure 2). 
Figure 2 Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event 
 
ACE910  emicizumab (also known as RO5534262) 
● Joint bleed 
O Non-joint bleed 
 

 
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Broken line  target exposure level of 45 g/mL. 
NOTE:  Once-weekly loading dose of 3 mg/kg for first 4 weeks followed by every 4 weeks 
maintenance dose of 6 mg/kg was applied. 
 
Overall, a Q4W dosing regimen with 6 mg/kg is expected to provide favorable safety and 
efficacy in patients with hemophilia A with or without inhibitors.  A global Study BO39182 
is planned to investigate the efficacy, safety, and pharmacokinetics of Q4W SC 
administration of emicizumab.  It is estimated that the study results of BO39182 will be 
available before the initiation of Study YO39309.  A re-assessment of Q4W dosing 
schedule based on the results of BO39182 will be performed. 
The loading doses of 3 mg/kg QW for 4 weeks were chosen in order to rapidly achieve 
the effective trough concentration of 45 g/mL without exceeding the maximum dose of 
3 mg/kg QW investigated in the Phase I and Phase I/II studies.  The two maintenance 
dosing regimens will offer flexibility of dosing frequency to patients.  Therefore, these 
prophylaxis regimens (i.e., 3 mg/kg QW for 4 weeks followed by 1.5 mg/kg QW or 
6 mg/kg Q4W) will be investigated in this study. 
Due to the similarity of the disease between adults/adolescents and children, as well as 
the availability of a physiologically functioning coagulation system from 6 months 
onwards (including the targets of emicizumab, FIX and FX), there are no anticipated 
differences in the action of emicizumab in pediatric patients compared with adults.  
Indeed, pediatric and adult patients with hemophilia A have shown a similar response to 
treatment with FVIII compounds (Mahlangu et al. 2014; Young et al. 2015) and 
bypassing agents (Young et al. 2012).  In the Japanese Phase I/II clinical studies with 
emicizumab, adolescent patients (aged 1218 years) with hemophilia A have 
demonstrated similar safety and efficacy results to those observed in adults.  
Furthermore, in the Phase III HAVEN 2 study, enrolling pediatric (  12 years of age) 
hemophilia A patients with inhibitors, no effects of age on PK parameters were found. 
Given emicizumab PK characteristics and analysis of patient characteristics, no dose 
adjustment appears to be required for specific patient populations (i.e., children, 
adolescents, the elderly, or patients with renal or hepatic impairment).  Therefore, the 
dosing regimen to be investigated in the present study in patients  12 years of age is to 
be selected to target a similar plasma emicizumab concentration trough level as the one 
being targeted in adolescents and adults (i.e., 45 g/mL). 
3.3.2 
Rationale for Patient Population 
This study will include patients with hemophilia A, irrespective of the presence of FVIII 
inhibitors.  The mode of action of emicizumab is identical in the presence or absence of 
FVIII inhibitors, and data from the Phase I and Phase I/II studies did not show a 
difference in the pharmacokinetics, safety, or efficacy between patients with or without 
inhibitors against FVIII.  There are four global pivotal studies to investigate the efficacy 
and safety profile of emicizumab in patients with hemophilia A, with or without inhibitors.  
The results from these studies provided more data for further assessment of the patient 

 
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population.  To ensure a representative variety of patients with hemophilia A enrolled in 
this study, for the randomized part of Arms A, B, and C, enrollment of up to 
55 non-inhibitor patients will be permitted.  Although the severity of a patient’s 
hemophilia A is directly related to the FVIII activity, interpatient variability may exist 
based on level of physical activity, bleeding history, and other features.  Therefore, 
patients previously treated with episodic FVIII or bypassing agents will be required to 
have had at least five bleeds in the 24 weeks prior to study entry to be eligible for 
enrollment into the study.  This requirement is intended to select a group of patients with 
hemophilia A who have a high, unmet medical need and to enable evaluation of 
adequate control of bleeding in this population.  In order to exclude patients who might 
have a higher chance of showing an immune response to foreign protein regimens 
(e.g., FVIII), patients without FVIII inhibitors (  0.6 BU/mL) who completed successful ITI 
at least five years before screening must have no evidence of inhibitor recurrence 
(permanent or temporary), indicated by detection of an inhibitor, FVIII half-life  6 hours, 
or FVIII recovery  66% since ITI (Antun et al. 2015). 
3.3.3 
Rationale for Control Group 
The control group for the primary efficacy endpoint will be a concurrent, no prophylaxis 
“usual care” arm, in which patients who were on episodic therapy prior to study entry will 
be randomized (2:2:1 prophylactic emicizumab 1.5 mg/kg QW:prophylactic emicizumab 
6 mg/kg Q4W:no prophylaxis), which will enable an inter-patient comparison of the 
treatment and control groups. 
A second comparison will be a comparison to an individual patient’s bleed rate 
calculated over the 24 weeks prior to study entry, from the medical record.  This will 
enable intrapatient analyses of bleed rates to be performed. 
All patients, whether assigned to receive prophylactic emicizumab or no prophylaxis, will 
continue to receive FVIII or rFVIIa on an episodic basis for the treatment of breakthrough 
bleeds during the study.  Specific doses of FVIII or rFVIIa will not be mandated in the 
study but investigators should review with patients and approve the appropriate dose to 
be used to treat breakthrough bleeds.  For patients receiving emicizumab, breakthrough 
bleeds should be treated with the lowest FVIII or rFVIIa dose expected to achieve 
hemostasis, which may be lower than the patients’ prior FVIII or rFVIIa dose. 
3.3.4 
Rationale for the Primary Efficacy Analysis 
For Arms A, B, and C, the objective of the primary efficacy analysis is to evaluate the 
clinical effect of prophylactic emicizumab compared with no prophylaxis based on the 
number of bleeds over time (i.e., bleed rate).  As mentioned in Section 3.1, the primary 
analysis will take place at the earliest timepoint when all randomized patients have either 
completed 24 weeks of treatment or discontinued from the study.  This will lead to a 
range of observation periods from 6 to 12 months or longer in the prophylactic 

 
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emicizumab arm and is deemed to be sufficient to reliably assess the effect of 
prophylactic emicizumab on bleed rate reduction. 
Primary efficacy analyses for Arm D will occur at the time of the last enrolled patient 
have completed 24 weeks in the study. 
Additional efficacy analyses may be performed at the end of the study and as needed to 
support regulatory interactions. 
In the multiple ascending dose (MAD) Phase I study (ACE001JP) involving Japanese 
patients with hemophilia A, a reduction in median ABR to 0 after 12 weeks of treatment 
(approximately 3 months) in the 1 and 3 mg/kg/wk emicizumab dose cohorts was 
demonstrated.  In the Japanese Phase I/II extension study (ACE002JP), the median 
ABR of the 1 and 3 mg/kg/wk dose cohorts continued to remain zero in patients who 
continued to receive prophylactic emicizumab after a minimum of 24 weeks, which is 
consistent with evidence suggesting longer duration of prophylactic therapy is 
associated with maintenance of ABR reduction (Antunes et al. 2014).  Patients in the 
1 and 3 mg/kg/wk cohorts in Study ACE001JP/Study ACE002JP have been observed for 
at least 72 and 48 weeks, respectively, except for 1 patient in the 3 mg/kg/wk group who 
has only been followed for 44 weeks as of the cutoff date (17 April 2015). 
3.3.5 
Rationale for Patient-Reported Outcome Assessments 
The study design uses the electronic capture of HRQoL, health status, and days of 
work/school missed using an electronic, handheld device.  HRQoL is an important 
outcome in the care of patients with hemophilia (Brown et al. 2009).  HRQoL in 
hemophilic patients is multifaceted and impacted by disease symptoms (e.g., pain, 
bleeding), treatment (prophylactic, on demand, side effects), limitations on daily 
functioning, anxiety/depression, and time spent in hospital. 
The goal of measuring HRQoL is to quantify the benefit of treatment from the patient 
perspective.  Previous studies that have used the Haemo-QoL, a measure of dimensions 
of HRQoL affected by hemophilia in children and adolescents, have reported 
improvements in physical health, feelings, view of self, family relations, friend relations, 
perceived support, relation with others, participation in sports, dealing with hemophilia, 
views of treatment, views of the future, and relationships (Santagostino et al. 2014).  
Improvements in physical health, feelings, view of self, and participation in work and 
school have also been observed on the adult version of the measure, the Haem-A-QoL 
(Stasyshyn et al. 2014). 
Managing a serious chronic diease like hemophilia in children, which is further 
complicated by inhibitors, has direct impact on the family.  Therefore, it is equally 
important to assess the potential burden and impact on HRQoL that this may have on 
caregivers.  In a study of caregivers of hemophilic children with inhibitors, an increased 
burden and higher impact of the disease on the family was reported (Lindvall 

 
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et al. 2014).  This burden was reported in a variety of areas including financial, 
emotional, general strain, isolation, and activities. 
The inclusion of HRQoL measures for Arms A, B, and C will allow for the assessment of 
the effect of prophylactic treatment with emicizumab in adolescents and adults with 
hemophilia A and evaluate the changes in HRQoL in patients receiving prophylaxis with 
emicizumab compared with patients receiving only episodic treatment for breakthrough 
bleeds. 
For Arm D, the inclusion of HRQoL measures will allow for the assessment of the impact 
of prophylactic treatment with emicizumab in children with hemophilia A and their 
caregivers, and an evaluation of the changes in HRQoL in patients prior to and following 
treatment with emicizumab. 
3.3.6 
Rationale for Biomarker Assessments 
Some biomarkers to measure the PD effect of emicizumab on hemostasis have not been 
fully validated to date and require further testing to determine which assays and 
technical conditions are most suitable for use with emicizumab treatment.  See 
Section 5.1.4 for more information about the effects of emicizumab on existing laboratory 
assays.  Plasma samples will be collected for PD biomarker assessment in parallel with 
PK samples at all clinic visits to demonstrate evidence of biologic activity of emicizumab 
in patients.  These PD biomarkers include, but are not limited to, coagulation assays 
such as aPTT, thrombin generation, and FVIII activity assays.  All of these assays were 
previously shown in the Phase I/II study to exhibit a dose-response relationship to 
emicizumab concentration (for more information, see the Emicizumab Investigator’s 
Brochure).  In addition, clot waveform analysis may be run as an exploratory PD 
coagulation assay.  Exploratory plasma biomarkers will include FVIII antigen, FIX 
antigen, and FX antigen to assess whether drug treatment causes a change in the 
circulating levels of these coagulation factors, which are the binding targets of 
emicizumab, and may include measurement of other coagulation or hemophilia-related 
factors as well.  Finally, residual blood from collected samples may be stored for 5 years 
and used for additional emicizumab-related research. 
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 utilized 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 ethical considerations for clinical trials on medicinal products with the 
paediatric population.  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 

 
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samples, followed by biomarker and PD samples.  See the laboratory manual for 
detailed weight-based blood sampling guidelines. 
3.3.7 
Rationale for Pharmacokinetic Sample Schedule 
One of the aims of this study is to provide dosing recommendations for Chinese 
hemophilia A patients.  A median ABR of 0 has been predicted to be achieved for an 
emicizumab trough plasma concentration of  45 g/mL based on data in adolescent 
and adult patients with hemophilia A (Study ACE001JP/ACE002JP). 
Plasma samples will be collected weekly during the loading dose period and at 
subsequently less frequent intervals while at steady state in order to document the 
exposure.  This will ultimately allow for optimization of the dosing regimen of emicizumab 
in Chinese patients. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
A total of 70 patients with severe hemophilia A who previously received episodic therapy 
with either FVIII or bypassing agents will be enrolled in Arms A, B, and C. 
A total of 15 pediactric patients with hemophilia A with inhibitors from China mainland 
who previously received episodic therapy with bypassing agents will be enrolled in 
Arm D. 
4.1.1 
Inclusion Criteria 
4.1.1.1 
Arms A, B, and C 
Patients in Arms A, B, and C must meet the following criteria for study entry: 
 
Signed Informed Consent Form by the patient or a legal guardian 
 
Able to comply with the study protocol, in the investigator’s judgment 
 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the completion of PRO questionnaires 
and bleed and medication diary through the use of an electronic device 
 
Aged 12 years or older at the time of informed consent 
 
Body weight  40 kg at the time of screening 
 
Diagnosis of severe congenital hemophilia A (intrinsic FVIII level  1%) or 
hemophilia A with FVIII inhibitors 
 
Patients without FVIII inhibitors ( 0.6 BU/mL) who completed successful ITI must 
have done so at least 5 years before screening and have no evidence of inhibitor 
recurrence (permanent or temporary) indicated by detection of an inhibitor 
 0.6 BU/mL since ITI (Antun et al. 2015) 
 
Documentation of the details of episodic therapy (FVIII or bypassing agents) and of 
number of bleeding episodes for at least the last 24 weeks 

 
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 
 5 bleeds in the last 24 weeks prior to study entry 
 
Adequate hematologic function, defined as platelet count  100,000/L and 
hemoglobin  8 g/dL (4.97 mmol/L) at the time of screening 
 
Adequate hepatic function, defined as total bilirubin  1.5  the upper limit of normal 
(ULN; excluding Gilbert’s syndrome) and AST and ALT  3  ULN at the time of 
screening; no clinical signs or known laboratory/radiographic evidence consistent 
with cirrhosis 
 
Adequate renal function, defined as serum creatinine  2.5  ULN and creatinine 
clearance by Cockcroft-Gault formula  30 mL/min 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of  1% 
per year during the treatment period and for at least 5 elimination half-lives 
(24 weeks) after the last dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 1 year of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of  1% per year include 
proper use of combined oral or injected hormonal contraceptives, bilateral tubal 
ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  Alternatively, two methods (e.g., two barrier methods such 
as a condom and a cervical cap) may be combined to achieve a failure rate 
of  1% per year.  Barrier methods must always be supplemented with the use 
of a non-lipid-based spermicide. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
4.1.1.2 
Arm D 
Patients in Arm D must meet the following criteria for study entry: 
 
Written informed consent must be obtained from parent/legally acceptable 
representative and an assent from the child when applicable (latest approved 
version by the Independent Ethics Committee [IEC]/Institutional Review Board 
[IRB]) prior to any of the study-specific assessments and procedures being 
performed. 
 
Children  12 years of age at time of informed consent 
 
Body weight  3 kg at time of informed consent 
 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the completion of applicable PRO 
questionnaires 

 
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 
Caregivers of all children must have the willingness and ability to comply with all 
study procedures, including the completion of the bleed/medication questionnaire 
and applicable HRQoL questionnaires 
 
Diagnosis of congenital hemophilia A of any severity and documented history of 
high-titer inhibitor (i.e.,  5 BU/mL) 
 
Requires treatment with bypassing agents 
 
Adequate hematologic function, defined as platelet count of  100  109 cells/L and 
hemoglobin  8 g/dL (4.97 mmol/L) at the time of screening 
 
Adequate hepatic function, defined as total bilirubin  1.5  age-adapted ULN 
(excluding Gilbert’s syndrome) and both AST and ALT  3  age-adapted ULN at the 
time of screening 
 
Adequate renal function:  serum creatinine must be  1.5  ULN for age 
If serum creatinine is  1.5  ULN, creatinine clearance by Bedside Schwartz 
formula must be  70 mL/min/1.73m2. 
 
For female patients who are of childbearing potential, follow the same contraception 
criteria as listed above for Arms A, B, and C. 
 
4.1.2 
Exclusion Criteria 
4.1.2.1 
Arms A, B, and C 
Patients in Arms A, B, and C who meet any of the following criteria will be excluded from 
study entry: 
 
Inherited or acquired bleeding disorder other than hemophilia A 
 
Patients who are at high risk for thrombotic microangiopathy (e.g., have a previous 
medical or family history of thrombotic microangiopathy), in the investigator’s 
judgment 
 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 
 
Previous (within the past 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 increase risk of 
bleeding or thrombosis 
 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
 
Known HIV infection with CD4 count  200 cells/L within 24 weeks prior to 
screening.  Patients with HIV infection who has CD4  200 cells/L and meet all 
other criteria are eligible 
 
Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use 
during the study, with the exception of anti-retroviral therapy 

 
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 
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could 
interfere with the conduct of the study, may pose additional risk, or would, in the 
opinion of the investigator, preclude the patient’s safe participation in and 
completion of the study 
 
Planned surgery (excluding minor procedures such as tooth extraction or incision 
and drainage) during the study 
 
Receipt of: 
Emicizumab in a prior investigational study 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
A non-hemophilia-related investigational drug concurrently, within last 30 days 
or 5 half-lives, whichever is shorter 
 
Inability to comply with the study protocol in the opinion of the investigator 
 
Pregnant or lactating, or intending to become pregnant during the study 
Women with positive serum pregnancy test result within 7 days prior to initiation 
of study drug. 
 
4.1.2.2 
Arm D 
Patients in Arm D who meet any of the following criteria will be excluded from 
study entry: 
 
Inherited or acquired bleeding disorder other than hemophilia A 
 
Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment 
with FVIII 
Patients awaiting initiation of ITI will be eligible. 
Patients in whom ITI has failed will be eligible with a 72-hour washout period 
prior to the first emicizumab administration. 
 
Previous (in the past 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 diseases (i.e., certain autoimmune diseases [e.g., systemic lupus 
erythematosus], cardiovascular disease) that may increase risk of bleeding or 
thrombosis 
 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
 
Known infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) 
 
Patients who are at high risk for thrombotic microangiopathy (e.g., have a previous 
medical or family history of thrombotic microangiopathy), in the investigator’s 
judgment 

 
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 
Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrollment 
or planned use during the study 
 
Planned surgery (excluding minor procedures such as tooth extraction or incision 
and drainage) during the study 
 
Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood 
products (or any standard-of-care treatment for a life-threatening condition) 
 
Receipt of: 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
An investigational drug concurrently 
 
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could 
interfere with the conduct of the study or that would, in the opinion of the investigator 
or Sponsor, preclude the patient’s safe participation in and completion of the study 
or interpretation of the study results 
 
Pregnant or lactating, or intending to become pregnant during the study 
Female patients with a positive serum pregnancy test result within seven days 
prior to initiation of study drug. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study with randomized and non-randomized arms.  Adolescents 
and adult patients who received episodic therapy with FVIII or bypassing agents prior to 
study entry will be randomized in a 2:2:1 ratio to receive either prophylactic emicizumab 
at 3 mg/kg QW subcutaneously for 4 weeks, followed by 1.5 mg/kg QW (Arm A) or 
6 mg/kg Q4W (Arm B) subcutaneously, or to the control arm (no prophylaxis; Arm C).  
A central randomization procedure will be used for all patients who fulfill the entry criteria 
at screening.  A block-based randomization method will be used, stratified by the 
number of bleeds in the last 24 weeks ( 9 or  9).  The proposed randomization method 
is designed to balance treatment group assignment within the prognostic stratification 
factor. 
This study will open one additional non-randomized arm (Arm D) to investigate the 
1.5 mg/kg QW regimen in pediatric patients aged  12 years with inhibitors.  All patients 
will be recruited to Arm D. 
4.3 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is emicizumab. 

 
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4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Emicizumab 
Emicizumab Drug Product will be supplied by the Sponsor as a sterile liquid for SC 
injection, contains no preservatives, and requires storage at 2C8°C (do not freeze and 
protect from light).  Each single-use vial contains 30 mg 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, 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 more dilute 30-mg vials are intended for 1.5-mg/kg 
maintenance dosing for patients in Arm D with body weight  20 kg and will enable safe 
subcutaneous weight-based dosing of small children with sufficient precision.  It is 
important to note that vials of different emicizumab concentrations must not be combined 
in the same syringe.  For information on the formulation and handling of emicizumab, 
see the Emicizumab Investigator's Brochure. 
4.3.2 
Dosage, Dose Adjustment, and Administration 
As discussed in Section 3.3.1, each patient starting on prophylactic emicizumab will 
receive 3 mg/kg QW for 4 weeks as loading doses, followed by 1.5 mg/kg QW (Arm A) 
or 6 mg/kg Q4W (Arm B), for a total of at least 24 weeks or as long as they continue to 
derive sufficient clinical benefit.  After completion of 24 weeks observation in the study, 
patients in Arm C could switch to receive emicizumab prophylaxis at the Arm B dosing 
regimen (emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed 
by 6 mg/kg Q4W). 
After at least 24 weeks on prophylactic emicizumab, patients in Arms A, B, and C will 
have the opportunity to increase their emicizumab dose to 3 mg/kg QW if they meet the 
following criteria and after consulting with the Medical Monitor: 
 
 2 spontaneous and clinically significant bleeds in the last 24 weeks on 
emicizumab, both of which occur after the end of the loading dose period 
 
At least one of the bleeds must be verified by a physician (e.g., with diagnostic 
imaging, photograph) 
 
Patients in Arm D will receive 3 mg/kg QW for 4 weeks as loading doses, followed by 
1.5 mg/kg QW as maintenance during the 24-week treatment period.  Individual patients 
experiencing suboptimal bleeding control on emicizumab may also have their dose 
up-titrated if they meet the same criteria as required for patients in Arm A, B and C and 
after consulting with the Medical Monitor. 
If the investigator believes that a specific patient warrants dose up-titration based on a 
different reason (e.g., traumatic bleed out of proportion to the degree of injury), they 
must discuss the case with the Medical Monitor for consideration. 

 
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In order to minimize the number of injections for patients in certain weight categories, the 
administration per single injection of up to 2 mL drug product solution may be permitted, 
pending approval from the Sponsor, individual countries, and participating sites.  This 
will require combining emicizumab drug product solution from more than 1 vial (i.e., vial 
pooling) into a single syringe, using a new transfer needle for each vial.  Upon Sponsor 
approval, the detailed procedure for vial pooling will be described in the Instructions for 
Use.  Vials of different emicizumab concentrations must not be combined. 
If a patient has a systemic hypersensitivity reaction or severe adverse reaction that may 
be attributable to emicizumab, subsequent doses should be held until the situation is 
discussed with the Medical Monitor.  Should certain, unanticipated events occur during 
the study that require treatment with multiple daily administrations of FVIII concentrates 
or bypassing agents, such as non-elective surgery or severe/life-threatening bleeds, the 
investigator should contact the Medical Monitor immediately to discuss such cases and 
the management of future emicizumab doses.  Due to emicizumab’s unique mechanism 
of action and the characteristics of its binding to FIX and FX, co-administration of FVIII or 
bypassing agents and emicizumab is believed to be safe and in general should be 
continued without withholding emicizumab; however, an individualized decision should 
be made in consultation with the Medical Monitor.  Any other emicizumab dose 
adjustment request will require discussion of the clinical case with the Medical Monitor. 
Study site healthcare providers (HCPs) will be trained on how to properly prepare the 
study medication and administer the correct calculated dose subcutaneously as 
described in the “Instructions for Use” (IFU) document.  Patients will, in turn, be trained 
by an HCP on study medication preparation and self-administration at the recommended 
sites of injection, as detailed in the IFU.  In the event that a caregiver will ultimately 
administer study drug to the patient in the home setting, the caregiver will be trained.  
The HCP will inform the patient/caregiver of the volumetric dose to be administered and 
dosing frequency.  Note that during the course of the study, should the patient’s body 
weight change to affect the dose (e.g.,  10%), the new volumetric dose to be 
administered must be communicated to the patient/caregiver. 
Details on the devices to be used for study medication withdrawal from vial and SC 
injection are provided in the Pharmacy Manual. 
Emicizumab will be administered as a SC injection in the home setting, with one dose 
every week or every 4 weeks, after a period of in-clinic administration and training.  The 
first five drug administrations must be performed in a monitored setting, such as an 
infusion center, clinic, or hospital, with a 60-minute observation period following each of 
the first three doses.  The observation period for the fourth and fifth doses will be at the 
investigator’s discretion.  For patients with a previous history of a clinically significant 
hypersensitivity reaction, additional precautions as described in Section 5.1.2.2 should 
be considered.  At that time, the patient/caregiver will also have the opportunity to ask 
any questions of the HCP before the scheduled start of home administration.  The 

 
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patient ( 7 years of age)/caregiver will observe at least one SC injection performed by 
the HCP and successfully administer at least one SC injection while being observed by a 
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, 
arrangements may be made to identify an alternative trained caregiver or HCP to 
administer the SC injections.  At the investigator’s discretion, study drug may be 
administered by a trained mobile nursing professional at the patient's home or another 
suitable location, if the patient has given written informed consent to participate in mobile 
nurse visits. 
Patients/caregivers will be provided with the clinic contact information, to use in case 
they have questions related to self-administration between visits. 
Medication administration errors during training 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 reviewing reported emicizumab use and recording collected used and 
unused vials at each site visit. 
Patients shall administer study medication on the schedule dosing days.  On days when 
trough plasma samples are to be collected, patients will be dosed after samples are 
drawn, potentially at the clinic (self-administration).  On the other days, for patients on 
once weekly dosing, if the patient forgets or cannot administer study medication on the 
scheduled dosing day, study medication should be administered as soon as possible 
within a window of 3 days from the scheduled dosing date.  If more than 3 days has 
passed, the missed dose should be skipped, and the patient should take his or her next 
dose at the next scheduled time with the study medication dosing resumed in 
accordance to the original dosing schedule.  For patients on once every 4 weeks dosing, 
if the patient forgets or cannot administer study medication on the scheduled dosing day, 
study medication should be administered as soon as possible within a window of 
14 days from the scheduled dosing date.  If more than 14 days has passed, the patient 
should take his or her next dose at the next scheduled time with the study medication 
dosing resumed in accordance with the original dosing schedule. 
Patients and/or the caregiver will be provided with patient cards, which they will be 
requested to carry at all times.  These will include guidance on recognizing 
signs/symptoms of thromboembolic events or allergic/anaphylactic/anaphylactoid 
reactions and how to obtain emergency care.  In addition, patient cards are designed to 
notify an external health care provider that emicizumab will interfere with certain 
coagulation laboratory tests (see Section 3.1) and the investigator should be contacted 
for assistance. 

 
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Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.3. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
Emicizumab, the only IMP in Study YO39309, is required for completion of this study 
and will be provided by the Sponsor, and accountability for each vial is required 
throughout the study.  The study site will acknowledge receipt of IMPs using the 
interactive voice or web-based response system (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 IMPs.  All IMPs must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions, with access limited to the investigator and authorized staff. 
Used and unused IMP vials will be returned by study patients to the site and 
appropriately accounted for.  Used vials will then be disposed of at the study site 
according to the study site’s institutional standard operating procedure.  Instructions 
regarding how to handle unused vials should be obtained from the Sponsor.  The site's 
method of IMP destruction must be agreed to by the Sponsor.  The site must obtain 
written authorization from the Sponsor before any IMP is destroyed, and IMP destruction 
must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Emicizumab 
The Sponsor will offer post-trial access to the study drug (emicizumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 

 
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A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
 
The patient is eligible and has access to a study providing access to the drug 
 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for hemophilia A 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for hemophilia A 
 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT AND RESCUE THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
4 weeks prior to screening to the study completion/discontinuation visit.  In addition, use 
of long-acting medications taken infrequently (e.g., zoledronic acid, denosumab) will be 
recorded as well.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy 
Concomitant use of the following drugs and therapies will be permitted: 
 
Drugs intended to control bleeds, including FVIII products or bypassing agents as 
standard-of-care episodic treatment.  Exact dosages will not be specified in the 
study; however, investigators should consider that circulating emicizumab may 
increase patients’ coagulation potential.  Investigators should review with patients 
the dose to be used to treat breakthrough bleeds. Breakthrough bleeds should be 
treated with the lowest FVIII or rFVIIa dose expected to achieve hemostasis, which 
may be lower than the patients’ prior FVIII or rFVIIa dose. 
Caution should be taken for patients who are using rFVIIa (e.g., consideration of 
using no more than 90 g/kg of rFVIIa as an initial dose). 
Use of aPCC/PCC in combination with emicizumab should be avoided completely in 
patients who have the option of using other bypassing agents to treat bleeds.  In the 
event that aPCC/PCC is the only available bypassing agent, the lowest dose 
expected to achieve hemostasis should be prescribed, with no more than 
50 units/kg of aPCC/PCC to be administered as an initial dose. 

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Other bypassing agents (e.g., Byclot®) should be avoided.  In cases where such 
agents are the only available bypassing agent, the lowest dose expected to 
achieve hemostasis should be prescribed, with no more than the lowest dose 
described in the prescribing information to be administered as an initial dose (e.g., 
no more than 60 µg/kg of Byclot®). 
Exact dose and schedule of bypassing agents should be discussed with patients at 
the beginning and throughout the study.  Repeated dosing of rFVIIa, aPCC/PCC, 
or other bypassing agents should be performed only under medical supervision, 
which includes laboratory monitoring by additional local laboratory assessments 
(see Appendix 1-A), and consideration should be given to verifying bleeds prior to 
repeated dosing. 
Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in 
patients receiving emicizumab. 

Drugs and therapies to treat adverse events and use of topical antiseptics,
anesthetics, eye drops, etc., that are not considered to result in systemic exposure

Drugs to treat an existing medical condition ongoing at study entry that do not
violate the eligibility criteria (e.g., anti-retroviral therapy for HIV infections)

Local anesthetic cream for emicizumab SC administration

Vaccinations should be administered following national immunization schedules. As
per the World Federation of Hemophilia recommendations for vaccinations (World
Federation of Hemophilia 2012), patients with hemophilia should be vaccinated.
Thus, vaccinations should be administered according to the World Federation of
Hemophilia recommendations and local Hemophilia Treating Center practice and
ideally during a period when the bleeding status of the child is well controlled and
stable. Vaccinations should not be administered on the same day as an emicizumab
administration but ideally at a timepoint between two emicizumab administrations
(  48 hours after emicizumab administration).  Children who receive vaccinations
must be carefully followed for any adverse reactions in the subsequent days
following vaccine administration.
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 4 weeks 
prior to initiation of study treatment: 

Drugs that would affect hemostasis (e.g., aspirin, non-steroidal anti-inflammatory
drugs that are not selective or preferential cyclooxygenase-2 inhibitors, or
anticoagulants [other than to flush, dwell, or de-clot a venous access device]) but
excluding drugs intended to control bleeding episodes or used in the context of
minor surgery (e.g., tooth extraction) or injuries (e.g., concussion) to prevent
deterioration

Systemic immunomodulators (e.g., rituximab, interferon) other than anti-retroviral
therapy

Elective surgery (excluding minor procedures such as tooth extraction, CVAD
removal, or incision and drainage as well as emergency surgeries)

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
Use of aPCC/PCC for short-term prophylaxis
Note:  This criterion does not apply to the 4 weeks prior to initiation of study 
treatment. 

Use of other investigational drugs

Use of anti-fibrinolytics in conjunction with aPCC/PCC or other bypassing agents
(e.g., Byclot®)

Use of concomitant prophylactic regimen with FVIII or rFVIIa
Note:  This criterion does not apply to the 4 weeks prior to initiation of study 
treatment. 
Intermittent, prophylactic doses or short-term prophylaxis (e.g., around the time 
of surgery), however, are permitted 
If prohibited therapy is administered for any reason, it should be recorded on the eCRF. 
If prohibited treatment is prescribed or considered medically necessary, the Medical 
Monitor should be consulted to discuss any changes in the benefit/risk and determine 
whether the patient should continue on the study. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1-A for the schedule of assessments to be performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained from the 
parent/legally acceptable representative and an Assent from the child when applicable 
before performing any study-specific screening tests or evaluations.  Informed Consent 
Forms for enrolled patients and for patients who are not enrolled will be maintained at 
the study site.  For adolescents (i.e., 1217 years of age), an Informed Assent Form will 
be completed instead.  Parents or legally authorized representatives of pediatric patients 
and adolescents will also complete an Informed Consent Form. 
All screening evaluations must be completed within 4 weeks prior to the first dose and 
reviewed to confirm that patients meet all eligibility criteria before enrollment and 
randomization.  The investigator will maintain a detailed record of all patients screened 
and to document eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, procedures, abuse of alcohol and 
drugs within the past year, and medication allergies.  In particular, sites should record 
whether the patient has any history of prior immune tolerance induction, anaphylaxis, or 
known thrombophilia.  It should also include all medications taken within the 4 weeks 
prior to screening (including prescription, over-the-counter, and herbal/homeopathic 
remedies and therapies), or in the 24 weeks prior to screening for medications intended 
to treat osteopenia or osteoporosis.  If the interval between screening and Week 1 is 

 
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longer than 2 weeks, all medications taken during this period should be reviewed and 
recorded.  If imaging tests of bone health (e.g., densitometry, dual energy X-ray 
absorptiometry [DEXA] scan) were performed in the year prior to screening, the results 
should be recorded. 
Additionally, the number of bleeds during the 24 weeks prior to study enrollment should 
be documented, as well as the number of school/work days missed and number of days 
hospitalized during the 24 weeks prior to study entry. 
Demographic data will include age, sex, and self-reported race and ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should include but not necessarily be limited to the 
evaluation of head, eye, ear, nose, and throat and include cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  
Any abnormality identified during screening should be recorded on the General Medical 
History and Baseline Conditions eCRF.  Subsequently, a targeted (i.e., musculoskeletal, 
dermatological) and/or symptom-driven examination should be conducted as noted in 
the schedule of assessments or as clinically indicated.  New or worsened abnormalities 
from screening should be recorded as adverse events.  A complete physical examination 
will be performed at screening and at least targeted physical examinations will be 
performed at subsequent visits. 
4.5.4 
Vital Signs 
Vital signs will include measurement of pulse and respiratory rate, temperature (oral or 
tympanic), systolic and diastolic blood pressure, height, and weight and should be 
recorded before study drug administration.  Frequency of vital sign assessments should 
follow the schedule of assessments but may also be taken anytime as unscheduled 
assessments as judged by the investigator. 
4.5.5 
Laboratory, Biomarker, and Other Biological Samples 
Local laboratory assessments will be performed as indicated on the schedule of 
assessments.  When study drug administration is scheduled on days of clinic visit, 
laboratory samples should be drawn before the administration of study drug.  Laboratory 
assessments will include the following: 
 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, and 
basophils], mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, and RBC distribution width) 
 
Serum chemistries (sodium, potassium, glucose, blood urea nitrogen, creatinine, 
calcium, phosphorus, magnesium, total and direct bilirubin, albumin, alanine 
aminotransferase, aspartate aminotransferase, and alkaline phosphatase) 


In patients who receive bypassing agents, the following local laboratory tests will be
performed within 2448 hours of initial bypassing agent use so the investigator may
monitor for potential thromboembolic events and thrombotic microangiopathy:
–
Platelet count
–
Serum creatinine
–
Lactate dehydrogenase (LDH)
–
Peripheral blood smear analysis to evaluate for schistocytes
A plasma sample should also be provided for laboratory monitoring of:
–
Fibrinogen
–
D-dimer
For patients who require multiple doses of bypassing agents, local laboratory monitoring 
should be performed every 2448 hours thereafter until 2448 hours following the last 
dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory 
results should be recorded on the Unscheduled Visit eCRFs. 

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 the Sponsor or a designee for centralized analysis: 

Plasma samples for PK analysis

Plasma samples for immunogenicity assessment (ADA)

Serum and plasma for PD and exploratory PD biomarker assessments (aPTT, PT,
FVIII activity, and others as listed in Appendix 2)

Plasma samples for anti-FVIII antibody measurement (inhibitor titer) will be sent to
the Sponsor throughout the study, with the exception of the test needed at
screening for patients who do not have a documented negative inhibitor test
(  0.6 BU) within 6 weeks prior to enrollment.
Please see the schedule of assessments, Appendix 1-A , for detailed information.  For 
sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual. 
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. 
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4.5.6 
Electrocardiograms 
ECG recordings will be obtained at study sites at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1-A) 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.  The following parameters will be 
obtained:  heart rate, QT, respiratory rate, QT interval corrected using Bazett’s formula, 
QT interval corrected using Fridericia’s formula, PR and QRS, and T-and U-wave 
morphology.  ECG recordings must be performed after the patient has been resting in a 
supine position for at least 10 minutes. 
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g.,vital sign measurements, blood draws) and should ideally not be obtained within 
3 hours after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. 
Any ECG changes that are deemed clinically significant by the investigator 
(e.g.,associated with symptoms or lead to a change in study treatment or concomitant 
treatment, or discontinuation from study treatment), must be reported as an adverse 
event on the adverse event eCRF.  The investigator or designee must review, sign, and 
date all ECG tracings.  The ECG may be repeated if investigator deems it appropriate.  
Paper copies will be kept as part of the patient’s permanent study file at the site. 
4.5.7 
Patient-Reported Outcomes 
To capture bleed and hemophilia medication use data, as well as HRQoL and health 
status data during study treatment, patients/caregivers will complete the 
Bleed/Medication questionnaires on an electronic, handheld device that will be provided 
to them during their Week 1 visit at the site.  This device will remain with the 
patients/caregiver for the duration of the study to enter bleed and medication data on a 
weekly basis at minimum before the study extension phase. After the start of the 
extension phase, bleed and medication data will not be collected.  Patients and/or 
caregivers will complete HRQoL, proxy HRQoL-SF, and aspects of caregiver burden 
questionnaires at designated timepoints during clinic visits on a separate electronic, 
handheld device (tablet) that will remain at sites. The electronic, handheld device and 
instructions for completing the questionnaires will be provided by the investigator staff.  
The questionnaires should be completed by the patient or their caregivers at the site at 
the start of the visit and prior to all other study assessments. 
After bleed, medication, HRQoL, proxy HRQoL, and aspects of caregiver burden entries 
have been saved, the data will be transmitted automatically from the respective devices 
to a centralized vendor database.  Bleed and medication use data entered since the 

patient’s previous clinic visit will be reviewed at subsequent clinic visits, as per the 
schedule of assessments, for completeness and accuracy.  Investigators will review the 
bleed and bleed medication data as per the schedule of assessments (see Appendix 1) 
and have the ability to correct or complete entries once verified with the patient/
caregiver using a Data Change Request Form process or via a Web-based portal, once 
implemented. 
4.5.7.1 
Health-Related Quality of Life 
The Haem-A-QoL and the Haemo-QoL-SF (only for patients aged 8−17 years) will be 
used to measure HRQoL in adults and adolescents/pediatric patients, respectively 
(see  Appendix 2, Appendix 3 , and Appendix 4, respectively).  The Haem-A-QoL was 
designed for adult patients with hemophilia.  It consists of 46 items comprising 
10 dimensions (physical health, feelings, view, sport and leisure time, work and school, 
dealing, treatment, future, family planning, and relationships/partners) and a scale 
representing total score.  Items are rated along 5 response options, although for some 
items there is also a “not applicable” option (von Mackensen and Gringeri 2005; 2010). 
The Haemo-QoL-SF was developed as a series of age-related questionnaires to 
measure HRQoL in children and adolescents with hemophilia (Bullinger et al. 2002; von 
Mackensen and Bullinger 2004; Pollak et al. 2006).  These versions include a 77-item 
long form, a 35-item as well as a 16-item short form, and an 8-item index form.  The 
short version for older children containing 35 items was selected for this study.  This 
version covers nine dimensions considered relevant for the children’s HRQoL (physical 
health, feelings, view of yourself, family, friends, other people, sports and school, dealing 
with hemophilia and treatment).  Items are rated with five respective response options:  
never, seldom, sometimes, often, and always.  Higher scores for both HRQoL measures 
are indicative of poorer HRQoL. 
4.5.7.2 
Health Status 
The EQ-5D-5L (see Appendix 5) is a generic, preference-based health utility measure 
that assesses health status and is used to inform pharmacoeconomic evaluations, which 
will only be assessed for patients from Arms A, B, and C.  The EQ-5D-5L consists of two 
parts.  The first part, health state classification, contains five dimensions of health:  
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (Herdman et 
al. 2011; Janssen et al. 2013).  Published weights are available that allow for the 
creation of a single summary score.  Overall scores typically range from 0 to 1, although 
a score below 0 is theoretically possible representing a state worse than death, with low 
scores representing a higher level of dysfunction.  The second part is a 0 to 100-point 
visual analog scale (VAS) that assesses current health status; higher scores are 
reflective of better health. 
4.5.7.3 
Adapted Inhib-QoL, Including Aspects of Caregiver Burden 
Proxy assessment of HRQoL-SF and aspects of caregiver burden for all children, 
regardless of age, will be collected using the Adapted Inhibitor-Specific Quality of Life 
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(Inhib-QoL) with Aspects of Caregiver Burden questionnaire (see Appendix 6). This will 
be completed by caregivers as per the schedule of assessments during clinic visits (see 
Appendix 1). 
4.5.7.4 
Daycare/School Absences and Hospitalizations 
All patients or their caregivers will be asked to report on an electronic, handheld device 
the number of days of daycare/school that were missed (if applicable).  The number of 
days the child was hospitalized (if applicable) will be derived from data collected on 
eCRF. 
4.5.8 
Definition of a Bleed 
For the purposes of the efficacy analyses, a standardized definition of bleed, adapted 
from criteria defined by the Subcommittee on Standards and Criteria, FVIII/FIX 
subcommittee of the International Society of Thrombosis and Hemostasis and similar to 
that used in a recent clinical study, will be used in this study (Blanchette et al. 2014; 
Mahlangu et al. 2014), which includes the following additional criteria: 
 
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. 
 
An additional definition of all bleeds (i.e., both treated and not treated with coagulation 
factors) will be applied for certain secondary efficacy analyses. 
4.5.8.1 
Bleed Sites 
 
Target joints:  defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and 
ankle) into which repeated bleeds occur (frequency of  3 bleeds into the same joint 
over the last 24 weeks prior to study entry) 
 
Joint bleeds:  having an unusual sensation (“aura”) in the joint in combination with 
any of the following: 
Increasing swelling or warmth of the skin over the joint 
Increasing pain 
Progressive loss of range of motion or difficulty in using the limb as compared 
with baseline 
 
Muscle bleeds (sites as per the Bleed and Medications Questionnaire) 
 
Other bleeds (sites as per the Bleed and Medications Questionnaire) 
 
 
 

 
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4.5.8.2 
Bleed Types 
In addition, the assessment of a bleed will be separated into spontaneous bleeds, 
traumatic bleeds, and bleeds related to procedure/surgery.  Both spontaneous bleeds 
(i.e., the occurrence of hemorrhage where neither the patient nor a caregiver can identify 
a reason) and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such 
as trauma, “strenuous” activity, or “overuse”) will be collected. 
 
Spontaneous bleeds:  Bleeds will be classified as spontaneous if a patient records a 
bleed when there is no known contributing factor such as definite trauma, 
antecedent “strenuous” activity, “overuse,” or procedure/surgery.  The determination 
of what constitutes “strenuous” or “overuse” will be at the discretion of the patient.  
For example, light jogging may be considered “non-strenuous” while sprinting may 
be considered “strenuous,” lifting of weights for a short period of time may be 
considered “moderate use” while repetitive weightlifting may be considered 
“overuse.” 
 
Traumatic bleeds:  Bleeds should be classified as traumatic if a patient records a 
bleed when there is a known or believed reason for the bleed.  For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 
obvious injury, the bleed would be recorded as a traumatic bleed because, although 
no injury occurred, there was antecedent “strenuous” activity.  Bleeds subsequent to 
injuries would certainly be classified as traumatic. 
 
Bleeds related to procedure/surgery:  such as hematomas resulting from any 
surgeries or invasive procedures (e.g., tooth extractions, venipuncture, or SC drug 
administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy, etc.) would not be counted 
as bleeds.  Bleeds related to procedure/surgery are not associated with any trauma 
except procedure/surgery-induced trauma. 
 
Patients (or patient’s legally authorized representative) or their caregivers will complete 
an electronic Bleed and Medication Questionnaire whenever a bleed occurs, or at least 
weekly to confirm all bleeds have been recorded until the patient starts the study 
extension phase.   After the start of the extension phase, bleed and medication data will 
not be collected. For each bleeding episode, they will provide information on the above 
topics as well as on the medication used to treat the bleed.  Hemophilia medications that 
were taken will also be collected through the Bleed and Medication Questionnaire.  In 
the event that the electronic Bleed and Medication Questionnaire is not available, a 
paper version of the Bleed and Medication Questionnaire may be used.  The data will be 
reviewed by sites during site visits. 

 
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4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient’s inability or unwillingness to comply with protocol requirements, 
non-compliance despite appropriate education measures taken by the clinical site 
 
Patients may elect to withdraw from the activity monitoring but continue participation in 
the remainder of the study.  If a patient decides to withdraw only from the activity 
monitoring prematurely, the patient will continue treatment and follow-up as per the 
study protocol.  The primary reason for withdrawal from activity monitoring should be 
documented on the appropriate eCRF. 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 
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.  Patients who become pregnant should immediately stop treatment and be 
managed as per local guidelines. 
If the patient discontinues study treatment, bleed, hemophilia medication, HRQoL, health 
status, and missed days of school or work should be recorded by the patient on the 
electronic, handheld device until the safety follow-up visit (i.e., 24 weeks after the last 
study drug administration). 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 

 
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 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence (e.g., bleed/medication questionnaire data not checked by 
investigator/co-investigator for  8 weeks) 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference 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 
The safety plan for this study is designed to ensure patient safety and will include 
specific eligibility criteria and monitoring assessments as detailed below. 
5.1.1 
Patient Selection 
The inclusion and exclusion criteria in this study are designed to select patients who are 
not at increased risk based on the current understanding of the investigational 
medication.  See Section 4.1.1 and Section 4.1.2 for full inclusion and exclusion criteria, 
respectively. 
5.1.2 
Risks Associated with Emicizumab 
5.1.2.1 
Identified Risks 
Thrombotic Microangiopathy (Associated with Emicizumab and aPCC) 
Thrombotic microangiopathy is a very rare, but serious condition whereby microvascular 
thrombosis leads to organ damage. 
As of October 2018, among 417 patients in five studies (ACE002JP, BH29884, 
BH29992, BH30071, and BO39182), there were 3 patients (1.0%), all in Study BH29884, 
who experienced thrombotic microangiopathy while receiving emicizumab prophylaxis.  
These events are believed to be caused by an interaction between emicizumab and 
aPCC, as all 3 patients received cumulative doses of  100 U/kg/day on average of 
aPCC for  24 hours for the treatment of breakthrough bleeds just prior to developing 
symptoms.  These events were reported as serious adverse events (two Grade 4 events 
and one Grade 3 event).  One patient died due to a serious adverse event of 
Grade 4 rectal haemorrhage (assessed as unrelated to emicizumab).  From additional 
analyses, including data on the thrombotic microangiopathy and thromboembolic events, 

 
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there is evidence to support a drug-drug interaction between aPCC and emicizumab.  
Please see the Emicizumab Investigator’s Brochure for a complete summary of 
safetyinformation. 
Specific guidance regarding the use of bypassing agents in combination with 
emicizumab is detailed in Section 4.4.1. 
Any thrombotic microangiopathy 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 
Section 5.2.2 and Section 5.2.3). 
Guidelines for management of patients who develop thrombotic microangiopathy are 
provided in Section 5.1.3. 
Hypercoagulation and Risk of Thrombosis 
As of October 2018, four thromboembolic events have been reported in 3 patients with 
hemophilia A with inhibitors while receiving emicizumab in Study BH29884.  
Two patients who administered cumulative doses of  100 U/kg/day on average of aPCC 
for  24 hours while receiving emicizumab developed thromboembolic events.  The 
thromboembolic events were reported as serious adverse events (Grade 3 cavernous 
sinus thrombosis, Grade 3 skin necrosis, and Grade 2 thrombophlebitis superficial); 
however, none were life-threatening or fatal.  No anticoagulation was started and 
symptoms in both patients improved with supportive care.  These adverse events are 
believed to be caused by a drug-drug interaction between emicizumab and aPCC.  
There was 1 patient who experienced a thromboembolic event of Grade 1 device 
occlusion in Study BH29884 while receiving emicizumab.  This patient was receiving 
emicizumab prophylaxis; however, this adverse event was assessed as being unrelated 
to emicizumab.  Of note, this patient did not receive treatment with aPCC or other 
bypassing agents when he had this device occlusion. 
No cases of thromboembolic events have been observed in patients who only received 
emicizumab, who only received emicizumab and rFVIIa alone, or who were treated with 
single doses of aPCC up to 100 U/kg/infusion. 
Thromboembolic events have not been observed in any of the other completed 
(ACE001JP and JP29574) or ongoing clinical studies (ACE002JP, BH29992, BH30071, 
and BO39182).  Please see the Emicizumab Investigator’s Brochure for more details. 
Specific guidance regarding the use of bypassing agents in combination with 
emicizumab is detailed in Section 4.4.1. 
Thromboembolic events should be reported as an adverse event of special interest and 
also as a serious adverse event, if it meets criteria for such (see Section 5.2.2 and 
Section 5.2.3). 

 
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HCPs should educate patients/caregivers 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/caregivers will also receive two patient cards to remind them of this information 
and these instructions should thromboembolism be suspected. 
Guidelines for management of patients who develop hypercoagulation thromboembolic 
events are provided in Section 5.1.3. 
Injection-Site Reactions 
In the completed and ongoing clinical studies of emicizumab, injection-site reactions 
have been observed in some patients with hemophilia A.  As of October 2018, 
among 417 patients, 113 patients (27.1%) developed injection-site reactions.  All were 
assessed to be mild or moderate in intensity.  Reported events include injection site 
erythema, injection site pruritus, injection site swelling, injection site haematoma, 
injection site bruising, injection site urticaria, injection site papule, injection site warmth, 
injection site induration, injection site pallor, injection site discomfort, injection site pain, 
injection site rash, general signs and symptoms of necrotizing enterocolitis (NEC), 
purpura and related conditions, and rash, eruptions and exanthems NEC.  One patient 
reported non-site specific procedural complications.  In Study ACE001JP, two episodes 
of injection site erythema in a
year-old patient resulted in discontinuation of 
emicizumab treatment. 
Directions for emicizumab administration should be followed, as outlined in 
Section 3.3.1 , Section 4.3.2, and in the Instructions for Use.  This includes alternating 
the site of injection, from one injection to the next, in the recommended injection-site 
locations listed in the IFU. 
Guidelines for management of patients who develop injection-site reactions are provided 
in Section 5.1.3. 
5.1.2.2 
Potential Risks 
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 on the Bethesda assay) are not reliable and do not 
accurately reflect a patient’s underlying hemostatic status while receiving emicizumab 
prophylaxis.  Owing to 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 if a patient is treated by practitioners 

 
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other than emicizumab-prescribing practitioners in settings such as an emergency room 
or in an acute care setting. 
Emicizumab mechanism of action and resulting interference were clearly demonstrated 
in a wide variety of coagulation laboratory tests approved for in vitro diagnostic use.  
Clinical trials also demonstrated the effects of emicizumab on laboratory tests.  
However, as of October 2018, no instances of under-treatment of bleeding events due to 
unreliable standard coagulation tests and inhibitor assays in the setting of emicizumab 
had been observed. 
See Section 5.1.4 for interpretation of coagulation assays for patients receiving 
emicizumab. 
Anaphylaxis, Anaphylactoid, and Systemic Hypersensitivity Reactions 
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, 
including anaphylaxis and anaphylactic reactions, may occur.  In completed and ongoing 
clinical studies of emicizumab, no severe hypersensitivity reactions have been reported.  
These events should be reported as Serious Adverse Events or Adverse Events of 
Special Interest as described in Section 5.2.3. 
Patients with a history of hypersensitivity associated with monoclonal antibody therapies 
or to the components of the emicizumab injection will be excluded from study 
participation.  HCPs administering the study medication in the clinic must be trained in 
the appropriate administration procedures, be able to recognize the signs and symptoms 
associated with potential hypersensitivity, anaphylactic, and anaphylactoid reactions, 
and should be familiar with Sampson’s criteria for defining anaphylaxis (Sampson 
et al. 2006; see Appendix 7). 
HCPs should also instruct patients how to recognize the signs and symptoms of 
hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an HCP or 
seek emergency care in case of any such occurrence.  Patients/caregivers will also 
receive two alert cards to remind them of this information and these instructions should 
any of these reactions occur. 
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. 
Guidelines for management of patients who develop anaphylaxis, anaphylactoid, and 
systemic hypersensitivity reactions are provided in Section 5.1.3. 

 
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Immunogenicity 
As with administration of any exogenous protein, a potential exists for the development 
of ADAs.  Such antibodies can be neutralizing and/or sensitizing, producing the potential 
for reduced efficacy and/or allergic reactions.  As discussed in Section 1.2.2.4, patients 
with hemophilia were reported to have positive ADAs.  There were 4 positive ADA 
patients with declining PK profiles (ADA with neutralizing potential) of which one 
discontinued due to lack of efficacy.  For additional information please see the 
Emicizumab Investigator’s Brochure. 
5.1.3 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of specific adverse events are outlined in Table 4. 
Table 4 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events 
Event 
Action to Be Taken 
Thrombotic 
Microangiopathy 
 Please see Section 3.1 and Section 3.3.3 for guidance on management of 
breakthrough bleeds, including required laboratory monitoring. 
 HCPs should be vigilant for patients who exhibit signs/symptoms consistent 
with thrombotic microangiopathy and immediately begin work-up and 
treatment, as per local guidelines. 
 If a patient has a thrombotic microangiopathy event, further administration 
of study drug should be interrupted.  The decision to resume emicizumab 
after an event of thrombotic microangiopathy must be discussed with the 
Medical Monitor. 
Hypercoagulation 
and 
Thromboembolic 
Events 
 Please see Section 3.1 and Section 3.3.3 for guidance on management of 
breakthrough bleeds, including required laboratory monitoring. 
 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, administration of study drug 
should be interrupted.  The decision to resume emicizumab after a 
thromboembolic event must be discussed with the Medical Monitor. 
Injection-Site 
Reaction 
 Injection-site reactions should be treated as clinically indicated. 
 Emicizumab should not be injected into areas where the skin is red, 
bruised, tender, or hard or into areas where there are moles or scars. 
 In the clinic setting, patients will be monitored for signs of injection-site 
reactions in the period immediately following injections.  Patients will be 
given guidance on reporting injection-site reactions when administering 
drug at home or after they leave the clinic. 

 
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Event 
Action to Be Taken 
Hypersensitivity 
Reaction, 
Anaphylaxis, 
Anaphylactoid 
Reaction 
 Suspected cases should be fully evaluated and treated as clinically 
indicated. 
 Medicinal products for the treatment of hypersensitivity reactions 
(e.g., epinephrine, antihistamines, and glucocorticoids) and resuscitation 
equipment must be available for immediate use during the initial 
administrations in the infusion center, clinic, or hospital. 
 If a patient has symptoms of anaphylaxis or severe hypersensitivity, 
administration of study drug must be immediately stopped and treatment of 
the reaction be initiated. 
 No re-challenge should be performed in patients who experience a severe 
hypersensitivity, anaphylactic, or anaphylactoid reaction unless, after 
careful discussion with the medical monitor, the clinical benefit clearly 
outweighs the risk.  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. 
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. 
 
5.1.4 
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab 
Emicizumab interacts with standard laboratory assays used in the management of 
patients with hemophilia A.  In one-stage assays, emicizumab is associated with a 
supra-physiologically short time to clot formation and thus normalization of aPTT at 
subtherapeutic levels and an overestimation of true FVIII activity.  Emicizumab is not 
recognized or neutralized by FVIII inhibitors and, therefore, cannot be detected by a 
functional test such as Bethesda or Nijmegen-Bethesda assays, which use a one-stage 
clotting-based readout.  Emicizumab activity cannot be detected by chromogenic assays 
using purified bovine coagulation proteins and can only be detected using an assay 
composed of human proteins.  Table 5 summarizes the coagulation tests affected and 
unaffected by emicizumab.  See the RO5543262 (Emicizumab) Investigator's Brochure 
for additional details on which tests can be used and how the test results can be 
interpreted. 
 
 

 
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Table 5 
Coagulation Test Results Affected and Unaffected by 
Emicizumab 
Results Affected by Emicizumab 
Results Unaffected by Emicizumab 
 aPTT 
 Activated clotting time (ACT) 
 One-stage, aPTT-based, single-factor 
assays 
 aPTT-based Activated Protein C 
Resistance (APC-R) 
 Bethesda assays (clotting-based) for FVIII 
inhibitor titers 
 Thrombin time (TT) 
 One-stage, PT-based, single-factor assays 
 Chromogenic-based single-factor assays 
other than FVIIIa 
 Immuno-based assays (e.g., ELISA, 
turbidometric methods) 
 Bethesda assays (bovine chromogenic) for 
FVIII inhibitor titers 
 Genetic tests of coagulation factor 
mutations (e.g., Factor V Leiden, 
Prothrombin 20210) 
FVIII  factor VIII. 
a 
For important considerations regarding FVIII chromogenic activity assays, please see 
information provided above in Section 5.1.4. 
 
5.1.5 
Procedure-Related Risks 
Emicizumab is administered subcutaneously. Patients should be properly instructed to 
handle and prepare the injection and understand the risk for injection site reactions. See 
Section 5.1.2.1 for more information. 
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.  Therefore, an adverse event 
can be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 

 
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 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
Bleeds considered as serious adverse events should be reported as serious adverse 
events on the eCRF.  New nonserious bleeds, consistent with patients’ pre-study 
disease, will not be considered adverse events and will not be recorded on the eCRF 
(but should be captured on the bleed/medication questionnaire). 
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 Grades 14, according to the WHO Toxicity Grading 
Scale for Determining The Severity of Adverse Events criteria; see Section 5.3.3); the 
event itself may be of relatively minor medical significance (such as severe headache 
without any further findings). 

 
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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). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  These may include suspected or confirmed 
cases.  Adverse events of special interest for this study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
(see Sampson’s Criteria in Appendix 7) 
 
Thromboembolic events 
 
Microangiopathic hemolytic anemia or thrombotic microangiopathy (e.g., thrombotic 
thrombocytopenic purpura, hemolytic uremic syndrome) 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 

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After informed consent has been obtained but prior to randomization (randomized arms) 
or initiation of study drug (non-randomized arm), 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). 
After randomization (randomized arms) or initiation of study drug (non-randomized arm), 
all adverse events will be reported until the patient completes his or her last study visit.  
After this period, the investigator should report any serious adverse events that are 
believed to be related to prior study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
5.3.3 
Assessment of Severity of Adverse Events 
The WHO toxicity grading scale (sHH Appendix 8) will be used for assessing 
adverse event severity (WHO 2003).  Table 6 will be used for assessig severity for 
adverse events that are not specifically listed in the WHO toxicity grading scale. 
Table 6 
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 

 
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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) 
 
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 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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 in 
the investigator’s opinion are judged to be related to study drug injection should be 
captured as an “injection-site reaction” on the Adverse Event eCRF.  An injection-related 
reaction that is localized should be marked as a “local injection-site 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 
For adverse events, other than injection-site reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF.  If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 

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

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

 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (  3  baseline value) in combination with either 
an elevated total bilirubin (  2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event of 
special interest the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice in the absence of cholestasis or other causes of hyperbilirubinemia 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of hemophilia. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of hemophilia, "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 Hemophilic Bleeds 
At any time during the study an unexpected worsening of hemophilia-related bleeding, 
as judged by the investigator, should be recorded as an adverse event.  For example, 
increased severity (e.g., increased number of FVIII doses required to stop bleeds 
compared with before study entry) or frequency of bleeds.  Hemophilia worsening should 
be documented as an adverse event on the Adverse Event eCRF, conveying that the 
underlying condition has changed by including applicable descriptors (e.g., "increased 
clinical severity of hemophilia").  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 expected pattern of the underlying disease and do not indicate 
an unexpected worsening in severity or frequency should not be recorded as adverse 
events.  These data will be reflected in efficacy assessment data only. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for drug administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 

 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded 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). 
No safety data related to overdosing or drug administration error of emicizumab are 
available, as no such instances have been observed to date.  To minimize the risk of 
errors associated with future home administration of emicizumab, data related to 
medication errors with observed patient/caregiver administration of emicizumab during 
the first 5 weeks at the site by the investigator and/or clinical staff will be recorded and 
corrected at the time of occurrence.  In addition, the recording of medication and 
handling errors associated with home administration, as well as drug compliance, will be 
collected at each clinic visit. 
5.3.5.13 
Patient-Reported Outcome Data 
The PRO measurements are described in Section 4.5.7.  The methods for collecting and 
analyzing PRO data are different from those for the ascertainment of observed or 
volunteered adverse events.  Because of these differences, PRO data will not be 
reported as adverse events and no attempt will be made to resolve any noticeable 
discrepancies between PRO data and observed or volunteered adverse events.  All 
adverse events will be reported by the investigator on the Adverse Event eCRF.  The 
PRO data will be presented in separate tables, figures, and data listings from the 
adverse event data, and will be included in the appropriate section of the final study 
report. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 

 
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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (see Section 5.4.2 for further details) 
 
Adverse events of special interest (see Section 5.4.2 for further details) 
 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/Ethics Committee (EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites 
To ensure the safety of study participants, access to Medical Monitors is available 
24 hours per day, 7 days per week.  The Emergency Medical Call Center will connect 
the investigator with an Emergency Medical Contact, provide medical translation 
services if nedessary, and track all calls.  Contact information, including, toll-free 
numbers for the Emergency Medical Call Center, 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 Randomization or Study Drug 
Initiation 
After informed consent has been obtained but prior to randomization (randomized arms) 
or initiation of study drug (non-randomized arm), only serious adverse events caused by 
a protocol-mandated intervention should be reported.  The Clinical Trial Adverse Event/ 
Special Situations Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and e-mailing the form with use of the fax number 
or e-mail address provided to investigators. 
5.4.2.2 
Events That Occur after Randomization or Study Drug Initiation 
After randomization (randomized arms) or initiation of study drug (non-randomized arm), 
serious adverse events and adverse events of special interest will be reported until the 
last scheduled study visit (see Section 5.6).  Investigators should record all case details 

 
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that can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system. 
In the event that the EDC system is unavailable, the Clinical Trial Adverse Event/Special 
Situations Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and e-mailing the form with use of the fax number 
or e-mail address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
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 last dose of study drug.  A Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and e-mailing the form with use of the fax number or e-mail address provided 
to investigators.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Although embryo-fetal development studies are not available, condom use will not be 
required in male patients enrolled in the study because the margin between the minimal 
anticipated biological effect level plasma concentration (7 ng/mL) and the estimated 
maternal Cmax (at both 1.5 and 3 mg/kg QW dosing regimens) is greater than 10-fold 
(Banholzer et al. 2012).  At this time, very little emicizumab is thought to transfer into 
semen, and there are no known reproductive risks to female partners of male patients 
treated with emicizumab.  Therefore, contraception use by male patients is not required 
for participation in the study, and proactive collection of pregnancy information for female 
partners of male patients treated with emicizumab will not be required during the study. 

 
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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 study-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
At the time of pregnancy outcome, reporting instructions provided in Section 5.4.3.1 
should be followed. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 

 
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hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
LPLV), if the event is believed to be related to prior study drug treatment. 
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and e-mailing the Clinical Trial Adverse Event/ Special 
Situations Form with use of the fax number or e-mail address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest (see Section 5.2.3) against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
 
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 
This section provides a general overview of the methods.  If any of the items require a 
unique approach that differs from the general overview, it will be noted in the appropriate 
section. 
All continuous variables will be summarized using the following descriptive statistics:  
n (non-missing sample size), mean, standard deviation, median, maximum, and 
minimum.  The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures. 

 
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All summary tables will be structured with a column for each treatment arm and will be 
annotated with the total population size relevant to that table/treatment, including any 
missing observations. 
Efficacy analyses will follow the principle of intention-to-treat (i.e., based on randomized 
population). 
For Arm D, no formal hypothesis testing is planned.  All the analyses will be descriptive 
and performed separately. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for the randomized arms (including Arms A, B, and C) is based on 
clinical and statistical considerations, taking into account the limited number of patients 
with hemophilia A available for participation in clinical studies and in an effort to collect 
sufficient data to assess the safety and efficacy of emicizumab. 
The sample size calculation is based on the evaluation of the primary efficacy endpoint, 
defined as the number of bleeds over time (i.e., bleed rate) with emicizumab (treatment 
group, t) versus no prophylaxis (control group, c), which are said to follow a negative 
binomial (NB) distribution.  With consideration of enrollment feasibility, a sample size of 
70 patients, assuming an allocation ratio of 2:2:1 (28 patients in each randomized 
treatment group and 14 patients in control group), will achieve a power of more than 
90% assuming a mean ABR of 4 and 18 bleeds (with variances  mean  10) for the 
emicizumab treatment and control arms, respectively, representing an expected 78% 
reduction in the ABR compared with the control arm.  Initial sample size calculations 
were performed with East®, Version 6 (Cytel, Cambridge, MA), assuming the patients 
from each treatment group are followed up to 0.5 units of time (i.e., 24 weeks). 
However, the above approach to sample size calculation assumes similar follow up for 
each patient.  Because this is unlikely to be seen in the study, power was also estimated 
by simulation to account for different follow-up times among patients.  Conducting 
simulations on the basis of an NB regression model including an offset variable to 
account for variable follow-up times, with all other assumptions remaining the same as 
previously described, the sample size is projected to have greater than 90% power at 
the 2-sided 0.05 level of significance. 
Multiplicity will be accounted for by testing emicizumab QW arm versus no prophylaxis 
first, and upon successful testing, emicizumab Q4W (or Q2W, depending on global 
Study BO39182 data readout) versus no prophylaxis, each at 0.05 level. 
During the study, a re-assessment of the initially specified sample size based on 
aggregated (not by treatment arm) global data to date may be performed.  This may 
result in an increase in sample size, if necessary, to maintain adequate power without 

 
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affecting the type 1 error rate.  Study integrity will be upheld, as access to information via 
aggregated analyses and their results will be minimized to limit operational bias. 
The sample size for Arm D is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited 
number of pediatric patients with hemophilia A inhibitors available for participation.  
Hence, approximately 15 children  12 years of age with hemophilia A and FVIII 
inhibitors who are currently receiving treatment with bypassing agents will be enrolled in 
this study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Flow of patients through the study will be displayed in a “CONSORT” diagram.  A clear 
account of all patients who entered the study, who were enrolled and randomized, and 
who entered and completed each phase of the study will be displayed.  In addition, 
reasons for premature discontinuations from study treatment and reasons for 
withdrawing from the study (e.g., during follow-up) will be described. 
Variables from the eCRF used to establish how many patients reached the various 
stages of the study, how many dropped out and for what reasons will be described in the 
Statistical Analysis Plan (SAP). 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
For Arms A, B, and C, comparisons between the treatment arms of demographic data 
and baseline characteristics will be conducted to establish if any observed differences 
between the treatment arms are not due to imbalances in patient characteristics at 
baseline.  Only descriptive analyses are planned, and no formal statistical tests will be 
applied. 
For Arm D, a summary will be provided separately. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses to evaluate the clinical effect of 
prophylactic emicizumab compared with no prophylaxis will include all randomized 
patients (Arms A, B, and C), with patients grouped according to the treatment assigned 
at randomization. 
The clinical effect of prophylactic emicizumab treatment in pediatric patients with 
inhibitors (Arm D) will be descriptive and analyzed separately. 
6.4.1 
Primary Efficacy Endpoint 
For the randomized arms (Arms A, B, and C), the primary efficacy objective is to 
evaluate the clinical effect of prophylactic emicizumab compared with no prophylaxis on 
the number of bleeds over time.  The definition of a bleed for the primary analysis is 

 
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described in Section 4.5.8, with the primary endpoint comparing bleeds requiring 
treatment. 
The primary efficacy analysis will be conducted after all randomized patients have 
completed 24 weeks in the study or the last randomized patient, yet to complete 
24 weeks in the study, discontinues study participation, whichever occurs first, and using 
an intent-to-treat principle.  The separate comparison of the number of bleeds over time 
between each of the randomized emicizumab arms and control arm will be performed 
using an NB regression model, which accounts for different follow-up times, with the 
patient’s number of bleeds as a function of randomization and the time that each patient 
stays in the study included as an offset in the model.  The model also includes the 
number of bleeds (  9 or  9) in the last 24 weeks prior to study entry as a stratification 
factor in the randomization.  This analytic model estimates the rate ratio, t / c., which 
quantifies the risk of bleeding associated with prophylactic emicizumab (t) in 
comparison to no prophylaxis (c).  Statistical significance is controlled at the 2-sided, 
0.05 alpha () level.  Of note, hierarchical testing is used to account for multiple testing 
and the first test to be included in the hierarchy is the emicizumab 1.5 mg/kg QW 
maintenance dose versus control.  The second test will be 6 mg/kg Q4W maintenance 
dose versus control (or 3 mg/kg Q2W versus control, depending on global 
Study BO39182 data readout).  The description below covers both hypotheses to be 
tested: 
H0 (null hypothesis): Rate Ratio  1 versus H1 (alternative hypothesis): Rate Ratio ≠ 1. 
 
The treatment effect therein is based on a contrast statement in the model with use of 
the SAS GENMOD procedure.  Statistical significance at the pre-specified alpha level 
will be based on a Wald testing procedure.  Bleed rates for prophylactic emicizumab and 
no prophylaxis and the rate ratio will be presented and include 95% confidence intervals. 
The number of bleeds can also be annualized for each patient using the following 
formula:  ABR  (Number of bleeds during the efficacy period/Total number of days 
during the efficacy period)  365.25.  If the NB model converges, van Elteren test to 
compare the mean ABR between the randomized arms will be provided only as a 
sensitivity analysis.  However, if the convergence of the NB model is not achieved or is 
questionable, the primary efficacy analysis will be based on the van Elteren test of ABR. 
For Arm D, one efficacy objective is to evaluate the clinical effect of prophylactic 
emicizumab on the number of bleeds over time.  This analysis will be performed 
separately as well as overall as appropriate. 
A detailed description of the statistical methods for the primary and secondary efficacy 
analyses will be provided in the SAP. 

6.4.2 
Secondary Efficacy Endpoints 
For Arms A, B, and C, the number of all bleeds (i.e., those treated and not treated with 
coagulation factors) spontaneous bleeds, joint bleeds, and target joint bleeds over time 
in patients who receive prophylactic emicizumab compared with no prophylaxis will be 
evaluated by the NB regression model as specified for the primary efficacy endpoint. 
For patients in Arms A, B, and C, the number of treated bleeds and all bleeds will be 
compared with the patient’s historical bleed rate recorded in the medical record prior to 
study entry, using an NB regression model similar to the one described for the primary 
efficacy endpoint. 
In addition, the number of joint and target joint bleeds over time between the 
emicizumab prophylaxis and no prophylaxis arms will be evaluated by an NB regression 
model, as specified for the primary efficacy endpoint. 
For Arm D, descriptive analyses of characterizing the effect of emicizumab on-study 
treatment period for bleed over time as well as analyses of up-titration will be performed 
separately. 
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. 
Adherence with the HRQoL and health status measures will be summarized at the end 
of the study.  HRQoL (using the Haem-A-QoL or the Haemo-QoL-SF) and health status 
(using the EQ-5D-5L) will be assessed on a regular basis, as per the schedule of 
assessments (Appendix 1-A). 
Because different HRQoL measures (Haem-A-QoL and the Haemo-QoL-SF) are being 
used for the adult and adolescent/pediatric patients, all calculations and analyses will be 
conducted separately for adults and adolescents/pediatrics.  Scale scores for the 
Haem-A-QoL and Haemo-QoL-SF will be calculated and summarized descriptively for all 
timepoints in the study.  The HRQoL scale scores for all patients will be evaluated after 
24 weeks in the study, a timepoint that is consistent with other recent registrational 
studies in hemophilia (Lentz et al. 2013; Powell et al. 2013; Mahlangu et al. 2014) and 
analyses of such data (Santagostino et al. 2014; Wyrwich et al. 2015).  For Arms A, B, 
and C, an analysis of covariance model will be used to compare the 24-week and final 
assessments with the baseline scale scores for each HRQoL measure.  Within-subject 
and between-group changes from baseline on the different HRQoL scale scores will also 
be calculated at 24 weeks, and a descriptive analysis including patients between 8 to 
17 years old from Arms A, B, C and D will also be conducted.  For Arm D, 
proxy-reported HRQoL and aspects of caregiver burden using the Adapted Inhib-QoL 
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with Aspects of Caregiver Burden questionnaire (completed by caregivers) will be 
summarized by timepoint. 
For the assessments of the EQ-5D-5L, the number and percentage of patients in each of 
the five categories for each question for each group will be assessed.  Changes in the 
EQ-5D-5L index utility score from baseline will also be compared between groups.  
In addition, summary statistics including mean, standard deviation, median, minimum, 
and maximum will be displayed for the patients’ health state using the EQ-VAS both 
within and between groups.  The proportion of patients who report changes in each 
group exceeding the clinically meaningful threshold on the EQ-5D-5L index and EQ-VAS 
scores in each group will be reported at 24 weeks. 
6.5 
SAFETY ANALYSES 
The safety analyses population will be based on all enrolled patients grouped according 
to the actual treatment received.  For Arm C patients, all safety data reported up to the 
day prior to switching will be included in the “control arm” safety summaries, and all 
safety data reported on or after the date of switching to active treatment will be reported 
separately. 
Safety will be assessed for Arms A, B, and C and separately for Arm D through 
descriptive summaries of adverse events, laboratory test results (serum chemistry and 
hematology, including complete blood count with differential), ECGs, vital signs, and 
antibodies to emicizumab and FVIII. 
To evaluate the overall safety of prophylactic emicizumab compared with no prophylaxis, 
the incidence of adverse events will be summarized and presented by System Organ 
Class mapped term, appropriate thesaurus level, and toxicity grade for each treatment 
arm. 
For clinical laboratory data, summary statistics will be presented by treatment arm.  
In addition, shift tables describing changes from baseline will be presented using the 
WHO toxicity grading scale. 
Data on the effect of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or clinical pharmacology and pharmacokinetics will be summarized adopting 
standard language/terminology (Shankar et al. 2014). 
Although this is an open-label study, Sponsor personnel will not have access to safety 
summaries by treatment arm prior to the formal reporting of the study results.  HCPs at 
participating study sites, as well as the Sponsor’s drug safety and medical monitoring 
staff, will have access to the treatment assignments of patients for safety monitoring 
purposes only. 

 
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6.6 
PHARMACOKINETIC ANALYSES 
For all patients, predose (trough) plasma concentrations of emicizumab will be 
presented descriptively by treatment group, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation. 
Nonlinear mixed effects modeling may be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various 
covariates, such as age, sex, and body weight, on these parameters will be investigated 
graphically.  Secondary PK parameters, such as AUC, will be derived from individual 
post-hoc predictions.  Data may be pooled with data from other studies.  These analyses 
will be reported in a dedicated report. 
6.7 
EXPLORATORY ANALYSES 
Summary statistics of the number of work/school days missed and days hospitalized will 
be presented by treatment arm. 
PD parameters (e.g., aPTT, parameters derived from thrombin generation, FVIII activity) 
will be presented using summary statistics, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation. 
6.8 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.   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. 

 
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The Sponsor 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. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patient reported data will be collected electronically with use of electronic devices 
provided by a vendor.  The electronic device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. FDA regulations for electronic 
records (21 Code of Federal Regulations, Part 11).  The data will be transmitted 
electronically in real-time to a centralized database at the vendor.  The data from the 
electronic, handheld devices are available for view access only via secure access to a 
Web portal provided by the vendor.  Only identified and trained users may view the data, 
and their actions become part of the audit trail.  The Sponsor will have view access only.  
Regular data transfers will occur from the centralized database at the vendor to the 
database at the Sponsor.  The Sponsor will receive all data entered by patients on the 
electronic, handheld devices and all relevant study documentation. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all patient data in a machine-readable 
format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 

 
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pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (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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The Sponsor will retain study data for 25 years after the final Clinical Study Report 
has been completed 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).   
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 

 
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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. 
Patients who are declared legally incompetent or who are physically or mentally 
incapable of providing informed consent but otherwise meet the qualifications for 
participation in Study YO39309 will be included, as emicizumab prophylaxis may directly 
benefit this population with high unmet medical need.  In such cases, investigators will 
obtain informed consent from a guardian or legally authorized representative of the 
patient in accordance with applicable law.  In addition, the investigator must also obtain 
the assent of the patient when they are able to give assent to decisions made on their 
behalf.  Any indication on the part of the patient that they are not willing to participate in 
the study will be honored. 
In cases where there is reason to question the competence of a patient who has not 
been declared incompetent (e.g., a patient in the early stages of Alzheimer’s disease), a 
patient advocate will be involved in the consent process and throughout the duration of 
the patient’s participation in the study. 
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 

 
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authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
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 the analyses, data derived from 
exploratory biomarker specimens 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 Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 

 
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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 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will enroll approximately 85 patients:  approximately 70 patients in Arms A, B, 
and C; and approximately 15 patients in Arm D. 
Randomization and drug assignment will be performed by an IxRS, which will also 
manage emicizumab inventory for all sites globally. 
PROs will be captured electronically using a device provided by a third-party vendor for 
all patients globally. 
Central laboratories will be used for a subset of laboratory assessments specified in 
Section 4.5.5. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the final analyses of the study to healthcare professionals and to the 

 
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public, both 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/or other summaries of 
clinical study results may be available in health authority databases for public access, 
as required by local regulation, and will be made available upon request.  For more 
information, see the Roche Global Policy on Sharing of Clinical Study Information at the 
following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
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. 

 
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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. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
106/Protocol YO39309, Version 5 
10. 
REFERENCES 
Adynovate (antihemophilic factor) U.S. Package Insert, Baxalta US Inc. 2015. 
Ahnström J, Berntorp E, Lindvall K, et al. A 6-year follow-up of dosing, coagulation factor 
levels and bleedings in relation to joint status in the prophylactic treatment of 
haemophilia. Haemophilia 2004;10:68997. 
Antun A, Monahan PE, Manco-Johnson MJ, et al. Inhibitor recurrence after immune 
tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 
2015;13:19808. 
Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis 
and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B 
with inhibitors. Haemophilia 2014;20:6572. 
Banholzer ML, Buergin H, Wandel C, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partners. 
J Transl Med 2012;10:129. 
Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from 
the SSC of the ISTH. J Thromb Haemost 2014;12:19359. 
Bollard M, Teague LR, Berry EW, et al. The use of central venous catheters (portacaths) 
in children with haemophilia. Haemophilia 2000;6:6670. 
Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor 
VIII inhibitors – twenty years’ ‘bonn protocol’. Vax Sang 1996;70 Suppl 1:305. 
Brown TM, Lee WC, Joshi AV, et al. Health-related quality of life and productivity impact 
in haemophilia patients with inhibitors. Haemophilia 2009;15:9117. 
Bullinger M, Von Mackensen S, Fischer K, et al. Pilot testing of the ‘Haemo-QoL’ quality 
of life questionnaire for haemophiliac children in six European countries. 
Haemophilia 2002;8(Suppl.2):4754. 
Carcao M, Avila M, Aledort L, et al. Prophylaxis practices in children and adults with 
hemophilia A or B and inhibitors [abstract PO270-MON]. J Thromb Haemost 
2015;13 Suppl 2:360. 
Collins PW, Björkman S, Fischer K, et al. Factor VIII requirement to maintain a target 
plasma level in the prophylactic treatment of severe hemophilia A: influences of 
variance in pharmacokinetics and treatment regimens. J Thromb Haemost 
2010;8:26975. 
Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX 
in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124:38806. 
Coppola A, Franchini M, Di Palo M, et al. Enabling normal psychophysical development 
in children with hemophilia: the choice for prophylaxis. Pediatric Health 
2010;4:18399. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
107/Protocol YO39309, Version 5 
De Moerloose P, Urbancik W, Van Den Berg HM, et al. A survey of adherence to 
haemophilia therapy in six European countries: results and recommendations. 
Haemophilia 2008;14: 9318. 
Den Uijl IE, Mauser-Bunschoten EP, Roosendaal G, et al. Clinical severity of 
haemophilia A: does the classification of the 1950s still stand? Haemophilia 
2011;17:84953. 
DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, 
outcomes, outcome predictors. Thromb Haemost 2002;87:527. 
Eton DT, Elraiyah TA, Yost KJ, et al. A systematic review of patient-reported measures 
of burden of treatment in three chronic diseases. Patient Relat Outcome Meas 
2013;4:720. 
European Union. Ethical considerations for clinical trials on medicinal products with the 
paediatric population. Eur J Health Law. 2008 Jul;15:22350. Available from: 
http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf. 
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for 
use of central venous access devices in haemophilia. Haemophilia 
2004;10:62948. 
Fischer K, Steen-Carlsson K, Petrini P, et al. Intermediate-dose versus high-dose 
prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. 
Blood 2013;122:112936. 
Franchini M and Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:17984. 
Geraghty S, Dunkley T, Harrington C, et al. Practice patterns in haemophilia A 
therapyglobal progress towards optimal care. Haemophilia 2006;12:7581. 
Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor 
development in severe hemophilia A. N Engl J Med 2013;368:2319. 
Gringeri A, Lambert T, Street A, et al. Tertiary prophylaxis in adults: is there a rationale? 
Haemophilia 2012;18:7228. 
Gruppo RA, Kessler CM, Neufeld EJ, et al. Assessment of individual dose utilization vs. 
physician prescribing recommendations for recombinant activated factor VII 
(rFVIIa) in paediatric and adult patients with congenital haemophilia and 
alloantibody inhibitors (CHwI):the Dosing Observational Study in Hemophilia 
(DOSE). Haemophilia 2013;19:52432. 
Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis 
therapy in haemophilia. Haemophilia 2001;7:3926. 
Hay CR, DiMichele DM. The principal results of the International Immune Tolerance 
Study: a randomized dose comparison. Blood 2012;119:133544. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
108/Protocol YO39309, Version 5 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736. 
Ho S, Gue D, McIntosh K, et al. An objective method for assessing adherence to 
prophylaxis in adults with severe haemophilia. Haemophilia 2014;20:3943. 
Jackson SC, Yang M, Minuk L, et al. Prophylaxis in older Canadian adults with 
hemophilia A: lessons and more questions. BMC Hematol 2015;15:4. 
Jackson SC, Yang M, Minuk L, et al. Patterns of tertiary prophylaxis in Canadian adults 
with severe and moderately severe haemophilia B. Haemophilia 2014; 
20:e199204. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country 
study. Qual Life Res 2013;22:171727. 
Kavakli K, Yang R, Rusen L, et al. Prophylaxis vs. on-demand treatment with BAY 
81-8973, a full-length plasma protein-free recombinant factor VIII product: results 
from a randomized trial (LEOPOLD II). J Thromb Haemost 2015;13:3609. 
Keizer RJ, Huitema AD, Schellens JH, et al. Clinical pharmacokinetics of therapeutic 
monoclonal antibodies. Clin Pharmaockinet 2010;49(8):493507. 
Kempton CL, White GC 2nd. How we treat a hemophilia A patient with a factor VIII 
inhibitor. Blood 2009;113:117. 
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult 
patients with severe haemophilia: a beneficial effect on orthopaedic outcome and 
quality of life. Eur J Haematol 2012;88:32935. 
Kingdon HS, Lundblad RL. An adventure in biotechnology: the development of 
haemophilia A therapeuticsfrom whole-blood transfusion to recombinant DNA to 
gene therapy. Biotechnol Appl Biochem 2002;35:1418. 
Kovaltry (antihemophilic factor) U.S. Package Insert, Bayer HealthCare LLC. 2016. 
Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of 
recombinant factor VIIa for secondary prophylaxis in hemophilia patients with 
inhibitors. J Thromb Haemost 2007;5:190413. 
Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant 
factor VIII for prophylactic and on-demand treatment of severe hemophilia A. 
Blood. 2015;126:107885. 
Kraft J, Blanchette V, Babyn P, et al. Magnetic resonance imaging and joint outcomes in 
boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. 
J Thromb Haemost 2012;10:2494502. 
Kreuz W, Becker S, Lenz E, et al. Factor VIII inhibitors in patients with hemophilia A: 
epidemiology of inhibitor development and induction of immune tolerance for factor 
VIII. Semin Thromb Hemost 1995;21:3829. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
109/Protocol YO39309, Version 5 
Kreuz W, Escuriola Ettingshausen C, Funk M, et al. Prevention of joint damage in 
hemophilic children with early prophylaxis. Orthopade. 1999;28:3416. [Article in 
German; abstract only in English] 
Krishnan S, Vietri J, Furlan R, et al. Adherence to prophylaxis is associated with better 
outcomes in moderate and severe haemophilia: results of a patient survey. 
Haemophilia 2015;21:6470. 
Kroner BL. Comparison of the international immune tolerance registry and the North 
American Immune Tolerance Registry. Vox Sang 1999;77 Suppl 1:337. 
Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in 
hemophilia with inhibitors. N Engl J Med 2011;365:168492. 
Lentz SR, Misgav M, Ozelo M, et al. Results from a large multinational clinical trial 
(guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and 
adult patients with severe haemophilia A: safety and efficacy. Haemophilia 
2013;19:6917. 
Lindvall K, Colstrup L, Wollter IM, et al. Compliance with treatment and understanding of 
own disease in patients with severe and moderate haemophilia. Haemophilia 
2006;12:4751. 
Lindvall K, von Mackensen S, Elmstahl S, et al. Increased Burden on Caregivers of 
Having a Child With Haemophilia Complicated by Inhibitors Pediatr Blood Cancer 
2014;61:70611. 
Ljung R and Gretenkort-Andersson N. The current status of prophylactic replacement 
therapy in children and adults with haemophilia. BR J Haematol. 2015;169:77786. 
Llewellyn CD, Miners AH, Lee CA, et al. The illness perceptions and treatment beliefs of 
individuals with severe haemophilia and their role in adherence to home treatment. 
Psychol Health 2003;18:185200. 
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc 
fusion protein in severe hemophilia A. Blood 2014;123:31725. 
Mair FS and May CR. Thinking about the burden of treatment. BMJ 2014;349:g6680. 
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic 
treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 
2007;357:53544. 
Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, controlled, 
parallel-group trial of routine prophylaxis vs. on-demand treatment with 
sucrose-formulated recombinant factor VIII in adults with severe hemophilia A 
(SPINART). J Thromb Haemost 2013;11:111927. 
Mannucci PM and Tuddenham EG. The hemophiliasfrom royal genes to gene therapy. 
N Engl J Med 2001;344:17739. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
110/Protocol YO39309, Version 5 
Mariani G, Kroner B. International immune tolerance registry, 1997 update. Vox Sang 
1999;77 Suppl 1:257. 
Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, et al. Low-dose immune 
tolerance induction in hemophilia A patients with inhibitors. Blood 
1995;86(3):9838. 
Noone D, O'Mahony B, van Dijk JP, et al. A survey of the outcome of prophylaxis, 
on-demand treatment or combined treatment in 1835-year old men with severe 
haemophilia in six countries. Haemophilia 2013;19:4450. 
O’Mahony B, Noone D, Giangrande PLF, et al. Haemophilia care in Europea survey of 
35 countries. Haemophilia 2013;19:e23947. 
Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations 
of current prophylactic regimens. Blood 2015;125:203844. 
Oldenburg J, Brackmann HH. Prophylaxis in adult patients with severe haemophilia A. 
Thromb Res 2014;134 (Suppl 1):S337. 
Olivieri M, Kurnik K, Pfluger T, et al. Identification and long-term observation of early 
joint damage by magnetic resonance imaging in clinically asymptomatic joints in 
patients with haemophilia A or B despite prophylaxis. Haemophilia 
2012;18:36974. 
Ozgonenel B, Zia A, Callaghan MU, et al. Emergency department visits in children with 
hemophilia. Pediatr Blood Cancer 2013;60:118891. 
Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, et al. Bleeding in carriers of 
hemophilia. Blood 2006;108:526. 
Pollak E, Mühlan H, Von Mackensen S, et al. The Haemo-QoL Index: developing a short 
measure for health-related quality of life assessment in children and adolescents 
with haemophilia. Haemophilia 2006;12:38492. 
Powell JS, Pasi JK, Ragni MV, et al. Phase 3 Study of Recombinant Factor IX Fc Fusion 
Protein in Hemophilia B. N Engl J Med 2013;369:231323. 
Richards M, Altisent C, Batorova A, et al. Should prophylaxis be used in adolescent and 
adult patients with severe haemophilia? An European survey of practice and 
outcome data. Haemophilia 2007;13:4739. 
Rocino A, de Biasi R. Successful immune tolerance treatment with monoclonal or 
recombinant factor VIII concentrates in high responding inhibitor patients. Vox 
Sang 1999;77 Suppl 1:659. 
Rodriguez V, Mancuso ME, Warad D, et al. Central venous access device (CVAD) 
complications in Haemophilia with inhibitors undergoing immune tolerance 
induction: Lessons from the international immune tolerance study. Haemophilia. 
2015;21:e36974. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
111/Protocol YO39309, Version 5 
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. 
Santagostino E, Morfini M, Auerswald GK, et al. Paediatric haemophilia with inhibitors: 
existing management options, treatment gaps and unmet needs. Haemophilia 
2009;15:9839. 
Santagostino E, Lentz SR, Busk AK, et al. Assessment of the impact of treatment on 
quality of life of patients with haemophilia A at different ages: insights from two 
clinical trials on turoctocog alfa. Haemophilia 2014;20:52734. 
Schrijvers LH, Kars MC, Beijlevelt-Van Der Zande M, et al. Unravelling adherence to 
prophylaxis in haemophilia: a patients' perspective. Haemophilia 2015;21:61221. 
Schrijvers LH, Uitslager N, Schuurmans MJ, et al. Barriers and motivators of adherence 
to prophylactic treatment in haemophilia: a systematic review. Haemophilia 
2013;19:35561. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and 
tactical recommendations. AAPS J 2014;16:65873. 
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. ASA 
Hematol 2013;2013:3743. 
Skinner MW. WFH: closing the global gap—achieving optimal care. Haemophilia 
2012;18 (Suppl 4):112. 
Smith MP, Spence KJ, Waters EL, et al. Immune tolerance therapy for haemophilia A 
patients with acquired factor VIII alloantibodies: comprehensive analysis of 
experience at a single institution. Thromb Haemost 1999;81:35
8. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management 
of hemophilia. Haemophilia 2013;19:e147. 
Stasyshyn O, Antunes S, Mamonov V, et al. Prophylaxis with anti-inhibitor coagulant 
complex improves health-related quality of life in haemophilia patients with 
inhibitors: results from FEIBA NF Prophylaxis Study. Haemophillia 
2014;20:64450. 
Tagliaferri, A, Franchini, M, Coppola, A, et al. Effects of secondary prophylaxis started in 
adolescent and adult haemophiliacs. Haemophilia 2008;14: 94551. 
Teal S, Brohan E, Hettema Y, et al. Development and psychometric evaluation of a 
novel tool for assessing patient perception and preference for haemophilia 
treatment (HaemoPREF). Haemophilia 2014;20:66673. 
Valentino LA, Ewenstein B, Navickis RJ, et al. Central venous access devices in 
haemophilia. Haemophilia 2004;10(2):1346. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
112/Protocol YO39309, Version 5 
Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two 
prophylaxis regimens and a paired comparison of on-demand and prophylaxis 
treatments in hemophilia A management. J Thromb Haemost 2012;10:35967. 
Van den Berg HM, Fischer K, Roosendaal G, et al. The use of the Port-A-Cath in 
children with haemophilia—a review. Haemophilia 1998;4:41820. 
van Dijk K, Van Der Bom JG, Bax KN, et al. Use of implantable venous access devices 
in children with severe hemophilia: benefits and burden. Haematologica 
2004;89:18994. 
Vepsalainen K, Lassila R, Arola M, et al. Complications associated with central venous 
access device in children with haemophilia: a nationwide multicentre study in 
Finland. Haemophilia 2015;21:74753. 
von Mackensen S, Bullinger M. Development and testing of an instrument to assess the 
Quality of Life of Children with Haemophilia in Europe (Haemo-QoL). Haemophilia 
2004;10(Suppl 1):1725. 
von Mackensen S, Gringeri A. Health related quality of life in adult patients with 
haemophilia – assessment with a new disease-specific questionnaire (Haem-A-
QoL) [abstract]. J Thromb Haemost 2005;3:P0813. 
von Mackensen S, Gringeri A. Quality of life in hemophilia, Chapter 112. In: Preedy VR, 
Watson RR eds. Handbook of Disease Burdens and Quality of Life. Heidelberg: 
Springer, 2010:1896920. 
Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. 
Haemophilia 2003; 9:41835. 
Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of 
BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre 
phase I/III study in previously treated patients with severe (FIX level <1%) or 
moderately severe (FIX level  2%) haemophilia B. Haemophilia 2014;20:1524. 
[WFH] World Federation of Hemophilia. Annual Global Survey Data 2013. Accessed 
April 22, 2015, from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx. 
[WFH] World Federation of Hemophilia. Guidelines for the management of hemophilia 
2nd ed. [resource on the Internet]. July 2012 [cited 2 May 2019]. Available from: 
http://www1.wfh.org/publication/files/pdf-1472.pdf. 
[WHO] World Health Organization Toxicity grading scale for determining the severity of 
adverse events.  Available from: 
http://www.icssc.org/Documents/Resources/AEManual2003Appendices 
February_06_2003%20final.pdf. 
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of 
life change using the Haem-A-QoL. Haemophilia 2015;21:57884. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
113/Protocol YO39309, Version 5 
Xuan M, Xue F, Fu R, et al. Retrospective analysis of 1,226 Chinese patients with 
haemophilia in a single medical centre. J Thromb Thrombolysis. 2014 Jul;38:927. 
Xue F, Zhou Z-P, Yang R-C, et al. Survey of medical care and prognosis in patients with 
severe hemophilia A from certain cities in China. Chin J Hematol 2011;7:4813. 
Young G, Auerswald G, Jimenez-Yuste V, et al. PRO-PACT: Retrospective 
observational study on the prophylactic use of recombinant factor VIIa in 
hemophilia patients with inhibitors. Thrombosis Research 2012;130:86470. 
Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the 
prevention and treatment of bleeding in children with severe hemophilia A. J 
Thromb Haemost. 2015;13:96777. 
Zappa S, McDaniel M, Marandola J, et al. Treatment trends for haemophilia A and 
haemophilia B in the United States: results from the 2010 practice patterns survey. 
Haemophilia 2012;18:e14053. 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
114/Protocol YO39309, Version 5 
Appendix 1-A 
 
Schedule of Assessments 
Schedule of AssessmentsArms A and B 
 
Screen-
ing a 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Q8W 
from 
Wk 33 
Wk  
49 
Q12W 
from 
Wk 61 
Daily/ 
weekly b 
Study 
Comp/
ET c 
Early Disc. 
Safety  
F/U Visit before 
Study Comp d  
Informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including 
weight) g 
x 
x 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
Vital signs h 
x 
x h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x h 
x 
x h 
x 
 
x h 
x 
Serum pregnancy test i 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test i 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Concomitant medications j 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECG k 
x 
x k 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
x 
 
Safety laboratory assessments i 
x i 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Bleed/medication questionnaire l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bleed/medication data review l 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Adverse events m 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
IMP management n 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
HRQoL and health status 
(EQ-5D-5L) o 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
 
x 
 
Emicizumab administration p 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
PK/PD/ADA assessment q 
See Appendix 2-A for details 
Following treatment with 
bypassing agents  r 
Monitoring for thromboembolic events and thrombotic microangiography r 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
115/Protocol YO39309, Version 5 
Schedule of AssessmentsArm C (Screening to Switch to Emicizumab) 
 
Screening a 
Wk 1 
Wk 5 
Wk 9 Wk 13 
Wk 17 
Wk 21 
Daily/weekly b 
Informed consent e 
x 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
Medical history and demographics f 
x 
 
 
 
 
 
 
 
Physical examination (including weight) g 
x 
x 
 
 
 
 
 
 
Vital signs h 
x 
x h 
x 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
Serum pregnancy test i 
x 
x 
 
 
 
 
 
 
Urine pregnancy test i 
 
x 
 
 
 
 
 
 
Concomitant medications j 
x 
x 
x 
x 
x 
x 
x 
 
ECG k 
x 
x k 
 
 
 
 
 
 
Safety laboratory assessments i 
x i 
x 
 
 
 
 
 
 
Anti-FVIII antibodies 
x 
 
 
 
 
 
 
 
Bleed medication questionnaire l 
 
 
 
 
 
 
 
x 
Bleed/injection data review s 
 
x 
x 
x 
x 
x 
x 
 
Adverse events m 
 
x 
x 
x 
x 
x 
x 
 
HRQoL and health status o 
 
x 
 
 
x 
 
 
 
PD biomarkers assessment  q 
 
x 
 
 
 
 
 
 
 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
116/Protocol YO39309, Version 5 
Schedule of AssessmentsArm C (Continued, at Time of Switch to Emicizumab) 
 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
29 
Wk 
31 
Wk 
33 
Wk 
37 
Wk 
41 
Wk 
45 
Wk 
49 
Q12W from 
Wk 61 
Wk 
73 
Wk 
85 
Daily/ 
weekly b 
Study 
Comp/ 
ET c 
Early Disc. 
Safety F/U Visit 
before Study 
Comp d 
Physical examination (including 
weight) g 
x 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
x 
Vital signs h 
x h 
x 
x 
x 
x 
 
x 
x 
x 
x 
x h 
x 
x h 
x 
 
x h 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
Serum pregnancy test i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test i 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Concomitant medications j 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECG k 
x 
 
 
 
x k 
 
 
 
 
 
x 
 
 
 
 
x 
 
Safety laboratory assessments i 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Bleed/medication questionnaire l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bleed/medication data review s 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Adverse events m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
IMP management n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
HRQoL and health status o 
x 
 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
 
x 
 
Emicizumab administration p 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
PK/PD/ADA assessment q 
See Appendix 2-A for details 
Following treatment with 
bypassing agents r 
Monitoring for thromboembolic events and thrombotic microangiopathy r 
 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
117/Protocol YO39309, Version 5 
Schedule of AssessmentsArm D 
 
Screen
-ing a 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Wk 
29 
Wk 
33 
Wk 
37 
Wk 
41 
Wk 
49 
Q12W 
from 
Wk 61 
Daily/ 
weekly b 
Study 
Comp/ 
ET c 
Early Disc. 
Safety F/U 
Visit before 
Study Comp d 
Informed consent e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including 
weight) g 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
x 
 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
Vital signs h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Serum pregnancy test i 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test i 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Concomitant medications j 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECG k 
x 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Safety laboratory assessments i 
x 
 
x 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Bleed/medication questionnaire l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Bleed/medication data review s 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Adverse events m 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
IMP management n 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Haemo-QoL-Short Form o 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
Adapted Inhib-QoL 0 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
Emicizumab administration p 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
PK/PD/ADA assessment q 
See Appendix 2-A for details. 
Following treatment with 
bypassing agents r 
Monitoring for thromboembolic events and thrombotic microangiopathy r 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
118/Protocol YO39309, Version 5 
Disc  discontinuation; eCRFelectronic Case Report Form; ETearly termination; F/Ufollow-up; FVIIIfactor VIII; HRQoLhealth-related Quality of 
Life; IMPinvestigational medicinal product; Adapted Inhib-QoL  Inhibitor-Specific Quality of Life (with Aspects of Caregiver Burden); 
PDpharmacodynamic; PKpharmacokinetic; Q8Wevery 8 weeks; Q12Wevery 12 weeks; study comp.study completion; Wkweek. 
Notes:  All assessments should be performed within  2 days of the scheduled visit for the first 3 months, then 7 days thereafter.  PD and PK 
(trough) samples will be collected within  2 days of the scheduled visit and linked to the timing from the dose.  Clinic visits should coincide with the 
day of emicizumab dosing, and on those days the dose should be administered after blood draws and other assessments are conducted.  
Unscheduled assessments may be performed at the discretion of the investigator and as clinically indicated.  Except for the bleed/injection 
questionnaire, HRQoL, and health status, all other patient data will be collected during office or nurse visits.  Evaluation at Week 25 or 49 will occur 
after a full 24 or 48 weeks in the study, respectively.  Study completion evaluation occurs when a patient discontinues emicizumab or transitions 
into another study. 
a Screening may occur up to 4 weeks before Week 1 dosing. 
b Patients will complete the bleed/medication questionnaire at least weekly and at the time of a bleed, or when they take a hemophilia-related 
medication (including emicizumab).  Arm B patients should indicate at least weekly whether or not they had a bleed. 
c There will be an Extension Phase in this study for all patients who have completed at least 52 weeks of treatment with prophylactic emicizumab 
and are still deriving clinical benefit.  The study will be extending for 3 years after the last Arm D patient completes 1 year of treatment and 
patients still having clinical benefit are transferred to a post-trial continued access solution per Roche Global Policy on Continued Access to 
Investigational Medicinal Products (Section 4.3.4).  The study will end earlier, before 3 years after the last Arm D patient completes 1 year 
treatment, should the post-trial continued access solution be available earlier. 
d In the event a patient discontinues emicizumab early before the study completion, an early discontinuation safety follow-up visit should be 
performed 24 weeks after discontinuation of emicizumab.  If a patient enters extension phase, follow Appendix 1-B for study completion or 
early discontuation safety follow up.  
e Obtain written informed consent (or patient’s assent and caregiver written informed consent if patient is an adolescent/pediatric) before 
distribution of electronic, handheld device and collection of any data.  Patients will be enrolled and randomized after giving informed consent, 
and assent when appropriate. 
f Collected from patient medical records and documented on the eCRF, including information on target joint(s). 
g Calculation of dose based on weight is required.  A complete physical examination will be performed at screening and at least a targeted physical 
examination will be performed at subsequent visits.  Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for 
bruises, hematomas, and injection-site reactions) as clinically indicated and/or with report of new or worsening adverse event. 
h Body temperature (oral or tympanic), blood pressure, pulse rate, and respiratory rate only to be used to monitor hypersensitivity reactions during 
and after injection and not to be entered on eCRF, except at Weeks 1, 25, 49, study completion/early termination, and at the Early 
Discontinuation Safety Follow-up visit before study completion (i.e., 24 weeks after discontinuing emicizumab for patients in Arms A and B and at 
Week 73 for patients in Arm C).  Weight will be measured and recorded in the eCRF at each clinic visit prior to any injections (if applicable.)  
Height will be measured at screening and annually. 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
119/Protocol YO39309, Version 5 
i Laboratory data (performed locally) include:  complete blood count with differential (i.e., neutrophils, hemoglobin, platelet count), serum 
chemistries (i.e., sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, 
albumin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase).  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.  Patients with childbearing potential will be required to have a negative serum 
pregnancy test result at screening (and within 7 days of study drug initiation, if applicable) and urine pregnancy tests performed at every clinic 
visit, with the exception of Weeks 24 and 7.  Patients on Arm C will have urine pregnancy test performed at screening and before starting 
emicizumab (Week 25). 
j Concomitant medications (e.g., extra pain medication with bleed) will be asked about at the time of the monthly assessment, excluding 
treatments for bleeds (i.e., FVIII and other medications to treat bleeds), which will be collected on the bleeding questionnaire. 
k Performed locally.  If screening ECG is abnormal, repeat at Week 1 (or Week 2 if screening and Week 1 occur on the same day), otherwise do 
not repeat.  ECGs will also be performed 48 and 24 weeks after starting emicizumab or dose up-titration, as well as at study completion/early 
termination. 
l Reported by the patient or their caregivers and includes:  start date and time, reason, type, location, and associated symptoms for joint and 
muscle bleeds, as well as start date and time, reason, type, and dose of each injection, excluding emicizumab. 
m Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected worsening of the 
patient’s hemophilia in terms of severity (e.g., increased number of doses of FVIII to stop bleeds compared with before study entry), frequency of 
bleeds, or nature at any time during the study, this should be documented as an adverse event on the Adverse Event eCRF, conveying that the 
underlying condition has changed by including applicable descriptors (e.g., "increased clinical severity of hemophilia"). 
n Drug accountability will not be performed at the first visit that includes emicizumab receipt.  Drug dispensation will not occur at the study 
completion/early termination visit. 
o Patient-reported outcomes will be captured on-site by a device and transmitted to the patient-reported outcome database.  The questionnaires 
should be completed by the patient or their caregivers at the site at the start of the visit and prior to all other study assessments.  For patients in 
Arms A, B and C, questionnaires include Haem-A-QoL questionnaire (age  18 years) and Haemo-QoL-Short Form (age 1217 years), and 
health status questionnaire EQ-5D-5L.  For patients from Arm D and their caregivers, questionnaires include Haemo-QoL-Short Form (age 
812 years) and Adapted InhibQoL including Aspects of Caregiver Burden (completed by caregivers, regardless of age).  Days of work/school 
missed will be captured, as applicable to each arm. 
p For patients randomized to Arm A:  emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed by 1.5 mg/kg QW 
subcutaneously.  For patients randomized to Arm B:  emicizumab prophylaxis at 3 mg/kg QW subcutaneously for 4 weeks, followed by 6 mg/kg 
Q4W subcutaneously.  For patients randomized to Arm C, following 24 weeks of no prophylaxis:  emicizumab prophylaxis at 3 mg/kg QW 
subcutaneously for 4 weeks, followed by 6 mg/kg Q4W subcutaneously.  For patients in Arm D:  emicizumab prophylaxis at 3 mg/kg QW 
subcutaneously for 4 weeks, followed by 1.5 mg/kg QW subcutaneously.  There will be an extension phase in this study for all patients who 
complete at least 52 weeks of treatment with prophylactic emicizumab and still deriving clinical benefit.  The study will be extending for 3 years 
after the last Arm D patient completes 1 year of treatment or until China’s reimbursement of emicizumab is received, whichever comes first and 
patients still having clinical benefit are transferred to a post-trial continued access solution per Roche Global Policy on Continued Access to 
Investigational Medicinal Products (see Section 4.3.4).  The study will end earlier, before 3 years after the last Arm D patient completes 1 
year treatment, should the post-trial continued access solution be available earlier. 

Appendix 1-A (cont.)  
Schedule of Assessments 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
120/Protocol YO39309, Version 5 
q See Appendix 2-A for detailed explanation of PD biomarker assessments (Sets 1 and 2).  Blood samples will be banked for 5 years for future 
exploratory PD biomarker analyses.  Blood samples may also be drawn to conduct biomarker assays at the central laboratory on an unscheduled 
basis (at the clinical judgment of the investigator) at any time. 
r Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic 
microangiopathy for platelet count, serum creatinine, LDH, and peripheral blood smear analysis for schistocytes within 2448 hours of initial 
bypassing agent use.  A plasma sample should also be provided for local laboratory monitoring of fibrinogen and D-dimer.  For patients who require 
multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 2448 hours following the last 
dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory results should be recorded in the Unscheduled Visit eCRFs 
s At the Week 1 visit, patients or their caregivers will be trained on how to use, and be provided with, their own electronic, handheld device.  At 
subsequent visits, as marked, investigator review of patient-reported bleed/injection questionnaire information will be conducted.  Information 
regarding trauma events in the preceding month will be collected in the eCRF by the investigator. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
121/Protocol YO39309, Version 5 
Appendix 1-B  
Schedule of Assessments - Extension Phase 
Extension Phase Schedule of Assessments  Arm A, B, C, and D 
 
Extension Phase Day 1 a 
Every 24 Weeks a 
Extension Phase Completion/Extension 
Phase Early Termination b 
Extension Phase Early 
Disc. Safety F/U Visit  
Informed consent c 
x 
 
 
 
Physical examination (including 
weight and height) d 
x 
x 
x 
x 
Vital signs e 
x 
x 
x 
x 
Concomitant medications f 
x 
x 
x 
x 
Safety laboratory Assessments g 
x 
x 
x 
x 
Adverse events h 
x 
x 
x 
x 
IMP management i 
x 
x 
 
 
Emicizumab dispensing and 
administration j 
x 
x 
 
 
Following treatment with bypassing 
agents k 
Monitoring for thromboembolic events and thrombotic microangiopathy 

Appendix 1-B (cont.)  
Schedule of Assessments - Extension Phase  
Emicizumab—F. Hoffmann-La Roche Ltd 
122/Protocol YO39309, Version 5 
Disc  discontinuation; ET  early termination; eCRF  electronic case reporting form; F/Ufollow-up. 
a Assessments performed within  14 day of visit.   
b In the event a patient discontinues emicizumab early before the study completion (with the exception where the reason for discontinuation is the patient 
switching to commercial emicizumab product), an early discontinuation safety follow-up visit should be performed 24 weeks after discontinuation of 
emicizumab 
c Obtain a separate written informed consent (or patient’s assent and caregiver written informed consent if patient is an adolescent/pediatric) before 
transferred to extension phase. 
d Calculation of dose based on weight is required.  A complete physical examination will be performed at extension phase Day 1 and at least a targeted 
physical examination will be performed at subsequent visits.  Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for 
bruises, hematomas, and injection-site reactions) as clinically indicated and/or with report of new or worsening adverse event. Height will be measured at 
extension phase Day 1 and annually. 
e Body temperature (oral or tympanic), blood pressure, pulse rate, and respiratory rate only to be used to monitor hypersensitivity reactions during and after 
injection and not to be entered on eCRF, except at study completion/early termination. Weight will be measured and recorded in the eCRF at each visit 
prior to any injections (if applicable). 
f Concomitant medications (e.g., extra pain medication with bleed) will be asked about at the time of the scheduled visit, excluding treatments for bleeds 
(i.e., FVIII and other medications to treat bleeds), which will not be collected during the study extension phase. 
g Safety laboratory assessments should be performed at least once every 12 months, including complete blood count with differential (i.e., neutrophils, 
hemoglobin, platelet count) and  serum chemistries (i.e., potassium, creatinine, total and direct bilirubin, albumin, alanine aminotransferase, aspartate 
aminotransferase, and alkaline phosphatase), PT, APTT, and INR.  Investigators may choose to add any additional tests to be processed in the local 
lab at clinical discretion. 
h Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected worsening of the patient’s 
hemophilia in terms of severity (e.g., increased number of doses of FVIII to stop bleeds compared with before study entry), frequency of bleeds, or nature 
at any time during the study, this should be documented as an adverse event on the Adverse Event eCRF, conveying that the underlying condition has 
changed by including applicable descriptors (e.g., "increased clinical severity of hemophilia"). 
i Drug dispensation will not occur at the study completion/early termination visit. 
j For patients randomized to Arm A:  emicizumab 1.5 mg/kg QW subcutaneously.  For patients randomized to Arm B:  emicizumab 6 mg/kg Q4W 
subcutaneously.  For patients randomized to Arm C: 6 mg/kg Q4W subcutaneously.  For patients in Arm D: 1.5 mg/kg QW subcutaneously. Patients 
should record their actual Emicizumab administer in their handheld device. 
k Following bypassing agent treatment, patients are recommended to provide a sample for local laboratory monitoring of thromboembolic events and 
thrombotic microangiopathy for platelet count, serum creatinine, LDH, and peripheral blood smear analysis of schistocytes wit hin 24−48 hours of 
initial bypassing agent use.  A plasma sample can also be provided for local laboratory monitoring of fibrinogen and D-dimer.  For patients who 
require multiple doses of bypassing agents, laboratory monitoring is recommended every 24−48 hours thereafter until 24−48 hours following the last 
dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory results should be recorded in the Un scheduled Visit eCRFs. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
123/Protocol YO39309, Version 5 
Appendix 2-A 
 
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm A, QW) a 
Schedule of AssessmentsArm A (QW) 
 
Screen-
ing 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Q8W 
from 
Wk 33 
Wk  
49 
Q12W  
from 
Wk 61 
Daily/ 
weekly 
Study 
Comp./
ET b 
Safety  
F/U Visit c 
PK assessment d 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Anti-emicizumab antibodies e 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
PD biomarkers Set 1 f, g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
PD biomarkers Set 2 g, h 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
Anti-FVIII antibodies i 
x 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
x 
 
ADA  anti-drug antibody; CWA  clot waveform analysis; ET  early termination; F/U  follow-up; FIX  factor IX; FVIII  factor VIII; FX  factor X; 
FXIII  factor XIII; PD  pharmacodynamic; PK  pharmacokinetic; Q2W  every 2 weeks; Q8W  every 8 weeks; Q12W  every 12 weeks; QW  every 
week; study comp  study completion; VWF  von Willebrand factor; Wk  week. 
Note:  Blood samples should always be drawn pre-dose (if taken on days of emicizumab administration); consult the Sample Handling Manual for 
details.  In order to characterize pharmacokinetics, it is mandatory that assessments are being performed within  2 days of the scheduled visits. 
a If Arm B is switched to a Q2W dosing schedule in the future (based on emerging global data), the schedule for a QW dosing schedule is also 
applicable to a Q2W dosing schedule. 
b Study completion visit for PK, PD biomarker, and ADA sample collection is defined as when either the patient completed the study as defined in 
Section 3.2 or after the last patient completed 24 weeks of treatment with emicizumab, whichever occurs first.  Sample collection has stopped 
since March 2021. 
c Anti-emicizumab antibody blood samples may also be drawn if a hypersensitivity event occurs or on an unscheduled basis (at the clinical 
judgment of the investigator) at any time. 
d Emicizumab concentration.  Plasma samples for this assessment should be taken prior to injection.  Patients will be dosed at the clinics 
(self-administration) on days where trough plasma samples are to be collected. 
e Anti-emicizumab antibody blood samples may also be drawn if a hypersensitivity event occurs or on an unscheduled basis (at the clinical 
judgment of the investigator) at any time. 
f Set 1:  Standard aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, D-dimer, pro-thrombin fragment 1.2. 

Appendix 2-A (cont.)  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm A, QW) a 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
124/Protocol YO39309, Version 5 
g PD samples will be citrate plasma.  Biomarker assays will include, but are not limited to, those listed.  Additional samples will be frozen and 
banked for future exploratory research related to emicizumab, which may include coagulation tests such as CWA and others.  Blood volumes 
and processing procedures will be specified in the Central Laboratory Services Manual.  Unscheduled samples might be taken at the discretion 
of the investigator, while on emicizumab.  Reasons for unscheduled samples may include evaluation or treatment for bleeds or hypersensitivity 
reactions. 
h Set 2:  FXIII activity (will only be run at baseline), VWF antigen, fibrinogen. 
i Starting at Week 1, all anti-FVIII antibodies will be measured at a central laboratory using an aliquot of the citrate plasma collected for PD 
biomarker assessments.  Local tests for anti-FVIII antibodies will not work after the first dose of study drug, as emicizumab interferes with all 
forms of the Bethesda assay.  Please consult the Central Laboratory Services Manual for details. 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
125/Protocol YO39309, Version 5 
Appendix 2-B 
 
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm B, Q4W) 
Schedule of Assessments:  Arm B Q4W 
 
Screen-
ing 
Treatment Period 
From Wk 25 
to Study 
Comp. 
Study 
Comp./ET a 
Safety  
F/U Visit 
Week 
 
1 
2 
3 
4 
5 
7 
9 
13 
17 
21 
25 
 
 
 
Emicizumab PK 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Anti-emicizumab 
antibody b 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
PD biomarker set 1 c, d 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
PD biomarker set 2 d, e 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Anti-FVIII antibodies f 
x 
x 
 
 
 
 
 
x 
 
x 
 
x 
Q12W 
x 
x 
 
ADA  anti-drug antibody; CWA  clot waveform analysis; ET  early termination; F/U  follow-up; FIX  factor IX; FVIII  factor VIII; FX  factor X; 
FXIII  Factor XIII; PD  pharmacodynamic; PK  pharmacokinetic; Q4W  every 4 weeks; Q12W  every 12 weeks; study comp.  study 
completion; VWF  von Willebrand factor; Wk  week. 
Note:  Blood samples should always be drawn pre-dose (if taken on days of emicizumab administration); consult the Sample Handling Manual 
for details.  PD biomarker tests will include, but are not limited to, those listed here.  In order to characterize pharmacokinetics, it is 
mandatory that assessments are being performed within  2 days of the scheduled visits. 
a Study completion visit for PK, PD biomarker, and ADA sample collection is defined as when either the patient completed the study as 
defined in Section 3.2 or after the last patient completed 24 weeks of treatment with emicizumab, whichever occurs first. Sample collection 
has stopped since March 2021. 
b Anti-emicizumab antibody blood samples may also be drawn if a hypersensitivity event occurs or on an unscheduled basis (at the clinical 
judgment of the investigator) at any time. 
c Set 1:  Standard aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, D-dimer, pro-thrombin fragment 1.2. 

Appendix 2-B (cont.)  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm B, Q4W) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
126/Protocol YO39309, Version 5 
d PD samples will be citrate plasma.  Biomarker assays will include, but are not limited to, those listed.  Additional samples will be frozen and 
banked for future exploratory research related to emicizumab, which may include coagulation tests such as CWA and others.  Blood 
volumes and processing procedures will be specified in the Central Laboratory Services Manual.  Unscheduled samples might be taken at 
the discretion of the investigator, while on emicizumab.  Reasons for unscheduled samples may include evaluation or treatment for bleeds or 
hypersensitivity reactions. 
e Set 2:  FXIII activity (will only be run at baseline), VWF antigen, fibrinogen. 
f Starting at Week 1, all anti-FVIII antibodies will be measured at a central laboratory using an aliquot of the citrate plasma collected for PD 
biomarker assessments.  Local tests for anti-FVIII antibodies will not work after the first dose of study drug, as emicizumab interferes with all 
forms of the Bethesda assay.  Please consult the Central Laboratory Services Manual for details.  Anti-FVIII antibodies will be collected for 
central analysis at Week 1, Week 25, every 12 weeks starting from Week 25, and at the completion visit for all patients.  Testing at Week 9 
and Week 17 for non-inhibitor patients only. 
 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
127/Protocol YO39309, Version 5 
Appendix 2-C 
 
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
(Arm C, at Time of Switch to Emicizumab) 
Arm C, at Time of Switch to Emicizumab 
Week 
Wk 25 Wk 26 Wk 27 Wk 28 Wk 29 Wk 31 Wk 33 Wk 37 Wk 41 Wk 45 Wk 49 
From 
Wk 61 
Study 
Comp./ET a 
Safety F/U 
Visit 
Emicizumab PK 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
Anti-emicizumab antibody b 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
PD biomarker Set 1 c, d 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Q12W 
x 
x 
PD biomarker Set 2 d, e 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Anti-FVIII antibodies f 
x 
 
 
 
 
 
x 
 
x 
 
x 
Q12W 
x 
x 
ADA  anti-drug antibody; CWA  clot waveform analysis; ET=early termination; F/U  follow-up; FIX  factor IX; FVIII  factor VIII; FX  factor X; 
FXIII  Factor XIII; PD  pharmacodynamic; PK  pharmacokinetic; Q12W  every 12 weeks; study comp.=study completion; VWF  von Willebrand 
factor; Wk  week. 
Note:  Blood samples should always be drawn pre-dose (if taken on days of emicizumab administration); consult the Sample Handling Manual for 
details.  PD biomarker tests will include, but are not limited to those listed here.  In order to characterize pharmacokinetics, it is mandatory that 
assessments are being performed within  2 days of the scheduled visits. 
a Study completion visit for PK, PD biomarker, and ADA sample collection is defined as when either the patient completed the study as defined in 
Section 3.2 or after the last patient completed 24 weeks of treatment with emicizumab, whichever occurs first. Sample collection has stopped 
since March 2021. 
b Anti-emicizumab antibody blood samples may also be drawn if a hypersensitivity event occurs or on an unscheduled basis (at the clinical 
judgment of the investigator) at any time. 
c Set 1:  Standard aPTT, PT, FVIII activity, thrombin generation, FIX antigen, FX antigen, D-dimer, pro-thrombin fragment 1.2. 
 

Appendix 2-C (cont.)  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
(Arm C, at Time of Switch to Emicizumab) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
128/Protocol YO39309, Version 5 
d PD samples will be citrate plasma, EDTA plasma, or serum.  Biomarker assays will include, but are not limited to, those listed.  Additional 
samples will be frozen and banked for future exploratory research related to emicizumab, which may include coagulation tests such as CWA 
and others.  Blood volumes and processing procedures will be specified in the Central Laboratory Services Manual.  Unscheduled samples 
might be taken at the discretion of the investigator, while on emicizumab.  Reasons for unscheduled samples may include evaluation or 
treatment for bleeds or hypersensitivity reactions. 
e Set 2:  FXIII activity (will only be run at baseline), VWF antigen, fibrinogen. 
f Starting at Week 1, all anti-FVIII antibodies will be measured at a central laboratory using an aliquot of the citrate plasma collected for PD 
biomarker assessments.  Local tests for anti-FVIII antibodies will not work after the first dose of study drug, as emicizumab interferes with all 
forms of the Bethesda assay.  Please consult the Central Laboratory Services Manual for details.  Anti-FVIII antibodies will be collected for 
central analysis at Week 25, Week 49, every 12 weeks starting from Week 49, and at the completion visit for all patients.  Testing at Week 33 
and Week 41 for non-inhibitor patients only. 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
129/Protocol YO39309, Version 5 
Appendix 2-D 
 
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm D, QW) 
Schedule of Assessments: a  Arm D QW 
 
Screening 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Q8W from 
Wk 33 
Wk 
49 
Q12W 
from 
Wk 61 
Study 
Comp/ 
ET b 
Safety  
F/U Visit 
Anti-FVIII antibodies 
c, d  
x 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
x 
 
x 
 
Anti-emicizumab 
antibodies c, e, f  
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
PK assessment c, e, g  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
PD biomarkers 
Set 1 c, e, h, i 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
PD biomarkers 
Set 2 c, e, h, j, k 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
F/U  follow-up; FIX  factor IX; FVIII  factor VIII; FX  factor X; PD  pharmacodynamic; PK  pharmacokinetic; Q12W  every 12 weeks; study 
comp  study completion; Wk  Week. 
Notes: On treatment days, pre-injection blood collection should be made 0120 minutes before the injection. 
a All samples are to be collected on Day 1 of the indicated week, prior to emicizumab injection (if applicable).  All PD samples will be citrate plasma. 
b Collection of PK/ADA/Biomarker samples from Arm D patients will stop when the patient completes the study or after Week 49, whichever occurs 
first. 
c When blood is drawn via catheter or CVAD, a discard tube must be used prior to collection of samples for any laboratory assessment, due to the 
possibility of contamination by saline or anticoagulants used to flush the device.  Please consult the study Laboratory Manual for details on sample 
collection and processing. 
d Anti-FVIII antibodies will be measured at a central laboratory using citrate plasma. Anti-FVIII antibodies is the only biomarker sample taken at 
screening. In case a patient screen fails or does not enroll in the study for any reason, the sample should be destroyed and not sent to the central 
laboratory. Throughout the study, additional blood samples may also be drawn on an unscheduled basis (at the clinical judgment of the investigator) for 
analysis at a central laboratory. Reasons for unscheduled visits may include evaluation or treatment for bleeds or hypersensitivity reactions. 

Appendix 2-D (cont.)  
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (Arm D, QW) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
130/Protocol YO39309, Version 5 
e In case of up-titration, additional assessments including PK, PD biomarkers, anti-emicizumab antibodies, safety laboratory samples, and ECG will be 
required, with the schedule of assessments resetting back to Week 1, including an ECG. 
f Samples to detect anti-emicizumab antibodies will be collected prior to emicizumab injection at Weeks 1, 5, 9, 13, 17, 21, 25, 33, 41, 49, and every 
12 weeks starting from Week 61, study completion/early termination and at the 24-week safety follow-up visit. If patients continue on emicizumab past 
49 weeks of treatment, anti-emicizumab antibodies will be collected every 12 weeks. If any of these samples are positive and/or if there is suboptimal 
clinical response or low pharmacokinetic exposure, additional samples may be collected and analyzed for anti-emicizumab antibodies.  
Anti-emicizumab antibodies should also be drawn at the time of systemic hypersensitivity events.  For each additional anti-emicizumab sample, a PK 
sample should be concomitantly drawn. 
g Emicizumab concentration. Plasma samples for this assessment should be taken prior to emicizumab injection. 
h PD biomarkers will be measured at a central laboratory. Blood samples may also be drawn to conduct biomarker assays at the central laboratory on an 
unscheduled basis (at the clinical judgment of the investigator) at any time. 
i PD set 1: PT/INR, D-Dimer, aPTT (Stago), fibrinogen. 
j PD set 2: FVIII activity% (Biophen). 
k These plasma samples will only be collected if the permitted blood volumes allow (based on patient body weight as described in Section 3.3.6).  Please 
refer to the Laboratory Manual for details. 
 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
147/Protocol YO39309, Version 5 
Appendix 7  
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* 
 
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. 
* 
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg  [2  age]) from 1 to 10 years, and less than 90 mmHg from 
11 to 17 years. 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
148/Protocol YO39309, Version 5 
Appendix 8  
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
HEMATOLOGY 
Item 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Hemoglobin 
9.510.5 g/dL 
8.09.4 g/dL 
6.57.9 g/dL 
 6.5 g/dL 
Absolute neutrophil count 
10001500/mm3 
750999/mm3 
500749/mm3 
 500/mm3 
Platelets 
75,00099,999/mm3 
5,000074,999/mm3 
20,00049,999/mm3 
 20,000/mm3 
Prothrombin time  
1.011.25  ULN 
1.261.5  ULN 
1.513.0  ULN 
 3  ULN 
Activated partial 
thromboplastin  
1.011.66  ULN 
1.672.33  ULN 
2.343  ULN 
 3  ULN 
Fibrinogen 
0.750.99  LLN 
0.500.74  LLN 
0.250.49  LLN 
 0.25 x LLN 
Fibrin split product 
2040 mcg/mL 
4150 mcg/mL 
5160 mcg/mL 
 60 mcg/mL 
Methemoglobin 
59.9% 
10.014.9% 
15.019.9% 
 20 % 
LIVER ENZYMES 
AST (SGOT) 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
ALT (SGPT) 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
GGT 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
Alkaline phosphatase 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
Amylase 
1.11.5  ULN 
1.62.0  ULN 
2.15.0  ULN 
 5.0  ULN 

Appendix 8 (cont.):  WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
Emicizumab—F. Hoffmann-La Roche Ltd 
149/Protocol YO39309, Version 5 
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 
 

Appendix 8 (cont.):  WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
Emicizumab—F. Hoffmann-La Roche Ltd 
150/Protocol YO39309, Version 5 
CHEMISTRIES continued 
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 inc.  20 mm; 
no Rx 
recurrent, chronic, 
 20 mm, 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 
 
 

Appendix 8 (cont.):  WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
Emicizumab—F. Hoffmann-La Roche Ltd 
151/Protocol YO39309, Version 5 
RESPIRATORY 
Cough 
transient; no Rx 
treatment-associated 
cough 
local Rx 
uncontrolled 
 
Bronchospasm, Acute 
transient; no Rx 
< 80%70% FEV1 
(or peak flow) 
requires Rx normalizes 
with bronchodilator; FEV1 
50%70% 
(or peak Flow) 
no normalization with 
bronchodilator; 
FEV1 25%50% 
(or peak flow retractions) 
cyanosis: FEV1 
 25% 
(or peak flow) or intubated 
GASTROINTESTINAL 
Stomatitis 
mild discomfort; no limits 
on activity 
some limits on 
eating/drinking 
eating/talking very 
limited 
requires IV fluids 
Nausea 
mild discomfort; 
maintains reasonable 
intake 
moderate discomfort; 
intake decreased 
significantly; some 
activity limited 
severe discomfort; no 
significant intake; 
activities limited 
minimal fluid intake 
Vomiting 
transient emesis 
occasional/moderate 
vomiting 
orthostatic hypotension 
or IV fluids required 
hypotensive shock or 
hospitalization required for 
IV fluid therapy 
Constipation 
mild 
moderate 
severe 
distensions w/vomiting 
Diarrhea 
transient 34 loose 
stools/day 
57 loose stools/day 
orthostatic hypotension 
or 
 7 loose stools/day or 
required IV fluids 
hypotensive shock or 
hospitalization for IV fluid 
therapy required 
 

Appendix 8 (cont.):  WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
Emicizumab—F. Hoffmann-La Roche Ltd 
152/Protocol YO39309, Version 5 
NEURO AND NEUROMUSCULAR 
Neuro-cerebellar 
slight incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Mood 
mild anxiety or 
depression 
moderate anxiety or 
depression and therapy 
required 
severe anxiety or 
depression or mania; 
needs assistance 
acute psychosis; 
incapacitated, requires 
hospitalization 
Neuro control 
(ADL  activities of daily 
living) 
mild difficulty 
concentrating; no Rx; 
mild confusion/agitation; 
ADL unaffected 
moderate 
confusion/agitation some 
limitation of ADL; minimal 
Rx 
severe confusion/agitation 
needs assistance for ADL; 
therapy required 
toxic psychosis; 
hospitalization 
Muscle strength 
subjective weakness 
no objective 
symptoms/signs 
mild objective 
signs/symptoms no 
decrease in function 
objective weakness 
function limited 
paralysis 
OTHER PARAMETERS 
Fever: oral,  12 hours 
37.738.5 C or 
100.0101.5 F 
38.639.5 C or 
101.6102.9 F 
39.640.5 C or 103105 F 
 40 C or 
 105 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 
 

Appendix 8 (cont.):  WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
Emicizumab—F. Hoffmann-La Roche Ltd 
153/Protocol YO39309, Version 5 
OTHER PARAMETERS (continued) 
Local Reaction 
tenderness or erythema 
induration  10 cm or 
phlebitis or inflammation 
induration  10 cm or 
ulceration 
necrosis 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo-papular 
rash, dry desquamation 
vesiculation, moist 
desquamation, or 
ulceration 
exfoliative dermatitis, 
mucous membrane 
involvement or erythema, 
multiforme or suspected 
Stevens- Johnson or 
necrosis requiring surgery 

 
Emicizumab—F. Hoffmann-La Roche Ltd 
154/Protocol YO39309, Version 5 
Appendix 9  
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients on Emicizumab 
The use of bypassing agents is not expected in hemophilia A patients without inhibitors.  
For completeness, this appendix includes guidelines provided for treatment of 
breakthrough bleeds in patients with inhibitors.  Careful consideration of the risks and 
potential benefits is advised when combining emicizumab, factor VIII (FVIII), and 
bypassing agent. 
Drugs intended to control bleeds, including bypassing agents, should be used at the 
lowest dose expected to achieve hemostasis.  Given that circulating emicizumab may 
increase patients’ coagulation potential, the doses required to achieve hemostasis may 
be lower than the FVIII or bypassing agent doses used prior to starting the study. 
Caution should be taken for patients who are using recombinant activated factor VII 
(rFVIIa [e.g., consideration of using no more than 90 g/kg of rFVIIa as an initial dose]). 
Use of activated prothrombin complex concentrate (aPCC) or PCC in combination with 
emicizumab should be avoided completely in patients who have the option of using other 
bypassing agents to treat bleeds. In the event that aPCC/PCC is the only available 
bypassing agent, the lowest dose expected to achieve hemostasis should be prescribed, 
with no more than 50 units/kg of aPCC/PCC to be administered as an initial dose. 
Other bypassing agents (e.g., Byclot) should be avoided.  In cases where such agents 
are the only available bypassing agent, the lowest dose expected to achieve hemostasis 
should be prescribed, with no more than the lowest dose described in the prescribing 
information to be administered as an initial dose (e.g., no more than 60 g/kg of Byclot). 
Exact dose and schedule of bypassing agents should be discussed with patients at the 
beginning and throughout the study.  Repeated dosing of rFVIIa, aPCC/PCC, or other 
bypassing agents should be performed only under medical supervision, which includes 
laboratory monitoring by additional local and central laboratory assessments, and 
consideration should be given to verifying bleeds prior to repeated dosing.  Caution 
should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab.  The use of anti-fibrinolytics in conjunction with aPCC/PCC or 
Byclot is prohibited. 
MONITORING 
In the event of a bleed treated with bypassing agents, the following local laboratory tests 
will be performed within 2448 hours of initial bypassing agent use so the investigator 
may monitor for of potential thromboembolic events and thrombotic microangiopathy: 
platelet count, serum creatinine, LDH, and peripheral blood smear analysis to evaluate 

Appendix 9 (cont.):  Guidelines for Dosing and Monitoring 
Bypassing Agents for Patients on Emicizumab 
Emicizumab—F. Hoffmann-La Roche Ltd 
155/Protocol YO39309, Version 5 
for schistocytes.  A plasma sample should also be provided for local laboratory 
monitoring of fibrinogen and D-dimer.  For patients who require multiple doses of 
bypassing agents, laboratory monitoring should be performed every 2448 hours 
thereafter until 2448 hours following the last dose of bypassing agents administered to 
treat a given bleed.  If applicable, laboratory results should be recorded in the 
Unscheduled Visit electronic Case Report Forms (eCRFs). 

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