Clinical trial NCT03380780
Conditions: Healthy Volunteers Hemophilia A
Sponsor: Hoffmann-La Roche
Start date: 2018-03-12; Completion date: 2018-09-18
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This single-center, open-label study will evaluate the pharmacokinetics, safety, and tolerability of emicizumab following a single subcutaneous (SC) administration to healthy Chinese subjects.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: Participants will receive a single 1 milligram per kilogram of body weight (mg/kg) subcutaneous dose of emicizumab on Day 1.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title:  
 
A SINGLE-CENTER, OPEN-LABEL, SINGLE-DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, SAFETY, AND 
TOLERABILITY OF EMICIZUMAB IN HEALTHY CHINESE 
VOLUNTEERS 
NCT Number: 
NCT03380780 
Document: 
Version & Date:  
PROTOCOL 
Version 4: 25-Jan-2018 
 


FINAL PROTOCOL 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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 YP39308, Version 4
PROTOCOL
TITLE:
A SINGLE-CENTER, OPEN-LABEL, SINGLE-DOSE 
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, SAFETY, AND 
TOLERABILITY OF EMICIZUMAB IN HEALTHY 
CHINESE VOLUNTEERS
PROTOCOL NUMBER:
YP39308
VERSION:
4
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  31 May 2016
DATE AMENDED:
Version 2: 19 March 2017
Version 3: 10 October 2017
Version 4: See electronic date stamp below.
 
25-Jan-2018 18:07:18
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Emicizumab—F. Hoffmann-La Roche Ltd
2/Protocol YP39308, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol YP39308 has been primarily amended to update the exclusion criteria and 
study assessments. Changes to the protocol, along with a rationale for each change, 
are summarized below:

The exclusion criterion of a positive T-SPOT.TB test result at screening has been 
updated. The positive result represents confirmed active tuberculosis (TB) disease 
or potentially latent TB infection in the population. There should not be an impact on 
subjects' safety based on the mechanism of action of emicizumab.  Only subjects 
with a positive T-SPOT.TB test result and with a confirmed active TB infection in 
clinical at screening should be excluded (Section 4.2.2).

Specific ECG assessment has been revised to clarify timing of the three consecutive
12-lead ECGs to within 5 minutes (Section 4.6.1.2 and Appendix 1).

Specific laboratory assessments have been revised:  C-reactive protein (CRP) has 
been modified as "high-sensitivity" CRP;  in viral serology, HIV-1 and HIV-2 Ab have 
been amended to HIV antibody; and testing for TB with T-SPORT.TB test has been 
added (Section 4.6.1.5 and Appendix 1).
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
3/Protocol YP39308, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND AND RATIONALE ............................................................ 18
1.1
Background on Hemophilia A ................................................ 18
1.2
Background on Emicizumab.................................................. 19
1.2.1
Previous Non-Clinical Studies ............................................... 19
1.2.2
Previous Clinical Studies ....................................................... 21
1.3
Study Rationale and Benefit–Risk Assessment..................... 23
2.
OBJECTIVES.............................................................................................. 24
2.1
Primary Objective .................................................................. 24
2.2
Secondary Objective ............................................................. 24
3.
STUDY DESIGN......................................................................................... 24
3.1
Description of the Study......................................................... 24
3.1.1
Overview of Study Design ..................................................... 24
3.2
End of Study.......................................................................... 25
3.3
Rationale for Study Design.................................................... 25
3.3.1
Rationale for Dosage Selection ............................................. 25
3.3.2
Rationale for Study Population .............................................. 25
3.4
Outcome Measures ............................................................... 25
3.4.1
Pharmacokinetic Outcome Measures.................................... 25
3.4.2
Safety Outcome Measures .................................................... 26
4.
MATERIALS AND METHODS .................................................................... 26
4.1
Center.................................................................................... 26
4.2
Study Population ................................................................... 26
4.2.1
Inclusion Criteria.................................................................... 26
4.2.2
Exclusion Criteria................................................................... 27
4.3
Method of Treatment Assignment.......................................... 28
4.4
Study Treatment.................................................................... 28
4.4.1
Formulation, Packaging, and Handling.................................. 28


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4.4.2
Dosage, Administration, and Compliance.............................. 28
4.4.2.1
Emicizumab........................................................................... 28
4.4.3
Investigational Medicinal Product Accountability ................... 29
4.5
Concomitant Therapy and Food ............................................ 29
4.5.1
Permitted Therapy................................................................. 30
4.5.2
Prohibited Therapy ................................................................ 30
4.5.3
Prohibited Food ..................................................................... 30
4.6
Study Assessments ............................................................... 30
4.6.1
Description of Study Assessments ........................................ 30
4.6.1.1
Medical History and Demographic Data ................................ 31
4.6.1.2
Electrocardiograms................................................................ 31
4.6.1.3
Vital Signs.............................................................................. 32
4.6.1.4
Physical Examinations........................................................... 32
4.6.1.5
Laboratory Assessments ....................................................... 32
4.6.1.6
Pharmacokinetic Samples ..................................................... 34
4.6.1.7
Additional Coagulation Samples............................................ 34
4.6.1.8
Anti-Emicizumab Antibody Samples...................................... 34
4.6.1.9
Total Blood Loss.................................................................... 35
4.6.2
Timing of Study Assessments ............................................... 35
4.6.2.1
Screening and Pretreatment Assessments............................ 35
4.6.2.2
Assessments during Treatment............................................. 35
4.6.2.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 35
4.7
Subject, Study, and Site Discontinuation............................... 35
4.7.1
Subject Discontinuation ......................................................... 35
4.7.1.1
Withdrawal from Study........................................................... 36
4.7.2
Study and Site Discontinuation.............................................. 36
5.
ASSESSMENT OF SAFETY....................................................................... 37
5.1
Safety Parameters and Definitions ........................................ 37
5.1.1
Adverse Events ..................................................................... 37
5.1.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 38
5.1.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 38


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5/Protocol YP39308, Version 4
5.2
Safety Plan ............................................................................ 39
5.2.1
Risks Associated with Emicizumab ....................................... 39
5.2.1.1
Injection-Site Reactions......................................................... 39
5.2.1.2
Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid Reaction......................................................... 39
5.2.1.3
Hypercoagulation and Thromboembolic Events .................... 40
5.2.1.4
Thrombotic Microangiopathy ................................................. 40
5.2.1.5
Life-Threatening Bleeding because of Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
in the Setting of Emicizumab ................................................. 41
5.2.2
Management of Specific Adverse Events .............................. 42
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 43
5.3.1
Adverse Event Reporting Period ........................................... 43
5.3.2
Eliciting Adverse Event Information....................................... 43
5.3.3
Assessment of Severity of Adverse Events ........................... 43
5.3.4
Assessment of Causality of Adverse Events ......................... 44
5.3.5
Procedures for Recording Adverse Events............................ 44
5.3.5.1
Injection-Site Reactions......................................................... 44
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 45
5.3.5.3
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 45
5.3.5.4
Persistent or Recurrent Adverse Events................................ 45
5.3.5.5
Abnormal Laboratory Values ................................................. 46
5.3.5.6
Abnormal Vital Sign Values ................................................... 47
5.3.5.7
Abnormal Liver Function Tests.............................................. 47
5.3.5.8
Deaths ................................................................................... 47
5.3.5.9
Preexisting Medical Conditions.............................................. 48
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 48
5.3.5.11
Overdoses ............................................................................. 49
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 49
5.4.1
Emergency Medical Contacts................................................ 49


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5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 50
5.4.3
Reporting Requirements for Pregnancies.............................. 50
5.4.3.1
Pregnancies in Female Partners of Male 
Subjects................................................................................. 50
5.5
Follow-Up of Healthy Subjects after 
Adverse Events ..................................................................... 50
5.5.1
Investigator Follow-Up........................................................... 50
5.5.2
Sponsor Follow-Up ................................................................ 51
5.6
Post-Study Adverse Events................................................... 51
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 51
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 51
6.1
Determination of Sample Size ............................................... 52
6.2
Summaries of Conduct of Study............................................ 52
6.3
Analysis Populations ............................................................. 52
6.3.1
Pharmacokinetic Analysis Population.................................... 52
6.3.2
Safety Analysis Population .................................................... 52
6.3.3
Immunogenicity Analysis Population ..................................... 52
6.4
Summaries of Treatment Group ............................................ 52
6.5
Pharmacokinetic Analyses..................................................... 52
6.6
Safety Analyses..................................................................... 53
6.6.1
Adverse Events ..................................................................... 53
6.6.2
Clinical Laboratory Test Results............................................ 53
6.6.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 54
6.6.2.2
Definition of Laboratory Abnormalities................................... 54
6.6.3
Vital Signs.............................................................................. 54
6.6.4
ECG Data Analysis................................................................ 54
6.6.5
Concomitant Medications ...................................................... 54
6.7
Immunogenicity Analyses...................................................... 55
7.
DATA COLLECTION AND MANAGEMENT ............................................... 55


Emicizumab—F. Hoffmann-La Roche Ltd
7/Protocol YP39308, Version 4
7.1
Data Quality Assurance......................................................... 55
7.2
Electronic Case Report Forms............................................... 55
7.3
Source Data Documentation.................................................. 56
7.4
Use of Computerized Systems .............................................. 56
7.5
Retention of Records............................................................. 57
8.
ETHICAL CONSIDERATIONS.................................................................... 57
8.1
Compliance with Laws and Regulations ................................ 57
8.2
Informed Consent.................................................................. 57
8.3
Institutional Review Board or Ethics Committee.................... 58
8.4
Confidentiality........................................................................ 58
8.5
Financial Disclosure .............................................................. 59
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION............................................................................. 59
9.1
Study Documentation ............................................................ 59
9.2
Site Inspections ..................................................................... 59
9.3
Administrative Structure......................................................... 59
9.4
Publication of Data and Protection of 
Trade Secrets........................................................................ 60
9.5
Protocol Amendments ........................................................... 61
10. REFERENCES ........................................................................................... 62
LIST OF TABLES
Table 1
Guidelines for Managing Specific Adverse Events...................... 42
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 44
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 24


Emicizumab—F. Hoffmann-La Roche Ltd
8/Protocol YP39308, Version 4
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................... 64
Appendix 2
Formula for Calculation of Body Mass Index............................... 67
Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events........................................................................... 68
Appendix 4
Clinical Criteria for Diagnosing Anaphylaxis................................ 74


Emicizumab—F. Hoffmann-La Roche Ltd
9/Protocol YP39308, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A SINGLE-CENTER, OPEN-LABEL, SINGLE-DOSE 
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, SAFETY, AND 
TOLERABILITY OF EMICIZUMAB IN HEALTHY 
CHINESE VOLUNTEERS
PROTOCOL NUMBER:
YP39308
VERSION NUMBER:
4
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form in your study files. Please return a copy to 
your local study monitor.


Emicizumab—F. Hoffmann-La Roche Ltd
10/Protocol YP39308, Version 4
PROTOCOL SYNOPSIS
TITLE
A SINGLE-CENTER, OPEN-LABEL, SINGLE-DOSE STUDY 
TO INVESTIGATE THE PHARMACOKINETICS, SAFETY, 
AND TOLERABILITY OF EMICIZUMAB IN HEALTHY 
CHINESE VOLUNTEERS
PROTOCOL NUMBER
YP39308
VERSION NUMBER:
4
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase I
INDICATION:
Hemophilia A
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary
The primary objective of this study is:

To assess the pharmacokinetics of emicizumab in healthy Chinese subjects following a 
single subcutaneous (SC) administration of emicizumab.
Secondary
The secondary objective for this study is:

To assess the safety and tolerability of emicizumab in healthy Chinese subjects following a 
single SC administration of emicizumab. 
Study Design
Description of Study
This will be a single-center and open-label study and will evaluate the pharmacokinetics, safety, 
and tolerability of emicizumab following a single SC administration to healthy Chinese subjects.
Number of Subjects
A total of 16 healthy Chinese male subjects will be enrolled in the study to obtain at least 
12 evaluable subjects.
Target Population
Inclusion Criteria
Subjects must meet the following criteria for study entry:

Healthy Chinese male subjects, aged 20–45 years inclusive at the time of screening.

Chinese subjects must have Chinese parents and grandparents, all of whom were born in 
China.

Healthy status as defined by absence of evidence of any active or chronic disease following 
a detailed medical and surgical history, a complete physical examination including vital 
signs, 12-lead ECG, hematology, blood chemistry, coagulation, viral serology, urinalysis,
and immunology.

A body mass index between 19 and 24 kg/m2, inclusive.

Able to participate and willing to give written informed consent and to comply with the study 
requirements.


Emicizumab—F. Hoffmann-La Roche Ltd
11/Protocol YP39308, Version 4
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:

Any history or presence of clinically significant gastrointestinal, respiratory, renal, hepatic,
hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal,
genitourinary, immunological, metabolic, malignant, or dermatological disorder.

Major illness within 1 month prior to dosing, and/or any condition which could relapse during 
or immediately after the study.

Use of any prescribed or over-the-counter medication or herbal medicine taken within 
14 days prior to dosing or within 5 times the elimination half-life of the medication prior to 
dosing (whichever is longer), with some exceptions.

Confirmed supine systolic blood pressure (SBP) 140 or 90 mmHg, and diastolic blood
pressure (DBP) 90 or 50 mmHg.

Confirmed resting supine heart rate (HR) greater than 100 or less than 50 beats per minute.

History of drug abuse within the past 2 years or confirmed positive results for drugs of 
abuse at screening or Day 1.

Alcohol dependence or a history of this within the past 2 years or positive results for alcohol 
breath test at screening or Day 1.

Confirmed clinically relevant abnormal (as judged by the investigator) laboratory test results.

Any significant donation/loss of blood or plasma (450 mL) within the 3 months prior to 
dosing.

Regular smoker with consumption of more than 10 cigarettes per day or the equivalent 
amount of tobacco.

Any other condition or disease other than stated which, in the judgment of the investigator, 
would place the subject at undue risk; interfere with the absorption, distribution, metabolism, 
and excretion of emicizumab; or interfere with the ability of the subject to complete the 
study.

Participation within a clinical study with an investigational drug or device within the last 
3 months prior to dosing.

Any clinically relevant history of hypersensitivity or allergic reactions, either spontaneous or 
following drug administration or exposure to foods or environmental agents.

Previous or concomitant thromboembolic disease such as deep vein thrombosis (DVT) or 
signs of thromboembolic disease, or family history of thromboembolic disorder such as 
serious DVT.

At high risk for thrombotic microangiopathy (e.g., have a previous medical or family history 
of thrombotic microangiopathy), in the investigator’s judgment.

Protein C activity, protein S activity, antithrombin III activity, factor IX (FIX) activity, factor X
(FX) activity, lupus anticoagulant (T1/T2 ratio), or anti-cardiolipin-beta-2 glycoprotein I (GPI) 
complex antibody levels outside the reference range at screening, or factor VIII (FVIII)
activity 120% at screening.

Previous or concomitant autoimmune or connective tissue disease.

History of tuberculosis or active tuberculosis with positive T-SPOT.TB test result at 
screening.

Any other reason that, in the judgment of the investigator, would render the subject 
unsuitable for study participation. 
Length of Study
The total duration of the study for each subject will be up to 20 weeks divided as follows:
Screening:  Up to 4 weeks
In Clinic period:  Days -1 to 4
Ambulatory Visits:  Days 6, 8, 11, 15, 22, 29, 36, 43, 50, 57, 71, 85, and 113


Emicizumab—F. Hoffmann-La Roche Ltd
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End of Study
The end of the study is defined as the date when the last subject, last observation occurs and is
expected 113 3 days after the last subject dose administration unless a subject withdraws his 
consent.
Outcome Measures
Pharmacokinetic Outcome Measures
Plasma concentrations of emicizumab will be measured by a specific and validated method.  PK 
parameters will be estimated using standard non-compartmental methods.

Primary PK parameters: Maximum plasma concentration observed (Cmax) and area under 
the plasma concentration-time curve (AUC) between time zero extrapolated to infinity
(AUC0-) of emicizumab

Secondary PK parameters: Area under the plasma concentration-time curve between time 
zero and the time of the last quantifiable concentration (AUC0-last), time to maximum plasma 
concentration (tmax), terminal plasma half-life (t1/2), apparent clearance (CL/F), apparent 
volume of distribution (Vz/F), mean residence time (MRT) of emicizumab
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events

Incidence and clinical significance of anti-emicizumab antibodies

Laboratory test data (hematology, blood chemistry, coagulation screening test, urinalysis, 
viral serology, and immunology), vital signs, 12-lead ECG.

Coagulation tests 
Vital Signs
Vital signs will include measurements of temperature (tympanic), respiratory rate, pulse rate, 
and SBP and DBP while the subject is in a supine position after the subject has been resting for 
at least 5 minutes at each visit (10 minutes for the screening visit).  Vital signs should be 
measured prior to blood sampling.  When possible, the same arm should be used for all blood 
pressure (BP) measurements.
BP, respiratory rate, pulse rate, and body temperature (axillary) will be recorded at the 
timepoints specified in the Schedule of Assessments (SoA).
BP, respiratory rate, and pulse rate measurements will be performed in triplicate (can be as 
short as ranging from 20-second to 1-minute intervals between measurements).  The mean of 
three consecutive replicates will be used as the value for the defined timepoint.
Electrocardiograms
ECGs will be collected after the subject has been in a supine position for at least 10 minutes.  At 
the specified timepoints, 12-lead ECGs will be obtained in triplicate (i.e., three consecutive 
interpretable 12-lead ECGs within 5 minutes and recorded on the electronic Case Report Form 
[eCRF]).  Triplicate recordings should be taken for any unscheduled ECG.
All ECG recordings must be performed using a standard digital high-quality, high-fidelity ECG 
machine equipped with computer-based interval measurements.  Automated ECG intervals (PR 
[PQ], QRS duration, QT, and QT corrected for HR [QTc] using the Fridericia correction factor) 
and HR will be captured, and the changes in T-wave and U-wave morphology will be 
documented.  T-wave information will be captured as normal or abnormal, and U-wave 
information will be captured in two categories:  absent/normal or abnormal.
For safety monitoring purposes, the investigator or designee must review, sign, and date all 
ECG tracings.  Paper or electronic copies will be kept as part of the subject’s permanent study 
file at the site.  If considered appropriate by Roche, ECGs may be analyzed retrospectively at a 
central laboratory.


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13/Protocol YP39308, Version 4
The following are requirements for ECG assessments:

The absence of any environmental distractions (television, radio, and conversation) during 
the pre-ECG rest and the ECG recording in the clinic must be emphasized.

Avoid ECG recordings within 3 hours after meals, if allowed per predefined schedule.

If possible, the same machine, brand and model, should be used for the same subject 
throughout the study.

ECGs should be 12-lead and recorded at 25 mm/sec for at least 10 seconds.

ECG machines should have periodic calibration and service records (minimum of once a 
year).

If any QT/QTc values 500 msec or increases from predose on Day 1 QTc 60 msec (as 
provided by the machine) are observed, the site should repeat the ECG within the next 
5 minutes and notify the Sponsor.  If confirmed, ECG recordings should be repeated at 
least hourly until two successive ECGs show QTc values below the threshold value that 
triggered the repeated measurement.
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor before the 
study starts.  Laboratory safety tests shall be collected at timepoints specified in the SoA.
Additional blood or urine samples may be taken at the discretion of the investigator if the results 
of any test fall outside the reference ranges, or if clinical symptoms necessitate additional 
testing to monitor subject’s safety.  Where the clinical significance of abnormal laboratory
results is considered uncertain, screening laboratory tests may be repeated before admission to 
confirm eligibility.  If there is an alternative explanation for a positive urine or blood test for drugs 
of abuse, e.g., previous occasional intake of a medication or food containing for example 
codeine, benzodiazepines or opiates, the test could be repeated to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the tests 
should be repeated immediately and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  Results of clinical laboratory 
testing will be recorded on the eCRF or be received as electronically produced laboratory 
reports submitted directly from the local or central laboratory, if applicable.
Samples for the following blood and urine laboratory tests will be collected and sent to the local 
laboratory for analysis at timepoints indicated in the SoA:

Hematology: hemoglobin, hematocrit, total WBC count, differential WBC count (basophils,
eosinophils, lymphocytes, monocytes and neutrophils), platelet count, RBC, mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration.

Blood Chemistry: albumin/globulin ratio, AST, ALT, LDH, total and indirect bilirubin, alkaline 
phosphatase, gamma glutamyl transpeptidase, CK, BUN, total protein, serum albumin, 
serum creatinine, uric acid, total cholesterol, triglycerides, fasting glucose, sodium, chloride, 
potassium, high-sensitivity C-reactive protein.

Screening Coagulation Test: Protein C activity, Protein S activity, antithrombin III activity, 
FVIII activity, FIX activity, FX activity, lupus anti-coagulant (T1/T2 ratio).

Coagulation test 1:  Prothrombin time (PT), PT/International Normalized Ratio (INR), aPTT, 
fibrinogen, D- dimer.  Starting on Day 1 onward, blood samples will be drawn to conduct 
biomarker assays at the central laboratory (
 in the United States).  The same 
assays will be also conducted locally at screening, and on Day 1, Day 2, Day 11, Day 29, 
Day 57, and Day 113.

Coagulation test 2:  Prothrombin fragments 1+2, FVIII activity. The samples will be run 
centrally on frozen plasma (
).

Coagulation test 3:  FVIII inhibitors. The samples will be run centrally on frozen plasma 
(
).


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
Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick analysis 
of protein, blood, glucose, leukocytes, specific gravity and pH.  If there is a clinically 
significant positive result (i.e., confirmed by a positive repeated sample), urine will be sent 
to the laboratory for microscopy and culture.  If there is an explanation for the positive 
dipstick result, it should be recorded, and there is no need to perform microscopy.  Urine 
color may be evaluated from urinalysis if considered necessary.

Viral serology: hepatitis B surface antigen, hepatitis C virus (HCV) RNA or HCV antibodies,
and HIV antibody.

Immunology: non-specific IgG E antibodies and anti-cardiolipin-beta-2 GPI complex 
antibody levels.

Drugs of abuse (urine): cannabinoids, amphetamines, methamphetamines, opiates,
methadone, cocaine, benzodiazepines, and barbiturates.

Alcohol: alcohol breath test.

Tuberculosis: T-SPOT.TB test
Anti-Emicizumab Antibodies
Blood samples will be collected as indicated in the SoA for the detection of anti-emicizumab 
antibodies.
Investigational Medicinal Product(s)
Emicizumab is a recombinant humanized bispecific monoclonal antibody that binds to activated
blood coagulation FIX and blood coagulation FX, and has cofactor activity that substitutes for 
that of blood coagulation FVIII. Emicizumab will be injected SC into the abdomen at a single 
dose of 1 mg/kg on Day 1.
Procedures
Screening
Written informed consent for participation in the study must be obtained before performing any 
study‑specific screening tests or evaluations.  Informed Consent Forms for enrolled subject and 
for subjects who are not subsequently enrolled will be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to confirm that 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to record 
details of all subjects screened and to confirm eligibility or record reasons for screening failure.
An Eligibility Screening Form documenting the investigator’s assessment of each screened 
subject with regard to the protocol’s inclusion and exclusion criteria is to be completed by the 
investigator and kept at the investigational site.
A screening examination should be performed from Day 28 to Day 2 for healthy subjects.  
Subjects must fulfill all entry criteria to be accepted into the study.  Assessments as detailed in 
the SoA (Appendix 1) will be conducted.
Treatment
Subjects will be admitted to the clinical research unit on Day 1. On the morning of Day 1, 
subjects will receive a single 1 mg/kg SC dose of study medication (emicizumab). The study 
medication will be administered after fasting from midnight for at least 8 hours. A standard 
lunch will be provided 4 hours after dosing. Subjects will leave the unit after 72 hours after dose 
assessments are completed and will return to the unit for the collection of PK samples and for 
remaining assessments. Subjects will receive standard meals while in the unit.
All assessments must be performed as per SoA.
Withdrawal Criteria
The investigator has the right to withdraw a subject from the study at any time.  In addition, 
subjects have the right to voluntarily withdraw from the study at any time for any reason.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Subject withdrawal of consent at any time

The subject develops a treatment-related serious adverse event.


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
Any medical condition that the investigator or Sponsor determines may jeopardize the 
subject’s safety if he continues in the study

Investigator or Sponsor determines it is in the best interest of the subject

Subject non-compliance
Subjects who withdraw from the study for non-safety reasons may be replaced.  Subjects who 
withdraw from the study due to poor tolerability to study drug will not be replaced.  Early 
termination blood samples for emicizumab PK and safety laboratory assessment will be 
collected at the time of discontinuation. 
Statistical Methods
Pharmacokinetic Analyses
Individual plasma concentrations at each sampling timepoint for emicizumab will be presented 
by listings and appropriate descriptive summary statistics, including arithmetic means, 
geometric means, medians, minimums-maximums, SDs, and coefficients of variation.  Individual 
and mean plasma concentration versus time data will be plotted on semi-logarithmic scales.
All PK parameters will be presented by individual listings and summary statistics including 
arithmetic means, geometric means, medians, minimums-maximums, SDs, and coefficients of 
variation.
The primary emicizumab PK study parameters will be the Cmax and the AUC (AUC0-if it can be 
derived, otherwise truncated as appropriate).  All other PK parameters will be regarded as 
secondary. 
Non-compartmental analysis will be employed for estimation of the following PK parameters: 

tmax:  Time to maximum observed plasma concentration

Cmax:  Maximum observed plasma concentration 

AUC0-:  Area under the plasma concentration-time curve between time zero extrapolated 
to infinity

AUC0-last:  Area under the plasma concentration-time curve between time zero and the time 
of the last quantifiable concentration

t1/2: Apparent terminal half-life, computed as (ln2/z)

CL/F:  Apparent clearance

Vz/F:  Apparent volume of distribution

MRT: Mean residence time
Safety Analyses
All safety analyses will be based on the safety analysis population.
Sample Size Justification
The number of subjects (12 evaluable subjects) is chosen based on practical clinical judgment 
(AUC and Cmax variability of emicizumab in Caucasian and Japanese healthy subjects) and 
China regulatory requirement.
Prohibited Therapy
As a general rule, no concomitant medications (including herbal products and vitamins) will be 
permitted, with the exception of medications to treat adverse events unless the rationale for 
exception is discussed and clearly documented between the investigator, the Medical and 
Safety Monitors, and the Roche clinical pharmacologist.  All concomitant medications 
throughout the duration of the study should be recorded on the Concomitant Medications eCRF.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
Ab
antibody
ADA
anti-drug antibody
A/G
albumin/globulin
ALP
alkaline phosphatase
aPCC
activated prothrombin complex concentrate
AUC
area under the plasmaconcentration curve
AUC0-
area under the plasma concentrationtime curve between time zero 
extrapolated to infinity
AUC0-last
area under the plasma concentrationtime curve between time zero and 
the time of the last quantifiable concentration
BA
bioavailability
BMI
body mass index
BP
blood pressure
CK
creatine kinase
Cmax
maximum plasma concentration observed
CL/F
apparent clearance
CRO
contract research organization
CRP
C-reactive protein
DBP
diastolic blood pressure
DVT
deep vein thrombosis
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
(U.S.) Food and Drug Administration
FIX
factor IX
FIXa
activated factor IX
FVIII
factor VIII
FVIIIa
activated factor VIII
FX
factor X
GCP
Good Clinical Practice
GPI
glycoprotein I
HbsAg
hepatitis B surface antigen
HCP
healthcare provider
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate


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Abbreviation
Definition
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgE
immunoglobulin E
IgG4
immunoglobulin G4
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous
MAD
multiple ascending doses
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MRT
mean residence time
OTC
over-the-counter
PD
pharmacodynamic
PK
pharmacokinetic
PT
prothrombin time
QRS
QRS complex
QTc
QT corrected for heart rate
rFVIIa
recombinant activated factor VII
SBP
systolic blood pressure
SC
subcutaneous
SoA
schedule of assessments
tmax
time to maximum plasma concentration
t1/2
terminal plasma half-life
ULN
upper limit of normal
Vz/F
apparent volume of distribution
-GTP
-Glutamyltranspeptidase


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1.
BACKGROUND AND RATIONALE
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 in 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 of his sons and an abnormal X chromosome 
to all of his daughters, his sons will not be affected and all of his daughters will be 
carriers.  The offspring of a female carrier have a 50% chance of receiving a mutated 
FVIII gene, thus half of the male infants will have hemophilia A, and half of the female 
infants will be carriers of the mutated gene.  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).
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 of 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).
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).  Current prophylactic regimens commonly 
use infusion therapy administered 23 times weekly (Adynovat® eU.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 because adequate prophylaxis requires a lifetime of 
self-administered intravenous (IV) infusion of FVIII 34 times each week.  In addition to 
treatment burden, other reasons, including venous access and cost concerns, underlie 


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this problem (Gringeri et al. 2012), which contributes to hemophilia-associated long-term 
morbidity.
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 (Wang et al. 2010).  Inhibitors 
neutralize the activity of endogenous FVIII as well as of FVIII administered as 
replacement therapy.  For patients with a history of a high-titer (5 BU/mL) inhibitor 
following a re-challenge with FVIII administration (high-responding inhibitor), the only 
hemostatic options currently available are prothrombotic coagulation factors that 
augment other parts of the coagulation cascade (i.e., “bypassing agents”). 
The development of effective prophylactic treatment options with decreased
immunogenicity and less frequent dosing requirements is important to reduce the time
and burden associated with frequent IV dosing and the impact of the disease on aspects
of physical health and other areas of function.  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
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 because emicizumab shares no sequence 
homology with FVIII.  In addition, emicizumab offers the possibility of subcutaneous (SC) 
administration, removing the need for venous access.  Finally, because the 
pharmacokinetic properties of this antibody are expected to enable marked extension of 
the dosing interval to once weekly or even less frequently, this novel compound has the 
potential to dramatically change the treatment of patients with hemophilia A with and 
without FVIII inhibitors who are in need of effective, safe, and low-burden prophylactic 
therapy.
1.2.1
Previous Non-Clinical Studies
Binding studies of emicizumab to cynomolgus monkey factor IX (FIX) and FX showed
similar affinities as those to the human factors.  Mechanistic in vitro studies were 
conducted in human and cynomolgus FVIII-neutralized plasma and in various 
coagulation factor-specific assay-testing systems, which revealed that emicizumab 
shortened aPTT and promoted thrombin generation.  Emicizumab bound to human Fc
receptor, cynomolgus monkey Fcreceptor, human neonatal Fc receptor, and 


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cynomolgus monkey neonatal Fc receptor with similar affinities as a human IgG4 
antibody, natalizumab.
In vivo pharmacology experiments in cynomolgus monkeys were conducted in a
hemophilia A model where endogenous FVIII levels were neutralized by a FVIII-specific
monoclonal antibody.  This model mimics essential characteristics of patients with
hemophilia A and was used to test in vivo pharmacodynamics and efficacy under
spontaneous or local trauma-induced bleeding conditions.  In summary, emicizumab
demonstrated the ability to significantly reduce bleeding tendency under both sets of 
conditions.
Potential prothrombotic risks associated with emicizumab-induced FVIII mimetic activity 
were further explored in an in vivo cynomolgus monkey venous stasis model.  In this 
model, thrombus formation in the presence of emicizumab was compared with that in the 
presence of FVIII or bypassing agents recombinant activated factor VII (rFVIIa) or 
activated prothrombin complex concentrate (aPCC).  Thrombus formation with 
emicizumab did not markedly exceed formation observed with rFVIIa, aPCC, or FVIII.
The pharmacokinetics/toxicokinetics of emicizumab were assessed in cynomolgus 
monkeys after single and multiple doses were administered intravenously and via the 
intended clinical SC route.  After a single IV dose of 6 mg/kg of emicizumab in male 
cynomolgus monkeys, the plasma clearance was 3.62 mL/day/kg and the terminal 
plasma half-life (t1/2) of emicizumab was 19.4 days.  The single SC administration study 
(dose levels: 0.06, 0.6, and 6 mg/kg) indicated slow (time to maximum plasma 
concentration [tmax]: 3.005.33 days) and complete absorption (bioavailability [BA]: 102% 
at 6 mg/kg).  The IV and SC multiple dosing studies (toxicokinetic monitoring) revealed a 
t1/2 in the range of 14.930.8 days.  Overall, exposures in terms of maximum plasma 
concentration observed (Cmax) and area under the plasma-concentration curve (AUC) 
increased in an approximately dose-proportional manner.
A subfraction of the cynomolgus monkeys treated with repeated doses of emicizumab 
showed the formation of anti-emicizumab antibodies (which is expected with humanized 
monoclonal antibodies), with few animals also showing neutralizing antibodies.
Aspects of acute as well as repeated-dose toxicity including local tolerance assessment 
were evaluated in cynomolgus monkeys in 4-, 13-, and 26-week SC dose toxicity studies 
(at doses up to 30 mg/kg weekly), and a 4-week IV dose toxicity study (at doses up to 
100 mg/kg weekly).  No toxicologically relevant changes attributable to SC or IV 
administration of emicizumab were observed; the no observed adverse effect level was 
the highest tested dose in each toxicity study.
See the Emicizumab (RO5534262) Investigator's Brochure (IB) for additional details on 
nonclinical studies with emicizumab.


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1.2.2
Previous Clinical Studies
Currently available experience with emicizumab in humans includes data from one 
completed Phase I study (ACE001JP) and its ongoing extension Phase I/II study 
(ACE002JP) and one completed BA study conducted in healthy volunteers (JP29574).  
ACE001JP was a single study conducted in three parts, including both healthy subjects 
(Part A and Part B) and patients with hemophilia A (Part C).  The objectives of Parts A 
and B in healthy subjects were to investigate the tolerability, safety, and pharmacokinetic 
(PK), and pharmacodynamic (PD) response of SC-administered emicizumab in adult 
Japanese and Caucasian men and to evaluate the racial differences, if any, in their PK 
and PD response. Healthy men aged 2044 years were eligible for enrollment.  A total 
of 64 healthy subjects were enrolled in Parts A and B from August 2012 to April 2013.  In
Part C, the objective was to investigate the tolerability, safety, PK, and PD response of 
SC-administered emicizumab in patients with hemophilia A.  Patients were eligible for 
enrollment if they were 1259 years of age, 40 kg in weight, had a diagnosis of severe 
congenital hemophilia A, and had documentation of bleeds and/or treatment with 
coagulation factor in the last 6 months.  A total of 18 patients with hemophilia A were 
enrolled from May 2013 to June 2014.
Parts A and B of Study ACE001JP consisted of a randomized, placebo-controlled, 
single-ascending dose study, which was conducted in Japanese (n40; Part A) and 
Caucasian (n24; Part B) healthy men; 48 subjects received a single SC injection of 
0.001 to 1 mg/kg of emicizumab, and 16 subjects received a single SC injection of 
placebo.  Part C of Study ACE001JP was an open-label, multiple ascending dose (MAD) 
study in 18 Japanese patients with hemophilia A, both with and without inhibitors.  Of the 
18 patients in Part C of Study ACE001JP, 6 patients were dosed with 0.3 mg/kg/wk SC 
following a single loading dose of 1 mg/kg SC, 6 patients were dosed with 1 mg/kg/wk 
SC following a single loading dose of 3 mg/kg, and 6 patients received 3 mg/kg/wk of 
emicizumab without a loading dose.
Study ACE002JP is an extension study that allows patients enrolled in Part C of 
Study ACE001JP to continue treatment with emicizumab.  All continuing patients in 
Study ACE002JP have been observed for at least 96, 72, or 48 weeks in the 0.3, 1, and 
3 mg/kg/wk dosing groups, respectively, except for 1 patient in the 3 mg/kg/wk group 
who has only been followed for 44 weeks.
Study JP29574 was a single-dose study in healthy Japanese male subjects.  The 
objective was to investigate (1) the relative bioavailability (BA) of the new emicizumab 
material (G2.1) among different sites of SC administration (abdominal, upper arm, and 
thigh), (2) the absolute bioavailability of the new emicizumab material (G2.1), and (3) the 
relative bioavailability of the new emicizumab material (G2.1, 150 mg/mL) versus the
previous emicizumab material (G1, 80 mg/mL).  A total of 60 healthy male subjects were 
enrolled in five groups (12 subjects in each group) [Group A: G 1 SC injection 1 mg/kg in 
the abdomen; Group B: G2.1 SC injection 1 mg/kg in the abdomen; Group C: G2.1 SC 


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injection 1 mg/kg in the upper arm; Group D: G2.1 SC injection 1 mg/kg in the thigh; 
Group E: G2.1 IV infusion 0.25 mg/kg].
From Study ACE001JP in healthy subjects, all adverse events were of mild intensity, 
except for one moderate adverse event (nasopharyngitis in 1 subject on the 0.1 mg/kg 
dose).  No racial differences were detected, and there were no dose-dependent 
increases in the incidence of adverse events.  A causal relationship to emicizumab could 
not be ruled out for two adverse events (both in 1 volunteer) reported in the 1 mg/kg 
group (blood bilirubin increased and bilirubin conjugated increased).  There were no 
serious adverse events, adverse events leading to discontinuation, or deaths in this 
study.  From Study JP29574 in healthy subjects, all adverse events were mild to 
moderate in severity, and there were no severe adverse events, adverse events
resulting in study discontinuation, or serious adverse events.  A total of 27 adverse 
events in 22 out of 60 subjects have been observed after single SC or IV administration 
of emicizumab.  Three adverse events (abdominal pain, oropharyngeal pain, and hot 
flush) have been considered to be related to emicizumab.
Emicizumab was safe and well tolerated in patients with hemophilia A in the Phase I/II 
studies (see Emicizumab IB).  The majority of adverse events were of mild intensity,
except for 5 moderate adverse events (upper respiratory tract infection, bipolar I disorder, 
hemophilia [i.e., left hip joint bleeding due to hemophilia], headache, and asthma) and 
2 severe adverse events (appendicitis and mesenteric hematoma).  Both severe events 
were considered to be serious adverse events and not related to emicizumab
administration.  A total of 7 patients reported injection-site reactions (including erythema,
hematoma, rash, pain, discomfort, and pruritus).  All injection-site reactions were of mild 
intensity.  Besides injection-site reactions, the most frequently reported adverse events 
(reported in 4 patients) were nasopharyngitis, pharyngitis, dental caries, excoriation,
and headache.  There were no dose dependent increases in adverse events, and the 
majority of the adverse events were not considered related to emicizumab. Treatment 
was discontinued for 1 patient with injection-site erythema in the 1 mg/kg weekly group; 
the event was mild in intensity and resolved.  This same patient also reported 
one non-related serious adverse event (hemophilia [i.e., left hip joint bleeding due to 
hemophilia]) approximately 22 weeks after the last dose of study drug. No 
thromboembolic adverse events have been reported when emicizumab has been 
administered alone or concomitantly with FVIII products or bypassing agents as episodic 
therapy.
In Study BH29884, as of April 2017, thrombotic microangiopathy had been observed in 
3 patients receiving emicizumab and bypassing agents, and thromboembolic events 
were observed in 2 patients receiving emicizumab and bypassing agents.  For more
details refer to Section 5.2.1.3 and Section 5.2.1.4.
Emicizumab exhibited linear pharmacokinetics after single SC administration.  Following 
single SC injection, its mean elimination t1/2 (45 weeks) was similar to that of other 


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human immunoglobulin G antibodies.  Furthermore, comparison of PK profiles between 
Japanese and Caucasian healthy subjects did not reveal racial differences.  Similar PK 
profiles were observed in healthy Japanese subjects following abdominal SC injection of 
1 mg/kg with two different emicizumab formulations (G1 [80 mg/mL] and 
G2.1 [150 mg/mL]). Also, similar PK profiles were observed following SC injections in 
abdomen, upper arm, and thigh, which suggest that emicizumab can be interchangeably 
injected in each of these three locations. In addition, emicizumab was almost completely 
absorbed following SC injection, with an absolute bioavailability of 80.4%93.1%, 
depending on the injection site. In patients with hemophilia A, emicizumab trough 
plasma concentrations increased in a dose-proportional manner with weekly dosing to 
achieve a plateau after approximately 12 weeks in the first two dosing groups, in which a 
loading dose was administered, and after approximately 24 weeks in the highest dose 
group, in which no initial loading dose was administered.
In the Phase I/II studies ACE001JP, ACE002JP, and JP29574, emicizumab has been 
administered to 108 healthy subjects and 18 patients with hemophilia A.  A total of 
10 subjects/patients tested positive for anti-drug antibodies (ADAs) on at least one 
occasion.  Seven subjects/patients developed an ADA after exposure, and in 3 other 
patients, ADA was detected before first exposure to emicizumab.  No clinically relevant 
changes in the pharmacokinetics and pharmacodynamics of emicizumab have been 
detected in any of the hemophilia A patients who tested positive for ADA (i.e., none of 
the ADA have been neutralizing), and the presence of ADA did not have an effect on the 
annualized bleeding rate reduction in these patients. 
Based on these compelling Phase I/II data, a clinical development program in adult and 
pediatric patients with hemophilia A (both with and without FVIII inhibitors) has been 
initiated.  See the IB for additional details on clinical studies with emicizumab.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
This study is designed to evaluate the pharmacokinetics, safety, and tolerability of 
emicizumab following single SC administration to healthy Chinese male subjects.
As this is a Phase I study in healthy subjects, no therapeutic benefit is anticipated for 
these subjects.  Under a controlled setting, this study should provide a better 
understanding of pharmacokinetics, safety, and tolerability to guide future clinical studies 
and optimize the benefit-risk in Chinese hemophilia A patients. 
The target exposure-range of emicizumab has been shown to be safe and well tolerated 
in previous clinical studies and no ethnic difference in pharmacokinetics is observed
between Asian (Japanese) and Caucasian healthy subjects.  The investigated dosing 
regimen in this study (1 mg/kg, single dose) is associated with a safety margin 
(compared with corresponding exposure values achieved at NOAEL in the GLP 
cynomolgus monkey study after subcutaneous administration) of 228-fold and 244-fold 
based on Cmax in Japanese and Caucasian healthy subjects, respectively, and of


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33.7-fold and 30.0-fold based on AUClast, respectively.  The risks for an individual subject 
due to a single dose of emicizumab or study-related procedures are considered to be 
minimal.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary objective of this study is:

To assess the pharmacokinetics of emicizumab in healthy Chinese subjects
following a single SC administration of emicizumab.
2.2
SECONDARY OBJECTIVE
The secondary objective for this study is:

To assess the safety and tolerability of emicizumab in healthy Chinese subjects
following a single SC administration of emicizumab. 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This will be a single-center and open-label study and will evaluate the pharmacokinetics, 
safety, and tolerability of emicizumab following a single SC administration to healthy 
Chinese subjects.
Figure 1
Overview of Study Design
Screening
In Clinic Period
Ambulatory Visits
Days 28 to 2
Days 1 to 4
(Discharge: the morning of Day 4)
Days 6 to 113
Admission to 
Clinic
Study Drug 
Administration
Day 1
Day 1
The total duration of the study for each subject will be up to 20 weeks divided as follows:

Screening: Up to 4 weeks

In Clinic period: Days 1 to 4

Ambulatory visits: Days 6, 8, 11, 15, 22, 29, 36, 43, 50, 57, 71, 85, and 113
Subjects will be admitted to the clinical research unit on Day 1. On the morning of 
Day 1, subjects will receive a single 1 mg/kg SC dose of study medication (emicizumab). 
The study medication will be administered after fasting from midnight for at least 8 hours. 
A standard lunch will be provided 4 hours after dosing. Subjects will leave the unit after 
72 hours after dose assessments are completed and will return to the unit for the 


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collection of PK samples and for remaining assessments. Subjects will receive standard 
meals while in the unit.
A total of 16 healthy Chinese male subjects will be enrolled in the study to obtain at least 
12 evaluable subjects.
3.2
END OF STUDY
The end of the study is defined as the date when the last subject, last observation 
occurs and is expected 1133 days after the last subject dose administration unless a
subject withdraws his consent.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Dosage Selection
In the healthy subject studies (ACE001JP and JP29574), single doses of up to 1 mg/kg
emicizumab were well tolerated. Emicizumab exposure in Japanese healthy subjects
was comparable to that in Caucasians.  These data and emicizumab PK properties did
not reveal or support the likelihood of ethnicity differences in emicizumab 
pharmacokinetics. In the MAD patient study (ACE001JP Part C and its extension
ACE002JP), emicizumab exhibited linear pharmacokinetics over the dose range from 
0.3 mg/kg to 3 mg/kg. To evaluate the pharmacokinetics in Chinese healthy subjects, 
the maximal tested dose in healthy subjects (1 mg/kg) has been selected for this study.  
This is considered to be adequate to assess the emicizumab PK profile in a Chinese 
healthy population and to compare the results with those from Caucasian and Japanese 
populations.
3.3.2
Rationale for Study Population
Healthy Chinese subjects have been chosen in this study as the absence of confounding
disease processes in healthy subjects leads to a clear and more consistent assessment 
of drug disposition, and healthy subjects are unlikely to require concomitant treatments
which could interfere with the study drug.  In addition, the safety, tolerability, and
pharmacokinetic profiles of emicizumab have been well evaluated and established in
healthy Caucasian and Japanese subjects.  The drug was safe and well tolerated in 
healthy subjects as evidenced by studies ACE001JP and JP29574.
3.4
OUTCOME MEASURES 
3.4.1
Pharmacokinetic Outcome Measures
Plasma concentrations of emicizumab will be measured by a specific and validated 
method.  PK parameters will be estimated using standard non-compartmental methods.

Primary PK parameters: Cmax and area under the plasma concentration-time curve 
between time zero extrapolated to infinity (AUC0-) of emicizumab


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
Secondary PK parameters: Area under the plasma concentrationtime curve 
between time zero and the time of the last quantifiable concentration (AUC0-last), tmax, 
t1/2, apparent clearance (CL/F), apparent volume of distribution (Vz/F), mean 
residence time (MRT) of emicizumab
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events

Incidence and clinical significance of anti-emicizumab antibodies

Laboratory test data (hematology, blood chemistry, coagulation screening test, 
urinalysis, viral serology, and immunology), vital signs, 12-lead ECG 

Coagulation tests 
4.
MATERIALS AND METHODS
4.1
CENTER
This is a single-center study.  An additional site(s) may be included for back-up purposes 
and may be activated if needed.
Administrative and contact information and the list of investigators are provided 
separately.
4.2
STUDY POPULATION
This study will enroll 16 healthy male subjects.
Subjects who drop out of the study for non-safety reasons may be replaced to ensure 
sufficient data to characterize the PK and safety profile.  Subjects who withdraw from the 
study due to poor tolerability to a study drug-related adverse event will not be replaced.
4.2.1
Inclusion Criteria
Subjects must meet the following criteria for study entry:

Healthy Chinese male subjects, aged 20–45 years inclusive at the time of screening.

Chinese subjects must have Chinese parents and grandparents, all of whom were 
born in China.

Healthy status as defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, hematology, blood chemistry, coagulation, viral 
serology, urinalysis, and immunology.

A body mass index (BMI) between 19 and 24 kg/m2, inclusive.

Able to participate and willing to give written informed consent and to comply with 
the study requirements.


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4.2.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from study entry:

Any history or presence of clinically significant gastrointestinal, respiratory, renal, 
hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, 
musculoskeletal, genitourinary, immunological, metabolic, malignant, or
dermatological disorder.

Major illness within 1 month prior to dosing, and/or any condition which could 
relapse during or immediately after the study.

Use of any prescribed or over-the-counter (OTC) medication or herbal medicine 
taken within 14 days prior to dosing or within 5 times the elimination half-life of the 
medication prior to dosing (whichever is longer), with some exceptions (see
Section 4.5.2).

Confirmed supine systolic blood pressure (SBP) 140 or 90 mmHg, and diastolic 
blood pressure (DBP) 90 or 50 mmHg.

Confirmed resting supine heart rate (HR) greater than 100 or less than 50 beats per 
minute.

History of drug abuse within the past 2 years or confirmed positive results for drugs 
of abuse at screening or Day 1.

Alcohol dependence or a history of this within the past 2 years or positive results for 
alcohol breath test at screening or Day 1.

Confirmed clinically relevant abnormal (as judged by the investigator) laboratory test
results.

Any significant donation/loss of blood or plasma (450 mL) within the 3 months prior 
to dosing.

Regular smoker with consumption of more than 10 cigarettes per day or the 
equivalent amount of tobacco.

Any other condition or disease other than stated which, in the judgment of the 
investigator, would place the subject at undue risk; interfere with the absorption, 
distribution, metabolism, and excretion of emicizumab; or interfere with the ability of 
the subject to complete the study.

Participation within a clinical study with an investigational drug or device within the 
last 3 months prior to dosing.

Any clinically relevant history of hypersensitivity or allergic reactions, either 
spontaneous or following drug administration or exposure to foods or environmental 
agents.

Previous or concomitant thromboembolic disease such as deep vein thrombosis 
(DVT) or signs of thromboembolic disease, or family history of thromboembolic 
disorder such as serious DVT.

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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
Protein C activity, protein S activity, antithrombin III activity, FIX activity, FX activity, 
lupus anticoagulant (T1/T2 ratio), or anti-cardiolipin-beta-2 glycoprotein I (GPI) 
complex antibody levels outside the reference range at screening, or FVIII activity 
120% at screening.

Previous or concomitant autoimmune or connective tissue disease.

History of tuberculosis or active tuberculosis with positive T-SPOT.TB test result
at screening.

Any other reason that, in the judgment of the investigator, would render the subject 
unsuitable for study participation.
4.3
METHOD OF TREATMENT ASSIGNMENT 
This study is open-label and consists of one cohort.  A total of 16 healthy male subjects 
will be enrolled in the study in order to obtain at least 12 evaluable subjects.  Each 
subject will be assigned to receive a 1 mg/kg single SC dose of emicizumab.  Subject 
number will be allocated sequentially in the order in which the subjects are enrolled.
4.4
STUDY TREATMENT
The investigational medicinal product (IMP) for this study is emicizumab (RO5534262).
4.4.1
Formulation, Packaging, and Handling
Emicizumab (RO5534262) will be supplied by the Sponsor as a sterile liquid for SC 
injection, contains no preservatives, and requires storage at 2°C8°C (do not freeze and 
protect from light).  Each single-use vial contains 150 mg (nominal) of emicizumab at 
pH 6.0.  The Drug Product is formulated as 150 mg/mL emicizumab in 150 mmol/L 
arginine, 0.5 mg/mL poloxamer 188, and 20 mmol/L histidine-aspartic acid buffer 
(pH 6.0).  For further information on the formulation and handling of emicizumab, see 
the IB.
4.4.2
Dosage, Administration, and Compliance
4.4.2.1
Emicizumab
Each subject will receive a single abdominal SC injection of 1 mg/kg emicizumab under 
fasting conditions.
Details on the devices to be used for study medication withdrawal from vial and SC
injection are provided in the Pharmacy Manual.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF).
Adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.
Subjects will be observed for a minimum of 60 minutes after the administration.


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4.4.3
Investigational Medicinal Product Accountability
Emicizumab, the only IMP in this study, will be provided by the Sponsor.  Accountability 
for each vial is required throughout the study.  The study site will acknowledge receipt of 
IMPs.  Any damaged shipments will be replaced.
The investigator is responsible for the control of drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained.  The Drug Dispensing Log must be kept 
current and should contain the following information:

The identification of the subject to whom the study drug was dispensed (e.g.,
subject initials and date of birth).

All records and drug supplies must be available for inspection by the Roche Monitor 
(at every monitoring visit).
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons.  In these cases, it may be acceptable for investigational study 
site staff to destroy dispensed investigational product before a monitoring inspection 
provided that source document verification is performed on the remaining inventory and 
reconciled against the documentation of quantity shipped, dispensed, returned, or 
destroyed and provided that adequate storage and integrity of drug has been confirmed.
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Written documentation of destruction must contain the following:

Identity of investigational product(s) destroyed

Quantity of investigational product(s) destroyed

Date of destruction

Method of destruction

Name and signature of responsible person (or company) who destroyed 
investigational products(s)
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.
4.5
CONCOMITANT THERAPY AND FOOD
Concomitant therapy consists of any medication (e.g., prescription drugs, OTC, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by a patient in addition 
to protocol-mandated treatment from 4 weeks prior to initiation of study drug to the study 


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completion/discontinuation visit  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF).
4.5.1
Permitted Therapy
Acetaminophen/paracetamol is allowed up to a maximum dose of 1 g/day up to 48 hours 
prior to dosing, not to exceed 4 g total during the week prior to dosing.
4.5.2
Prohibited Therapy
As a general rule, no concomitant medications (including herbal products and vitamins) 
will be permitted, with the exception of medications to treat adverse events unless the 
rationale for exception is discussed and clearly documented between the investigator, 
the Medical and Safety Monitors, and the Roche clinical pharmacologist.  All 
concomitant medications throughout the duration of the study should be recorded on the 
Concomitant Medications eCRF.
4.5.3
Prohibited Food

The consumption of foods and beverages containing caffeine or methylxanthine
(e.g., tea, coffee, cola, and, chocolate) will not be permitted during the in-house 
periods.  During the non-resident period, subjects will be asked to consume 6 cups 
of coffee or tea per day and 1 L per day of methylxanthine-containing drinks.

Alcohol will not be allowed 48 hours before the dose and whilst staying in the study 
center.  During the periods that subjects are not a resident in the unit, alcohol 
consumption has to be less than 2 drinks per day of alcohol (1 drink equates to 
approximately 330 mL of beer, 125 mL of wine, or 25 mL of spirits).

The use of tobacco is not permitted during the in-house period.
4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
All examinations listed below will be performed according to the schedule of 
assessments (SoA) outlined in Appendix 1.
At timepoints when several assessments coincide, the following sequence should be 
followed with the PK blood sample to be taken as close as possible to the nominal 
timepoint:

ECG recordings

Vital signs

Physical examination

Blood draws, taken in standard order of collection:
Coagulation blood samples (citrate plasma)
Serum or EDTA plasma for safety, PK, and ADA samples

Urine collection

Study drug administration


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4.6.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, reproductive status, smoking 
history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
OTC drugs, herbal or homeopathic remedies, and nutritional supplements) used by the 
subject within 30 days prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.6.1.2
Electrocardiograms
ECGs will be collected after the subject has been in a supine position for at least 
10 minutes.  At the specified timepoints, 12-lead ECGs will be obtained in triplicate 
(i.e., three consecutive interpretable 12-lead ECGs within 5 minutes and recorded on the 
eCRF).  Triplicate recordings should be taken for any unscheduled ECG.
All ECG recordings must be performed using a standard digital high-quality, high-fidelity 
ECG machine equipped with computer-based interval measurements.  Automated ECG
intervals (PR [PQ], QRS duration, QT, and QT corrected for HR (QTc) using the 
Fridericia correction factor) and HR will be captured, and the changes in T-wave and 
U-wave morphology will be documented.  T-wave information will be captured as normal 
or abnormal, and U-wave information will be captured in two categories: absent/normal 
or abnormal.
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper or electronic copies will be kept as part of the subject’s 
permanent study file at the site.  If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
The following are requirements for ECG assessments:

The absence of any environmental distractions (television, radio, and conversation) 
during the pre-ECG rest and the ECG recording in the clinic must be emphasized.

Avoid ECG recordings within 3 hours after meals, if allowed per predefined schedule.

If possible, the same machine, brand and model, should be used for the same 
subject throughout the study.

ECGs should be 12-lead and recorded at 25 mm/sec for at least 10 seconds.

ECG machines should have periodic calibration and service records (minimum of 
once a year).

If any QT/QTc values 500 msec or increases from predose on Day 1 QTc
60 msec (as provided by the machine) are observed, the site should repeat the
ECG within the next 5 minutes and notify the Sponsor.  If confirmed, ECG 
recordings should be repeated at least hourly until two successive ECGs show QTc 
values below the threshold value that triggered the repeated measurement.


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4.6.1.3
Vital Signs
Vital signs will include measurements of temperature (axillary), respiratory rate, pulse 
rate, and systolic and diastolic blood pressure (BP) while the subject is in a supine
position after the subject has been resting for at least 5 minutes at each visit (10 minutes 
for the screening visit).  Vital signs should be measured prior to blood sampling.  When 
possible, the same arm should be used for all BP measurements.
BP, respiratory rate, pulse rate, and body temperature (axillary) will be recorded at the 
timepoints specified in the SoA (see Appendix 1).
BP, respiratory rate, and pulse rate measurements will be performed in triplicate (can be 
as short as from 20-second to 1-minute intervals between measurements).  The mean of 
three consecutive replicates will be used as the value for the defined timepoint.
4.6.1.4
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck, and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  A genitourinary 
examination may be performed in the case of evocative symptoms at the investigator’s 
discretion.
Any abnormality identified at screening or at baseline should be recorded on the General 
Medical History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), abbreviated, symptom-directed physical 
examinations should be performed at the discretion of the investigator.  Changes from 
baseline abnormalities should be recorded in subject’s notes.  New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
Body weight will be recorded at screening and Day 1.  Height will only be recorded at 
screening.  BMI will be calculated at screening in accordance with the formula provided 
in Appendix 2.
4.6.1.5
Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor
before the study starts.  Laboratory safety tests shall be collected at timepoints specified 
in the SoA (Appendix 1).
Additional blood or urine samples may be taken at the discretion of the investigator if the 
results of any test fall outside the reference ranges, or if clinical symptoms necessitate 
additional testing to monitor subject’s safety.  Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
admission to confirm eligibility.  If there is an alternative explanation for a positive urine 
or blood test for drugs of abuse, e.g., previous occasional intake of a medication or food 


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containing for example codeine, benzodiazepines or opiates, the test could be repeated 
to confirm washout.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.  Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory, if 
applicable.
Samples for the following blood and urine laboratory tests will be collected and sent to 
the local laboratory for analysis at timepoints indicated in the SoA (Appendix 1):

Hematology: hemoglobin, hematocrit, total WBC count, differential WBC count 
(basophils, eosinophils, lymphocytes, monocytes and neutrophils), platelet count, 
RBC, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and 
mean corpuscular hemoglobin concentration (MCHC).

Blood Chemistry: albumin/globulin (A/G) ratio, AST, ALT, LDH, total and indirect 
bilirubin, alkaline phosphatase (ALP), gamma glutamyl transpeptidase (-GTP), CK, 
BUN, total protein, serum albumin, serum creatinine, uric acid, total cholesterol, 
triglycerides, fasting glucose, sodium, chloride, potassium, high-sensitivity
C-reactive protein (CRP).

Screening Coagulation Test: Protein C activity , Protein S activity, antithrombin III 
activity, factor VIII activity, factor IX activity, factor X activity, lupus anti-coagulant 
(T1/T2 ratio).

Coagulation test 1: Prothrombin time (PT), PT/International Normalized Ratio (INR), 
aPTT, fibrinogen, D- dimer. Starting on Day 1 onward, blood samples will be drawn 
to conduct biomarker assays at the central laboratory (
 in the United 
States). The same assays will be also conducted locally at screening, and on Day 
1, Day 2, Day 11, Day 29, Day 57, and Day 113.

Coagulation test 2: Prothrombin fragments 12, FVIII activity. The samples will be
run centrally on frozen plasma (
).

Coagulation test 3: FVIII inhibitors. The samples will be run centrally on frozen 
plasma (
).

Urinalysis: A mid-stream, clean catch urine specimen will be collected for dipstick 
analysis of protein, blood, glucose, leukocytes, specific gravity and pH.  If there is a 
clinically significant positive result (i.e., confirmed by a positive repeated sample), 
urine will be sent to the laboratory for microscopy and culture.  If there is an 
explanation for the positive dipstick result, it should be recorded, and there is no 
need to perform microscopy.  Urine color may be evaluated from urinalysis if 
considered necessary.

Viral serology: hepatitis B surface antigen (HBsAg), HCV RNA or HCV antibodies, 
and human immunodeficiency virus (HIV antibody).


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
Immunology: non-specific immunoglobulin E (IgE) antibodies and anti-cardiolipin-
beta-2 GPI complex antibody levels.

Drugs of abuse (urine): cannabinoids, amphetamines, methamphetamines, opiates,
methadone, cocaine, benzodiazepines, and barbiturates.

Alcohol: alcohol breath test.

Tuberculosis: T-SPOT.TB test
4.6.1.6
Pharmacokinetic Samples
Blood samples for the determination of plasma concentrations of emicizumab will be
collected as specified in the SoA (see Appendix 1) and will be sent to the Sponsor or a 
designee for centralized analysis.
The actual date and time of each blood sample collection will be recorded on the PK 
Sampling Information eCRF. 
Emicizumab plasma concentrations will be measured by a specific and validated
enzyme-linked immunosorbent assay method.  For blood draws, when the PK
assessment is scheduled for the same nominal time as another scheduled assessment,
the PK sample will take precedence.
Details on sampling procedures, sample storage, and shipment are given in the Sample
Handling Manual.
PK parameters will be estimated using standard non-compartmental methods for 
emicizumab:

Primary PK parameters: Cmax and AUC0-of emicizumab

Secondary PK parameters: AUC0-last, tmax, t1/2, CL/F, Vz/F, and MRT of emicizumab
4.6.1.7
Additional Coagulation Samples
Blood samples for determination of additional coagulation parameters will be collected 
as specified in the SoA (see Appendix 1) and will be sent to the Sponsor or a designee 
for centralized analysis.  Please consult the laboratory manual for details on sample 
collection and processing.
The actual date and time of each blood sample collection will be recorded on the 
Coagulation Sampling Information eCRF. 
4.6.1.8
Anti-Emicizumab Antibody Samples
Blood samples will be collected as indicated in the SoA (Appendix 1) for the detection of 
anti-emicizumab antibodies, and the samples will be run centrally on frozen plasma
(
 in the Netherlands).


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4.6.1.9
Total Blood Loss
A total of approximately 300 mL of blood over the 113 days (for comparison, a standard 
blood donation is 200400 mL collected at one blood draw) will be drawn from each 
subject participating.
Blood samples will be used to perform pharmacokinetics, to assess anti-emicizumab 
antibodies, and to assess clinical laboratory measurements listed above.
4.6.2
Timing of Study Assessments
4.6.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations.  Informed Consent Forms 
for enrolled subject and for subjects who are not subsequently enrolled will be 
maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that subjects meet all eligibility criteria.  The investigator will maintain a 
screening log to record details of all subjects screened and to confirm eligibility or record 
reasons for screening failure.
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator and kept at the investigational site.
A screening examination should be performed from Day 28 to Day 2 for healthy 
subjects.  Subjects must fulfill all entry criteria to be accepted into the study.  
Assessments as detailed in the SoA (Appendix 1) will be conducted.
4.6.2.2
Assessments during Treatment
All assessments must be performed as per SoA (see Appendix 1). 
Under no circumstances will subjects who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new subject number and re-enroll 
in the study.
4.6.2.3
Assessments at Study Completion/Early Termination Visit
Subjects who complete the study or discontinue from the study early will be asked to 
return to the clinic 1133 days after the dosing of study drug for a follow-up visit unless 
the subject withdraws his consent.
4.7
SUBJECT, STUDY, AND SITE DISCONTINUATION
4.7.1
Subject Discontinuation
The investigator has the right to withdraw a subject from the study at any time.  In 
addition, subjects have the right to voluntarily withdraw from the study at any time for 


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any reason.  Reasons for withdrawal from the study may include, but are not limited to, 
the following:

Subject withdrawal of consent at any time

The subject develops a treatment-related serious adverse event.

Any medical condition that the investigator or Sponsor determines may jeopardize 
the subject’s safety if he continues in the study

Investigator or Sponsor determines it is in the best interest of the subject

Subject non-compliance
Subjects who withdraw from the study for non-safety reasons may be replaced.  
Subjects who withdraw from the study due to poor tolerability to study drug will not be 
replaced.  Early termination blood samples for emicizumab PK and safety laboratory 
assessment will be collected at the time of discontinuation. 
4.7.1.1
Withdrawal from Study
Every effort should be made to obtain information on subjects who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, subjects will not be followed for any reason after consent 
has been withdrawn.
When a subject voluntarily withdraws from the study, or is withdrawn by the investigator, 
samples collected until the date of withdrawal will be analyzed, unless subject
specifically requests for these to be discarded or local laws require their immediate 
destruction.
4.7.2
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 subjects.

Subject enrollment is unsatisfactory.
The Sponsor will notify the investigator, Ethics Committee (EC) and Health Authorities if 
the study is placed on hold, or if the Sponsor decides to discontinue the study or 
development program.
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording


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
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice (GCP)
5.
ASSESSMENT OF SAFETY
Emicizumab is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with emicizumab in completed and 
ongoing studies.  The anticipated important safety risks for emicizumab are outlined 
below.  Please refer to the Emicizumab IB for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
5.1
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and 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.
5.1.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition)

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


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
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.1.2
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 
subject 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 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the subject’s ability to conduct normal life 
functions)

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to the WHO 
toxicity grading scale; [see Section 5.3.3]); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.1.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
Non-serious 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 an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.7

Microangiopathic hemolytic anemia or thrombotic microangiopathy (e.g., thrombotic 
thrombocytopenic purpura, hemolytic uremic syndrome)


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
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 subject exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
(see Appendix 3 and Appendix 4) 

Thromboembolic events
5.2
SAFETY PLAN
Emicizumab is currently in clinical development and is not approved.  Thus, the 
complete safety profile is not known at this time.  The safety plan for this study is 
designed to ensure subject safety and will include specific eligibility criteria and 
monitoring assessments as detailed below.  Please refer to the Emicizumab IB for a 
complete summary of safety information.
5.2.1
Risks Associated with Emicizumab
5.2.1.1
Injection-Site Reactions
In the completed and ongoing Japanese studies, injection-site reactions have been
observed in some patients with hemophilia A.  These local injection-site reactions
included injection-site erythema, injection-site hematoma, injection-site rash,
injection-site discomfort, injection-site pain, and injection-site pruritus.  All local
injection-site reactions were of mild intensity.  Further details of the observed
injection-site reactions are available in the IB.
Directions for emicizumab administration should be followed as outlined in Section 4.4.2.
5.2.1.2
Hypersensitivity Reaction, Anaphylaxis, Anaphylactoid
Reaction
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions,
including anaphylaxis and anaphylactic reactions, may occur.  In completed and ongoing
clinical studies of emicizumab, no severe hypersensitivity reactions have been reported.  
These events should be reported as serious adverse events or adverse events of special
interest as described in Sections 5.1.1 and 5.1.3, respectively.
Healthcare providers (HCPs) administering the study medication in the clinic must be 
trained in the appropriate administration procedures, be able to recognize the signs and 
symptoms associated with potential hypersensitivity, anaphylactic, and anaphylactoid 
reactions, and should be familiar with Sampson’s criteria for defining anaphylaxis 
(Sampson et al. 2006; see Appendix 3 and Appendix 4).
Subjects will be observed for a minimum of 60 minutes after the administration.


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5.2.1.3
Hypercoagulation and Thromboembolic Events
As of April 2017, thromboembolic events had been reported in 2 patients with 
hemophilia A with inhibitors while receiving emicizumab in Study BH29884.  
 
 
 
  
 
 
 
These events should be reported as Serious Adverse Events or Adverse Events of
Special Interest as described in Section 5.1.2 and Section 5.1.3, respectively.
5.2.1.4
Thrombotic Microangiopathy
Thrombotic microangiopathy is used to describe a group of disorders with clinical 
features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage 
that can include the kidneys, gastrointestinal system, or central nervous system, etc.  
As of April 2017, 3 cases of thrombotic microangiopathy had been observed in 
Study BH29884 involving patients with hemophilia A with inhibitors while receiving 
emicizumab.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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For more details, please refer to Emicizumab IB.
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 5.1.2 and Section 5.1.3).
5.2.1.5
Life-Threatening Bleeding because of Unreliable Standard 
Coagulation Tests and Inhibitor Assays in the Setting of 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII activity, 
and FVIII inhibitor measurement by the Bethesda assay) are not reliable and do not 
accurately reflect the patient’s underlying hemostatic status while receiving emicizumab
prophylaxis (see Section 5.2.1.4). Because of the long half-life of emicizumab, these
effects on coagulation assays may persist for up to 6 months after the last dose.
There is a risk of life-threatening bleeding due to unreliable standard coagulation tests
and inhibitor assays in the setting of emicizumab in the market setting by practitioners,
particularly for emergency care practitioners.
Emicizumab mechanism of action and resulting interference was clearly demonstrated in 
a wide variety of coagulation laboratory tests approved for in vitro diagnostic use.
Clinical trials also demonstrated the effects of emicizumab on laboratory tests. However, 
as of April 2017, 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.


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5.2.2
Management of Specific Adverse Events
Table 1
Guidelines for Managing Specific Adverse Events
Event
Actions to Be Taken
Injection-Site Reaction

Injection-site reactions should be treated as clinically indicated.

Emicizumab should not be injected into areas where the skin is 
red, bruised, tender, or hard or into areas where there are 
moles or scars.  

In the clinic setting, subjects will be monitored for signs of 
injection-site reactions in the period immediately following 
injections. 
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 subject has symptoms of anaphylaxis or severe 
hypersensitivity, administration of study drug must be 
immediately stopped and treatment of the reaction be initiated. 

Investigators may order any pertinent laboratory tests, including 
an unscheduled anti-drug antibody in the event any of these 
reactions occur.

In the clinic setting, subjects will be monitored for signs of 
hypersensitivity reaction, anaphylaxis, anaphylactoid reaction
for 60 minutes following injections.
Hypercoagulation and 
Thromboembolic Events

HCPs should be vigilant for subjects who exhibit 
signs/symptoms consistent with thromboembolic events and 
immediately begin work-up and treatment, as per local 
guidelines.  
Thrombotic 
microangiopathy

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.  
Coagulation Disorder and 
Risk of Bleeding

HCPs should be vigilant for abnormal or unusual bleeding 
tendencies.  Coagulation tests or other work-up may be 
indicated if judged to be appropriate by the investigator.  If 
bleeding is observed, appropriate action as per local guidelines 
must be taken immediately.
HCPhealthcare provider.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.1.1 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 5.1.2 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 subject contact.  All 
adverse events, whether reported by the subject or noted by study personnel, will be 
recorded in the subject’s medical record.  Adverse events will then be reported on the 
Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies).  Any 
other adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the subject completes his 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.  Instructions for reporting adverse events that occur after the 
adverse event reporting period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all subject evaluation timepoints.  Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 3) will be used for assessing adverse
event severity (WHO 2003).  Table 2 provides guidance for assessing adverse event 
severity.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically
Listed in WHO Toxicity Grading Scale
Severity
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
Note: 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 5.1.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, discontinuation of study drug, or reintroduction of study drug 
(where 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 subject or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection-Site Reactions
Local adverse events that occur within 24 hours after study drug administration and are
judged to be related to study drug injection should be captured as an “injection-site 
reaction” on the Adverse Event eCRF.  Associated signs and symptoms (e.g.,


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injection-site erythema or injection-site rash) should be recorded on the dedicated
Injection-Site Reaction eCRF.  If a subject 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 with signs and symptoms also recorded 
separately on the dedicated Injection Reaction eCRF.  Only for local injection-site 
reactions should the dedicated Injection-Site Reaction eCRF be used to capture the 
individual signs/symptoms.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, other than injection-site reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF.  If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 subsequent fracture, all three 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 
subject evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 


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worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
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 subject evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately 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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification or treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
ALP and bilirubin 5 times the upper limit of normal (ULN) associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) 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 if 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


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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 or treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

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 BP), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event of special interest the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 2
ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice 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) 
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 a non-serious adverse event of special 
interest (see Section 5.1.2 and 5.1.3).
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). 


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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").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
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
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.1.2), 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

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 subject has not suffered an adverse event
An event that leads to hospitalization under the following circumstances is not
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available


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5.3.5.11
Overdoses
An overdose is the accidental or intentional use of the drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study drug is not an 
adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
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, 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).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest
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/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D.
Telephone No.:
Mobile Telephone No.:


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To ensure the safety of study subjects, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible contact information, will be distributed to all 
investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3), investigators should record all case details that can be 
gathered on the Serious Adverse Reporting Form and forward this form to the Serious 
Adverse Event Responsible within 24 hours.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Partners of Male Subjects
Although embryo-fetal development studies are not available, condom use will not be
required in male subjects 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 a single SC dose of 1 mg/kg) 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 subjects treated with 
emicizumab, so contraception use by male subjects is not required for participation in 
the study.  Therefore, no proactive collection of pregnancy information for female 
partners of male subjects treated with emicizumab will be required.
5.5
FOLLOW-UP OF HEALTHY SUBJECTS 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 subject
is lost to follow-up, or the subject withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the subject’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.


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5.5.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
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
16 weeks after the last subject dosing of study drug), if the event is believed to be 
related to prior study drug treatment.  These events should be reported through use of 
the Adverse Event eCRF.  However, if the electronic data capture (EDC) system is not 
available, the investigator should report these events directly to the Sponsor or its 
designee, either by faxing or by scanning and e-mailing the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of the fax number or e-
mail address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Emicizumab (RO5534262) IB
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary objective of this study is to characterize the pharmacokinetic profile of
emicizumab in healthy Chinese subjects following single SC administration of 
emicizumab.  Statistical summaries will be descriptive in nature.  All subjects who 
receive any amount of study medication and with at least one post-baseline safety 
assessment will be included in the safety analysis.


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6.1
DETERMINATION OF SAMPLE SIZE
The number of subjects (12 evaluable subjects) is chosen based on practical clinical 
judgment (AUC and Cmax variability of emicizumab in Caucasian and Japanese healthy 
subjects) and China regulatory requirement.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of subjects who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Protocol deviations will be listed and evaluated for their potential impact on interpretation 
of study results.  Study drug administration will be summarized.
6.3
ANALYSIS POPULATIONS
6.3.1
Pharmacokinetic Analysis Population
Subjects will be excluded from the PK analysis population if they deviate significantly 
from the protocol or if data are unavailable or incomplete which may influence the PK
analysis.  Excluded cases will be documented together with the reason for exclusion.  All 
decisions on exclusions from the analysis will be made prior to database closure.
6.3.2
Safety Analysis Population
All subjects who have received any amount of study medication, whether prematurely 
withdrawn from the study or not, and with at least one post-baseline safety assessment, 
will be included in the safety analysis.
6.3.3
Immunogenicity Analysis Population
The immunogenicity analyses will include subjects with at least one predose and one 
postdose ADA assessment.
6.4
SUMMARIES OF TREATMENT GROUP
Demographic and baseline characteristics (including age, sex, etc.) will be summarized
using means, SDs ranges for continuous variables and proportions for categorical 
variables, as appropriate.
6.5
PHARMACOKINETIC ANALYSES
Individual plasma concentrations at each sampling timepoint for emicizumab will be 
presented by listings and appropriate descriptive summary statistics, including arithmetic
means, geometric means, medians, minimums-maximums, SDs, and coefficients of 
variation.  Individual and mean plasma concentration versus time data will be plotted on 
semi-logarithmic scales.
All PK parameters will be presented by individual listings and summary statistics
including arithmetic means, geometric means, medians, minimums-maximums, SDs and 
coefficients of variation.


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The primary emicizumab PK study parameters will be the Cmax and the AUC (AUC0-if it 
can be derived, otherwise truncated as appropriate).  All other PK parameters will be 
regarded as secondary. 
Non-compartmental analysis will be employed for estimation of the following PK 
parameters: 

tmax: Time to maximum observed plasma concentration

Cmax: Maximum observed plasma concentration 

AUC0-: Area under the plasma concentration-time curve between time zero 
extrapolated to infinity

AUC0-last: Area under the plasma concentration-time curve between time zero and 
the time of the last quantifiable concentration

t1/2: Apparent terminal half-life, computed as (ln2/z)

CL/F: Apparent clearance

Vz/F:  Apparent volume of distribution

MRT: Mean residence time
6.6
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.
6.6.1
Adverse Events
The original terms recorded on the eCRF by the investigator for adverse events will be 
standardized by the sponsor.
Adverse events will be summarized by mapped term and appropriate thesaurus level.
6.6.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported.  Subjects listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités).  Laboratory data not reported in SI units will be converted to SI units before 
processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
The proportion of subjects with laboratory abnormalities will be summarized.  
Additionally, the value and change from baseline for each laboratory test will be 
summarized by visit using descriptive statistics.


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6.6.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the investigator, 
will be used for all parameters.  For most parameters, the measured laboratory test 
result will be assessed directly using the Roche standard reference range.  Certain 
laboratory parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of investigator ranges, e.g., enzyme tests 
that include AST, ALT, alkaline phosphatase, and total bilirubin.  Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
6.6.2.2
Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range.  Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in subject listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter.  The marked reference range is 
broader than the standard reference range.  Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant).  If a baseline value is not 
available for a subject, the midpoint of the standard reference range will be used as the 
subject’s baseline value for the purposes of determining marked laboratory abnormalities.  
Marked laboratory abnormalities will be labeled in the subject listings as “HH” for very 
high or “LL” for very low.
6.6.3
Vital Signs
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities.  In addition, tabular summaries will 
be used, as appropriate.
6.6.4
ECG Data Analysis
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities.  In addition, tabular summaries will 
be used, as appropriate.
6.6.5
Concomitant Medications
The original terms recorded on the subjects’ eCRF by the investigator for concomitant 
medications will be standardized by the sponsor by assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.


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6.7
IMMUNOGENICITY ANALYSES
The numbers and proportions of ADA-positive subjects and ADA-negative subjects will 
be summarized.  Subjects are considered to be ADA positive if they are ADA negative at 
baseline but develop an ADA response following study drug administration (treatment-
induced ADA response), or if they are ADA positive at baseline and the titer of one or 
more post-baseline samples is at least 4-fold greater than the titer of the baseline 
sample (treatment-enhanced ADA response).  Subjects are considered to be ADA 
negative if they are ADA negative at baseline and all post-baseline samples are negative, 
or if they are ADA positive at baseline but do not have any post-baseline samples with a 
titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected).
The relationship between ADA status and safety and PK results will be analyzed and 
reported descriptively via subgroup analyses.
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.  Sites will be responsible for data entry into the EDC system.
A comprehensive validation check program will verify the data.  Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the investigator.
The Sponsor will produce a Data Handling Manual that describes the quality checking to 
be performed on the data.  Laboratory electronic data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line EDC system.  The data collected in the 
source documents will be entered onto the study eCRF.  An audit trail will maintain a 
record of initial entries and changes made, reasons for change, time and date of entry,
and user name of person authorizing entry or change.  For each subject enrolled, an 
eCRF must be completed and electronically signed by the principal investigator or 
authorized delegate from the study staff.  If a subject withdraws from the study, the 
reason must be noted on the eCRF.  If a subject is withdrawn from the study because of 
a treatment‑related adverse event, thorough efforts should be made to clearly document 
the outcome.


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The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor or contract research organization (CRO) on the eCRFs and in 
all required reports.
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO.
At the end of the study, the investigator will receive subject 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
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 subject data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X‑rays, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
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 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor with direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
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 


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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.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-reported outcome data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for at least 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.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. Food and Drug Administration (FDA) regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's 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.
The Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his participation in the study.  The case history or 
clinical records for each subject shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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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 
subject to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Subjects 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 subject 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 subject or the subject’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the subject, 
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 subject 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 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety‑related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number.  This means that 
subject names are not included in data sets that are transmitted to any Sponsor location.
Subject 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 


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authorization for use and disclosure of personal health information) signed by the subject, 
unless permitted or required by law.
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the 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., last subject, last 
visit).
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 subject data, which includes an audit trail containing a complete record of all 
changes to data.
Roche shall also submit an Development Safety Update Report once a year to the IEC 
and competent authorities according to local regulatory requirements and timelines of 
each country participating in the study.
9.2
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ 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.
9.3
ADMINISTRATIVE STRUCTURE
The Sponsor of the trial is F. Hoffmann-La Roche Ltd.  The Sponsor is responsible for 
the study management, data management, statistical analysis, and medical writing for 
the clinical study report. 


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The Sponsor is also responsible for managing CROs used in the study.
9.4
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
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.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.5
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to subjects or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
Adynovate® (antihemophilic factor) U.S. Package Insert, Baxalta US Inc. 2015.
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.
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.
Franchini M and Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:17984.
Gringeri A, Lambert T, Street A, et al. Tertiary prophylaxis in adults: is there a rationale? 
Haemophilia 2012;18(5):7228.
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult 
patients with severe haemophilia: a beneficial effect on orthopaedic outcome and 
quality of life. Eur J Haematol 2012;88(4):32935.
Kovaltry® (antihemophilic factor) U.S. Package Insert, Bayer HealthCare LLC. 2016.
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.
Mannucci PM and Tuddenham EG. The hemophiliasfrom royal genes to gene therapy. 
N Engl J Med 2001;344:17739.
Plug I and Mauser-Bunschoten EP, Brocker-Vriends AH, et al. Bleeding in carriers of 
hemophilia. Blood 2006;108:526.
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. 
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Am Soc 
Hematol Educ Program 2013;2013:3743. 
Wang XF, Zhao YQ, Yang RC, et al. The prevalence of factorVIII inhibitors and genetic 
aspects of inhibitor developmentin Chinese patients with haemophilia A.
Haemophilia 2010;16:632-9.
World Health Organization. Adherence to Long-Term Therapies: Evidence for Action.
Geneva: World Health Organization; 2003.


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World Federation of Hemophilia. Annual Global Survey Data 2013 [resource on the 
Internet]. 2013 [cited 2015 April 22]. Available from.from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx.


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Appendix 1
Schedule of Assessments
Screen
Treatment Period
Week


0
1
2
3
4
5
6
7
8
10
12
16
Scheduled Time (Days)
(28 to 
2)
1
1
2
4
6
8
11
15
22
29
36
43
50
57
71
85
113a
Informed consent
x
Inclusion/exclusion criteria
x
x
Demography
x
Medical history
x
Physical examination b
x
x
x c
x d
x d
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs e
x
x
x c
x d
x d
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG-12 lead f
x
x
x c
x d
x d
x
x
x
x
x
x
x
x
x
Hematology g
x
x
x d
x d
x
x
x
x
x
x
x
x
Clinical chemistry h
x
x
x d
x d
x
x
x
x
x
x
x
x
Urinalysis i
x
x
x d
x
x
x
x
x
Serology j
x
Immunology k
x
Tuberculosis T-SPOT.TB test
x
Screening coagulation test l
x
Substance use testing m
x
x
Admission
x
Discharge
x
Ambulatory visit n
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
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Screen
Treatment Period
Week


0
1
2
3
4
5
6
7
8
10
12
16
Scheduled Time (Days)
(28 to 
2)
1
1
2
4
6
8
11
15
22
29
36
43
50
57
71
85
113a
Coagulation test 1 o
x
x
x c
x d, o
x d
x
x o
x
x o
x
x o
x
x
x o
Coagulation test 2 p
x c
x d
x d
x
x
x
x
x
x
x
x
x
Coagulation test 3 q
x c
x
PK blood Sampling (EDTA plasma)
x c
x d
x d
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-emicizumab antibodies (EDTA 
Plasma)
x c
x
x
Administration of study medication r
x
Injection-site reaction
x
Adverse events
x
Previous and concomitant 
treatments
x
Abantibody; ALPalkaline phosphatase; A/G albumin/globulin ratio; BMIbody mass index; BPblood pressure; CKcreatine kinase; 
CRPC-reactive protein; eCRF electronic case report form; GPIglycoprotein I; HBsAghepatitis B surface antigen; HCVhepatitis C virus; 
HIV-1human immunodeficiency virus 1; HIV-2human immunodeficiency virus 2; IgEimmunoglobulin E; INRInternational normalized ratio; 
LDHlactate dehydrogenase; MCHmean corpuscular hemoglobin; MCHCmean corpuscular hemoglobin concentration; MCVmean 
corpuscular volume; PKpharmacokinetic; PT prothrombin time; -GTPgamma glutamyl transpeptidase.
a In the event of early termination, all assessments indicated for Day 113 will be conducted.
b Body weight will only be recorded at screening and on Day 1.  Height will only be recorded at screening.  BMI will be calculated at screening in 
accordance with the formula provided in Appendix 2.  At subsequent visits (or as clinically indicated), abbreviated, symptom-directed physical 
examinations should be performed at the discretion of the investigator.
c Activity will be conducted or samples will be collected before study drug administration.


Appendix 1
Schedule of Assessments (cont.)
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d Time matching dosing on Day 1.
e Vital signs will include measurements of temperature (axillary), respiratory rate, pulse rate, and systolic and diastolic BP while the subject is in a
supine position after the subject has been resting for at least 5 minutes at each visit (10 minutes for the screening visit).  Vital signs should be 
measured prior to blood sampling.  When possible, the same arm should be used for all BP measurements.  BP, respiratory rate, and pulse rate 
measurements will be performed in triplicate (can be as short as ranging from 20-second to 1-minute intervals between measurements).  The 
mean of three consecutive replicates will be used as the value for the defined timepoint.
f
ECGs will be collected after the subject has been in a supine position for at least 10 minutes.  At the specified timepoints, 12-lead ECGs will be 
obtained in triplicate (i.e., three consecutive interpretable 12-lead ECGs within 5 minutes and recorded on the eCRF).  Triplicate recordings 
should be taken for any unscheduled ECG.
g Hematology will include analysis of the following:  hemoglobin, hematocrit, total WBC count, differential WBC count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, RBC, MCV, MCH, and MCHC.
h Blood chemistry will include analysis of the following:  A/G ratio, AST, ALT, LDH,  total and indirect bilirubin, ALP, -GTP, CK, BUN, total protein, 
serum albumin, serum creatinine, uric acid, total cholesterol, triglycerides, fasting glucose, sodium, chloride, potassium, and high-sensitivity 
CRP.
i
A mid-stream, clean catch urine specimen will be collected for dipstick analysis of protein, blood, glucose, leukocytes, specific gravity, and pH.  If 
there is a clinically significant positive result (i.e., confirmed by a positive repeated sample), urine will be sent to the laboratory for microscopy 
and culture.  If there is an explanation for the positive dipstick result, it should be recorded, and there is no need to perform microscopy.  Urine 
color may be evaluated from urinalysis if considered necessary.
j
Viral serology will include analysis of the following:  HBsAg, HCV RNA or HCV Ab, and HIV antibody.
k Immunology will include analysis of the following:  non-specific IgE antibodies and anti-cardiolipin-beta-2 GPI complex antibody levels.
l Protein C activity, Protein S activity, antithrombin III activity, factor VIII activity, factor IX activity, factor X activity, lupus anticoagulant (T1/T2 ratio).  
These tests will be run locally.
m Substance use testing will include analysis of the following:  cannabinoids, amphetamines, methamphetamines, opiates, methadone, cocaine, 
benzodiazepines, and barbiturates in urine; and alcohol levels by an alcohol breath test.
n Permissible time windows for Days 6 and 8 is 2 hr of the time matching dosing on Day 1; for Days 11, 15, 22, and 29 is 1 day; for Days 36, 43, 
50, and 57 is 2 days, and for Days 71, 85, and 113 is 3 days.
o Coagulation test 1 is aPTT, PT, PT/INR, fibrinogen, and D-dimer. Starting on Day 1 onward, blood samples will be drawn to conduct biomarker 
assays at the central laboratory (
 in the United States). The same assays will be also conducted locally at screening, Day 1, Day 2, 
Day 11, Day 29, Day 57, and Day 113.
p Coagulation test 2 is Prothrombin fragments 12 and FVIII activity. The samples are run centrally on frozen plasma (
).
q Coagulation test 3 is FVIII inhibitors. The samples are run centrally on frozen plasma (
).
r
The study medication will be administered after fasting from midnight for at least 8 hours. A standard lunch will be provided 4 hours after dosing.


Emicizumab—F. Hoffmann-La Roche Ltd
67/Protocol YP39308, Version 4
Appendix 2
Formula for Calculation of Body Mass Index
Formula for calculation of BMI
BMI (kg/m2)=
Weight (kg)
Height (m)2
Unit Conversion: 1 kg 
= 2.2 lb
1 inch = 2.54 cm
Example:
BMI of a subject being 1.70 m tall and weighing 80 kg:
80
= 27.7 kg/m2
(1.70)2
The subject’s standing height will be measured in bare feet standing with his heels and 
back in contact with the vertical bar of a wall mounted measuring device. The head is 
held so the subject looks straight forward. A level will be placed on the subject’s head to 
ensure that the subject is looking straight forward. The point at which the lower surface 
of the level intersects with the vertical measuring device will be the standing height.


Emicizumab—F. Hoffmann-La Roche Ltd
68/Protocol YP39308, Version 4
Appendix 3
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
7500099999/mm3
5000074999/mm3
2000049999/mm3
20000/mm3
Prothrombin time (PT)
1.011.25ULN
1.261.5ULN
1.513.0ULN
3ULN
Activated partial thromboplastin
(APPT)
1.011.66ULN
1.672.33ULN
2.343ULN
3ULN
Fibrinogen
0.750.99LLN
0.500.74LLN
0.25 - 0.49LLN
0.25 x LLN
Fibrin split product
2040 mcg/mL
4150 mcg/mL
5160 mcg/mL
60 mcg/mL
Methemoglobin
5%9.9%
10.0%14.9%
15.0%19.9%
20%
LIVER ENZYMES
AST (SGOT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
ALT (SGPT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
GGT
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Alkaline phosphatase
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Amylase
1.11.5ULN
1.62.0ULN
2.15.0ULN
5.0ULN


Appendix 3
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
69/Protocol YP39308, Version 4
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 3
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
70/Protocol YP39308, Version 4
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 increase 20 mm;
no Rx required
recurrent, chronic, 20 mm,
Rx required
requires acute Rx; no
hospitalization required
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 required
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 3
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
71/Protocol YP39308, Version 4
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 3
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
72/Protocol YP39308, Version 4
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C 38.5C or
100.0F101.5F
38.6C39.5C or
101.6F102.9F
39.6C40.5C or
103F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 3
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
73/Protocol YP39308, Version 4
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
NOTE:  For coding purposes, the following toxicity grades may be used interchangeably: 1mild; 2moderate; 3severe; 4life threatening.


Emicizumab—F. Hoffmann-La Roche Ltd
74/Protocol YP39308, Version 4
Appendix 4
Clinical Criteria for Diagnosing Anaphylaxis
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network (Sampson et al. 2006).  
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 (BP) 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, itching/flushing, 
swollen lips/tongue/uvula)
Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)
Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence)
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
Infants and children: low systolic blood pressure (SBP, age specific) or greater 
than 30% decrease in SBP
Low SBP for children is defined as 70 mmHg from 1 month to 1 year, 
(70 mmHg[2age]) from 1 to 10 years, and 90 mmHg from 11 to 
17 years.
Adults: SBP of 90 mmHg or 30% decrease from that person’s baseline
REFERENCE
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.