Clinical trial NCT02847637
Conditions: Hemophilia A
Keywords: Hemophilia A Emicizumab
Sponsor: Hoffmann-La Roche
Start date: 2016-09-27; Completion date: 2022-05-12
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, global, multicenter, open-label, Phase 3 clinical study in participants with severe hemophilia A without inhibitors against Factor VIII (FVIII) who are 12 years or older. The study evaluates two prophylactic emicizumab regimens versus no prophylaxis in this population with emphasis on efficacy, safety, and pharmacokinetics.

Detailed description:

Arms: arm 1: Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. arm 2: Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. arm 3: Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study. arm 4: Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
Interventions: intervention 1: Emicizumab intervention 2: Factor VIII (FVIII)
Intervention descriptions: intervention 1: Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study. intervention 2: FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
F. Hoffmann-La Roche Ltd of Basel, Switzerland, and Chugai Pharmaceutical Co. Ltd.* of Tokyo, Japan, will 
act as co-sponsors of this global study. However, it may be implemented in individual countries by Roche’s 
local affiliates, including Genentech, Inc. in the United States, or Chugai Pharmaceutical Co. Ltd.* in South 
Korea, Taiwan, and Japan. The information contained in this document, especially any unpublished data, is 
the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence 
as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics 
Committee or Institutional Review Board. It is understood that this information will not be disclosed to others 
without written authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered.
*Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan. The specific details of the 
legal/regulatory entity within the relevant country are provided within the clinical trial agreement with the 
Investigator/Institution and the Clinical Trial Application with the Competent Authority.
RO5534262—F. Hoffmann-La Roche Ltd
Protocol BH30071, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III CLINICAL TRIAL TO EVALUATE THE
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF PROPHYLACTIC EMICIZUMAB VERSUS NO 
PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
WITHOUT INHIBITORS
PROTOCOL NUMBER:
BH30071
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000072-17
IND NUMBER:
122,954
NCT NUMBER:
NCT02847637
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd and 
Chugai Pharmaceutical Co. Ltd.*
DATE FINAL:
3 February 2016
DATE(S) AMENDED:
Version 2:  12 September 2016
Version 3:  30 November 2016
Version 4:  See electronic date stamp below.
 
20-Dec-2019 00:58:30
Title
Approver's Name
Date and Time (UTC)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
2/Protocol BH30071, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol BH30071 has been amended primarily to extend study duration to enable 
collection of long-term safety and efficacy data; patients will be able to continue in the 
study until 5 years after the last patient is enrolled.  Changes to the protocol, along with 
a rationale for each change, are summarized below:

The duration of the study has been extended to enable the collection of additional 
safety and efficacy data, including data on adverse events and anti-drug antibody 
development.  Thromboembolic events and thrombotic microangiopathy, both 
protocol-defined adverse events of special interest, have been reported when an 
average cumulative dose of 100 units/kg/24 hours of activated prothrombin 
complex concentrate (aPCC) was co-administered with emicizumab.  Continued 
collection of data related to concomitant hemophilia medications, emicizumab 
administration, and bleeds will contribute to a better understanding of these adverse 
events of special interest should they occur.  The total length of the study, from 
screening of the first patient to the end of study, has been extended from 2 years to 
6 years accordingly (Sections 3.1 and 3.2).

The opportunity to switch to a preferred dosing regimen (1.5 mg/kg weekly, 3 mg/kg
every 2 weeks, or 6 mg/ kg every 4 weeks) during study prolongation has been 
added to provide the same flexibility in choosing preferred dosing regimen as with 
commercial drug (Sections 3.1 and 4.3.2).
Additional changes made to the protocol are as follows:

The Background and Safety sections have been updated, including information 
regarding a fourth case of thromboembolic event observed in the Phase IIIb study 
MO39129 of prophylactic emicizumab in patients with congenital hemophilia A who 
have inhibitors; and a third case of thrombotic microangiopathy observed in the 
Phase III study BH29884 of prophylactic emicizumab in patients with hemophilia A 
who have inhibitors (Sections 1.2.2, 1.3, 5.1.2.3, and 5.1.2.4). 

Testing of factor IX antigen and factor X antigen after Week 24 will no longer be 
performed, as no emicizumab-induced changes in these biomarkers have been 
observed across the emicizumab program (Sections 3.1 and 3.3.6; Appendix 2).  A 
footnote has been added to Appendix 2 to indicate that factor XIII (FXIII) activity 
testing was conducted only at Week 1 due to emicizumab interference with the FXIII 
assay.

Language has been added to clarify that continued use of antiplatelet and 
anticoagulation treatment is allowed if deemed medically necessary (Section 4.4.2).

Language has been added to clarify that, after withdrawal of consent for participation 
in the RCR, remaining RCR samples will be destroyed or will no longer be linked to 
the patient.  However, if RCR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data
(Section 4.5.10.6).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
3/Protocol BH30071, Version 4

To align with other studies in the emicizumab program and the current Emicizumab 
Investigator’s Brochure, life- threatening bleeding due to unreliable standard 
coagulation tests and inhibitor assays has been added as an additional risk 
associated with emicizumab (Section 5.1.2.5).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

To align with other studies in the emicizumab program, additional clarification has
been added on adverse event reporting for patients who experience a worsening of 
hemophilia (Section 5.3.5.10).

Adverse event reporting for hospitalization has been clarified (Section 5.3.5.11).

A global change has been made to update the Medical Monitor and emergency 
contact information (Section 5.4.1).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable) (Section 7.6).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).

Language has been revised to clarify that data posting will include clinical trial 
registries and to clarify that redacted Clinical Study Reports and other summary 
reports will be made available upon request (Section 9.6).

Appendix 10 (Anaphylaxis Precautions) has been added for alignment with the 
Roche protocol template.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
4/Protocol BH30071, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 23
1.1
Background on Hemophilia A ................................................ 23
1.1.1
Management.......................................................................... 24
1.2
Background on Emicizumab.................................................. 25
1.2.1
Molecule and Preclinical Data ............................................... 25
1.2.2
Clinical Experience ................................................................ 27
1.3
Study Rationale and Benefit-Risk Assessment...................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
2.1
Efficacy Objectives ................................................................ 32
2.1.1
Primary Efficacy Objective..................................................... 32
2.1.2
Secondary Efficacy Objectives .............................................. 32
2.1.3
Exploratory Objectives........................................................... 33
2.2
Safety Objective .................................................................... 34
2.3
Pharmacokinetic Objective .................................................... 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of Study .............................................................. 34
3.2
End of Study and Length of Study......................................... 39
3.3
Rationale for Study Design.................................................... 40
3.3.1
Rationale for Emicizumab Dose and Schedule...................... 42
3.3.2
Rationale for Patient Population ............................................ 44
3.3.3
Rationale for Control Group................................................... 44
3.3.4
Rationale for the Primary Efficacy Analysis ........................... 45
3.3.5
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 46
3.3.6
Rationale for Biomarker Assessments................................... 47
3.3.7
Rationale for Activity Assessment ......................................... 47
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
5/Protocol BH30071, Version 4
4.
MATERIALS AND METHODS .................................................................... 48
4.1
Patients.................................................................................. 48
4.1.1
Inclusion Criteria.................................................................... 48
4.1.2
Exclusion Criteria................................................................... 50
4.2
Method of Treatment Assignment.......................................... 51
4.3
Study Treatment.................................................................... 51
4.3.1
Formulation, Packaging, and Handling.................................. 51
4.3.1.1
Emicizumab........................................................................... 51
4.3.2
Dosage, Dose Adjustment, and Administration ..................... 51
4.3.3
Investigational Medicinal Product Accountability ................... 54
4.3.4
Post-Study Access to Emicizumab........................................ 55
4.4
Concomitant and Rescue Therapy ........................................ 55
4.4.1
Permitted Therapy................................................................. 55
4.4.2
Prohibited Therapy ................................................................ 56
4.5
Study Assessments ............................................................... 57
4.5.1
Informed Consent Forms and Screening Log........................ 57
4.5.2
Medical History and Demographic Data ................................ 57
4.5.3
Physical Examinations........................................................... 57
4.5.4
Vital Signs.............................................................................. 58
4.5.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 58
4.5.6
Electrocardiograms................................................................ 59
4.5.7
Electronic Patient-Reported Outcomes.................................. 59
4.5.8
Definitions.............................................................................. 61
4.5.9
Activity Assessments............................................................. 62
4.5.10
Samples for Roche Clinical Repository.................................. 63
4.5.10.1
Overview of the Roche Clinical Repository............................ 63
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 64
4.5.10.3
Sample Collection.................................................................. 64
4.5.10.4
Confidentiality........................................................................ 64
4.5.10.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 65
4.5.10.6
Withdrawal from the Roche Clinical Repository..................... 65
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
6/Protocol BH30071, Version 4
4.5.10.7
Monitoring and Oversight....................................................... 66
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 66
4.6.1
Patient Discontinuation.......................................................... 66
4.6.2
Study Treatment Discontinuation........................................... 67
4.6.3
Study and Site Discontinuation.............................................. 67
5.
ASSESSMENT OF SAFETY....................................................................... 67
5.1
Safety Plan ............................................................................ 67
5.1.1
Patient Selection.................................................................... 68
5.1.2
Risks Associated with Emicizumab ....................................... 68
5.1.2.1
Injection-Site Reactions......................................................... 68
5.1.2.2
Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid Reaction......................................................... 68
5.1.2.3
Hypercoagulation and Thromboembolic Events .................... 69
5.1.2.4
Thrombotic Microangiopathy ................................................. 70
5.1.2.5
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
Associated with Emicizumab ................................................. 71
5.1.3
Management of Specific Adverse Events .............................. 72
5.1.4
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab .......................................................... 73
5.2
Safety Parameters and Definitions ........................................ 73
5.2.1
Adverse Events ..................................................................... 74
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 74
5.2.3
Adverse Events of Special Interest (Immediately
Reportable to the Sponsor).................................................... 75
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 76
5.3.1
Adverse Event Reporting Period ........................................... 76
5.3.2
Eliciting Adverse Event Information....................................... 76
5.3.3
Assessment of Severity of Adverse Events ........................... 76
5.3.4
Assessment of Causality of Adverse Events ......................... 77
5.3.5
Procedures for Recording Adverse Events............................ 77
5.3.5.1
Injection-Site Reactions......................................................... 78
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
7/Protocol BH30071, Version 4
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 78
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 78
5.3.5.4
Persistent or Recurrent Adverse Events................................ 79
5.3.5.5
Abnormal Laboratory Values ................................................. 79
5.3.5.6
Abnormal Vital Sign Values ................................................... 80
5.3.5.7
Abnormal Liver Function Tests.............................................. 80
5.3.5.8
Deaths ................................................................................... 81
5.3.5.9
Preexisting Medical Conditions.............................................. 81
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic 
Bleeds.................................................................................... 81
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 82
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 82
5.3.5.13
Patient-Reported Outcome Data ........................................... 83
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 83
5.4.1
Emergency Medical Contacts................................................ 84
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 84
5.4.2.1
Events That Occur prior to Randomization or 
Study Drug Initiation .............................................................. 84
5.4.2.2
Events That Occur after Randomization or Study 
Drug Initiation ........................................................................ 84
5.4.3
Reporting Requirements for Pregnancies.............................. 85
5.4.3.1
Pregnancies in Female Patients............................................ 85
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 85
5.4.3.3
Abortions ............................................................................... 85
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 86
5.5
Follow-Up of Patients after Adverse Events .......................... 86
5.5.1
Investigator Follow-Up........................................................... 86
5.5.2
Sponsor Follow-Up ................................................................ 86
5.6
Post-Study Adverse Events................................................... 86
5.7
Expedited Reporting to Health Authorities,
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 87
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
8/Protocol BH30071, Version 4
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 87
6.1
Determination of Sample Size ............................................... 87
6.2
General.................................................................................. 88
6.3
Summaries of Conduct of Study............................................ 89
6.4
Summaries of Treatment Group Comparability ..................... 89
6.5
Efficacy Analyses .................................................................. 89
6.5.1
Primary Efficacy Endpoint...................................................... 89
6.5.2
Secondary Efficacy Endpoints............................................... 90
6.6
Safety Analyses..................................................................... 92
6.7
Pharmacokinetic Analyses..................................................... 92
6.8
Exploratory Analyses............................................................. 92
6.9
Interim Analysis ..................................................................... 93
7.
DATA COLLECTION AND MANAGEMENT ............................................... 93
7.1
Data Quality Assurance......................................................... 93
7.2
Electronic Case Report Forms............................................... 94
7.3
Electronic Patient-Reported Outcome Data........................... 94
7.4
Source Data Documentation.................................................. 95
7.5
Use of Computerized Systems .............................................. 96
7.6
Retention of Records............................................................. 96
8.
ETHICAL CONSIDERATIONS.................................................................... 96
8.1
Compliance with Laws and Regulations ................................ 96
8.2
Informed Consent.................................................................. 96
8.3
Institutional Review Board or Ethics Committee.................... 98
8.4
Confidentiality........................................................................ 98
8.5
Financial Disclosure .............................................................. 99
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 99
9.1
Study Documentation ............................................................ 99
9.2
Protocol Deviations................................................................ 99
9.3
Site Inspections ................................................................... 100
9.4
Administrative Structure....................................................... 100
9.4.1
Independent Data Monitoring Committee and
Independent Data Coordinating Center ............................... 100
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
9/Protocol BH30071, Version 4
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 101
9.6
Protocol Amendments ......................................................... 102
10. REFERENCES ......................................................................................... 103
LIST OF TABLES
Table 1
Mean Reduction (%) of Annualized Bleeding Rates in 
Inhibitor and Non-Inhibitor Patients Enrolled in 
ACE001JP/ACE002JP................................................................ 42
Table 2
Guidelines for Monitoring and Management of Specific 
Adverse Events........................................................................... 72
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 77
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 36
Figure 2
Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event............................................................................ 43
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 110
Appendix 2
Schedule of Pharmacodynamic Assessments .......................... 118
Appendix 3
Haemo-QoL-SF (United States/English) ................................... 120
Appendix 4
Haem-A-QoL (United States/English) ....................................... 122
Appendix 5
EQ-5D-5L (United Kingdom/English) ........................................ 129
Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of
Adverse Events......................................................................... 131
Appendix 7
Clinical Criteria for Diagnosing Anaphylaxis.............................. 138
Appendix 8
Hemophilia Joint Health Score (HJHS) ..................................... 139
Appendix 9
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients on Emicizumab ........................................................... 141
Appendix 10 Anaphylaxis Precautions ...................................................... 143
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
10/Protocol BH30071, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III CLINICAL TRIAL TO EVALUATE THE
EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF PROPHYLACTIC EMICIZUMAB VERSUS NO 
PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
WITHOUT INHIBITORS
PROTOCOL NUMBER:
BH30071
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000072-17
IND NUMBER:
122,954
NCT NUMBER:
NCT02847637
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd and 
Chugai Pharmaceutical Co. Ltd.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
11/Protocol BH30071, Version 4
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF PROPHYLACTIC EMICIZUMAB 
VERSUS NO PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
WITHOUT INHIBITORS
PROTOCOL NUMBER:
BH30071
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000072-17
IND NUMBER:
122,954
NCT NUMBER:
NCT02847637
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase III
INDICATION:
Hemophilia A without inhibitors
SPONSOR:
F. Hoffmann-La Roche Ltd and Chugai Pharmaceutical Co. Ltd.
Objectives and Endpoints
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of prophylactic 
emicizumab (i.e., administered on a scheduled basis with the intent to prevent bleeds) 
compared with no prophylaxis in patients with hemophilia A without factor VIII (FVIII) inhibitors 
on the basis of the following endpoint:

The number of bleeds over time (i.e., bleed rate)
The endpoint will be analyzed separately for the two emicizumab arms:  1.5 mg/kg/week (wk) 
and 3 mg/kg/every 2 weeks (2wks).  The primary endpoint is based on treated bleeds.
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of prophylactic emicizumab (in each individual emicizumab arm) on 
the basis of the following endpoint:
Change in the number of bleeds over time compared with the patient’s historical bleed 
rate *

To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk or 
3 mg/kg/2wks subcutaneously compared with no prophylaxis for patients previously treated 
with episodic FVIII on the basis of the following endpoints:
All bleeds over time
Spontaneous bleeds over time (spontaneous bleed rate)
Joint bleeds over time 
Target joint bleeds over time (target joints are defined as joints with 3 bleeds 
occurring in the same joint over the last 24 weeks prior to study entry)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
12/Protocol BH30071, Version 4
HRQoL of patients according to Haem-A-QoL (aged 18) or Haemo-QoL-Short Form 
(aged 1217) scores after 24 weeks
Health status of patients according to EuroQoL Five-Dimension-Five Levels 
Questionnaire (EQ-5D-5L) scores after 24 weeks

To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk 
subcutaneously for patients previously treated with prophylactic FVIII on the basis of the 
following endpoint:
Maintaining adequate control of bleeding by evaluation of the bleed rate *
* Analyses will be performed for treated bleeds and all bleeds.
Exploratory Objectives
The exploratory objectives for this study are as follows:

To assess satisfaction regarding treatment with emicizumab prophylaxis versus FVIII 
prophylaxis according to the Satisfaction QuestionnaireIntravenous Subcutaneous 
Hemophilia Injection (SQ-ISHI) in patients previously treated with prophylactic FVIII

To assess treatment preference for emicizumab prophylaxis versus FVIII prophylaxis or 
episodic therapy according to the preference survey 

To assess changes in number of days away from school/work during treatment with 
prophylactic emicizumab compared with no prophylaxis

To assess changes in number of hospitalization days during treatment with prophylactic 
emicizumab compared with no prophylaxis 

To assess potential pharmacodynamic (PD) biomarkers of emicizumab, including but not 
limited to aPTT, thrombin generation, and FVIII activity 

To assess potential serum and plasma biomarkers of bone and joint health

To evaluate the effect of emicizumab prophylaxis treatment on activity compared with 
activity at baseline.  

To evaluate the effect of emicizumab prophylaxis treatment on activity compared with no 
prophylaxis 
Safety Objective
The safety objective for this study is to evaluate the overall safety of prophylactic emicizumab 
compared with no prophylaxis in patients with hemophilia A without inhibitors on the basis of the 
following endpoints:

Incidence and severity of adverse events

Incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs 

Incidence of laboratory abnormalities 

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to drug discontinuation 

Incidence of severe hypersensitivity, anaphylaxis, or anaphylactoid reactions

Incidence and severity of thrombotic microangiopathy

Incidence and clinical significance of anti-emicizumab antibodies

Incidence of de novo development of FVIII inhibitors in patients receiving emicizumab 
prophylaxis
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the exposure (trough 
plasma concentration) to emicizumab in patients treated on weekly or every 2 weeks dosing 
schedule at the following timepoints:

Every week during Weeks 14 on emicizumab
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
13/Protocol BH30071, Version 4

Every 2 weeks during Weeks 58 on emicizumab

Every 4 weeks during Weeks 924 on emicizumab

Every 8 weeks during Weeks 2548 on emicizumab

Every 12 weeks thereafter while on emicizumab, until the end of the study
Study Design
Description of Study
This randomized, multicenter, open-label, Phase III clinical study will enroll patients aged 
12 years or older with severe hemophilia A (intrinsic FVIII level 1%) without inhibitors against 
FVIII.  Eighty-five patients who received episodic treatment with FVIII prior to study entry and 
experience at least 5 bleeds over the prior 24 weeks (annual bleed rate [ABR] 10) will be 
randomized in a 2:2:1 ratio (see protocol) to the following regimens:

Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
1.5 mg/kg/wk subcutaneously (Arm A), 

Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
3 mg/kg/2wks subcutaneously (Arm B), or 

No prophylaxis control arm (Arm C). 
Randomization will be stratified according to the number of bleeds patients experienced over 
the last 24 weeks prior to study entry—less than versus greater than or equal to 9 (or ABR 
18)—to ensure a balance of patients with lower versus higher number of bleeds in all arms.  All 
patients will use episodic treatment with FVIII at the lowest expected dose to achieve 
hemostasis in case of a breakthrough bleeding event (see below).   
In addition, 4060 patients with severe hemophilia A who received FVIII prophylaxis prior to 
study entry will be enrolled and will receive emicizumab prophylaxis at 3 mg/kg/wk 
subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk subcutaneously (Arm D; see protocol).  
A minimum of 40 patients in this group will complete at least 24 weeks of observation in an 
ongoing non-interventional study (BH29768) prior to enrollment in this study.  Eligibility for all 
patients in Arm D will be based on investigator’s attestation of adequate prophylaxis regimen in 
the 24 weeks prior to study entry.
To avoid bleeds before adequate emicizumab plasma concentration is reached, these patients 
will continue their regular FVIII prophylaxis until the second emicizumab loading dose.  At the 
end of the first week of treatment, 95% of patients are expected to achieve emicizumab level of 
8 μg/mL, which is projected to have FVIII activity equivalent to approximately 2%.  Thrombotic 
events were not found in the Japanese Phase I/II study where doses of FVIII were administered 
to treat breakthrough bleeds while patients had higher emicizumab steady-state level, 
supporting the safety of this approach.  Importantly, routine prophylaxis will be prohibited for all 
patients enrolled in Arms A, B, or C and for patients in Arm D immediately after the second 
emicizumab dose.
Study enrollment will take place at the Week 1 visit.  A patient who fulfills the inclusion and 
exclusion criteria should be enrolled and assigned to a treatment arm at the Week 1 visit, the 
same day when the first dose of emicizumab is due for patients in Arms A, B, and D.
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have already 
occurred).  The primary efficacy analysis, defined as comparing the number of bleeds over time 
for patients randomized to receive prophylactic emicizumab versus no prophylaxis will be 
conducted at the earliest timepoint when all randomized patients (Arms A, B, or C) and a 
minimum of 40 patients from Arm D have either completed 24 weeks in the study or 
discontinued from the study.  Therefore, there will be a range of observation periods from 6 to 
approximately 12 months, or longer.  Study patients will be enrolled globally from the Americas, 
Europe, Africa, and Asia-Pacific region.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
14/Protocol BH30071, Version 4
To obtain additional safety and efficacy data on emicizumab, patients who are randomized to 
the no prophylaxis arm (control arm, Arm C) will be expected to switch after 24 weeks to receive 
emicizumab prophylaxis at 3 mg/kg/2wks maintenance dose after 4 weeks of 3 mg/kg/wk 
loading dose.  This dose was chosen to enhance the safety and efficacy data obtained with 
Arm B patients.
After completing at least 24 weeks of treatment with prophylactic emicizumab, patients who 
receive emicizumab prophylaxis (Arms A, B, D, or Arm C after treatment switch) and derive 
clinical benefit will be allowed to continue emicizumab until marketing authorization as part of 
this study or a separate extension study, as long as they continue to derive clinical benefit and 
emicizumab is still in clinical development (see protocol).  Those who are well controlled 
(ABR 4) will continue treatment on their assigned emicizumab regimen; whereas, patients in 
Arms A, B, or C (after 24 weeks on emicizumab) who experience suboptimal control (ABR 4) 
will be offered the option to escalate to 3 mg/kg/wk after approval from the Medical Monitor.  
Patients in Arm D who experience suboptimal control while on emicizumab prophylaxis at the 
maintenance dose, will have the opportunity to escalate to 3 mg/kg/wk immediately after the 
second qualifying bleed.  Criteria and details of dose escalation are described in the protocol.
A 6 mg/kg every 4 weeks (4wks) maintenance dosing regimen is being evaluated in Phase III 
studies BH29992 and BO39182 in addition to the 1.5 mg/kg/wk and 3 mg/kg/2wks 
maintenance dosing regimens evaluated in this study.  The observed exposures (i.e., average 
concentration at steady state) of multiple doses of these three dosing regimens are comparable 
and lead to similar efficacy and safety profiles.  Hence, 6 mg/kg/4wks will be offered as a 
permitted dosing regimen for patients who continue in this study during study prolongation. 
Upon implementation of protocol Version 4, treatment duration will be extended until 5 years 
after the last patient is enrolled to enable the collection of additional safety and efficacy data.  
During this study prolongation, each patient may choose a preferred emicizumab dosing 
regimen among those permitted (i.e., emicizumab 1.5 mg/kg/wk, 3 mg/kg/2wks, or 
6 mg/kg/4wks) and continue on that dosing regimen until discontinuation from the study.  
Instructions for switching the dosing regimen are outlined in the protocol.
During the study, individual bleeds will be captured as they occur, while HRQoL, health status, 
patient safety, patient preference and satisfaction, activity level, and days of school or work 
missed will be assessed as outlined in the schedule of assessments.  Patients (or their 
caregiver) will be asked to record on an electronic, handheld device their bleeds (i.e., start date 
and time, reason, type, location, and associated symptoms of each bleed) and 
hemophilia-related medication use (i.e., start date and time, reason, type, dose of injection, and 
number of doses) at least weekly, when a bleed occurs, or when a hemophilia medication was 
taken at home or in the clinic.
Throughout the study, biomarkers related to thromboembolism (e.g., D-dimer, prothrombin 
1.2 fragment) and emicizumab trough concentrations will be collected as per the schedule of 
assessments.  Immunologic biomarkers (i.e., anti-emicizumab antibodies and anti-FVIII 
antibodies) will also be measured as per the schedule of assessments (see protocol).
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation assay) will be 
collected as per the schedule of assessments.  As values for some of these tests are 
normalized by low plasma concentrations of emicizumab, a variety of assay formats (one stage, 
chromogenic) and modifications (predilution of patient plasma) will be investigated for 
assessment of PD response at higher emicizumab plasma concentrations.  However, it is not 
expected that these biomarkers will be used to guide dosing or the selection of patients to be 
treated with emicizumab.  Rather, these biomarkers may be used to identify a future assay for 
the monitoring of emicizumab activity. 
Physical examinations, including Hemophilia Joint Health Score (HJHS; see protocol), vital 
signs assessments, ECGs, and laboratory assessments will be collected as per the schedule of 
assessments and will be the same for all patients, with the exception that emicizumab PK and 
ADAs will not be measured in patients in Arm C prior to the switch to emicizumab treatment.  
Adverse events will be captured as they occur for the duration of the study.
All patients who receive emicizumab in the study will undergo PK assessments.  A washout 
period from FVIII therapy is not required prior to inclusion because FVIII replacement does not 
interfere with emicizumab PK assessments, and some patients with hemophilia A require 
frequent dosing with FVIII to treat bleeds or for prophylaxis.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
15/Protocol BH30071, Version 4
An independent Data Monitoring Committee (iDMC) composed of at minimum 
hemostasis/thrombosis experts and a statistician will be in place for the duration of the study 
and will monitor patient safety at pre-specified intervals and ad hoc as needed throughout the 
study (to be described in the iDMC charter).   
Breakthrough bleeds for patients receiving emicizumab will be treated with FVIII at the lowest 
FVIII dose expected to achieve hemostasis and captured as they occur on the handheld device.  
Patients (or their caregiver) will report bleed information, including site of bleed, type of bleed, 
category of bleed, time of each individual bleed (day, start time), symptoms of bleed, and 
treatment for bleed.  During the study patients will enter bleed and medication data at least 
weekly.  Of note, the clinical experience in the ongoing Phase I and I/II clinical studies includes 
the treatment of breakthrough bleeds with FVIII or bypassing agents in patients receiving 
emicizumab (over 60 bleeds treated) without any related safety concerns reported.  However, in 
the ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with 
FVIII inhibitors), 3 events of TMA and 2 thromboembolic events were observed in patients on 
emicizumab who concomitantly used repeated doses of aPCC for the treatment of breakthrough 
bleeds (see protocol).  Although FVIII and aPCC are fundamentally different in their potential 
interaction with emicizumab, investigators should keep in mind that circulating emicizumab 
increases patients’ coagulation potential.  Therefore, it is recommended that:

Breakthrough bleeds should be treated with the lowest FVIII dose expected to achieve 
hemostasis, which may be lower than the patients’ prior FVIII dose.  Investigators should 
review with patients the dose to be used to treat breakthrough bleeds.

If breakthrough bleeding does not resolve after the first dose of FVIII, patients should be 
instructed to contact the treatment center before infusing multiple FVIII doses.

Investigators and patients should consider objective verification of bleeds.
Investigators will contact the Medical Monitor in the event of suspected lack or loss of efficacy of 
emicizumab in order to discuss potential laboratory evaluations (e.g., anti-emicizumab 
antibodies, coagulation tests) to be performed as well as to re-evaluate their patient’s 
benefit-risk of continued treatment.
The reason for the use of FVIII products will be documented (e.g., bleeding, one time 
prophylaxis, etc.).  A thorough documentation of the treatments for bleeds will be required, 
including agent, start time, dose, route of administration, and number of infusions needed to 
treat the bleed.  
A non-interventional study (BH29768) has been initiated to document the number and types of 
bleeds and current treatment with episodic or prophylactic FVIII agents, as well as to collect 
information on HRQoL, health status, and safety in patients with hemophilia A.  The 
assessments in the non-interventional study will mitigate the risk of underreporting of bleeds 
that likely occurs in the real world, and the resulting data will serve as a source of comparator 
information for some analyses conducted in the Phase III clinical studies, including this study.  
In addition, the non-interventional study will enable earlier identification and confirmation of 
patients who may qualify for the Phase III clinical study.  It is anticipated that a significant 
number of patients participating in Study BH29768 will enroll in this study, as long as they meet 
the inclusion and exclusion criteria and are able to enroll at a participating site while the study is 
open for enrollment.
Activity assessment will be conducted at all sites participating in this study, and all patients 
screened and enrolled will be expected to participate.  Participation will not be mandatory and 
will not impact participation in Study BH30071.  Patients will be asked to wear the study device 
for 2 weeks during Weeks 12, 2324, and 4748.  Patients will return their study devices to the 
respective site at Weeks 3, 25, and 49 and each site will transfer the data from the device to the 
database.  These data will be analyzed to generate the daily step count (DSC) values for each 
patient. 
Number of Patients
A total of 125145 patients with severe hemophilia A will be enrolled, including 85 patients who 
received episodic treatment with FVIII and 4060 who received FVIII prophylaxis prior to study 
entry.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
16/Protocol BH30071, Version 4
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by the patient or a legal guardian

Able to comply with the study protocol, in the investigator’s judgment

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of patient-reported outcome 
questionnaires and bleed and medication diary through the use of an electronic device

Aged 12 years or older at the time of informed consent

Body weight 40 kg at the time of screening 

Diagnosis of severe congenital hemophilia A (intrinsic FVIII level 1%) 

A negative test for inhibitor (i.e., 0.6 BU) within 8 weeks of enrollment

No documented inhibitor (i.e., 0.6 BU), FVIII half-life 6 hours, or FVIII recovery 66% in 
the last 5 years

Patients who completed successful immune tolerance induction (ITI) at least 5 years before 
screening are eligible, provided they have had no evidence of inhibitor recurrence 
(permanent or temporary) as may be indicated by detection of an inhibitor, FVIII half-life 
6 hours, or FVIII recovery 66% since completing ITI.

Documentation of the details of prophylactic or episodic FVIII treatment and of number of 
bleeding episodes for at least the last 24 weeks

For patients on no prophylaxis (episodic treatment) pre-study, 5 bleeds in the last 
24 weeks prior to study entry. 

Patients who were on FVIII prophylaxis for at least the last 24 weeks, can be enrolled 
regardless of the number of bleeds during this period.  Eligibility will be based on 
investigator’s attestation of adequate prophylaxis regimen.

At least 40 patients who were on FVIII prophylaxis pre-enrollment will have been enrolled 
for a minimum of 24 weeks in Study BH29768 (non-interventional)

Adequate hematologic function, defined as platelet count 100,000/L and hemoglobin 
8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5 the upper limit of normal (ULN) 
(excluding Gilbert’s syndrome) and both AST and ALT 3 ULN at the time of screening; 
no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis 

Adequate renal function, defined as serum creatinine 2.5 ULN and creatinine clearance 
by Cockcroft-Gault formula 30 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year and are approved by local health authorities and ethics committees during the 
treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of 
study drug.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (1 year of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal of ovaries 
and/or uterus).
Examples of highly effective contraceptive methods with a failure rate of 1% per year 
include proper use of combined oral or injected hormonal contraceptives, bilateral tubal 
ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
17/Protocol BH30071, Version 4
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment

Previous (in the past 12 months) or current treatment for thromboembolic disease (with the 
exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is 
not currently ongoing) or signs of thromboembolic disease 

Other conditions (e.g., certain autoimmune diseases) that may increase risk of bleeding or 
thrombosis 

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Known HIV infection with CD4 count 200 cells/L within 24 weeks prior to screening.  
Patients with HIV infection who has CD4 200 and meet all other criteria are eligible.

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy

Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment.

Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study, may pose additional risk, or would, in the opinion of the 
investigator, preclude the patient’s safe participation in and completion of the study

Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study

Receipt of:
Emicizumab in a prior investigational study
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A non-hemophilia-related investigational drug concurrently, within last 30 days or 
5 half-lives, whichever is shorter

Inability to comply with the study protocol in the opinion of the investigator

Pregnant or lactating, or intending to become pregnant during the study

Women who are not postmenopausal (48 weeks of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 7 days prior to 
initiation of study drug.
End of Study
The primary analysis will take place at the earliest timepoint when all randomized patients 
(Arms A, B, and C) and a minimum of 40 patients from Arm D have either completed 24 weeks 
of treatment or discontinued from the study.
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., LPLV), as defined below:

Completed 24 weeks of emicizumab and either transferred to a separate extension study to 
receive further emicizumab as per Roche Global Policy on Continued Access to 
Investigational Medicinal Products or to commercial product
OR

Completed the end of study safety follow-up visit 24 weeks after discontinuing emicizumab
OR

Consent has been withdrawn
OR

Lost to follow-up
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
18/Protocol BH30071, Version 4
Length of Study
The approximate length of the entire study from the first patient enrolled to the last patient last 
visit (LPLV [last patient, last visit]; see below) is 6 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Emicizumab, the only investigational medicinal product (IMP) in Study BH30071, is required for 
completion of this study and will be provided by the Sponsor, and accountability for each vial is 
required throughout the study.  The study site will acknowledge receipt of IMPs using the 
interactive voice or Web response system (IxRS) to confirm the shipment condition and content.  
Any damaged shipments will be replaced.
Used and unused IMP vials will be returned by study patients to the site and appropriately 
accounted for.  Used vials will then be disposed of at the study site according to the study site’s 
institutional standard operating procedure.  Instructions regarding how to handle unused vials 
should be obtained from the Sponsor.  The site's method of IMP destruction must be agreed to 
by the Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Inventory Log.
Non-Investigational Medicinal Products
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening to the study completion/discontinuation visit.  In addition, use of long-acting 
medications taken infrequently (e.g., zoledronic acid, Denosumab) will be recorded as well.  All 
such medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
Concomitant use of the following drugs and therapies will be permitted:

To avoid bleeds before adequate emicizumab level is reached, patients in Arm D will 
continue their regular FVIII prophylaxis until the second emicizumab loading dose.  
Concomitant routine FVIII prophylaxis is not permissible otherwise during the study. 

Drugs intended to treat bleeds on an episodic basis, including FVIII.  Specific dosages of 
FVIII will not be mandated in the study; however, investigators should consider that 
circulating emicizumab may increase patients’ coagulation potential.  Investigators should 
review with patients the dose to be used to treat breakthrough bleeds.  Breakthrough bleeds 
should be treated with the lowest FVIII dose expected to achieve hemostasis, which may be 
lower than the patients’ prior FVIII dose. For information on the formulation, packaging, and 
handling of agents, see the local prescribing information for the marketed drug in question.

Drugs and therapies to treat adverse events and use of topical antiseptics, anesthetics, eye 
drops, etc., that are not considered to result in systemic exposure
Statistical Methods
Efficacy Analysis
The primary and secondary efficacy analyses to evaluate the clinical effect of prophylactic 
emicizumab compared with no prophylaxis will include all randomized patients, with patients 
grouped according to the treatment assigned at randomization.  For patients previously treated 
with prophylactic FVIII, the efficacy analysis will include all enrolled patients.  
Safety Analysis
The safety analyses population will be based on all enrolled patients grouped according to the 
actual treatment received.  For Arm C patients, all safety data reported up to the day prior to 
switching will be included in the ‘control arm’ safety summaries, and all safety data reported on 
or after the date of switching to active treatment will be reported separately.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
19/Protocol BH30071, Version 4
Safety will be assessed through descriptive summaries of adverse events, laboratory test 
results (serum chemistry and hematology, including complete blood count with differential),
ECGs, vital signs, and antibodies to emicizumab and FVIII.
To evaluate the overall safety of prophylactic emicizumab compared to no prophylaxis, the 
incidence of adverse events will be summarized and presented by System Organ Class 
mapped term, appropriate thesaurus level, and toxicity grade for each treatment arm.  
For clinical laboratory data, summary statistics will be presented by treatment arm.  In addition,
shift tables describing changes from baseline will be presented using the WHO toxicity grading 
scale.
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, and/or 
clinical pharmacology and PK will be summarized adopting standard language/terminology.
Pharmacokinetic Analyses
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be presented 
descriptively by treatment group, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
gender, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as AUC, will be derived from individual post-hoc predictions.  Data may be 
pooled with data from other studies.  These analyses will be reported in a dedicated report.
Exploratory Analyses
Summary statistics of the number of work/school days missed and days hospitalized will be 
presented by treatment arm.  Summary statistics will also be presented for the SQ-ISHI and 
emicizumab Preference Survey.  PD parameters (e.g., aPTT, parameters derived from thrombin 
generation, FVIII activity) and markers related to bone and joint health will be presented using 
summary statistics, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation.
For the activity assessment all enrolled subjects that contribute reliable activity data (i.e., at 
least 8 valid days) will be analyzed.  There will be no imputation of missing data.  Subjects will 
be grouped according to the treatment regimen to which they are assigned in the main study.  
Because of the exploratory nature of the study, there will be no type-1 error control for 
multiplicity.  Enrollment, discontinuations, protocol violations/deviations, and duration of activity 
monitoring follow-up will be summarized.  Demographic and baseline characteristics, such as 
age, sex, race/ethnicity, and weight will be summarized using descriptive statistics.  Relative 
change is defined as 100 (DSCWeek nDSCbaseline)/DSCbaseline.
Relative change from baseline at Week 25 or 49 in mean DSC and activity counts (total, mean, 
and peak) will be calculated within each treatment group provided the patient has reported data 
on at least 8 days within the 14 day observation period.  Subject-level averages at each 
timepoint will be presented via dot-plots and descriptive statistics by treatment group.  
The main comparisons will be within-patient changes, calculated within each treatment group.  
Within the control arm, where patients are expected to switch to emicizumab prophylaxis 
treatment at 24 weeks, an additional comparison of the relative change from Week 25 to 
Week 49 will be performed.
Formal statistical modeling may be performed as appropriate.  Such analysis will be based on 
between-treatment comparisons of the change in activity from baseline to Week 25 between 
patients receiving emicizumab prophylaxis (Arms A or B) versus no prophylaxis (Arm C).
Determination of Sample Size  
The sample size for this study is based on clinical rather than statistical considerations, taking 
into account the limited number of patients with hemophilia A without inhibitors available for 
participation in clinical studies and in an effort to collect sufficient data to assess the safety and 
efficacy of emicizumab.
The sample size calculation is based on the evaluation of the primary efficacy endpoint, defined 
as the number of bleeds over time (i.e., bleed rate) with emicizumab (treatment group, t) 
versus no prophylaxis (control group, c), which are said to follow a negative binomial (NB) 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
20/Protocol BH30071, Version 4
distribution.  With consideration of enrollment feasibility, a sample size of 75 patients, assuming 
an allocation ratio of 2:2:1 (30 patients in each randomized treatment group and 15 patients in 
control group), will achieve a power of more than 90% assuming a mean ABR of 4 and 
14 bleeds (with variances mean 10) for the emicizumab treatment and control arms 
respectively, representing an expected 71% reduction in the ABR compared to the control arm.  
Initial sample size calculations were performed with East®, Version 6 (Cytel, Cambridge, MA), 
assuming the patients from each treatment group are followed up to 0.5 units of time 
(i.e., 24 weeks).
However, the above approach to sample size calculation assumes similar follow-up for each 
patient.  Because this is unlikely to be seen in the study, power was also estimated by 
simulation to account for different follow-up times among patients.  Conducting simulations on 
the basis of an NB regression model including an offset variable to account for variable 
follow-up times, with all other assumptions remaining the same as previously described, the 
sample size is projected to have greater than 90% power at the 2-sided 0.05 level of 
significance.
The analysis will include all enrolled patients regardless of their length of follow-up.  Therefore, 
to ensure the analysis is based on sufficient follow-up data and with 2:2:1 treatment to control 
randomization, approximately 34 patients in each randomized emicizumab treatment arm (68 in 
total) and 17 patients in the control arm (approximately 85 patients in total) will be enrolled.
With a minimum of 40 and a maximum of 60 patients enrolled in the open-label prophylactic 
emicizumab arm, and assuming a mean ABR of 4 and variance of 4 10, this number is 
considered sufficiently powered to evaluate the efficacy endpoint in this cohort; the treatment 
will be considered to provide adequate control if the upper limit of the one-sided 97.5% CI 
around the mean ABR is less than or equal to 6.
The primary safety consideration in determining the sample size was the ability to sufficiently 
evaluate the safety profile of emicizumab as assessed by adverse events.  Under the 
assumption that the occurrence of an adverse event can be adequately modeled using the 
binomial distribution, the planned sample size of 108128 patients in the emicizumab treatment 
groups allows observation of adverse events having a true incidence rate of 1% with a 
probability of 0.660.72.
During the study, a re-assessment of the initially specified sample size based on aggregated 
(not by treatment arm) data to-date (and potentially from the non-interventional study [BH29768] 
findings) may be performed.  This may result in an increase in sample size, if necessary, to 
maintain adequate power without affecting the type 1 error rate.  Study integrity will be upheld, 
as access to information via aggregated analyses and their results will be minimized to limit 
operational bias.
Regarding the effect of emicizumab on changes of DSC from baseline at Weeks 2324 or 
4748 in patients with hemophilia A, there is currently no published information on the variability 
or clinical significance of longitudinal changes in this measure with the study device in patients 
with hemophilia A.  No data are available to allow detailed sample size calculation of these 
exploratory objectives.  Participation will be offered to all patients in the study, leading to a 
maximum sample size of 145 patients.  Of note, 40 subjects (20 per treatment group) were 
deemed sufficient to evaluate the related objectives with an adequate level of precision in 
similar studies that enrolled patients with chronic obstructive pulmonary disease, such as 
WB29804 Activity Substudy.
Interim Analyses 
No interim analysis for efficacy is planned.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
21/Protocol BH30071, Version 4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
2wks
every 2 weeks
ABR
annualized bleeding rate
ADA
anti-drug antibody
aHUS
atypical hemolytic uremic syndrome
aPCC
activated prothrombin complex concentrate 
AUC
area under the curve
BA
bioavailability
BMI
body mass index
Cmax
maximum plasma concentration
cts
counts
CVAD
central venous access device
DSC
daily steps count
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels
FDA
U.S. Food and Drug Administration
FEIBA
Factor Eight Inhibitor Bypassing Activity
FIX
factor IX
FIXa
activated factor IX
FVIII
factor VIII
FX
factor X
FXIII
factor XIII
HCP
healthcare provider
HIPAA
Health Insurance Portability and Accountability Act
HJHS
Hemophilia Joint Health Score
HRQoL
health-related quality of life
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
ICH
International Council for Harmonisation
IFU
Instructions for Use
IgG4
immunoglobulin G4
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
22/Protocol BH30071, Version 4
Abbreviation
Definition
ITI
immune tolerance induction
IV
intravenous
IxRS
interactive voice or Web Response System
LPLV
last patient, last visit
MAD
multiple ascending dose
NB
negative binomial
NOAEL
no observed adverse effect level
PAQ
physical activity questionnaire
PD
pharmacodynamics
PK
pharmacokinetic
PRO
patient-reported outcome
QTcF
QT interval corrected using Fridericia’s formula
QoL
quality of life
RCR
Roche Clinical Repository
rFVIII
recombinant FVIII
rFVIIa
recombinant activated factor VII
SAD
single ascending dose
SAP
Statistical Analysis Plan
SC
subcutaneous
SQ-ISHI
Satisfaction QuestionnaireIntravenous 
Subcutaneous Hemophilia Injection
t1/2
half-life
TMA
thrombotic microangiopathy
tmax
time to maximum plasma concentration
ULN
upper limit of normal
VAS
visual analog scale
WHO
World Health Organization
wk
week
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
23/Protocol BH30071, Version 4
1.
BACKGROUND
1.1
BACKGROUND ON HEMOPHILIA A
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; 
Franchini and Mannucci 2013).  
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the 
Xq28 region of the X chromosome.  It occurs almost exclusively in males having one 
defective copy of the relevant gene on their X chromosome.  Because an affected man 
will transmit a normal Y chromosome to all his sons and an abnormal X chromosome to 
all his daughters, his sons will not be affected and all of his daughters will be carriers.  
The offspring of a woman carrier have 50% chance to receive a mutated FVIII gene, 
thus hemophilia A will be transmitted to half the male infants and half of female infants 
will be carriers.  Females who are carriers of hemophilia A may experience bleeding 
symptoms similar to those seen in men with mild hemophilia A, as approximately 10% of 
carriers have a FVIII activity that is less than 35% (Plug and Mauser-Bunschoten 2006).  
Rarely, women can have more severe bleeding symptoms requiring treatment and may 
develop FVIII inhibitors.  Approximately 30% of patients with hemophilia A do not have a 
family history of the disorder; these cases arise from spontaneous FVIII gene mutations.  
The absence or functional deficiency of FVIII leads to a lifelong bleeding tendency.  
Common clinical signs of hemophilia A include easy bruising; prolonged bleeding after 
trauma or surgery; spontaneous bleeding into joints, muscles, or soft tissues; and 
intracranial hemorrhage.  The severity of the disease roughly correlates with the residual 
endogenous level of FVIII activity.  Approximately 68% of people with hemophilia A have 
moderate (25%) or severe (43%) forms, characterized by FVIII activity levels 5% or 
1%, respectively, leading to frequent bleeding events with the sequelae of 
musculoskeletal complications (e.g., arthropathy), local functional deficits, hemorrhagic 
shock, neurocognitive defects, or even death (World Federation of Hemophilia 2013).  
A further complication is reduced bone mineral density, which is seen in both adults and 
children with hemophilia A (Paschou et al. 2014).  Potential underlying causes include 
reduced weight-bearing activity, vitamin D deficiency, hemarthropathy, and direct links 
between coagulation factors and function of osteoblasts and osteoclasts responsible for 
bone architecture (Kempton et al. 2015).  The significant negative impact of reduced 
bone mineral density was recently demonstrated in a single-center study of 316 patients.  
The incidence of bone fractures of individuals with hemophilia A was 22.9 fractures per 
1000 patient-years, compared with 9.6 for the general population, and was higher for 
those with severe versus mild or moderate hemophilia A but with no difference for those 
with or without inhibitors (Gay et al. 2015).  These disease-related issues can have a 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
24/Protocol BH30071, Version 4
significant impact on the health-related quality of life (HRQoL) of both adult and 
adolescent patients (Brown et al. 2009).
1.1.1
Management
Prophylactic FVIII replacement therapy (i.e., administered on a scheduled basis with the 
intent to prevent bleeds) has been proven to minimize bleeding events and 
complications (Manco-Johnson et al. 2007).  Since the 1990s, recombinant FVIII (rFVIII) 
concentrates have been standard-of-care treatment options for patients with 
hemophilia A (Kingdon and Lundblad 2002).  Treatment regimens to achieve optimal 
prevention of bleeding events vary between individuals: some patients tolerate trough 
FVIII levels of 1%, whereas, others require higher nadir FVIII levels to achieve the 
desired therapeutic outcome (Ahnstrom et al. 2004; Collins et al. 2010).  Current 
prophylactic regimens commonly use infusion therapy administered three times weekly; 
other regimens use every other day administration (Shapiro 2013). 
Prophylactic FVIII replacement therapy has been recognized as superior to episodic 
treatment of symptomatic bleeds for several decades (Khawaji et al. 2012) and was 
adopted by national and international organizations as the desired treatment approach.
However, the burden of treatment (Eton et al. 2013, Mair and May 2014) is 
extraordinarily onerous, as adequate prophylaxis requires a lifetime of self-administered 
intravenous (IV) infusion of FVIII 34 times each week.  In addition to the obvious toll on 
the quality of patients’ life (Teal et al. 2014), this burden results in suboptimal care for 
many who elect to avoid routine prophylaxis, despite its medical advantage
(Geraghty et al. 2006; Lindvall et al. 2006; De Moerloose et al. 2008; Collins et al. 2014; 
Oldenburg 2015).  Thus, episodic therapy is a standard-of-care for many patients with 
hemophilia in developed countries, where approximately one-third to one-half of the 
patients use FVIII on-demand and avoid continuous prophylaxis. For example, a recent 
analysis revealed that in North America and Europe only 44.3% of 1238 patients with 
severe hemophilia A are treated with routine FVIII prophylaxis
(Oldenburg and Brackmann 2014). Similarly, prophylaxis was routinely offered to adults 
in only 18 of 35 European countries surveyed, and in 12 out of those 18 countries, 50% 
or fewer adults received FVIII prophylaxis (O'Mahony et al. 2013).  In addition to 
treatment burden, other reasons including venous access and cost concerns underlie 
this problem (Gringeri et al. 2012), which contributes to hemophilia-associated long-term 
morbidity.
Although patients on FVIII prophylaxis experience a low number of bleeds, MRI scans 
demonstrate progressive arthropathy in up to two-thirds of patients who receive an
adequate primary prophylaxis regimen. These changes begin within the first decade of 
life and involve clinically “bleed-free” joints (Kraft et al 2012; Olivieri et al. 2012). 
Accordingly, 40% of men in the third decade of life reported presence of a target joint, 
reduced mobility, or chronic pain (Fischer et al. 2013; Noone et al. 2013). These 
findings indicate that FVIII prophylaxis delays, but does not completely prevent, 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
25/Protocol BH30071, Version 4
long-term skeletal morbidity (Oldenburg 2015). This is in part due to the challenges of 
adherence and in part due to micro-bleeds associated with low FVIII trough levels 
(Ljung and Gretenkort 2015). Due to the short half-life of FVIII, current prophylaxis 
regimens aim at maintaining FVIII levels at a trough of 1%, which restores hemostasis 
for only part of the time (Valentino et al. 2012).  A study of patients with varying 
severities of hemophilia suggests that protection from joint bleeds occurs only at 
continuous levels over 12% (Den Uijl et al. 2011), and achieving higher FVIII activity, 
though difficult to accomplish with current regimens, has been recognized as a goal for 
optimal care in a position paper from the World Federation of Haemophilia 
(Skinner 2012).  
Routine intravenous FVIII therapy relies on venous cannulation skills of patients and 
their care providers (Hacker et al. 2001).  In particular, this issue plagues the care of 
children with hemophilia, in whom central venous access devices (CVADs [i.e.,
port-a-cath]) have been used regularly to overcome technical difficulties.  Although 
CVADs make prophylaxis feasible in young children, they are associated with 
complications, including mechanical failure, dehiscence of the skin over the reservoir, 
infection, and thrombosis (Ewenstein et al. 2004). A recent prospective study reported 
that 183 lines were implanted in 99 patients and that 41% of patients had at least one 
infectious episode.  The median time to line removal was 483 days (IQR [1431071]) 
(Rodriguez et al. 2015).  A Finnish retrospective study similarly reported that 47% of 
106 catheters implanted in 58 patients had to be removed due to a complication 
(Vepsalainen et al. 2015). In addition, significant healthcare provider (HCP) efforts are 
required to manage optimal treatment solutions and to overcome identified issues 
(Schrijvers et al. 2013).  Thus, both the disease and its treatment affect patients’ HRQoL.
FVIII replacement therapy is the cornerstone of hemophilia A management, but 
unfortunately, it does not restore normal health and lifestyle to these patients. 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, and low treatment burden to prevent bleeding and minimize long-term morbidity 
of individuals with hemophilia A.
1.2
BACKGROUND ON EMICIZUMAB
1.2.1
Molecule and Preclinical Data
Emicizumab is a recombinant, humanized, bispecific, immunoglobulin G4 (IgG4) 
monoclonal antibody that binds with moderate affinity to activated factor IX (FIXa) and 
factor X (FX), mimicking the co-factor function of FVIII.  In patients with hemophilia A, 
hemostasis can be restored irrespective of the presence of FVIII inhibitors, as 
emicizumab shares no sequence homology with FVIII.  In addition, emicizumab offers 
the possibility of subcutaneous (SC) administration, removing the need for venous 
access.  Finally, because of the pharmacokinetic (PK) properties of this antibody are 
expected to enable marked extension of the dosing interval to once weekly or even less 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
26/Protocol BH30071, Version 4
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.
Binding studies of emicizumab to cynomolgus monkey factor IX (FIX) and FX showed a 
similar affinity as to the human factors.  Mechanistic in vitro studies were conducted in 
human and cynomolgus FVIII-neutralized plasma and in various coagulation 
factor-specific assay-testing systems, which revealed that emicizumab shortened aPTT 
and promoted thrombin generation. Emicizumab bound to human Fcreceptor (hFcR),
cynomolgus monkey Fcreceptor (cyFcR), human neonatal Fc receptor (hFcRn), and 
cynomolgus monkey neonatal Fc receptor (cyFcRn) with similar affinities as a 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 thrombus formation observed with rFVIIa, aPCC, 
or FVIII.
The pharmacokinetics/toxicokinetics of emicizumab were assessed in cynomolgus 
monkeys after single and multiple doses were administered intravenously and via the 
intended clinical SC route.  After a single IV dose of 6 mg/kg emicizumab in male 
cynomolgus monkeys, the plasma clearance was 3.62 mL/day/kg and the terminal 
plasma half-life (t1/2) of emicizumab was 19.4 days.  The single SC administration study 
(dose levels: 0.06, 0.6, and 6 mg/kg) indicated slow (time to maximum plasma 
concentration [tmax]: 3.005.33 days) and complete absorption (bioavailability [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 (Cmax) and area under the 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.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
27/Protocol BH30071, Version 4
Aspects of acute as well as repeated-dose toxicity including local tolerance assessment 
were evaluated in cynomolgus monkeys in 4-, 13-, and 26-week SC dose toxicity studies 
(at doses up to 30 mg/kg weekly), and a 4-week IV dose toxicity study (at doses up to 
100 mg/kg weekly).  No toxicologically relevant changes attributable to SC or IV 
administration of emicizumab were observed; the no observed adverse effect level
(NOAEL) was the highest tested dose in each toxicity study.
See the RO5543262 (Emicizumab) Investigator's Brochure for additional details on 
nonclinical studies with emicizumab.
1.2.2
Clinical Experience
Currently available experience with emicizumab in humans includes data from one 
completed Phase I study (ACE001JPLast Patient Last Visit on 17 April 2015) and its 
ongoing extension, a Phase I/II study (ACE002JP; see the RO5543262 [Emicizumab] 
Investigator's Brochure for additional details on clinical studies with emicizumab).  
ACE001JP was a single study conducted in 3 parts, including both healthy subjects 
(Part A and Part B) and patients with hemophilia A (Part C). The objective of Parts A 
and B in healthy subjects was to investigate the tolerability, safety, PK, and 
pharmacodynamic (PD) response of SC administered emicizumab in adult Japanese 
and Caucasian men and to evaluate for racial differences, if any, in their PK and PD 
response. Healthy men volunteers aged 2044 were eligible for enrollment. A total of
64 healthy volunteers were enrolled in Parts A and B from August 2012 to April 2013. In
Part C, the objective was to investigate the tolerability, safety, PK, and PD response of 
SC administered emicizumab in patients with hemophilia A.  Patients were eligible for 
enrollment if they were 1259 years of age, 40 kg in weight, had a diagnosis of severe 
congenital hemophilia A, and had documentation of bleeds and/or treatment with 
coagulation factor in the last 6 months. For those with inhibitors, patients must have had 
6 bleeds in the 6 months prior to enrollment, and for those without inhibitors, patients 
were required to have received 150 lifetime doses of FVIII replacement, including in the 
last 6 months. A total of 18 patients with hemophilia A were enrolled from May 2013 to 
June 2014.
Parts A and B of Study ACE001JP (completed) consisted of a randomized, 
placebo-controlled, single ascending dose (SAD) study, which was conducted in 
Japanese (n40; Part A) and Caucasian (n24; Part B) healthy men; 48 subjects 
received a single SC injection of 0.001 mg/kg to 1 mg/kg of emicizumab and 16 subjects 
received a single SC injection of placebo.  Part C of Study ACE001JP was an open-label, 
multiple ascending dose (MAD) study in 18 Japanese patients with hemophilia A, both 
with and without inhibitors.  Of note, patients received concurrent coagulation factor 
products to control breakthrough bleeds.  Of the 18 patients in Part C of 
Study ACE001JP, 6 patients were dosed with 0.3 mg/kg/week SC following a single 
loading dose of 1 mg/kg SC, 6 patients were dosed with 1 mg/kg/week SC following a 
"Use of this document is governed by the terms of use on the first page of this document."


"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
29/Protocol BH30071, Version 4
In the 0.3 mg/kg/week cohort, 1 patient transitioned to the observation period of the 
ACE001JP study after 12 weeks of treatment and restarted the study treatment in the 
ACE002JP study at the increased dose of 1 mg/kg/week, approximately 35 weeks later.  
Another patient in the 0.3 mg/kg/week cohort had his dose increased in Study 
ACE002JP after completing 12 weeks of treatment in Study ACE001JP.  Both of these 
patients eventually had their dose further increased to 3 mg/kg/week.  A third patient in 
this group started to receive 1 mg/kg/week just prior to the data cutoff.  At the data cutoff 
date of 17 April 2015, 6 patients in the 0.3 mg/kg/week group, 5 patients in the 
1 mg/kg/week group, and 5 patients in 3 mg/kg/week group have continued emicizumab 
treatment in Study ACE002JP (see the RO5543262 [Emicizumab] Investigator's 
Brochure for additional details on clinical studies with emicizumab).
The efficacy parameter of ABR was calculated by annualizing the number of bleeds that 
required treatment with coagulation factor products during the 6 months prior to study 
enrollment and during the treatment period after first emicizumab administration.  During 
the 6 months before study enrollment, the patients without inhibitors had received FVIII 
prophylactic replacement therapy, while the patients with inhibitors had received 
episodic therapy and/or prophylactic therapy with bypassing agents.  
During the course of emicizumab administration, the ABR decreased in all patients 
compared with the ABR prior to study enrollment, regardless of whether or not they had 
inhibitors, with the exception of 1 patient without inhibitors in the 3 mg/kg/week group.  
This patient, who was previously on FVIII prophylaxis, had a baseline ABR of 0 and 
maintained an ABR of 0 during treatment with emicizumab.  In the 0.3 mg/kg/week group, 
the ABR reduction ranged from 22.8%100% in all patients and 22.8%80.2% in 
patients without inhibitors.  In the 1 mg/kg/week group, the ABR reduction ranged from 
78.9%100% in all patients and 78.9%100% in patients without inhibitors (excluding 
the patients who were dose escalated from the 0.3 mg/kg/week group).  In the 
3 mg/kg/week group, the ABR reduction ranged from 86.4%100% in all patients and 
86.4%100% in patients without inhibitors (excluding the patient with the baseline ABR 
of 0 and patients who were dose escalated from the 1 mg/kg/week group). 
Emicizumab was safe and well tolerated in patients in the Phase I/II study (see 
Investigator's Brochure).  The majority of adverse events were of mild intensity, except 
for 5 moderate adverse events (upper respiratory tract infection, bipolar I disorder, 
hemophilia [i.e., left hip joint bleeding due to hemophilia], headache, and asthma) and
2 severe adverse events (appendicitis and mesenteric hematoma). Both severe events 
were considered to be serious adverse events and not related to emicizumab
administration.  A total of 7 patients reported injection-site reactions (including erythema,
hematoma, rash, pain, discomfort and pruritus).  All injection-site reactions were of mild 
intensity. Besides injection-site reactions, the most frequently reported adverse events 
(4 patients) were nasopharyngitis, pharyngitis, dental caries, excoriation, and 
headache. There were no dose dependent increases in adverse events, and the 
majority of the adverse events were not considered related to emicizumab. Treatment 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
30/Protocol BH30071, Version 4
was discontinued for 1 patient with injection-site erythema in the 1 mg/kg/week group; 
the event was mild in intensity and resolved.  This same patient also reported one 
non-related serious adverse event (hemophilia [i.e., left hip joint bleeding due to 
hemophilia]) approximately 24 weeks after the last dose of study drug.  In the Phase I/II 
studies ACE001JP and ACE002JP no thromboembolic adverse events have been 
reported when emicizumab has been administered alone or concomitantly with FVIII 
products as episodic therapy or bypassing agents as episodic therapy.
In Study BH29884, as of May 2019, thrombotic microangiopathy (TMA) was observed in
3 patients receiving emicizumab and bypassing agents; and 2 cases of thromboembolic 
events were observed in 2 patients receiving emicizumab and bypassing agents.  In 
addition, 1 patient experienced a serious adverse event of acute myocardial infarction in 
Phase IIIb study MO39129, a single-arm study of prophylactic emicizumab in patients 
with congenital hemophilia A who have persistent inhibitors against FVIII.  For more 
details refer to Sections 5.1.2.3 and 5.1.2.4 and the current RO5543262 (Emicizumab) 
Investigator's Brochure.  
Emicizumab exhibited linear PK after single SC administration.  Following single SC 
injection, its mean elimination t1/2 (45 weeks) was similar to that of other human IgG 
antibodies. Furthermore, comparison of PK profiles between Japanese and Caucasian 
healthy volunteers did not reveal racial differences.  In patients with hemophilia A, 
emicizumab trough plasma concentrations increased in a dose-proportional manner with 
weekly dosing to achieve a plateau after approximately 12 weeks in the first two dosing 
groups, in which a loading dose was administered, and after approximately 24 weeks in 
the highest dose group, in which no initial loading dose was administered.
Until the April 2018 cutoff in four Phase III clinical trials of emicizumab (Studies 
BH29884, BH29992, BH30071, and BO39182), 5% of patients tested positive for 
anti-drug antibodies (ADAs) to emicizumab and 1% of patients developed ADAs with 
neutralizing potential (based on declining pharmacokinetics).  A similar safety profile 
was observed in patients, irrespective of the presence of ADAs.  One patient who 
developed ADAs with neutralizing potential experienced loss of efficacy after 5 weeks of 
treatment and discontinued emicizumab treatment.  For further updated information, 
consult the current RO5534262 (Emicizumab) Investigator’s Brochure.
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 Investigator's Brochure for additional details on clinical studies with 
emicizumab.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The ultimate goal of treatment for patients with hemophilia A is continuous restoration of 
near normal FVIII activity. Indeed, effective prophylaxis was adopted as the desired 
approach.  Despite the availability of FVIII agents, patients and providers face significant 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
31/Protocol BH30071, Version 4
challenges. Due to the burden associated with therapy, a large proportion of patients 
decide against continuous prophylaxis, and there is an unmet need for an approach that 
will allow most patients to adopt effective prophylaxis. In part due to adherence and in 
part due to low FVIII trough levels, prophylaxis only reduces and postpones but does not 
eliminate long-term morbidity (Kraft et al. 2012, Noone et al. 2013, Oldenburg 2015).  
Thus, there is a need to ensure continuous FVIII activity higher than the approximately 1% 
trough activity achieved with current regimens to protect patients from long-term 
morbidity. FVIII replacement requires frequent IV dosing. This poses a challenge for all 
patients and in particular, to children, necessitating occasional placement of CVADs and 
exposing patients to the associated risks. In addition, frequent IV sticks is challenging 
for older patients plagued by significant arthropathy in hands, elbows, and shoulders and 
by vein scarring from repeated infusions.  There is, therefore, a need for agents that are 
bioavailable in a non-IV route.
The nonclinical and clinical data related to emicizumab support a positive benefit-risk 
assessment.  As described in Section 1.2, evaluation in vivo demonstrated the safety 
and efficacy of emicizumab in cynomolgus monkeys.  This was corroborated in the 
Phase I/II studies, where significant and stable ABR reductions of 85%100% were 
observed in patients receiving weekly emicizumab. In terms of safety, emicizumab did 
not induce thrombus formation in an in vivo cynomolgus monkey venous stasis model or 
in patients.  No toxicologically relevant changes attributable to SC (at doses up to 
30 mg/kg weekly) or IV (at doses up to 100 mg/kg weekly) administration of emicizumab 
were observed, and the NOAEL was the highest tested dose in each toxicity study.  In 
the Phase I/II Studies ACE001JP and ACE002JP, no thromboembolic or systemic 
hypersensitivity adverse events were seen; however, in Study BH29884, 3 cases of TMA 
and 2 thromboembolic events were observed in patients on emicizumab who received 
bypassing agents for the treatment of breakthrough bleeds.  Three out of these
5 patients have fully recovered and the fourth patient’s condition has improved.  One 
event of thrombotic microangiopathy (Grade 4) occurred in a patient who was 
experiencing a serious adverse event of rectal hemorrhage (Grade 4), with the latter 
serious adverse event associated with a fatal outcome.  In addition, 1 patient 
experienced a serious adverse event of acute myocardial infarction in Study MO39129
(see Sections 5.1.2.3 and 5.1.2.4 and the current RO5534262 [Emicizumab]
Investigator’s Brochure).
Rationale for physical activity monitoring in patients with hemophilia A
Hemophilia A is associated with prolonged bleeding after trauma; spontaneous bleeding 
into joints, muscles, or soft tissues; and intracranial hemorrhage leading to crippling 
musculoskeletal complications (e.g., arthropathy), local functional deficits, 
neurocognitive defects, or even death (World Federation of Hemophilia 2013).  These 
disease-related issues can have a significant impact on patients’ mobility and the 
HRQoL of both adult and adolescent patients (Brown et al. 2009). 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
32/Protocol BH30071, Version 4
Compared with control populations, people with hemophilia have been shown to have 
moderate impairment of balance and mobility and reduced levels of physical activity 
(Fearn et al. 2010; O’Donnell and Gebke 2014). Improving mobility and safely 
increasing activity level in this population are important goals that will result in significant 
health and quality-of-life benefits (von Mackensen et al. 2010; Czepa et al. 2013). 
Ample scientific evidence and guidelines support the health promoting value of physical 
activity underlining the importance of assessing activity in adolescents and adults with 
hemophilia (WHO 2010).  As expected, the degree of joint damage correlates with the 
level of activity. However, this parameter accounts for only a small fraction of the 
variability in the amount of activity performed by different people with hemophilia
(Baumgardner et al. 2013), which is not surprising as level of activity reflects both ability 
and motivation. Motivation (or lack thereof) is particularly important in people with 
hemophilia who are at risk of bleed with physical activity (Broderick et al. 2012), even 
when receiving standard therapies.  Therefore, we hypothesize that the superior bleed 
control provided by emicizumab prophylaxis will be associated with increased physical 
activity in people with hemophilia.
In conclusion, the management challenges of adults and children with hemophilia A 
highlight the unmet need for therapeutics that have reliable efficacy, long half-life, and 
reduced treatment burden to prevent bleeding for patients with hemophilia A.  Given this 
significant unmet medical need and the positive benefit-risk assessment, initiation of a 
larger, confirmatory Phase III study is indicated.
2.
OBJECTIVES AND ENDPOINTS
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of prophylactic 
emicizumab (i.e., administered on a scheduled basis with the intent to prevent bleeds) 
compared with no prophylaxis in patients with hemophilia A without FVIII inhibitors on 
the basis of the following endpoint:

The number of bleeds over time (i.e., bleed rate)
The endpoint will be analyzed separately for the two emicizumab arms:  1.5 mg/kg/week 
(wk) and 3 mg/kg/every 2 weeks (2wks).  The primary endpoint is based on treated 
bleeds.  
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of prophylactic emicizumab (in each individual emicizumab 
arm) on the basis of the following endpoint:
Change in the number of bleeds over time compared with the patient’s historical 
bleed rate *
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
33/Protocol BH30071, Version 4

To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk 
or 3 mg/kg/2wks subcutaneously compared with no prophylaxis for patients 
previously treated with episodic FVIII on the basis of the following endpoints:
All bleeds over time
Spontaneous bleeds over time (spontaneous bleed rate)
Joint bleeds over time 
Target joint bleeds over time (target joints are defined as joints with 3 bleeds 
occurring in the same joint over the last 24 weeks prior to study entry)
HRQoL of patients according to Haem-A-QoL (aged 18) or Haemo-QoL-Short 
Form (aged 1217) scores after 24 weeks
Health status of patients according to European Quality of Life 
5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) scores after 24 weeks

To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk 
subcutaneously for patients previously treated with prophylactic FVIII on the basis of 
the following endpoint:
Maintaining adequate control of bleeding by evaluation of the bleed rate *
* Analyses will be performed for treated bleeds and all bleeds.  
2.1.3
Exploratory Objectives
The exploratory objectives for this study are as follows:

To assess satisfaction regarding treatment with emicizumab prophylaxis versus
FVIII prophylaxis according to the Satisfaction QuestionnaireIntravenous 
Subcutaneous Hemophilia Injection (SQ-ISHI) in patients previously treated with 
prophylactic FVIII

To assess treatment preference for emicizumab prophylaxis versus FVIII 
prophylaxis or episodic therapy according to the preference survey 

To assess changes in number of days away from school/work during treatment with 
prophylactic emicizumab compared with no prophylaxis

To assess changes in number of hospitalization days during treatment with 
prophylactic emicizumab compared with no prophylaxis 

To assess potential PD biomarkers of emicizumab, including but not limited to aPTT, 
thrombin generation, and FVIII activity 

To assess potential serum and plasma biomarkers of bone and joint health

To evaluate the effect of emicizumab prophylaxis treatment on activity compared 
with activity at baseline.  

To evaluate the effect of emicizumab prophylaxis treatment on activity compared 
with no prophylaxis 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
34/Protocol BH30071, Version 4
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the overall safety of prophylactic 
emicizumab compared with no prophylaxis in patients with hemophilia A without 
inhibitors on the basis of the following endpoints:

Incidence and severity of adverse events

Incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs 

Incidence of laboratory abnormalities 

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to drug discontinuation 

Incidence of severe hypersensitivity, anaphylaxis, or anaphylactoid reactions

Incidence and severity of thrombotic microangiopathy

Incidence and clinical significance of anti-emicizumab antibodies

Incidence of de novo development of FVIII inhibitors in patients receiving 
emicizumab prophylaxis
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the exposure (trough plasma 
concentration) to emicizumab in patients treated on weekly or every 2 weeks dosing 
schedule at the following timepoints:

Every week during Weeks 14 on emicizumab

Every 2 weeks during Weeks 58 on emicizumab

Every 4 weeks during Weeks 924 on emicizumab

Every 8 weeks during Weeks 2548 on emicizumab

Every 12 weeks thereafter while on emicizumab, until the end of the study
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This randomized, multicenter, open-label, Phase III clinical study will enroll patients aged 
12 years or older with severe hemophilia A (intrinsic FVIII level 1%) without inhibitors 
against FVIII.  Eighty-five patients who received episodic treatment with FVIII prior to 
study entry and experience at least 5 bleeds over the prior 24 weeks (ABR 10) will be 
randomized in a 2:2:1 ratio (see Figure 1) to the following regimens: 

Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
1.5 mg/kg/wk subcutaneously (Arm A), 

Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
3 mg/kg/2wks subcutaneously (Arm B), or

No prophylaxis control arm (Arm C). 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
35/Protocol BH30071, Version 4
Randomization will be stratified according to the number of bleeds patients experienced 
over the last 24 weeks prior to study entry—less than versus greater than or equal to 9 
(or ABR 18)—to ensure a balance of patients with lower versus higher number of bleeds 
in all arms.  All patients will use episodic treatment with FVIII at the lowest expected 
dose to achieve hemostasis in case of a breakthrough bleeding event (see below).  
In addition, 4060 patients with severe hemophilia A who received FVIII prophylaxis 
prior to study entry will be enrolled and will receive emicizumab prophylaxis at 
3 mg/kg/wk subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk subcutaneously 
(Arm D; see Figure 1).  A minimum of 40 patients in this group will complete at least 
24 weeks of observation in an ongoing non-interventional study (BH29768) prior to 
enrollment in this study.  Eligibility for all patients in Arm D will be based on investigator’s 
attestation of adequate prophylaxis regimen in the 24 weeks prior to study entry. 
To avoid bleeds before adequate emicizumab plasma concentration is reached, these 
patients will continue their regular FVIII prophylaxis until the second emicizumab loading 
dose.  At the end of the first week of treatment, 95% of patients are expected to achieve 
emicizumab level of 8 μg/mL, which is projected to have FVIII activity equivalent to 
approximately 2%.  Thrombotic events were not found in the Japanese Phase I/II study 
where doses of FVIII were administered to treat breakthrough bleeds while patients 
had higher emicizumab steady-state level, supporting the safety of this approach.  
Importantly, routine prophylaxis will be prohibited for all patients enrolled in Arms A, B, or 
C and for patients in Arm D immediately after the second emicizumab dose. 
Study enrollment will take place at the Week 1 visit. A patient who fulfills the inclusion 
and exclusion criteria should be enrolled and assigned to a treatment arm at the Week 1 
visit, the same day when the first dose of emicizumab is due for patients in Arms A, B, 
and D. 
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have 
already occurred).  The primary efficacy analysis, defined as comparing the number of 
bleeds over time for patients randomized to receive prophylactic emicizumab versus no 
prophylaxis will be conducted at the earliest timepoint when all randomized patients 
(Arms A, B, or C) and a minimum of 40 patients from Arm D have either completed
24 weeks in the study or discontinued from the study.  Therefore, there will be a range of 
observation periods from 6 to approximately 12 months, or longer.  Study patients will be 
enrolled globally from the Americas, Europe, Africa, and Asia-Pacific region.
To obtain additional safety and efficacy data on emicizumab, patients who are
randomized to the no prophylaxis arm (control arm, Arm C) will be expected to switch 
after 24 weeks to receive emicizumab prophylaxis at 3 mg/kg/2wks maintenance dose 
after 4 weeks of 3 mg/kg/wk loading dose.  This dose was chosen to enhance the safety 
and efficacy data obtained with Arm B patients. 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
36/Protocol BH30071, Version 4
After completing at least 24 weeks of treatment with prophylactic emicizumab, patients 
who receive emicizumab prophylaxis (Arms A, B, D, or Arm C after treatment switch) 
and derive clinical benefit will be allowed to continue emicizumab until marketing 
authorization as part of this study or a separate extension study, as long as they 
continue to derive clinical benefit and emicizumab is still in clinical development (see 
Section 4.3.4).  Those who are well controlled (ABR 4) will continue treatment on their 
assigned emicizumab regimen; whereas, patients in Arms A, B, or C (after 24 weeks on 
emicizumab) who experience suboptimal control (ABR 4) will be offered the option to 
escalate to 3 mg/kg/wk after approval from the Medical Monitor.  Patients in Arm D who 
experience suboptimal control while on emicizumab prophylaxis at the maintenance 
dose, will have the opportunity to escalate to 3 mg/kg/wk immediately after the second 
qualifying bleed. Criteria and details of dose escalation are described in Section 4.3.2.
Figure 1
Study Schema
2wksevery 2 weeks; 6moBR6 months bleed rate; BRbleed rate; FVIIIfactor VIII; 
momonth; Rrandomization; wk week.
a All patients will receive loading with four weekly doses of emicizumab 3 mg/kg/wk prior to 
starting maintenance.
A 6 mg/kg every 4 weeks (4wks) maintenance dosing regimen is being evaluated in 
Phase III studies BH29992 and BO39182 in addition to the 1.5 mg/kg/wk and 
3 mg/kg/2wks maintenance dosing regimens evaluated in this study.  The observed 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
37/Protocol BH30071, Version 4
exposures (i.e., average concentration at steady state) of multiple doses of these three 
dosing regimens are comparable and lead to similar efficacy and safety profiles
(see Section 3.3.1).  Hence, 6 mg/kg/4wks will be offered as a permitted dosing regimen
for patients who continue in this study during study prolongation.
Upon implementation of protocol Version 4, treatment duration will be extended until 
5 years after the last patient is enrolled to enable the collection of additional safety and 
efficacy data.  During this study prolongation, each patient may choose a preferred 
emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg/wk, 
3 mg/kg/2wks, or 6 mg/kg/4wks) and continue on that dosing regimen until 
discontinuation from the study.  Instructions for switching the dosing regimen are 
outlined in Section 4.3.2. 
During the study, individual bleeds will be captured as they occur, while HRQoL, health 
status, patient safety, patient preference and satisfaction, activity level, and days of 
school or work missed will be assessed as outlined in the schedule of assessments.  
Patients (or their caregiver) will be asked to record on an electronic, handheld device
their bleeds (i.e., start date and time, reason, type, location, and associated symptoms of 
each bleed) and hemophilia-related medication use (i.e., start date and time, reason, 
type, dose of injection, and number of doses) at least weekly, when a bleed occurs, or 
when a hemophilia medication was taken at home or in the clinic.
Throughout the study, biomarkers related to thromboembolism (e.g., D-dimer, 
prothrombin 1.2 fragment) and emicizumab trough concentrations will be collected as 
per the schedule of assessments.  Immunologic biomarkers (i.e., anti-emicizumab
antibodies and anti-FVIII antibodies) will also be measured as per the schedule of 
assessments (see Appendix 1).
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation assay) will be 
collected as per the schedule of assessments.  As values for some of these tests are
normalized by low plasma concentrations of emicizumab, a variety of assay formats (one 
stage, chromogenic) and modifications (predilution of patient plasma) will be investigated 
for assessment of PD response at higher emicizumab plasma concentrations. However, 
it is not expected that these biomarkers will be used to guide dosing or the selection of 
patients to be treated with emicizumab.  Rather, these biomarkers may be used to 
identify a future assay for the monitoring of emicizumab activity.  
Physical examinations, including Hemophilia Joint Health Score (HJHS; see Appendix 8), 
vital signs assessments, ECGs, and laboratory assessments will be collected as per the 
schedule of assessments and will be the same for all patients, with the exception that 
emicizumab PK and ADAs will not be measured in patients in Arm C prior to the switch 
to emicizumab treatment.  Adverse events will be captured as they occur for the duration 
of the study.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
38/Protocol BH30071, Version 4
All patients who receive emicizumab in the study will undergo PK assessments.  A 
washout period from FVIII therapy is not required prior to inclusion because FVIII 
replacement does not interfere with emicizumab PK assessments, and some patients 
with hemophilia A require frequent dosing with FVIII to treat bleeds or for prophylaxis. 
An independent Data Monitoring Committee (iDMC) composed of at minimum 
hemostasis/thrombosis experts and a statistician will be in place for the duration of the 
study and will monitor patient safety at pre-specified intervals and ad hoc as needed 
throughout the study (to be described in the iDMC charter). 
Breakthrough bleeds for patients receiving emicizumab will be treated with FVIII at the
lowest FVIII dose expected to achieve hemostasis and captured as they occur on the 
handheld device.  Patients (or their caregiver) will report bleed information, including site 
of bleed, type of bleed, category of bleed, time of each individual bleed (day, start time), 
symptoms of bleed, and treatment for bleed.  During the study patients will enter bleed 
and medication data at least weekly.  Of note, the clinical experience in the ongoing 
Phase I and I/II clinical studies includes the treatment of breakthrough bleeds with FVIII 
or bypassing agents in patients receiving emicizumab (over 60 bleeds treated) without 
any related safety concerns reported.  However, in the ongoing Phase III 
Study BH29884 (adolescent and adult patients with hemophilia A with FVIII inhibitors),
3 events of TMA and 2 thromboembolic events were observed in patients on 
emicizumab who concomitantly used repeated doses of aPCC for the treatment of 
breakthrough bleeds (see Sections 1.2, 1.3, 5.1.2.4, and 5.1.3).  Although FVIII and 
aPCC are fundamentally different in their potential interaction with emicizumab, 
investigators should keep in mind that circulating emicizumab increases patients’ 
coagulation potential. Therefore, it is recommended that:

Breakthrough bleeds should be treated with the lowest FVIII dose expected to 
achieve hemostasis, which may be lower than the patients’ prior FVIII dose.  
Investigators should review with patients the dose to be used to treat breakthrough 
bleeds. 

If breakthrough bleeding does not resolve after the first dose of FVIII, patients 
should be instructed to contact the treatment center before infusing multiple FVIII 
doses. 

Investigators and patients should consider objective verification of bleeds.
Investigators will contact the Medical Monitor in the event of suspected lack or loss of 
efficacy of emicizumab in order to discuss potential laboratory evaluations (e.g., 
anti-emicizumab antibodies, coagulation tests) to be performed as well as to re-evaluate 
their patient’s benefit-risk of continued treatment.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
39/Protocol BH30071, Version 4
The reason for the use of FVIII products will be documented (e.g., bleeding, one time 
prophylaxis, etc.).  A thorough documentation of the treatments for bleeds will be 
required, including agent, start time, dose, route of administration, and number of 
infusions needed to treat the bleed.  
A non-interventional study (BH29768) has been initiated to document the number and 
types of bleeds and current treatment with episodic or prophylactic FVIII agents, as well 
as to collect information on HRQoL, health status, and safety in patients with 
hemophilia A. The assessments in the non-interventional study will mitigate the risk of 
underreporting of bleeds that likely occurs in the real world, and the resulting data will 
serve as a source of comparator information for some analyses conducted in the 
Phase III clinical studies, including this study.  In addition, the non-interventional study 
will enable earlier identification and confirmation of patients who may qualify for the 
Phase III clinical study.  It is anticipated that a significant number of patients participating 
in Study BH29768 will enroll in this study, as long as they meet the inclusion and 
exclusion criteria and are able to enroll at a participating site while the study is open for 
enrollment.
Activity assessment will be conducted at all sites participating in this study, and all 
patients screened and enrolled will be expected to participate.  Participation will not be 
mandatory and will not impact participation in Study BH30071.  Patients will be asked to 
wear the study device for 2 weeks during Weeks 12, 2324, and 4748. Patients will 
return their study devices to the respective site at Weeks 3, 25, and 49 and each site will 
transfer the data from the device to the database.  These data will be analyzed to 
generate the daily step count (DSC) values for each patient.
3.2
END OF STUDY AND LENGTH OF STUDY
LENGTH OF STUDY
The approximate length of the entire study from the first patient enrolled to the last 
patient last visit (LPLV [last patient, last visit]; see below) is 6 years.
END OF STUDY
The primary analysis will take place at the earliest timepoint when all randomized 
patients (Arms A, B, and C) and a minimum of 40 patients from Arm D have either 
completed 24 weeks of treatment or discontinued from the study.
The end of this study is defined as the date when the last remaining patient has 
completed the last visit (i.e., LPLV), as defined below:

Completed 24 weeks of emicizumab and either transferred to a separate extension 
study to receive further emicizumab as per Roche Global Policy on Continued 
Access to Investigational Medicinal Products or to commercial product
OR
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
40/Protocol BH30071, Version 4

Completed the end of study safety follow-up visit 24 weeks after discontinuing 
emicizumab
OR

Consent has been withdrawn
OR

Lost to follow-up
3.3
RATIONALE FOR STUDY DESIGN
The Sponsor proposes a randomized, multicenter, open-label, Phase III clinical study 
that will enroll patients aged 12 years or older with severe hemophilia A (intrinsic FVIII 
level 1%) without inhibitors against FVIII. In the randomized arms of the study, patients 
who received episodic treatment with FVIII prior to enrollment will be randomized to 
receive one of the following regimens:  

Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk
subcutaneously (Arm A), 

Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks
subcutaneously (Arm B), OR

No prophylaxis control arm (Arm C). 
This prospective, randomized design allows uniform collection of bleed data, medication 
use and patient-reported outcomes through the utilization of patient-validated 
measurement tools in all groups, enabling analysis of the effect of emicizumab versus 
episodic FVIII therapy on these important measures. Reporting of bleeds by patients to 
their providers (e.g., doctors, nurses) is not standardized and can be incomplete in 
routine clinical care.  In addition, the recording of bleeds by providers in medical records 
may be inconsistent.  Therefore, testing the primary endpoint using a prospective 
randomized design is superior to comparison to historical control in patients who were 
not on prophylaxis prior to enrollment.
Given the proven efficacy of FVIII prophylaxis, it can be expected that standard-of-care 
may evolve towards more widespread treatment of patients with prophylaxis regimens.  
However, for myriad of reasons currently only about half the patients in developed 
countries are managed with routine prophylaxis, making the episodic approach a 
commonly used standard care (Richards et al. 2007; Gringeri et al. 2012; 
Zappa et al. 2012; Jackson et al. 2014, 2015; Oldenburg and Brackmann 2014; 
Oldenburg 2015).  Thus, for the primary efficacy endpoint, patients on episodic FVIII will 
be compared with patients treated with prophylactic emicizumab.  Limiting the 
randomized portion of the study and primary efficacy analysis to patients who previously 
received episodic FVIII will reduce heterogeneity in the study population, which is 
appropriate since the bleed rates for patients receiving therapy on an episodic versus 
prophylactic basis are significantly different (Valentino et al. 2012;
Manco-Johnson et al. 2013; Powell et al. 2013; Antunes et al. 2014;
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
41/Protocol BH30071, Version 4
Mahlangu et al. 2014; Windyga et al. 2014).  To help balance measured and 
unmeasured covariates between the emicizumab and episodic FVIII groups, randomized 
patients will be stratified according to the number of bleeds they had over the 24 weeks 
prior to study entry (less than versus greater or equal to 9 bleeds).
The study will include a cohort of non-inhibitor patients treated with prophylactic FVIII 
agents prior to enrollment.  Prophylaxis was endorsed in 1994 by the World Health 
Organization as the optimal approach for patients with hemophilia (Berntorp et al. 1995), 
and, therefore, it is important to demonstrate that these patients are adequately 
controlled with emicizumab.  The design and conduct of a study comparing emicizumab 
to FVIII prophylaxis is challenging due to the low rate of bleeding events in this 
population.  Rarity of events precludes definition of a meaningful non-inferiority margin 
and would require an unfeasibly large sample size.  In determining a clinically 
meaningful bleed rate to define successful prophylaxis treatment in patients on previous 
FVIII prophylaxis, the Sponsor relies on findings from recent studies, which explored 
prophylaxis using novel rFVIII agents (Valentino et al. 2012; Mahlangu et al 2014; 
Kavakli et al. 2015; Konkle et al 2015).  Examining interquartile ranges for bleed rate in 
patients receiving FVIII prophylaxis reveals that approximately a quarter of patients 
experienced ABR higher than 6.5.  Therefore, clinically meaningful control of bleeding in 
this patient group can be characterized through an upper limit of a 95% CI for the mean 
bleed rate of 6.  The proposed threshold of upper limit of a 95% CI ABR 6 is lower 
than the previously reported outcome of patients on prophylactic treatment and is 
therefore clinically meaningful.  A similar approach, utilizing a predefined threshold 
based on published experience was recently utilized in assessing the efficacy of a novel 
long-acting FIX product (Collins et al. 2014).  In addition, to improve the validity of 
historical comparison in this group, a minimum of 40 patients will be observed on FVIII 
prophylaxis in the non-interventional study for a period of at least 24 weeks before 
enrolling in Arm D of this study. 
The primary efficacy analysis to assess the effect of emicizumab on bleed rate reduction 
will be performed at the earliest timepoint when all randomized patients (Arms A, B, and 
C) and a minimum of 40 patients from Arm D have either completed 24 weeks of study 
treatment or discontinued from the study.  Indeed, a similar follow up period was utilized 
in recent studies that investigated the safety and efficacy of novel FVIII formulations 
(Mahlangu et al. 2014; Kavakli et al. 2015; Konkle et al. 2015).  Further, patients who 
experience frequent bleeds may not find it acceptable to be randomized to their usual 
episodic FVIII therapy for longer than 24 weeks prior to receive emicizumab.  For this 
reason, individual patients in the control arm will be offered the opportunity to switch to
emicizumab after 24 weeks in the study.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
42/Protocol BH30071, Version 4
3.3.1
Rationale for Emicizumab Dose and Schedule
Emicizumab prophylaxis has been administered subcutaneously in 18 Japanese patients 
with hemophilia A (with and without FVIII inhibitors) in Study ACE001JP and in its 
ongoing extension Phase I/II Study ACE002JP.  Three dose groups (of 6 patients each) 
received the following treatment (administration period: 12 weeks):

A loading dose of 1 mg/kg followed by weekly doses of 0.3 mg/kg

A loading dose of 3 mg/kg followed by weekly doses of 1 mg/kg

Weekly doses of 3 mg/kg
Emicizumab was safe and well tolerated in these patients (see Section 1.2 and the 
RO5543262 [Emicizumab] Investigator's Brochure).  The maximum clinical dose of 
3 mg/kg/wk is associated with a 10.3-fold and 11.2-fold safety margin based on Cmax and 
AUC, respectively.  No clear difference in the plasma concentrations of emicizumab 
was observed between adolescents (1218 years) and adult (aged 1958 years) 
patients.
A substantial reduction in bleeding events has been observed with prophylactic 
emicizumab treatment, especially at doses 1 mg/kg/wk (see Table 1, based on data 
cutoff 17 April 2015.  See the RO5543262 (Emicizumab) Investigator's Brochure for 
additional details on clinical studies with emicizumab).  ABR decreased in all patients, 
regardless of age or the presence of FVIII inhibitors.
Table 1
Mean Reduction (%) of Annualized Bleeding Rates in Inhibitor 
and Non-Inhibitor Patients Enrolled in ACE001JP/ACE002JP
Emicizumab Dose
0.3 mg/kg/wk
1 mg/kg/wk
3 mg/kg/wk
ABR reduction
74.5%
95.3%
96.4%
ABRannualized bleeding rate; wk week.
A median ABR of 0 was achieved with weekly maintenance doses of 1 and 3 mg/kg.  
The number of bleeding events decreased with increased emicizumab plasma 
concentrations (see Figure 2).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
43/Protocol BH30071, Version 4
Figure 2
Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event
ACE910emicizumab (also known as RO5534262) 
●
Joint bleed
Ο
Non-joint bleed
The exposure-response relationship of emicizumab was quantitatively characterized and 
simulations suggested that a median ABR of 0 is achieved for emicizumab trough 
plasma 45 g/mL. On the basis of population PK modeling, a median trough plasma 
concentration of 45 g/mL is predicted to be achieved after one month of treatment with 
4 weekly doses of 3 mg/kg and maintained, thereafter, with either weekly doses of 
1.5 mg/kg or biweekly doses of 3 mg/kg.  The loading doses of 3 mg/kg/wk for 4 weeks 
were chosen in order to rapidly achieve the effective trough concentration of 45 g/mL 
without exceeding the maximum dose of 3 mg/kg/wk investigated in the Phase I/II 
studies.  The two maintenance dosing regimens, both predicted to maintain median 
plasma concentrations above 45 g/mL over the entire dosing interval, will offer flexibility 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
44/Protocol BH30071, Version 4
of dosing frequency to patients.  These prophylaxis regimens (i.e., 3 mg/kg/wk for 
4 weeks followed by 1.5 mg/kg/wk or 3 mg/kg/2wks) will, therefore, be investigated in 
this study.
The dose of 6 mg/kg/4wks being evaluated in Phase III studies BH29992 and BO39182 
is equivalent, in terms of cumulative dose, to dose levels of 1.5 mg/kg/wk or 
3 mg/kg/2wks.  Assuming linear PK up to 6 mg/kg, model-based simulations were used 
to explore whether a dosing regimen every 4 weeks could provide sufficient efficacy.  
Simulations showed that a once-weekly loading dose of 3 mg/kg for the first 4 weeks, 
followed by an every 4 weekmaintenance dose of 6 mg/kg would provide a steady-state 
Cmax and AUCof 78.1 20.9 g/mL and 1570 447 day·g/mL, respectively.  While 
more than half of the patients would not be expected to have a trough level of 
45 g/mL at steady state, the simulated ABR distribution was similar to the other 
planned dosing regimens.  This 6 mg/kg/4wks dosing regimen is therefore expected to 
maintain similar efficacy to the 1.5 mg/kg/wk and 3 mg/kg/2wks dosing regimens and it 
is being offered to patients as an optional maintenance dosing regimen after 
implementation of protocol Version 4. 
3.3.2
Rationale for Patient Population
As described in Section 3.3, patients with hemophilia A who were treated with episodic 
FVIII prior to study entry will comprise the primary population for this Phase III study of 
prophylactic emicizumab compared with no prophylaxis in investigating the efficacy, 
safety, and PK of emicizumab.  
Although the severity of a patient’s hemophilia A is directly related to the endogenous 
FVIII activity, inter-patient variability may exist based on level of physical activity, 
bleeding history and other features.  Therefore, patients previously treated with episodic 
FVIII will be required to have at least 5 bleeds in the last 24 weeks prior to study entry to 
be eligible for enrollment in the randomized portion of Study BH30071. This is to select 
a group of patients with hemophilia A without inhibitors who have a high, unmet medical 
need and to enable detection of a clinically and statistically significant difference in bleed 
rates in this population.  Similar approaches were previously employed 
(Manco-Johnson et al. 2013; Mahlangu et al. 2014).
Patients who were treated with prophylactic FVIII prior to enrollment are included in a 
separate arm in Study BH30071, as combining them with those previously treated with 
episodic FVIII would introduce significant heterogeneity in baseline bleed rates and 
goals of care.
3.3.3
Rationale for Control Group
The control group for the primary efficacy endpoint will be a concurrent, no prophylaxis 
“usual care” arm, to which patients who were on episodic FVIII prior to study entry will be 
randomized (2:2:1 prophylactic emicizumab 1.5 mg/kg/wk:prophylactic emicizumab 
3 mg/kg/2wks:no prophylaxis), which will enable an inter-patient comparison of the 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
45/Protocol BH30071, Version 4
treatment and control groups.  All patients, whether assigned to receive prophylactic 
emicizumab or no prophylaxis, will continue to receive FVIII on an episodic basis for the 
treatment of breakthrough bleeds during the study.  Specific doses of FVIII will not be 
mandated in the study, but investigators should review with patients the dose to be used 
to treat breakthrough bleeds. Breakthrough bleeds should be treated with the lowest 
FVIII dose expected to achieve hemostasis, which may be lower than the patients’ prior 
FVIII dose.
A second comparison will be an individual patient’s bleed rate calculated over the 
24 weeks prior to study entry, from the medical record and/or Study BH29768.  This will 
enable intra-patient analyses of bleed rates to be performed.
3.3.4
Rationale for the Primary Efficacy Analysis
The objective of the primary efficacy analysis is to evaluate the clinical effect of 
prophylactic emicizumab compared with no prophylaxis based on the number of bleeds 
over time (i.e., bleed rate).  As mentioned in Section 3.1, the primary analysis will take 
place at the earliest timepoint when all randomized patients (Arms A, B, and C) and a 
minimum of 40 patients from Arm D have either completed 24 weeks of treatment or 
discontinued from the study.  This will lead to a range of observation periods from 
612 months or longer in the prophylactic emicizumab arm and is deemed to be
sufficient to reliably assess the effect of prophylactic emicizumab on bleed rate reduction.  
In the MAD Phase I study involving Japanese patients with hemophilia A 
(Study ACE001JP), a statistically significant reduction in median ABR to 0 after 
12 weeks of treatment (approximately 3 months) in the 1 and 3 mg/kg/wk emicizumab
dose cohorts was demonstrated.  In the Japanese Phase I/II extension study 
(Study ACE002JP), the median ABR of the 1 and 3 mg/kg/wk dose cohorts continued to 
remain zero in patients who continued to receive prophylactic emicizumab after a 
minimum of 24 weeks, which is consistent with evidence suggesting longer duration of 
prophylactic therapy is associated with maintenance of ABR reduction 
(Antunes et al. 2014).  Patients in the 1 and 3 mg/kg/week cohorts in Study 
ACE001JP/Study ACE002JP have been observed for at least 72 and 48 weeks, 
respectively, except for 1 patient in the 3 mg/kg/week group who has only been followed 
for 44 weeks at the cutoff of 17 April 2015 (see the RO5543262 [Emicizumab] 
Investigator's Brochure for additional details on clinical studies with emicizumab).
A recent publication of hemophilia B patients with FIX activity levels 2% who received
episodic therapy showed no distinguishable trend in prospectively collected ABRs over 
approximately 59 weeks (Shafer et al. 2014), indicating that 24 weeks may be a 
sufficiently representative follow-up period.  As the number of bleeds over time is not 
expected to differ between patients with hemophilia A or B, it is reasonable to 
extrapolate this study’s findings to the hemophilia A population.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
46/Protocol BH30071, Version 4
In addition, because this will be a global study with enrollment from different 
continents occurring approximately over a year, all seasons will be represented in the 
bleed rate data.
3.3.5
Rationale for Patient-Reported Outcome Assessments
The study design utilizes the electronic capture of HRQoL, health status, satisfaction, 
preference, and days of work/school missed using a tablet device in the clinic. HRQoL 
is an important outcome in the care of patients with hemophilia (Brown et al. 2009).  
HRQoL in hemophilic patients is multifaceted and impacted by disease symptoms 
(e.g., pain, bleeding), treatment (prophylactic, on demand, side effects), limitations on 
daily functioning, anxiety/depression, and time spent in hospital.
The goal of measuring HRQoL is to quantify the benefit of treatment from the patient 
perspective.  Previous studies that have used the Haemo-QoL, a measure of dimensions 
of HRQoL affected by hemophilia in children and adolescents, have reported 
improvements in physical health, feelings, view of self, family relations, friend relations, 
perceived support, relation with others, participation in sports, dealing with hemophilia, 
views of treatment, views of the future, and relationships (Santagostino et al. 2014).  
Improvements in physical health, feelings, view of self, and participation in work and 
school have also been observed on the adult version of the measure, the Haem-A-QoL 
(Stasyshyn et al. 2014).
The inclusion of HRQoL measures in the current study will allow for the assessment of 
the impact of prophylactic treatment with emicizumab in adolescents and adults with 
hemophilia A and an evaluation of the changes in HRQoL in patients receiving 
prophylaxis with emicizumab compared with that of patients receiving only episodic 
treatment for breakthrough bleeds
The study will also include measures designed to capture patient satisfaction and 
preference with treatment. Patient satisfaction with treatment will be evaluated in order 
to understand whether satisfaction with hemophilia treatment is different between IV and 
SC administration of hemophilia treatment. Previous studies have noted that patients 
express preference for treatments that do not have negative effects (e.g., pain that 
results from infusions), are not time-consuming, are not associated with high treatment 
burden, and have a goal of achieving a “normal life” (Cimino et al. 2014). The inclusion 
of a fit-for-purpose satisfaction measure (SQ-ISHI) prior to and after 24 weeks of 
treatment with emicizumab in the group of patients previously treated with prophylactic 
IV FVIII will provide information on whether satisfaction levels differ by route of 
administration.  Additionally, a preference survey after completion of 17 weeks of 
emicizumab in Arms A, B, or D will provide information on whether SC emicizumab is 
preferred to IV FVIII administration and explore potential underlying reasons.  This 
assessment will be performed at Week 17 when patients gained sufficient experience 
with emicizumab and SC injection, while still reliably recall their experience with prior 
therapy. 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
47/Protocol BH30071, Version 4
3.3.6
Rationale for Biomarker Assessments
Biomarkers to measure the PD effect of emicizumab on hemostasis have not been fully 
validated to-date and require further testing to determine which assays and technical 
conditions are most suitable for use with emicizumab treatment.  Refer to Section 5.1.4
for more information about effects of emicizumab on existing laboratory assays. Plasma 
samples will be collected for PD biomarker assessment in parallel with PK samples at all 
clinic visits to demonstrate evidence of biologic activity of emicizumab in patients.  These 
PD biomarkers include but are not limited to coagulation assays such as aPTT, thrombin 
generation, and FVIII activity assays.  All of these assays were previously shown in the 
Phase I/II study to exhibit a dose-response relationship to emicizumab concentration (for 
more information, see the RO5543262 [Emicizumab] Investigator’s Brochure).  The 
aPTT assay will be run both in standard form and with a modification to ensure that the 
assay range covers all levels of emicizumab exposure.  In addition, clot waveform 
analysis may be run as an exploratory PD coagulation assay.  Exploratory plasma 
biomarkers will include FVIII antigen and may include measurement of other coagulation 
or hemophilia-related factors as well. Serum and plasma will be collected periodically for 
the assessment of bone and joint health related markers such as procollagen type 1 
amino-terminal propeptide (P1NP), C-terminal telopeptide of collagen 1 (CTX-1), 
osteoprotegerin (OPG), and soluble RANK-L.  Finally, residual blood from collected 
samples may be stored for 5 years and used for additional emicizumab-related research.
3.3.7
Rationale for Activity Assessment
This study provides an opportunity to evaluate whether activity levels of patients treated 
with emicizumab change over the course of treatment or when compared with patients 
who continue without prophylaxis.  There are two potential approaches to assess activity 
levels: physical activity questionnaires (PAQs) and actigraphy-based sensors (e.g., 
accelerometers).  PAQs can either be interviewer- or self-administered, and rely on the 
individual to recall, usually over a 7-day period, the type and duration of moderate or 
vigorous activities that were performed. Use of these measures in patients with 
hemophilia, as well as in patients with other diseases, revealed several weaknesses that 
limit the utility of this approach in the current study.  These issues include a tendency for 
patients to over report their activity level, averaging of activity over the course of the 
recall period (typically a week), and lack of sufficient resolution to capture modest
changes in daily activity.  In addition, methodological challenges such as multi-culture 
validation and test-retest fidelity make these instruments unsuitable to reliably, serially, 
quantify individuals’ activity within the population of interest (Craig et al. 2003; 
Wolin et al. 2008; Bull et al. 2009; Chinapaw et al. 2009; Garriguet et al. 2015). In 
contrast, accelerometer-based instruments provide a subject-independent, objective 
movement count.  However, these movement counts only modestly correlate with gold 
standard global activity assessment such as directly measured activity-related energy 
expenditure (Van Remoortel et al. 2012; Rabinovich et al. 2013). Weighing these 
considerations, we will employ an objective assessment using an accelerometer that is 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
48/Protocol BH30071, Version 4
worn on the waist and will focus on DSC as a reliably derived outcome measure with 
high clinical relevancy (Gironda et al. 2007; Garriguet et al. 2015).
Participants will be instructed to wear the device for 2 weeks at the beginning of the 
study and for 2 weeks approximately every 6 months subsequently. Intermittent 
sampling of approximately a week was commonly employed in similar studies that 
assessed physical activity in patients with chronic diseases (Lavie et al. 1992; 
Watz et al. 2014; Ahn et al. 2015; Chu et al 2015; Yu et al. 2015). The incremental 
added value of additional days of data collection (Briscoe et al. 2014) is likely offset by 
diminishing compliance with a longer observation period. Due to logistical 
considerations, baseline activity will be captured during the first 2 weeks after enrollment
rather than prior to starting treatment. Although patients will have started emicizumab, 
its level will be below steady state, and the relatively short duration on emicizumab at 
this time is unlikely to inspire a change in activity habits.  Therefore, activity during 
Weeks 1 and 2 is expected to be similar to pre-study activity, and a change, if any, from 
pre-enrollment will likely only underestimate the effect of emicizumab rather than 
overestimate it. The alternative approach of delaying initiation of therapy to allow 
measurement of baseline DSC may be unacceptable to many patients and investigators. 
The purpose of this activity assessment in this study is to evaluate the effects of 
emicizumab treatment on patients’ DSC as measured by a waist-worn ActiGraph (a 
medical device used to continuously monitor and measure activity through a triaxial 
accelerometer) in patients with hemophilia A. The data collected by the study device will 
be scored to identify active and rest periods for each patient within each 24-hour period. 
This device continuously captures frequency, duration, and intensity of acceleration and 
through a proprietary algorithm converts the pattern of motion into step counts and 
activity counts (a value used to quantify both intensity and duration of physical activity).  
Although steps are not counted directly, the number of steps for each individual can be 
reliably derived from data obtained by a waist-worn device (Gironda et al. 2007; 
Garriguet et al. 2015).  In general, the available technology is well suited to accurately 
capture DSC (Case et al. 2015), supporting its use in this study.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The target population will be patients with hemophilia A without FVIII inhibitors who have 
been treated with FVIII agents to control or prevent bleeds.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by the patient or a legal guardian

Able to comply with the study protocol, in the investigator’s judgment
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
49/Protocol BH30071, Version 4

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures, including the completion of patient-reported 
outcome questionnaires and bleed and medication diary through the use of an 
electronic device

Aged 12 years or older at the time of informed consent

Body weight 40 kg at the time of screening 

Diagnosis of severe congenital hemophilia A (intrinsic FVIII level 1%) 

A negative test for inhibitor (i.e., 0.6 BU) within 8 weeks of enrollment

No documented inhibitor (i.e., 0.6 BU), FVIII half-life 6 hours, or FVIII recovery 
66% in the last 5 years

Patients who completed successful immune tolerance induction (ITI) at least 5 years 
before screening are eligible, provided they have had no evidence of inhibitor 
recurrence (permanent or temporary) as may be indicated by detection of an 
inhibitor, FVIII half-life 6 hours, or FVIII recovery 66% since completing ITI 
(Antun et al. 2015).

Documentation of the details of prophylactic or episodic FVIII treatment and of 
number of bleeding episodes for at least the last 24 weeks

For patients on no prophylaxis (episodic treatment) pre-study, 5 bleeds in the last
24 weeks prior to study entry

Patients who were on FVIII prophylaxis for at least the last 24 weeks, can be 
enrolled regardless of the number of bleeds during this period. Eligibility will be 
based on investigator’s attestation of adequate prophylaxis regimen.

At least 40 patients who were on FVIII prophylaxis pre-enrollment will have been 
enrolled for a minimum of 24 weeks in Study BH29768 (non-interventional) 

Adequate hematologic function, defined as platelet count 100,000/L and 
hemoglobin 8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5 the upper limit of normal 
(ULN) (excluding Gilbert’s syndrome) and both AST and ALT 3 ULN at the time 
of screening; no clinical signs or known laboratory/radiographic evidence consistent 
with cirrhosis

Adequate renal function, defined as serum creatinine 2.5 ULN and creatinine 
clearance by Cockcroft-Gault formula 30 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year and are approved by local health authorities and ethics committees
during the treatment period and for at least 5 elimination half-lives (24 weeks) after 
the last dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (1 year of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
50/Protocol BH30071, Version 4
Examples of highly effective contraceptive methods with a failure rate of 
1% per year include proper use of combined oral or injected hormonal 
contraceptives, bilateral tubal ligation, male sterilization, hormone-releasing 
intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment

Previous (in the past 12 months) or current treatment for thromboembolic disease 
(with the exception of previous catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic 
disease 

Other conditions (e.g., certain autoimmune diseases) that may increase risk of 
bleeding or thrombosis 

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Known HIV infection with CD4 count 200 cells/L within 24 weeks prior to 
screening.  Patients with HIV infection who has CD4 200 and meet all other criteria 
are eligible.

Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use 
during the study, with the exception of anti-retroviral therapy

Patients who are at high risk for TMA (e.g., have a previous medical or family history 
of TMA), in the investigator’s judgment.

Concurrent disease, treatment, or abnormality in clinical laboratory tests that could 
interfere with the conduct of the study, may pose additional risk, or would, in the 
opinion of the investigator, preclude the patient’s safe participation in and 
completion of the study

Planned surgery (excluding minor procedures such as tooth extraction or incision 
and drainage) during the study

Receipt of:
Emicizumab in a prior investigational study
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A non-hemophilia-related investigational drug concurrently, within last 30 days
or 5 half-lives, whichever is shorter
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
51/Protocol BH30071, Version 4

Inability to comply with the study protocol in the opinion of the investigator

Pregnant or lactating, or intending to become pregnant during the study

Women who are not postmenopausal (48 weeks of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.
4.2
METHOD OF TREATMENT ASSIGNMENT
Patients who received episodic treatment with FVIII prior to study entry will be 
randomized in a 2:2:1 ratio to receive either prophylactic emicizumab at 3 mg/kg/wk 
subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk (Arm A) or 3 mg/kg/2wks (Arm B) 
subcutaneously, or to the control arm (no prophylaxis; Arm C).  The time between 
screening and enrollment of eligible patients should be 6 weeks; otherwise, patients 
must be re-screened to determine if they continue to meet the inclusion and exclusion 
criteria.  A central randomization procedure will be used for all patients who fulfill the 
entry criteria at screening.  A block-based randomization method will be used, stratified 
by the number of bleeds in the last 24 weeks (9 or 9).  The proposed randomization 
method is designed to balance treatment group assignment within the prognostic 
stratification factor.
Patients on prophylactic FVIII prior to study entry will be enrolled in a separate 
therapeutic arm to receive prophylactic emicizumab (Arm D).
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Emicizumab
Emicizumab Drug Product will be supplied by the Sponsor as a sterile liquid for SC 
injection, contains no preservatives, and requires storage at 2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, 20 mmol/L histidineaspartic acid buffer (pH 6.0).  
For information on the formulation and handling of emicizumab, see the Investigator's 
Brochure.  In order to minimize the number of injections for patients in certain 
weight categories, the administration per single injection of up to 2 mL drug product 
solution will be permitted.  This will require pooling of emicizumab drug product solution 
from up to two 1-mL vials into a single syringe, using a new transfer needle for each vial.  
The detailed procedure for vial pooling is described in the Instructions for Use (IFU).
4.3.2
Dosage, Dose Adjustment, and Administration
As discussed in Section 3.3.1, when each patient starts on prophylactic emicizumab, he 
or she will receive 3 mg/kg/wk for 4 weeks as loading doses, followed by 1.5 mg/kg/wk 
or 3 mg/kg/2wks, for a total of at least 24 weeks and as long as they continue to derive 
sufficient clinical benefit.  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
52/Protocol BH30071, Version 4
Patients in Arms A or B with 2 qualifying bleeds within 24 weeks, may have the 
opportunity to increase their emicizumab maintenance dose to 3 mg/kg/wk starting on 
Week 25, if they receive approval from the Medical Monitor. Qualifying bleeds are 
defined as spontaneous, verified by investigator (e.g., by imaging or physical 
examination) and occurring while on prophylactic emicizumab at steady-state on the 
maintenance dose (after the Week 5 visit). Similarly, patients in Arm C who switch to 
emicizumab at Week 25 and experience 2 qualifying bleeds may have the opportunity 
to increase their emicizumab maintenance dose to 3 mg/kg/wk starting on Week 49, if 
they receive approval from the Medical Monitor.
Patients in Arm D who experience suboptimal control (two qualifying bleeds or more) on 
prophylactic emicizumab at the maintenance dose may have the opportunity to escalate 
to 3 mg/kg/wk immediately after the second qualifying bleed, with approval from the 
Medical Monitor.
If the investigator believes that a specific patient warrants dose escalation based on a 
different reason, they may discuss the case with the Medical Monitor for consideration 
and potential approval.
During study prolongation. each patient may choose a preferred emicizumab dosing 
regimen among those permitted (i.e., emicizumab 1.5 mg/kg/wk, 3 mg/kg/2wks, or 
6 mg/kg/4wks) and continue on that dosing regimen until discontinuation from the 
study.  A change from 1.5 mg/kg/wk to 3 mg/kg/2wks or 6 mg/kg/4wks can be 
initiated at the next scheduled treatment of the QW dosing regimen.  A change from 
3 mg/kg/2wks to 1.5 mg/kg/wk or 6 mg/kg/4wks can be initiated at the next scheduled 
treatment of the Q2W dosing regimen.  A patient may switch dosing regimens only 
once.  However, if the investigator believes that a patient warrants an additional 
change in dosing regimen, he or she may discuss the case with the Medical Monitor for 
consideration and potential approval.
If a patient has a systemic hypersensitivity reaction or severe adverse reaction that may 
be attributable to emicizumab, subsequent doses should be held until the situation is 
discussed with the Medical Monitor and approval to resume dosing is given.  Should
certain, unanticipated events occur during the study that require treatment with multiple 
daily administrations of FVIII concentrates, such as non-elective surgery or 
severe/life-threatening bleeds, the investigator should contact the Medical Monitor 
immediately to discuss such cases and the management of future emicizumab doses.  
Due to emicizumab’s unique mechanism of action and the characteristics of its binding 
to FIX and FX, co-administration of FVIII and emicizumab is believed to be safe and in 
general should be continued on schedule.  However, an individualized decision should 
be made in consultation with the Medical Monitor.  Any other emicizumab dose 
adjustment request will require discussion of the clinical case with and approval from the 
Medical Monitor.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
53/Protocol BH30071, Version 4
Study site HCPs will be trained on how to properly prepare the study medication and 
administer the correct calculated dose subcutaneously as described in the IFU 
document.  Patients will in turn be trained on study medication preparation and 
self-administration by an HCP using the IFU as support.  In the event that a caregiver 
will ultimately administer study drug to the patient in the home setting, the caregiver is to 
be trained.  The HCP is to inform the patient/caregiver of the volumetric dose to be 
administered and dosing frequency.
Details on the devices to be used for study medication withdrawal from vial and SC 
injection are provided in the Pharmacy Manual.
Emicizumab will be administered as a SC injection in the home setting, with one dose 
every week or every 2 weeks, after a period of in-clinic administration and training. The 
first five drug administrations must be performed in a monitored setting, such as an 
infusion center, clinic, or hospital, with a 60-minute observation period following each of 
the first three doses.  For patients with a previous history of a clinically significant 
hypersensitivity reaction, additional precautions as described in Section 5.1.2.2 should 
be considered.  The fourth and fifth scheduled study drug administrations must also be
performed in the monitored setting.  At that time, the patient/caregiver will also have the 
opportunity to ask any questions to the HCP before the scheduled start of home 
administration.  The patient/caregiver will observe at least one SC injection performed by 
the HCP and successfully administer at least one SC injection while being observed by a
HCP prior to starting home administration.  Each site will have the discretion to provide 
additional training if deemed appropriate. If, despite additional training, the investigator 
determines that the patient/caregiver is unable to inject emicizumab correctly, 
arrangements may be made to identify an alternative trained caregiver or HCP to 
administer the SC injections. At the investigator’s discretion, study drug may be 
administered by a trained home nursing professional at the patient's home or another 
suitable location.
Patients/caregivers will be provided with the clinic contact information, to use in case 
they have questions related to self-administration between visits.
Medication administration errors during training will be recorded and competence of the 
patient or caregiver to administer at home will be documented in the electronic Case 
Report Form (eCRF).  If necessary, patients or their HCP may choose to continue 
administration of study drug in the clinic.  Compliance in the home setting is to be 
monitored by recording emicizumab administration on the handheld device and 
recording collected used and unused vials at each site visit.
Patients shall administer study medication on the schedule dosing days.  On days when 
trough plasma samples are to be collected, patients will be dosed after samples are 
drawn, potentially at the clinic (self-administration).  On the other days, for patients on 
once weekly dosing, if the patient forgets or cannot administer study medication on the 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
54/Protocol BH30071, Version 4
scheduled dosing day, study medication should be administered as soon as possible 
within a window of 3 days from the scheduled dosing date.  If more than 3 days has 
passed, the missed dose should be skipped and the patient should take his or her next 
dose at the next scheduled time with the study medication dosing resumed in 
accordance to the original dosing schedule.  For patients on once every 2 weeks dosing, 
if the patient forgets or cannot administer study medication on the scheduled dosing day, 
study medication should be administered as soon as possible within a window of 7 days 
from the scheduled dosing date.  If more than 7 days has passed, the patient should 
take his or her next dose at the next scheduled time with the study medication dosing 
resumed in accordance with the original dosing schedule. All emicizumab dosing should 
be clearly documented on the handheld device, both during patient’s visits in clinic and 
when the patient is out of the clinic.
Any overdose or incorrect administration of study drug will be determined from 
emicizumab data entered into the handheld device. Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.
Patients and/or the caregiver will be provided with alert cards, which they will be 
requested to carry at all times.  These will include guidance on recognizing 
signs/symptoms of thromboembolic events or allergic/anaphylactic/anaphylactoid 
reactions and how to obtain emergency care.  In addition, alert cards are designed to 
notify non-study HCPs that emicizumab will interfere with certain coagulation laboratory 
tests (see the RO5543262 [Emicizumab] Investigator’s Brochure for more information) 
and the investigator should be contacted for assistance in interpreting the test results.
Guidelines for dosage modification are discussed in Section 3.1, and those for treatment 
interruption or discontinuation are provided in Section 4.6.
4.3.3
Investigational Medicinal Product Accountability
Emicizumab, the only investigational medicinal product (IMP) in Study BH30071, is 
required for completion of this study and will be provided by the Sponsor, and 
accountability for each vial is required throughout the study.  The study site will 
acknowledge receipt of IMPs using the interactive voice or Web response system (IxRS)
to confirm the shipment condition and content.  Any damaged shipments will be replaced.
Used and unused IMP vials will be returned by study patients to the study site and 
appropriately accounted for.  Used vials will then be disposed of at the study site 
according to the study site’s institutional standard operating procedure.  Instructions 
regarding how to handle unused vials should be obtained from the Sponsor. If the 
investigator prefers to destroy the IMP at his or her site, the site's method of IMP 
destruction must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
55/Protocol BH30071, Version 4
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Emicizumab
The Sponsor will offer post-study access to the study drug (emicizumab) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and the treating physician comply with and satisfy any legal or 
regulatory requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The patient is eligible and has access to a study providing access to the drug.

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for hemophilia A 

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for hemophilia A 

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf.
4.4
CONCOMITANT AND RESCUE THERAPY
4.4.1
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
4 weeks prior to screening to the study completion/discontinuation visit.  In addition, use 
of long-acting medications taken infrequently (e.g., zoledronic acid, Denosumab) will be 
recorded as well.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
56/Protocol BH30071, Version 4
Concomitant use of the following drugs and therapies will be permitted:

To avoid bleeds before adequate emicizumab level is reached, patients in Arm D 
will continue their regular FVIII prophylaxis until the second emicizumab loading 
dose.  Concomitant routine FVIII prophylaxis is not permissible otherwise during the 
study. 

Drugs intended to treat bleeds on an episodic basis, including FVIII.  Specific 
dosages of FVIII will not be mandated in the study; however, investigators should 
consider that circulating emicizumab may increase patients’ coagulation potential.  
Investigators should review with patients the dose to be used to treat breakthrough 
bleeds.  Breakthrough bleeds should be treated with the lowest FVIII dose expected 
to achieve hemostasis, which may be lower than the patients’ prior FVIII dose.  For 
information on the formulation, packaging, and handling of agents, see the local 
prescribing information for the marketed drug in question.

The use of bypassing agents is unexpected in hemophilia A patients without 
inhibitors.  In the interest of completeness, Appendix 9 includes dosing and 
monitoring guidance for the use of bypassing agents for patients in Study BH30071, 
in case such unforeseen circumstances occur.  

Drugs and therapies to treat adverse events and use of topical antiseptics, 
anesthetics, eye drops, etc., that are not considered to result in systemic exposure
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 4 weeks
prior to initiation of study treatment:

Drugs that would affect hemostasis (e.g., aspirin, non-steroidal anti-inflammatory 
drugs that are not selective or preferential COX-2 inhibitors, or anticoagulants [other 
than to flush, dwell, or de-clot a venous access device])
Drugs intended to control bleeding episodes or used in the context of minor 
surgery (e.g., tooth extraction) or injuries (e.g., concussion) to prevent 
deterioration or given if deemed medically necessary for management of certain 
conditions (e.g., post cardiac surgery) are permitted.

Use of systemic immunomodulators (e.g., interferon) other than anti-retroviral 
therapy 

Elective surgery (excluding minor procedures such as tooth extraction, CVAD 
removal, or incision and drainage as well as emergency surgeries) 

Use of other investigational drugs 
Use of concomitant prophylactic regimen is prohibited during the study, except for 
patients on Arm D who will continue FVIII prophylaxis until the Week 2 dose.  
(Short-term prophylaxis [e.g., around the time of surgery], however, is permitted.)
If prohibited therapy is administered for any reason, it should be recorded on the eCRF
(except any hemophilia-related medication, which will be recorded on the 
Bleed/Medication Questionnaire).  If prohibited treatment is prescribed or considered 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
57/Protocol BH30071, Version 4
medically necessary, the medical monitor should be consulted to discuss any changes in 
the benefit/risk and determine whether the patient should continue on the study.
4.5
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of assessments performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Patients who elect not to 
sign the optional activity monitoring portion of the Informed Consent Form will continue 
to undertake the screening tests or evaluations for Study BH30071.  Informed Consent 
Forms for enrolled patients and for patients who are not enrolled will be maintained at 
the study site.  Parents or legally authorized representative of adolescents will complete 
an Informed Consent Form and adolescents will complete an Informed Assent Form.
All screening evaluations must be completed within 6 weeks prior to the first dose and 
reviewed to confirm that patients meet all eligibility criteria before enrollment and
randomization.  The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, procedures, use of alcohol and 
drugs of abuse within the past year, and medication allergies.  In particular, sites should 
record whether the patient has any history of FVIII inhibitor, anaphylaxis or known 
thrombophilia.  It should also include all medication taken in the 4 weeks prior to 
screening (including prescription, over-the-counter, and herbal/homeopathic remedies 
and therapies) or in the 24 weeks prior to screening for medications intended to treat 
osteopenia or osteoporosis.  If imaging tests of bone health (e.g., densitometry, dual 
energy X-ray absorptiometry [DEXA]) were performed in the year prior to screening, the 
results should be recorded.  Finally, number of bleeds during the 24 weeks prior to study 
enrollment should be documented, as well as the number of school/work days missed 
and number of days hospitalized during the 24 weeks prior to study entry.
Demographic data will include age, sex, and self-reported race and ethnicity.
4.5.3
Physical Examinations
A complete physical examination should include but not necessarily be limited to the 
evaluation of head, eye, ear, nose, and throat and include cardiovascular, 
dermatological, musculoskeletal (including HJHS; see Appendix 8), respiratory, 
gastrointestinal, and neurological systems, height, and weight.  Any abnormality 
identified during screening should be recorded on the General Medical History and 
Baseline Conditions eCRF.  Subsequently, a targeted (i.e., musculoskeletal, 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
58/Protocol BH30071, Version 4
dermatological) and/or symptom-driven examination should be conducted as noted in 
the schedule of assessments or as clinically indicated.  New or worsened abnormalities 
from screening should be recorded as adverse events.  A complete physical examination 
will be performed at screening and at least targeted physical examinations will be 
performed at subsequent visits.
4.5.4
Vital Signs
Vital signs will include measurement of heart and respiratory rate, temperature, systolic
and diastolic blood pressure, and weight and should be recorded before study drug 
administration.  Frequency of vital sign assessments should follow the schedule of 
assessments but may also be taken anytime as unscheduled assessments as judged by 
the investigator.
4.5.5
Laboratory, Biomarker, and Other Biological Samples
Local laboratory assessments will be performed as indicated on the schedule of 
assessments.  When study drug administration is scheduled on days of clinic visit, 
laboratory samples should be drawn before the administration of study drug.  Laboratory 
assessments will include the following:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells], mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width)

Serum chemistries, (sodium, potassium, chloride, glucose, blood urea nitrogen, 
creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, 
albumin, alanine aminotransferase, aspartate aminotransferase, lactate 
dehydrogenase, alkaline phosphatase, creatine phosphokinase, and uric acid).

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening and within 7 days 
prior to initiation of study medication, if applicable.
Urine pregnancy tests will be performed at specified subsequent visits.  If a 
urine pregnancy test result is positive, it must be confirmed by a serum 
pregnancy test.
The following samples will be sent to the Sponsor or a designee for centralized analysis:

Plasma samples for PK analysis

Plasma samples for immunogenicity assessment (ADA)

Serum and plasma for PD and exploratory PD biomarker assessments (aPTT, PT, 
FVIII activity, and others as listed in Appendix 2)

Plasma samples for anti-FVIII antibody measurement (inhibitor titer) will be sent to 
the Sponsor throughout the study, with the exception of the test needed at 
screening for patients who do not have a documented negative inhibitor test 
(0.6 BU) within 8 weeks prior to enrollment.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
59/Protocol BH30071, Version 4
4.5.6
Electrocardiograms
ECG recordings will be obtained at study sites at specified timepoints, as outlined in the 
schedule of assessments (see Appendix 1). 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  The following parameters will be 
obtained: QT, RR, HR, QTcB, QTcF, PR and QRS and T- and U-wave morphology.  
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes.
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and ideally should not be obtained within 
3 hours after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
Any ECG changes that are deemed clinically significant by the investigator (e.g., 
associated with symptoms or lead to a change in study treatment or concomitant 
treatment, or discontinuation from study treatment), must be reported as an adverse 
event on the adverse event eCRF.  The investigator or designee must review, sign, and 
date all ECG tracings. The ECG may be repeated if investigator deems it appropriate.  
Paper copies will be kept as part of the patient’s permanent study file at the site. 
4.5.7
Electronic Patient-Reported Outcomes
Patient reported data will be collected electronically using two devices:  a personal 
handheld mobile device for the Bleed/Medication Questionnaire and a tablet at study 
sites for HRQoL questionnaires.  To capture bleed data, emicizumab use, and other 
hemophilia medication use during study treatment, patients will complete the 
Bleed/Medication Questionnaire on a handheld device that will be provided to them 
during the Week 1 visit at the study site.  This device will remain with the patient for the 
duration of the study to enter bleed and medication data weekly at a minimum.  Patients 
who withdraw from emicizumab treatment will continue to record bleeds and hemophilia 
medication administration until they complete the safety follow-up visit. In addition, at 
specified visits, patients will complete HRQoL, health status, and satisfaction/preference 
questionnaires on a tablet device that will remain at study sites.  The instructions for 
completing the patient-reported outcome (PRO) questionnaires electronically will be 
provided by the investigator staff during the Week 1 visit at the site.  The data will be 
transmitted automatically after entry to a centralized secure database at the vendor.  Of 
note, if the electronic data collection system becomes unavailable, the Sponsor may 
instruct sites to collect PRO data (bleed data, emicizumab use, hemophilia medication 
use, and HRQoL) on paper.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
60/Protocol BH30071, Version 4
HRQoL:
The Haem-A-QoL and the Haemo-QoL-SF will be used to measure HRQoL in adults and 
adolescents, respectively (see Appendix 3 and Appendix 4). The Haem-A-QoL was 
designed for adult patients with hemophilia. It consists of 46 items comprising 
10 dimensions (physical health, feelings, view, sport and leisure time, work and school, 
dealing, treatment, future, family planning, and relationships/partners) and a scale 
representing total score.  Items are rated along 5 response options, although for some 
items there is also a ‘not applicable’ option (von Mackensen and Gringeri 2005; 2010). 
The Haemo-QoL has been developed in a series of age-related questionnaires to 
measure HRQoL in children and adolescents with hemophilia (Bullinger et al. 2002; 
von Mackensen and Bullinger 2004; Pollak et al. 2006). These versions include a 
77-item long form, a 35-item as well as a 16-item short form, and an 8-item index form. 
The short version for older children containing 35 items was selected for this study. This 
version covers nine dimensions considered relevant for the children’s HRQoL (physical 
health, feelings, view of yourself, family, friends, other people, sports and school, dealing 
with hemophilia and treatment). Items are rated with five respective response options: 
never, seldom, sometimes, often, and always.  Higher scores for both HRQoL measures 
are indicative of poorer HRQoL. 
Health Status:
The EQ-5D-5L (see Appendix 5) is a generic, preference-based health utility measure 
that assesses health status and is used to inform pharmacoeconomic evaluations.  The 
EQ-5D-5L consists of two parts.  The first part, health state classification, contains five 
dimensions of health:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (Herdman et al. 2011; Janssen et al. 2013).  Published weights are 
available that allow for the creation of a single summary score. Overall scores typically
range from 0 to 1, although a score below 0 is theoretically possible representing a state 
worse than death, with low scores representing a higher level of dysfunction. The 
second part is a 0 to 100-point visual analog scale (VAS) that assesses current health 
status; higher scores are reflective of better health.
Patient Preference and Satisfaction:
Patient preference and satisfaction will be assessed through two measures.  Preference 
for emicizumab treatment will be assessed through the Preference Survey, which asks 
patients to report which treatment they would prefer to continue to receive after having 
been treated with IV FVIII (episodic or prophylaxis) and SC emicizumab.  Patients who 
express a preference are then asked to identify which reasons may have influenced their 
decision and indicate the top three reasons for their choice.  Patients in Arms A, B, or D 
will complete the Patient Preference Survey at Week 17 on emicizumab.  In addition, 
understanding the preference and satisfaction of patients who were previously on FVIII 
prophylaxis is of particular interest.  Patients in Arm D will complete the Patient 
Satisfaction questionnaire, SQ-ISHI, at baseline and at the Week 21 or 25 visit.  This 
13-item measure was designed to assess satisfaction with SC emicizumab or with IV 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
61/Protocol BH30071, Version 4
FVIII prophylaxis by probing the general concepts of discomfort, worry, and difficulty with 
injections; confidence with treatment; duration, and frequency of treatment; ease of 
treatment; impact on daily activities; adherence; and overall satisfaction.
Missed Days of School or Work
Patients will also be asked to document the number of days of school or work missed in 
the previous 4 weeks at the timepoints outlined in the schedule of assessments (see 
Appendix 1). 
4.5.8
Definitions
DEFINITION OF A BLEED
For the purposes of the efficacy analyses, a standardized definition of bleed, adapted 
from criteria defined by the Subcommittee on Standards and Criteria, FVIII/FIX 
subcommittee of the International Society of Thrombosis and Hemostasis, and similar to 
that used in a recent clinical study, will also be utilized in this study 
(Blanchette et al. 2014; Mahlangu et al. 2014).
An event is considered a treated bleed if coagulation factors are administered to treat 
signs or symptoms of bleeding (e.g., pain, swelling, etc.).

Bleeds starting from the first sign of bleed and ending 72 hours after the last 
treatment for the bleed, within which any symptoms of bleeding at the same location 
or injections are 72 hours apart, are considered the same bleed.

Any injection to treat the bleed, taken 72 hours after the preceding injection, is 
considered the first injection to treat a new bleed at the same location.

Any bleed at a different location is considered a separate bleed regardless of time 
from last injection.
An additional definition of all bleeds (i.e., both treated and not treated with coagulation 
factors) will be applied for certain secondary efficacy analyses.
DEFINITIONS OF BLEED SITES

Target joints:  defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and 
ankle) into which repeated bleeds occur (frequency of 3 bleeds into the same joint 
over the last 24 weeks prior to study entry)

Joint bleeds (sites per the Bleed/Medication Questionnaire) 

Muscle bleeds (sites as per the Bleed/Medication Questionnaire)

Other bleeds (sites as per the Bleed/Medication Questionnaire)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
62/Protocol BH30071, Version 4
DEFINITIONS OF BLEED TYPES
In addition, the assessment of a bleed will be separated into spontaneous bleeds, 
traumatic bleeds, and bleeds related to procedure/surgery.  Both spontaneous bleeds 
(i.e., the occurrence of hemorrhage where neither the patient nor a caregiver can identify 
a reason) and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such 
as trauma, “strenuous” activity, or “overuse”) will be collected.

Spontaneous bleeds:  Bleeds should be classified as spontaneous if a patient 
records a bleed when there is no known contributing factor such as definite trauma, 
antecedent “strenuous” activity or “overuse” or “procedure/surgery.”  The 
determination of what constitutes “strenuous” or “overuse” will be at the discretion of 
the patient.  For example, light jogging may be considered “non-strenuous” while 
sprinting may be considered “strenuous,” lifting of weights for a short period of time 
may be considered “moderate use” while repetitive weightlifting may be considered
“overuse.” 

Traumatic bleeds:  Bleeds should be classified as traumatic if a patient records a 
bleed when there is a known or believed reason for the bleed.  For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 
obvious injury, the bleed would be recorded as a traumatic bleed because, although 
no injury occurred, there was antecedent “strenuous” activity. Bleeds subsequent to 
injuries would certainly be classified as traumatic.  

Bleeds related to procedure/surgery:  such as hematomas resulting from any 
surgeries or invasive procedures (e.g., tooth extractions, venipuncture, or SC drug 
administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy, etc.) would not be counted 
as bleeds but will be collected on the Bleed/Medication Questionnaire.  Bleeds 
related to procedure/surgery are not associated with any trauma except 
procedure/surgery-induced trauma.  
Patients (or patient’s legally authorized representative) will complete an electronic 
Bleed/Medication Questionnaire whenever a bleed occurs, or at least weekly to confirm 
all bleeds have been recorded.  For each bleeding episode, they will provide information 
on the above topics as well as on the medication used to treat the bleed.  Hemophilia 
medications that were taken will also be collected through the Bleed/Medication 
Questionnaire.
4.5.9
Activity Assessments
Patients who chose to participate in this part of the study should wear the study device 
while awake every day during three 2-week periods in the study: Weeks 12, 
Weeks 2324, and Weeks 4748.  Patients will be instructed to wear the accelerometer 
on an elastic belt (supplied with the device) at the natural waistline on the right hip in line 
with the right axilla upon arising in the morning and continuously until retiring at night for 
14 consecutive days.  Patients will be instructed to charge the device weekly.  A valid 
day of monitoring is defined as 10 or more wear hours per day.  Wear time will be 
determined by subtracting non-wear time from 24 hours.  Non-wear is defined by an 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
63/Protocol BH30071, Version 4
interval of at least 60 consecutive minutes of zero activity intensity counts, with 
allowance for 12 minutes of counts between 0 and 100.  To provide reliable estimates, 
analyses will be restricted to participants with at least 8 valid days of accelerometer 
monitoring during each observation period (Troiano et al. 2008; Ahn et al. 2015).
The data will be collected using the study device to provide daily measures of DSC:  
DSC, mean activity (counts [cts]/min), peak activity (the largest activity value [cts/min]), 
and total activity counts (total cts/min over a 24-hour period) recorded each day.  Mean 
daily activity is the average of the activity counts among all epochs (e.g., 1-minute period) 
that falls within the active periods during a 24-hour period.
An activity count is a measure of the acceleration that is measured by the device.  The 
device measures acceleration as the sum of the maximum acceleration values each 
second during the epoch (acceleration is sampled 30 times/second).  While DSC will be 
referenced as the primary physical activity measurement, it should be noted that activity 
counts (total, mean, and peak) do provide a secondary alternative for measuring 
physical activity relevant to the magnitude of energy expended by the subject.  While 
DSC might provide more reliable correlation data, activity counts can help identify the 
possibility of increased activity intensity in the event that DSC remains relatively 
unchanged over time.
The number of hours the device was worn each day will also be derived from the activity 
counts data.
Patients will return their devices to the respective site at Weeks 3, 25, and 49 in order for 
the site to transfer the data from the device to the database.
4.5.10
Samples for Roche Clinical Repository
4.5.10.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research. RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
64/Protocol BH30071, Version 4

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (see Section 4.5.10) will not be 
applicable at that site.
4.5.10.3
Sample Collection
The following samples will be collected for research purposes, including but not limited 
to research on genetic (inherited) biomarkers related to emicizumab, hemophilia A, or 
other coagulation disorders:

Blood for DNA extraction (at Week 2, 3, 4, or 5)
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the central laboratory services manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The genetic biomarker specimens will undergo additional processes to ensure 
confidentiality, as described below.  
4.5.10.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, the blood sample is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
65/Protocol BH30071, Version 4
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient or 
patient guardian the objectives, methods, and potential hazards of participation in the 
RCR.  Patients will be told that they are free to refuse to participate and may withdraw 
their specimens at any time and for any reason during the storage period.  A separate, 
specific signature will be required to document a patient's agreement to provide optional 
RCR specimens.  Patients who decline to participate will not provide a separate 
signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.10.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RCR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the RCR Subject Withdrawal Form and, if 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
66/Protocol BH30071, Version 4
the study is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  A patient's withdrawal from Study BH30071 
does not, by itself, constitute withdrawal of specimens from the RCR.  Likewise, a 
patient's withdrawal from the RCR does not constitute withdrawal from Study BH30071.
4.5.10.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient’s inability or unwillingness to comply with protocol requirements 
non-compliance despite appropriate education measures taken by the clinical site.
Patients may elect to withdraw from the activity monitoring but continue participation in 
the remainder of the study.  If a patient decides to withdraw only from the activity 
monitoring prematurely, the patient will continue treatment and follow-up as per the 
study protocol.  The primary reason for withdrawal from activity monitoring should be 
documented on the appropriate eCRF.  Patients who withdraw from this part of the study
will not be replaced.
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
67/Protocol BH30071, Version 4
4.6.2
Study Treatment Discontinuation
Patients must stop study treatment if they experience the following:

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.  Patients who become pregnant should immediately stop treatment and be
managed as per local guidelines.  
If the patient discontinues study treatment, bleed and bleed medication data should be 
provided by the patient via the electronic, handheld device until the safety follow-up visit 
(24 weeks after last study drug administration).
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

Incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence (e.g., Bleed/Medication Questionnaire data not checked by 
investigator/co-investigator for 8 weeks)

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Emicizumab is not approved and is currently in clinical development.  Thus, the 
complete safety profile is not known at this time.  The safety plan for this study is 
designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
68/Protocol BH30071, Version 4
5.1.1
Patient Selection
The inclusion and exclusion criteria in this study are designed to select patients who are 
not at increased risk based on the current understanding of the investigational 
medication.  See Section 4.1.1 and Section 4.1.2 for full inclusion and exclusion criteria, 
respectively.
5.1.2
Risks Associated with Emicizumab
5.1.2.1
Injection-Site Reactions
In the completed and ongoing Japanese studies, injection-site reactions have been 
observed in some patients with hemophilia A.  These local injection-site reactions 
included injection-site erythema, injection-site hematoma, injection-site rash, 
injection-site discomfort, injection-site pain, and injection-site pruritus.  All local 
injection-site reactions were of mild intensity.  Further details of the observed 
injection-site reactions are available in the RO5543262 (Emicizumab) Investigator’s 
Brochure.
Directions for emicizumab administration should be followed, as outlined in Section 3.3.1, 
Section 4.3.2, and in the IFU.  
5.1.2.2
Hypersensitivity Reaction, Anaphylaxis, Anaphylactoid 
Reaction
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, 
including anaphylaxis and anaphylactic reactions, may occur.  In completed and ongoing 
clinical studies of emicizumab, no severe hypersensitivity reactions have been reported.  
These events should be reported as Serious Adverse Events or Adverse Events of 
Special Interest as described in Section 5.2.3.
HCPs administering the study medication in the clinic must be trained in the appropriate 
administration procedures, be able to recognize the signs and symptoms associated with 
potential hypersensitivity, anaphylactic, and anaphylactoid reactions, and should be 
familiar with Sampson’s criteria for defining anaphylaxis (Sampson et al. 2006;
see Appendix 7 and Appendix 10).  HCPs should also instruct patients how to recognize 
the signs and symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions
and to contact an HCP or seek emergency care in case of any such occurrence. 
Patients/caregivers will also receive two alert cards to remind them of this information 
and these instructions should any of these reactions occur.
For patients with a previous history of a clinically significant hypersensitivity reaction, 
after each of the first three doses, the site will call the patient 24 hours after each dose to 
assess the status of the patient.  Additional precautions following each of these doses 
may also be considered including having an extended observation period or IV access 
prior to dosing, etc.  The investigator may include these or other precautions, as deemed 
appropriate. 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
69/Protocol BH30071, Version 4
5.1.2.3
Hypercoagulation and Thromboembolic Events
As of May 2019, four thromboembolic events have been observed in 4 patients receiving 
emicizumab, as follows.  One event of Grade 1 device occlusion (non-serious) was 
reported in 1 patient (Study BH29884).  The event resolved and was assessed by the 
investigator as not related to emicizumab.  Also in Study BH29884, 2 patients 
experienced a total of two serious thromboembolic adverse events (thrombophlebitis 
superficial and cavernous sinus thrombosis).  In Study MO391291, 1 patient 
experienced a serious adverse event of acute myocardial infarction.  Details of the 
serious adverse events are described below.
The first patient from Study BH29884 experienced a right knee hemarthrosis and 
self-administered 200 units/kg/day of aPCC for 2 consecutive days.  The patient was 
hospitalized after a diagnosis (by MRI) of Grade 3 cavernous sinus thrombosis.  No 
anticoagulation was administered; treatment with emicizumab was withheld.  The 
patient was discharged after symptoms improved with supportive care.  A follow-up 
MRI was normal with no evidence of thrombus, and the event was considered resolved.  
Treatment with emicizumab was restarted.  The investigator assessed the event as being 
related to emicizumab and aPCC. 
The second patient from Study BH29884 experienced a spontaneous right knee 
hemarthrosis and self-administered 100 units/kg/day aPCC for 2 consecutive days.  The 
patient 
 his right shin for several hours to treat pain.  Extensive skin 
necrosis of the right shin and locally limited skin necrosis of the left shin subsequently 
developed.  The patient was hospitalized and an ultrasound indicated superficial 
thrombosis of the right saphenous vein (no evidence of deep vein or arterial thrombosis).  
The patient was treated with supportive care and his condition improved.  Emicizumab 
was permanently discontinued.  The investigator assessed the skin necrosis as due to 
the thromboembolic event and related it to emicizumab and aPCC.  Both skin necrosis 
(Grade 3) and thrombophlebitis superficial (Grade 2) were reported as recovering. 
The third patient, enrolled in Study MO39129, presented with chest pain, sweating,
and pallor and was diagnosed with ST-elevation myocardial infarction on Day 235 of 
the study.  ECG showed ST elevation, right bundle branch block, and inferior Q waves.  
Troponin was 0.46 ng/ml (reference range:  0.04 ng/ml).  Coronarography 
demonstrated stenosis of the right coronary artery due to thrombotic subocclusion.  
Treatment included stent, unfractionated heparin, clopidogrel, and aspirin.  The event 
resolved after 5 days and treatment with emicizumab was maintained. 
Hypercoagulation and thromboembolic events should be reported as serious adverse 
events or adverse events of special interest as described in Sections 5.2.2 and 5.2.3.  
HCPs should educate patients/caregivers to recognize signs and symptoms of potential 
thromboembolism (i.e., dyspnea, chest pain, leg pain or swelling; or if in the head, 
headache, numbness in the face, eye pain or swelling, or vision impairment) and ensure 
that they understand the importance of seeking appropriate medical attention.  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
70/Protocol BH30071, Version 4
Patients/caregivers will also receive two alert cards to remind them of this information 
and these instructions should thromboembolism be suspected.
5.1.2.4
Thrombotic Microangiopathy
Thrombotic microangiopathy is used to describe a group of disorders with clinical 
features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage 
that can include the kidneys, gastrointestinal system, or central nervous system, etc.  As 
of May 2019, 3 cases of TMA were observed in a Phase III clinical study involving 
patients with hemophilia A with inhibitors while receiving emicizumab.  The first patient 
self-administered 2 doses of aPCC 94 units/kg in 2 days to treat his left knee 
hemarthrosis.  The next day, he started experiencing icterus and severe back pain and 
the patient self-administered 2 doses of rFVIIa 85 g/kg and 2 doses of aPCC 
94 units/kg.  Then, the patient presented with thrombocytopenia, hyperbilirubinemia, and 
acute renal failure with schistocytes on peripheral blood smears. The patient was 
diagnosed with aHUS and treated with plasmapheresis, hemodialysis, and supportive 
care and his condition improved and resolved after 15 days.  The patient discontinued 
treatment with emicizumab.  The second patient self-administered 5 doses of aPCC 74 
units/kg over 3 consecutive days before the serious adverse event onset.  The patient 
had abdominal pain and emesis, acute renal failure, thrombocytopenia, elevated LDH, 
and a low haptoglobin with schistocytes on peripheral blood smears.  The patient was 
diagnosed with aHUS and recovered without plasmapheresis or hemodialysis after 9 
days.  The patient restarted treatment with emicizumab approximately 10 days after 
resolution of the serious adverse event.  
The third patient presented at the hospital complaining of rectal bleeding, postural 
dizziness, and exertional dyspnea.  Of note,
 
.  Multiple doses of rFVIIa were 
administered and various interventions (hemostatic powder application, absorbable 
hemostat packing, and embolization of rectal arteries) were used in an attempt to 
control bleeding.  Despite these measures, the patient continued to have rectal 
hemorrhage.  The patient’s bypassing agent treatment was then changed to aPCC and 
temporary cessation of bleeding was achieved.  Subsequently, the patient developed an 
serious adverse event of thrombotic microangiopathy following concomitant bypassing 
agent treatment.  Emicizumab prophylaxis and aPCC were discontinued and 
therapeutic plasma exchange with albumin was provided.  Three days later, 
investigators assessed the patient’s thrombotic microangiopathy to be improving based 
on laboratory assessments (LDH and platelet count).  However, the patient experienced 
recurrent rectal hemorrhage.  Surgery and arterial embolization were no longer deemed 
to be feasible and the patient was placed on comfort care before passing away the same 
day.  The investigator assessed the patient death as related to the serious adverse event 
of rectal hemorrhage and unrelated to emicizumab, and the thrombotic microangiopathy 
as related to emicizumab and aPCC.  For more details please refer to Investigator 
Brochure.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
71/Protocol BH30071, Version 4
TMA events should be reported as serious adverse events or adverse events of special 
interest (see Sections 5.2.2 and 5.2.3).  
5.1.2.5
Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays Associated with 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII 
activity, and FVIII inhibitor measurement by Bethesda assay) are not reliable and do 
not accurately reflect the patient’s underlying hemostatic status while receiving 
emicizumab prophylaxis (see Section 5.1.4).  Due to the long t1/2 of emicizumab, these 
effects on coagulation assays may persist for up to 6 months after the last dose.
Practitioners, especially emergency care practitioners, should note that life-threatening 
bleeding caused by unreliable standard coagulation tests and inhibitor assays poses a 
risk for patients receiving emicizumab treatment.
Emicizumab’s mechanism of action and resulting interference was clearly demonstrated
in a wide variety of coagulation laboratory tests approved for in vitro diagnostic use.  
Clinical trials also demonstrated the effects of emicizumab on laboratory tests.  
However, as of May 2019, no instances of under-treatment of bleeding events due to 
unreliable standard coagulation tests and inhibitor assays during and after emicizumab 
treatment were observed.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
72/Protocol BH30071, Version 4
5.1.3
Management of Specific Adverse Events
Table 2
Guidelines for Monitoring and Management of Specific Adverse 
Events
Event
Actions to Be Taken
Injection-Site Reaction

Injection-site reactions should be treated as clinically indicated.

Emicizumab should not be injected into areas where the skin is red, 
bruised, tender, or hard or into areas where there are moles or scars.  

In the clinic setting, patients will be monitored for signs of injection-site 
reactions in the period immediately following injections.  Patients will 
be given guidance on reporting injection-site reactions when 
administering drug at home or after they leave the clinic.
Hypersensitivity Reaction, 
Anaphylaxis, 
Anaphylactoid Reaction

Suspected cases should be fully evaluated and treated as clinically 
indicated.

Medicinal products for the treatment of hypersensitivity reactions (e.g., 
epinephrine, antihistamines, and glucocorticoids) and resuscitation 
equipment must be available for immediate use during the initial 
administrations in the infusion center, clinic, or hospital.

If a patient has symptoms of anaphylaxis or severe hypersensitivity, 
administration of study drug must be immediately stopped and 
treatment of the reaction be initiated. 

The investigator should contact the Medical Monitor to assess if the 
clinical benefit clearly outweighs the risk to determine if and when the 
patient should resume taking emicizumab and discuss the patient’s 
continued study participation. If patient continues in the study, the 
next two scheduled doses must be in a monitored setting with at least 
a 60-minute observation period and resuscitation treatment 
immediately available.  After each of these two doses in the clinic, the 
site will call the patient 24 hours after each dose to assess status of 
the patient. 

Investigators may order any pertinent laboratory tests, including an 
unscheduled anti-drug antibody, in the event any of these reactions 
occur.
Hypercoagulation and 
Thromboembolic Events

Please see Sections 3.1 and 3.3.3 for guidance on management of 
breakthrough bleeds.

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with thromboembolic events and immediately begin work-up 
and treatment, as per local guidelines.  

If a patient has a thromboembolic event, further administration of study 
drug should be interrupted.  Decision to resume emicizumab after a 
thromboembolic event must be discussed with and approved by the 
Medical Monitor. 
HCPhealthcare provider; TMAthrombotic microangiopathy.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
73/Protocol BH30071, Version 4
Table 2
Guidelines for Monitoring and Management of Specific Adverse 
Events (cont.)
Event
Actions to Be Taken
Thrombotic 
microangiopathy

Please see Sections 3.1 and 3.3.3 for guidance on management of 
breakthrough bleeds. 

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with TMA and immediately begin work-up and treatment, as 
per local guidelines.  

If a patient has a TMA event, further administration of study drug 
should be interrupted.  Decision to resume emicizumab after an event 
of TMA must be discussed with and approved by the Medical Monitor.
Coagulation Disorder and 
Risk of Bleeding

HCPs should be vigilant for abnormal or unusual bleeding tendencies.  
Coagulation tests or other work-up may be indicated if judged to be 
appropriate by the investigator.  If bleeding is observed, appropriate 
action as per local guidelines must be taken immediately.
HCPhealthcare provider; TMAthrombotic microangiopathy.
5.1.4
Interpretation of Coagulation Assays for Patients Receiving 
Emicizumab
Emicizumab interacts with standard laboratory assays used in the management of 
patients with hemophilia A.  In one-stage assays, emicizumab is associated with a 
supra-physiologically short time to clot formation and thus normalization of aPTT at 
subtherapeutic levels and an overestimation of true FVIII activity.  Emicizumab is not 
recognized or neutralized by FVIII inhibitors, and therefore FVIII inhibitors cannot be 
detected in patients receiving emicizumab by a functional test such as Bethesda or 
Nijmegen-Bethesda assays, which use a one-stage clotting based readout.  Emicizumab 
activity cannot be detected by chromogenic assays using purified bovine coagulation 
proteins and can only be detected using an assay composed of human proteins.  See 
the RO5543262 [Emicizumab] Investigator's Brochure for additional details on which 
tests can be used and how the test results can be interpreted.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
74/Protocol BH30071, Version 4
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
Bleeds considered as serious adverse events should be reported on the appropriate 
adverse event eCRF page regardless of whether the bleeds are consistent with patients’ 
pre-study disease state (the bleed will remain recorded as well on the Bleed/Medication 
Questionnaire).  New, non-serious bleeds consistent with patients’ pre-study disease 
state will not be considered adverse events and will not be recorded on the eCRF but 
will be captured on the Bleed/Medication Questionnaire.
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
75/Protocol BH30071, Version 4

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as grade 14, according to the World Health Organization 
[WHO] Toxicity Grading Scale for Determining The Severity of Adverse Events criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).  
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  These may include suspected or confirmed 
cases.  Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
(see Sampson’s Criteria in Appendix 7)

Thromboembolic events

Microangiopathic hemolytic anemia or thrombotic microangiopathy (e.g., thrombotic 
thrombocytopenic purpura, hemolytic uremic syndrome)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
76/Protocol BH30071, Version 4
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to randomization (randomized 
arms) or initiation of study drug (non-randomized arm), only serious adverse events 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events).
After randomization (randomized arms) or initiation of study drug 
(non-randomized arm), all adverse events will be reported until the patient completes
his or her last study visit (i.e., 24 weeks after the last dose of study drug).  After this 
period, the investigator should report any serious adverse events that are believed to be 
related to prior study drug treatment (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 6) will be used for assessing adverse 
event severity (WHO 2003).  Table 3 will be used for assessing severity for adverse 
events that are not specifically listed in the WHO toxicity grading scale.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
77/Protocol BH30071, Version 4
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not 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, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
78/Protocol BH30071, Version 4
5.3.5.1
Injection-Site Reactions
Local adverse events that occur within 24 hours after study drug administration and, in 
the investigator’s opinion, are judged to be related to study drug injection, should be 
captured as an “injection-site reaction” on the Adverse Event eCRF.  An injection-related 
reaction that is localized should be marked as a “local injection-site reaction.”  
Associated signs and symptoms (e.g., injection-site erythema or injection-site rash) 
should be recorded on the dedicated Injection-Site Reaction eCRF.  Systemic reactions 
should be recorded separately on the Adverse Event eCRF.  The dedicated Injection-
Site Reaction eCRF should only be used to capture the individual signs/symptoms for 
local injection-site reactions. 
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 That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
79/Protocol BH30071, Version 4
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating 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."
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
80/Protocol BH30071, Version 4
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
For concerns about laboratory findings on coagulation-related tests in patients receiving 
emicizumab, please see Section 5.1.4 or contact the Medical Monitor.
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event of 
special interest the occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice in the absence of cholestasis or other causes of hyperbilirubinemia
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
81/Protocol BH30071, Version 4
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of hemophilia.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of hemophilia, "hemophilia progression" should 
be recorded on the Adverse Event eCRF.  
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic Bleeds
Medical occurrences or symptoms of deterioration that are anticipated as part of 
hemophilia should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in terms of severity (e.g., increased number of doses of 
bypassing agents to stop bleeds with emicizumab, in the absence of neutralizing 
anti-emicizumab antibodies, compared with before study entry), frequency of bleeds, or 
nature of hemophilia at any time during the study.  Should any of these occur 
(according to the investigator’s clinical assessment), they should be documented as an 
adverse event on the Adverse Event eCRF, conveying that the underlying condition has 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
82/Protocol BH30071, Version 4
changed by including applicable descriptors (e.g., "increased clinical severity of 
hemophilia").
Events that are clearly consistent with the anticipated pattern of the underlying disease 
and do not indicate an unexpected worsening in severity or frequency should not be 
recorded as adverse events.  These data will be reflected in efficacy assessment data only.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care 

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing or drug administration error of emicizumab are 
available, as no such instances have been observed to-date.  To minimize the risk of 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
83/Protocol BH30071, Version 4
errors associated with future home administration of emicizumab, data related to 
medication errors with observed patient/caregiver administration of emicizumab during 
the first 5 weeks at the site by the investigator and/or clinical staff will be recorded and 
corrected at the time of occurrence.  In addition, the recording of medication and 
handling errors associated with home administration, as well as drug compliance, will be 
collected at each clinic visit.  
5.3.5.13
Patient-Reported Outcome Data
The PRO measurements are described in Section 4.5.7.  The methods for collecting and 
analyzing PRO data are different from those for the ascertainment of observed or 
volunteered adverse events.  Adverse event reports will not be derived from PRO data 
by the Sponsor, and safety analyses will not be performed using PRO data.  Although 
sites are not expected to review the PRO data pertaining to the health-related quality of 
life, health status, preference or satisfaction measures, they are expected to review the 
BMQ.  Given that, it is possible that an investigator could become aware of PRO data 
that may be indicative of an adverse event.  Under these circumstances, the investigator 
will determine whether the criteria for an adverse event have been met and, if so, will 
report the event on the Adverse Event eCRF.  The PRO data will be presented in 
separate tables, figures, and data listings from the adverse event data, and will be 
included in the appropriate section of the final study report.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
"Use of this document is governed by the terms of use on the first page of this document."


"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
85/Protocol BH30071, Version 4
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and e-mailing the form with 
use of the fax number or e-mail address provided to investigators.  Once the EDC 
system is available, all information will need to be entered and submitted via the EDC 
system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and e-mailing the form with 
use of the fax number or e-mail address provided to investigators.  Pregnancy should 
not be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
drug and counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Although embryo-fetal development studies are not available, condom use will not be 
required in male patients enrolled in the study because the margin between the minimal 
anticipated biological effect level (MABEL) plasma concentration (7 ng/mL) and the 
estimated maternal Cmax (at both 1.5 and 3 mg/kg/wk dosing regimens) is greater than 
10-fold (Banholzer et al. 2012).  At this time, very little emicizumab is thought to transfer 
into semen, and there are no known reproductive risks to female partners of male 
patients treated with emicizumab.  Therefore, contraception use by male patients is not 
required for participation in the study, and to be consistent with this, no proactive 
collection of pregnancy information for female partners of male patients treated with 
emicizumab will be required.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
86/Protocol BH30071, Version 4
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
At the time of pregnancy outcome, reporting instructions provided in Section 5.4.3.1
should be followed.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
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 
LPLV), if the event is believed to be related to prior study drug treatment.  
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and e-mailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form with use of the fax number or e-mail address provided 
to investigators.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
87/Protocol BH30071, Version 4
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES,
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest (see Section 5.2.3) against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO5543262 (Emicizumab) Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on clinical rather than statistical considerations, 
taking into account the limited number of patients with hemophilia A without inhibitors 
available for participation in clinical studies and in an effort to collect sufficient data to 
assess the safety and efficacy of emicizumab.
The sample size calculation is based on the evaluation of the primary efficacy endpoint, 
defined as the number of bleeds over time (i.e., bleed rate) with emicizumab (treatment 
group, t) versus no prophylaxis (control group, c), which are said to follow a negative 
binomial (NB) distribution.  With consideration of enrollment feasibility, a sample size of 
75 patients, assuming an allocation ratio of 2:2:1 (30 patients in each randomized 
treatment group and 15 patients in control group), will achieve a power of more than 
90% assuming a mean ABR of 4 and 14 bleeds (with variancesmean10) for the 
emicizumab treatment and control arms respectively, representing an expected 71% 
reduction in the ABR compared to the control arm.  Initial sample size calculations were 
performed with East®, Version 6 (Cytel, Cambridge, MA), assuming the patients from 
each treatment group are followed up to 0.5 units of time (i.e., 24 weeks).
However, the above approach to sample size calculation assumes similar follow-up for 
each patient.  Because this is unlikely to be seen in the study, power was also estimated 
by simulation to account for different follow-up times among patients.  Conducting 
simulations on the basis of an NB regression model including an offset variable to 
account for variable follow-up times, with all other assumptions remaining the same as 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
88/Protocol BH30071, Version 4
previously described, the sample size is projected to have greater than 90% power at 
the 2-sided 0.05 level of significance.
The analysis will include all enrolled patients regardless of their length of follow-up.  
Therefore, to ensure the analysis is based on sufficient follow-up data and with 2:2:1 
treatment to control randomization, approximately 34 patients in each randomized 
emicizumab treatment arm (68 in total) and 17 patients in the control arm (approximately 
85 patients in total) will be enrolled.
With a minimum of 40 and a maximum of 60 patients enrolled in the open-label 
prophylactic emicizumab arm, and assuming a mean ABR of 4 and variance of 410, 
this number is considered sufficiently powered to evaluate the efficacy endpoint in this 
cohort; the treatment will be considered to provide adequate control if the upper limit of 
the one-sided 97.5% CI around the mean ABR is less than or equal to 6.
The primary safety consideration in determining the sample size was the ability to 
sufficiently evaluate the safety profile of emicizumab as assessed by adverse events.  
Under the assumption that the occurrence of an adverse event can be adequately 
modeled using the binomial distribution, the planned sample size of 108128 patients in 
the emicizumab treatment groups allows observation of adverse events having a true 
incidence rate of 1% with a probability of 0.660.72.
During the study, a re-assessment of the initially specified sample size based on 
aggregated (not by treatment arm) data to-date (and potentially from the 
non-interventional study [BH29768] findings) may be performed.  This may result in an 
increase in sample size, if necessary, to maintain adequate power without affecting the 
type 1 error rate.  Study integrity will be upheld, as access to information via aggregated 
analyses and their results will be minimized to limit operational bias.
Regarding the effect of emicizumab on changes of DSC from baseline at Weeks 2324 
or 4748 in patients with hemophilia A, there is currently no published information on the 
variability or clinical significance of longitudinal changes in this measure with the study 
device in patients with hemophilia A. No data are available to allow detailed sample size 
calculation of these exploratory objectives.  Participation will be offered to all patients in 
the study, leading to a maximum sample size of 145 patients.  Of note, 40 subjects
(20 per treatment group) were deemed sufficient to evaluate the related objectives with 
an adequate level of precision in similar studies that enrolled patients with chronic 
obstructive pulmonary disease, such as WB29804 Activity Substudy.
6.2
GENERAL
This section provides a general overview of the methods.  If any of the items require a 
unique approach that differs from the general overview, then it will be noted in the 
appropriate section.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
89/Protocol BH30071, Version 4
All continuous variables will be summarized using the following descriptive statistics:  
n (non-missing sample size), mean, standard deviation, median, maximum, and 
minimum.  The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical measures.
All summary tables will be structured with a column for each treatment arm and will be 
annotated with the total population size relevant to that table/treatment, including any 
missing observations.
Analyses will follow the principle of intention-to-treat (i.e., based on randomized 
population).
6.3
SUMMARIES OF CONDUCT OF STUDY
Flow of patients through the study will be displayed in a “CONSORT” diagram.  A clear 
account of all patients who entered the study, who were enrolled and randomized, and 
who entered and completed each phase of the study will be displayed. In addition, 
reasons for premature discontinuations from study treatment and reasons for 
withdrawing from the study (e.g., during follow-up) will be described.
Variables from the eCRF used to establish how many patients reached the various 
stages of the study, how many dropped out and for what reasons will be described in the 
Statistical Analysis Plan (SAP).
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Comparisons between the treatment arms of demographic data and baseline 
characteristics will be conducted to establish if any observed differences between the 
treatment arms are not due to imbalances in patient characteristics at baseline. Only 
descriptive analyses are planned, and no formal statistical tests will be applied.
6.5
EFFICACY ANALYSES
The primary and secondary efficacy analyses to evaluate the clinical effect of 
prophylactic emicizumab compared with no prophylaxis will include all randomized 
patients, with patients grouped according to the treatment assigned at randomization.  
For patients previously treated with prophylactic FVIII, the efficacy analysis will include 
all enrolled patients.  
6.5.1
Primary Efficacy Endpoint
The primary efficacy objective is to evaluate the clinical effect of prophylactic 
emicizumab compared with no prophylaxis on the number of bleeds over time.  The 
definition of a bleed is described in Section 4.5.8.  The primary endpoint is based on 
treated bleeds.
The primary efficacy analysis will be conducted after all randomized patients (and a 
minimum of 40 patients previously treated with prophylactic FVIII) have completed 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
90/Protocol BH30071, Version 4
24 weeks in the study or the last randomized patient yet to complete 24 weeks in the 
study discontinues study participation, whichever occurs first, and using an intent-to-treat 
principle.  The comparison of the number of bleeds over time between the randomized 
treatment arms will be performed using an NB regression model, which accounts for 
different follow-up times, with the patient’s number of bleeds as a function of 
randomization and the time that each patient stays in the study included as an offset in 
the model.  The model also includes the number of bleeds (9 or 9) in the last 
24 weeks prior to study entry as a stratification factor in the randomization.  This analytic 
model estimates the rate ratio, t/c, which quantifies the risk of bleeding associated with 
prophylactic emicizumab (t) in comparison to no prophylaxis (c).  Statistical 
significance is controlled at the 2-sided, 0.05 alpha () level.  Of note, hierarchical 
testing is used to account for multiple testing and the first test to be included in the 
hierarchy is the emicizumab 1.5 mg/kg/wk maintenance dose versus control.  The 
second test will be 3 mg/kg/2wks maintenance dose versus control.  The description 
below covers both hypotheses to be tested:
H0 (null hypothesis): Rate Ratio1 versus H1 (alternative hypothesis): Rate Ratio ≠ 1.
The treatment effect therein is based on a contrast statement in the model with use of 
the SAS GENMOD procedure.  Statistical significance at the prespecified alpha level will 
be based on a Wald testing procedure.  Bleed rates for prophylactic emicizumab and no 
prophylaxis and the rate ratio will be presented and include 95% confidence intervals.
The number of bleeds can also be annualized for each patient using the following 
formula:  ABR(Number of bleeds during the efficacy period/Total number of days 
during the efficacy period)365.25.  If the NB model converges, Van Elteren test to 
compare the mean ABR between the randomized arms will be provided only as a 
sensitivity analysis.  However, if the convergence of the NB model is not achieved or is 
questionable, the primary efficacy analysis will be based on the Van Elteren test of ABR.
A detailed description of the statistical methods that will be used for the primary and 
secondary efficacy analyses will be provided in the SAP.
6.5.2
Secondary Efficacy Endpoints
For all patients, the number of bleeds over time will be compared with the patient’s 
historical bleed rate, recorded in the medical record, and/or for the duration of their 
participation in the non-interventional study using an NB regression model similar to the 
one described for the primary efficacy endpoint.
In addition, the number of all bleeds (treated and not treated), spontaneous, joint and 
target joint bleeds over 24 weeks’ time between the emicizumab prophylaxis and no 
prophylaxis arms will be evaluated by an NB regression model, as specified for the 
primary efficacy endpoint. 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
91/Protocol BH30071, Version 4
The efficacy of prophylactic emicizumab treatment in the cohort of non-inhibitor patients 
previously treated with prophylactic FVIII will be evaluated to demonstrate that these 
patients remain adequately controlled on emicizumab.  The mean ABR will be estimated 
for each patient using the NB model and the one-sided 97.5% CI constructed around the 
estimated overall mean ABR.  If the upper limit of the CI is less than or equal to 6, the 
treatment regimen will be considered to provide adequate control.  This endpoint will be 
included as the third test in the hierarchical testing strategy.
Adherence with the HRQoL and health status measures will be summarized at the end 
of the study.  
HRQoL (using the Haem-A-QoL or the Haemo-QoL-SF) and health status (using the 
EQ-5D-5L) will be assessed on a regular basis, as per the schedule of assessments
(scheduled). 
Because different HRQoL measures (Haem-A-QoL and the Haemo-QoL-SF) are being 
used for the adult and adolescent patients, all calculations and analyses will be 
conducted separately for adults and adolescents.  Scale scores for the Haem-A-QoL and 
Haemo-QoL-SF will be calculated and summarized descriptively for all time points in the 
study.  The HRQoL scale scores for all patients will be evaluated after 24 weeks in the 
study, a timepoint that is consistent with other recent registrational studies in hemophilia 
(Lentz et al. 2013; Powell et al. 2013; Mahlangu et al. 2014) and analyses of such data 
(Santagostino et al. 2014; Wyrwich et al. 2015).  For each treatment arm, ANCOVA 
model will be used to compare the 24-week and final assessments with the baseline 
scale scores for each HRQoL measure.  Within-subject and between-group changes 
from baseline on the different HRQoL scale scores will also be calculated at 24 weeks 
and the final HRQoL assessment.  Statistical analysis of the Haemo-QoL-SF endpoints 
will be subject to sufficient adolescent patients being enrolled in the study to make 
meaningful statistical comparisons.  Further details will be provided in the SAP after the 
completion of enrollment into the study if deemed necessary.
For the assessments of the EQ-5D-5L, the number and percentage of patients in each of 
the five categories for each question for each group will be assessed.  Changes in the 
EQ-5D-5L index utility score from baseline will also be compared between groups.  In 
addition, summary statistics including mean, standard deviation, median, minimum and 
maximum will be displayed for the patients’ health state using the EQ-VAS both within 
and between groups.  The proportion of patients who report changes in each group 
exceeding the clinically meaningful threshold on the EQ-5D-5L index and EQ-VAS 
scores in each group will be reported at 24 weeks and the final, scheduled EQ-5D-5L 
assessment.
Secondary endpoints used for labeling and those that are solely for scientific interest will 
be specified in the SAP.  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
92/Protocol BH30071, Version 4
6.6
SAFETY ANALYSES
The safety analyses population will be based on all enrolled patients grouped according 
to the actual treatment received.  For Arm C patients, all safety data reported up to the 
day prior to switching will be included in the ‘control arm’ safety summaries, and all 
safety data reported on or after the date of switching to active treatment will be reported
separately.
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry and hematology, including complete blood count with 
differential), ECGs, vital signs, and antibodies to emicizumab and FVIII.
To evaluate the overall safety of prophylactic emicizumab compared to no prophylaxis, 
the incidence of adverse events will be summarized and presented by System Organ 
Class mapped term, appropriate thesaurus level, and toxicity grade for each treatment
arm.  
For clinical laboratory data, summary statistics will be presented by treatment arm. In 
addition, shift tables describing changes from baseline will be presented using the WHO 
toxicity grading scale.
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or clinical pharmacology and PK will be summarized adopting standard 
language/terminology (Shankar et al. 2014).
6.7
PHARMACOKINETIC ANALYSES
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be 
presented descriptively by treatment group, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various 
covariates, such as age, gender, and body weight, on these parameters will be 
investigated graphically.  Secondary PK parameters, such as AUC, will be derived from 
individual post-hoc predictions.  Data may be pooled with data from other studies.  
These analyses will be reported in a dedicated report.
6.8
EXPLORATORY ANALYSES
Summary statistics of the number of work/school days missed and days hospitalized will 
be presented by treatment arm.  Summary statistics will also be presented for the 
SQ-ISHI and emicizumab Preference Survey.  PD parameters (e.g., aPTT, parameters 
derived from thrombin generation, FVIII activity) and markers related to bone and joint 
health will be presented using summary statistics, including arithmetic and geometric 
means, median, range, standard deviations, and coefficients of variation.  
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
93/Protocol BH30071, Version 4
For the activity assessment all enrolled subjects that contribute reliable activity data (i.e., 
at least 8 valid days) will be analyzed. There will be no imputation of missing data.  
Subjects will be grouped according to the treatment regimen to which they are assigned 
in the main study.  Because of the exploratory nature of the study, there will be no type-1 
error control for multiplicity.  Enrollment, discontinuations, protocol violations/deviations, 
and duration of activity monitoring follow-up will be summarized. Demographic and 
baseline characteristics, such as age, sex, race/ethnicity, and weight will be summarized 
using descriptive statistics.  Relative change is defined as 
100(DSCWeek nDSCbaseline)/DSCbaseline.
Relative change from baseline at Week 25 or 49 in mean DSC and activity counts (total, 
mean, and peak) will be calculated within each treatment group provided the patient has 
reported data on at least 8 days within the 14 day observation period.  Subject-level 
averages at each timepoint will be presented via dot-plots and descriptive statistics by 
treatment group.  
The main comparisons will be within-patient changes, calculated within each treatment 
group.  Within the control arm, where patients are expected to switch to emicizumab 
prophylaxis treatment at 24 weeks, an additional comparison of the relative change from 
Week 25 to Week 49 will be performed.
Formal statistical modeling may be performed as appropriate.  Such analysis will be 
based on between-treatment comparisons of the change in activity from baseline to 
Week 25 between patients receiving emicizumab prophylaxis (Arms A or B) versus no 
prophylaxis (Arm C).
6.9
INTERIM ANALYSIS
No interim analysis for efficacy is planned.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.   Data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
94/Protocol BH30071, Version 4
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
ActiGraph will be responsible for data management of the activity monitoring, including 
quality checking of the data.  Sites will be responsible for setting up (initializing) activity 
monitors and downloading data from the monitors using ActiGraph’s CentrePoint 
software, a web-based physical activity monitoring logistics platform.  The CentrePoint 
solution consists of two components: a client-side software application (ActiSync), which 
directly interacts with the monitors on each site’s computer and remotely distributed 
storage and processing servers hosted by AmazonWeb Services and MicrosoftAzure 
cloud computing platforms located in the United States.  ActiGraph is in the process of 
completing the implementation of full server-side audit logging.  Once complete, the 
CentrePoint solution will be fully CFR Part 11 compliant.
Actigraph will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Data will be transmitted to the Sponsor using the Sponsor’s 
standard procedures to handle and process the electronic transfer of these data
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
PRO data will be collected electronically with use of electronic devices provided by a
vendor.  The electronic device is designed for entry of data in a way that is attributable, 
secure, and accurate, in compliance with U.S. Food and Drug Administration (FDA) 
regulations for electronic records (21 Code of Federal Regulations, Part 11).  The data 
will be transmitted electronically in real-time to a centralized secure database at the 
vendor.  The data from the devices are available for view access only via secure access
to a Web portal provided by the vendor.  Only identified and trained users may view the 
data, and their actions become part of the audit trail.  The Sponsor will have view access 
only.  Regular data transfers will occur from the centralized database at the vendor to 
the database at the Sponsor.  The Sponsor will receive all data entered by patients on 
the devices and all relevant study documentation.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
95/Protocol BH30071, Version 4
Once the study is complete, the data, audit trail, and study and system documentation 
will be archived.  The investigator will receive patient data for the site in both human-
and machine-readable formats on an archival-quality compact disc that must be kept 
with the study records as source data.  Acknowledgement of receipt of the compact disc 
is required.  In addition, the Sponsor will receive all patient data in a machine-readable 
format on a compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
The entire activity data collection, transmission, and analysis process is 21 CFR Part 11 
compliant and includes a complete audit trail. The “source data” from ActiGraph will 
consist of the raw data, the epoch data (counts), and steps.  Derived endpoints (such as 
calories or any other measure that is derived from raw, epoch, or steps data is not 
considered source data.  ActiGraph will maintain all of the data in multiple redundant 
data centers hosted on the Amazon Web Services platform. ActiGraph will provide this 
information as needed for audits by Roche and/or appropriate regulatory agencies.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
96/Protocol BH30071, Version 4
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 15 years after completion or discontinuation of the study, or for the length 
of time required by relevant national or local health authorities, whichever is longer.  
After that period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
reported or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Adolescent’s Informed Assent Form or Home Nursing Informed 
Consent Form, if applicable) will be provided to each site.  If applicable, it will be 
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
97/Protocol BH30071, Version 4
provided in a certified translation of the local language.  The Sponsor or its designee 
must review and approve any proposed deviations from the Sponsor's sample Informed 
Consent Forms or any alternate consent forms proposed by the site (collectively, the 
"Consent Forms") before IRB/EC submission.  The final IRB/ECapproved Consent 
Forms must be provided to the Sponsor for health authority submission purposes 
according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
98/Protocol BH30071, Version 4
Patients who are declared legally incompetent or who are physically or mentally 
incapable of providing informed consent but otherwise meet the qualifications for 
participation in Study BH30071 will be included, as emicizumab prophylaxis may directly 
benefit this population with high unmet medical need.  In such cases, investigators will
obtain informed consent from a guardian or legally authorized representative of the 
patient in accordance with applicable law. In addition, the investigator must also obtain 
the assent of the patient when they are able to give assent to decisions made on their
behalf. Any indication on the part of the patient that they are not willing to participate in 
the study will be honored.
In cases where there is reason to question the competence of a patient who has not 
been declared incompetent (e.g., a patient in the early stages of Alzheimer’s disease), a 
patient advocate will be involved in the consent process and throughout the duration of 
the patient’s participation in the study.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
99/Protocol BH30071, Version 4
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
100/Protocol BH30071, Version 4
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This global study will enroll approximately 125145 patients.
Randomization and drug assignment will be performed by an IxRS, which will also 
manage emicizumab inventory for all sites globally.
PROs will be captured on electronic devices provided by a third-party vendor for all 
patients globally.
Central laboratories will be used for a subset of laboratory assessments specified in 
Section 4.5.5. 
9.4.1
Independent Data Monitoring Committee and Independent Data 
Coordinating Center
An iDMC will be assembled to review the safety data collected during the study. The 
iDMC members will consist of, at minimum, independent hemostasis/thrombosis experts 
and a statistician, none of whom will be otherwise involved in the conduct of study.  All
analyses for review by the iDMC will be prepared by an independent Data Coordinating 
Committee (iDCC) that is independent of the Sponsor. At the beginning of the study, 
intensive monitoring and analysis of all significant safety events will be performed. 
Safety analyses of significant safety events will be conducted as prespecified intervals, 
the timing of which will be defined in the iDMC Charter. Thereafter, the iDMC will meet 
at a frequency determined by the iDMC and the Sponsor according to the emerging 
safety profile.
An iDCC will perform unblinded analyses and provide tables and listings to support the 
iDMC reviews of safety data.  The safety data will include demographic data, adverse 
events, serious adverse events, and laboratory abnormalities (coagulation, hematology, 
and chemistry).  Further information will be given on request.  
Following each meeting, the iDMC will recommend to the Sponsor whether the study 
should continue according to the protocol or may suggest changes to the protocol based
on the outcome of the data review. In exceptional cases, the iDMC may recommend
stopping the study or closing a treatment arm for safety reasons. The iDMC will monitor 
the incidence of the anticipated adverse events, as well as the overall safety of patients, 
during the study.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
101/Protocol BH30071, Version 4
The meeting schedule and all other iDMC-related activities will be specified in a separate 
iDMC charter. All results will be confidential and will not be divulged to non-members of 
the iDMC, including the Sponsor. All closed meetings will be summarized in written 
minutes available only to iDMC members and the iDCC statistician and kept by the iDCC 
statistician until the end of the study.  The recommendations can be communicated to 
the Sponsor verbally but have to be confirmed in writing according to a predefined 
timeframe. Strict confidentiality rules will be applied to avoid any dissemination of either 
safety or efficacy interim results outside the iDMC.
The final decision of acting upon the iDMC’s recommendations will rest with the Sponsor.  
The policies and procedures will be detailed in a separate iDMC Charter document.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on both the interim and final analyses of the study to healthcare 
professionals and to the public, at scientific congresses, in clinical trial registries, and 
in peer-reviewed journals. The Sponsor will comply with all requirements for publication 
of study results.  Study data may be shared with others who are not participating in this 
study (see Section 8.4 for details), and redacted Clinical Study Reports and other 
summary reports will be made available upon request.  For more information, refer to 
the Roche Global Policy on Sharing of Clinical Trials Data at the following Website:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf.
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
102/Protocol BH30071, Version 4
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
103/Protocol BH30071, Version 4
10.
REFERENCES
Ahn GE., Chmiel JS, Dunlop DD, et al. Self-reported and objectively measured physical 
activity in adults with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 
2015;67(5):7017.
Ahnstrom J, Berntorp E, Lindvall K, et al. A 6-year follow-up of dosing, coagulation factor 
levels and bleedings in relation to joint status in the prophylactic treatment of 
haemophilia. Haemophilia 2004;10:68997. 
Antun A, Monahan PE, Manco-Johnson MJ, et al. Inhibitor recurrence after immune 
tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 
2015;13(11):19808.
Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis 
and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B 
with inhibitors. Haemophilia 2014;20:6572.
Banholzer ML, Buergin H, Wandel C, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partners. J 
Transl Med 2012;10:129.
Baumgardner JL, Elon L, Antun A, et al. Physical activity and functional abilities in adult 
males with haemophilia: a cross-sectional survey from a single US haemophilia 
treatment centre. Haemophilia 2013;19(4):5517.
Berntorp E, Boulyjenkov V, Brettler D, et al. Modern treatment of haemophilia. Bull World 
Health Organ 1995;73(5):691701.
Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from 
the SSC of the ISTH. J Thromb Haemost 2014;12:19359.
Briscoe SE, Hardy MF, Pengo C, et al. Comparison of 7 versus 14 days wrist actigraphy 
monitoring in a sleep disorders clinic population. Chronobiol Int 2014;31(3):35662.
Broderick CR, Herbert RD, Latimer J et al. Association between physical activity and risk 
of bleeding in children with hemophilia. JAMA 2012;308(14):14529.
Brown TM, Lee WC, Joshi AV, et al. Health-related quality of life and productivity impact 
in haemophilia patients with inhibitors. Haemophilia 2009;15:9117.
Bullinger M, Von Mackensen S, Fischer K, et al. Pilot testing of the Haemo-QoL quality 
of life questionnaire for haemophiliac children in six European countries. 
Haemophilia 2002;8:4754.
Bull FC, Maslin TS, Armstrong T. Global physical activity questionnaire (GPAQ): nine 
country reliability and validity study. J Phys Act Health 2009;6(6):790804.
Case MA, Burwick HA, Volpp KG, et al. Accuracy of smartphone applications and 
wearable devices for tracking physical activity data. JAMA 2015;313(6):6256.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
104/Protocol BH30071, Version 4
Chinapaw MJ, Slootmaker SM, Schuit AJ, et al. Reliability and validity of the Activity 
Questionnaire for Adults and Adolescents (AQuAA). BMC Med Res Methodol 
2009;9:58.
Chu AH, Ng SH, Koh D, et al. Reliability and validity of the self- and 
interviewer-administered versions of the global physical activity questionnaire 
(GPAQ). PLoS One 2015;10(9):e0136944.
Cimino E, Linari S, Malerba M, et al. Patient preference and ease of use for different 
coagulation factor VIII reconstitution device scenarios: a cross-sectional survey in 
five European countries. Patient Prefer Adher 2014;8:171320.
Collins PW, Björkman S, Fischer K, et al. Factor VIII requirement to maintain a target 
plasma level in the prophylactic treatment of severe hemophilia A: influences of 
variance in pharmacokinetics and treatment regimens. J Thromb Haemost 
2010;8:26975.
Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX 
in hemophilia B: a multinational randomized phase 3 trial. Blood 
2014;124(26):38806.
Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 
12-country reliability and validity. Med Sci Sports Exerc 2003;35(8):138195.
Czepa DS, von Mackensen S, Hilberg T. Haemophilia & Exercise Project (HEP): the 
impact of 1-year sports therapy programme on physical performance in adult 
haemophilia patients. Haemophilia 2013;19(2):1949.
De Moerloose P, Urbancik W, Van Den Berg HM, et al. A survey of adherence to 
haemophilia therapy in six European countries: results and recommendations. 
Haemophilia 2008;14(5):9318.
Den Uijl IE, Mauser-Bunschoten EP, Roosendaal G, et al. Clinical severity of 
haemophilia A: does the classification of the 1950s still stand? Haemophilia
2011;17(6):84953.
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.
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for 
use of central venous access devices in haemophilia. Haemophilia 
2004;10:62948.
Fearn M, Hill K, Williams S, et al. Balance dysfunction in adults with haemophilia. 
Haemophilia 2010;16(4):60614.
Fischer K, Steen K, Carlsson P, et al. Intermediate-dose versus high-dose prophylaxis 
for severe hemophilia: comparing outcome and costs since the 1970s. Blood 
2013;122(7):112936.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
105/Protocol BH30071, Version 4
Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:17984.
Garriguet DS, Tremblay S, Colley RC. Comparison of Physical Activity Adult 
Questionnaire results with accelerometer data. Health Rep 2015;26(7):1117.
Gay ND, Lee SC, Liel MS, et al. Increased fracture rates in people with haemophilia: a 
10-year single institution retrospective analysis. Br J Haematol 2015;170(4):5846.
Geraghty S, Dunkley T, Harrington C, et al. Practice patterns in haemophilia A 
therapyglobal progress towards optimal care. Haemophilia 2006;12(1):7581.
Gironda RJ, Lloyd J, Clark ME, et al. Preliminary evaluation of reliability and criterion 
validity of Actiwatch-Score. J Rehabil Res Dev 2007;44(2):22330.
Gringeri A, Lambert T, Street A, et al. Tertiary prophylaxis in adults: is there a rationale? 
Haemophilia 2012;18(5):7228.
Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with
haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: 
results from the Pro-FEIBA study. Haemophilia 2013;19:73643.
Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis 
therapy in haemophilia. Haemophilia 2001;7(4):3926.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Jackson SC, Yang M, Minuk L, et al. Prophylaxis in older Canadian adults with 
hemophilia A: lessons and more questions. BMC Hematol 2015;15:4.
Jackson SC, Yang M, Minuk L, et al. Patterns of tertiary prophylaxis in Canadian adults 
with severe and moderately severe haemophilia B. Haemophilia 
2014;20(3):e199204.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country 
study. Qual Life Res 2013;22:171727.
Kavakli K, Yang R, Rusen L, et al. Prophylaxis vs. on-demand treatment with BAY 
81-8973, a full-length plasma protein-free recombinant factor VIII product: results 
from a randomized trial (LEOPOLD II). J Thromb Haemost 2015;13(3):3609.
Kempton CL and White GC 2nd. How we treat a hemophilia A patient with a factor VIII 
inhibitor. Blood. 2009;113:117.
Kempton CL, Antoniucci DM, Rodriguez-Merchan ECl. Bone health in persons with 
haemophilia. Haemophilia 2015;21(5):56877.
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.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
106/Protocol BH30071, Version 4
Kingdon HS and Lundblad RL. An adventure in biotechnology: the development of 
haemophilia A therapeuticsfrom whole-blood transfusion to recombinant DNA to 
gene therapy. Biotechnol Appl Biochem 2002;35:1418.
Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor 
VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 
2015;126(9):107885.
Kraft J, Blanchette V, Babyn P, et al. Magnetic resonance imaging and joint outcomes in 
boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. 
J Thromb Haemost 2012;10(12):2494502.
Lavie PR, Epstein O, Tzischinsky D. et al. Actigraphic measurements of sleep in 
rheumatoid arthritis: comparison of patients with low back pain and healthy 
controls. J Rheumatol 1992;19(3):3625.
Lentz SR, Misgav M, Ozelo M, et al. Results from a large multinational clinical trial 
(guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and 
adult patients with severe haemophilia A: safety and efficacy. Haemophilia 
2013;19: 6917.
Ljung R, Gretenkort AN. The current status of prophylactic replacement therapy in 
children and adults with haemophilia. BR J Haematol. 2015;169(6):77786.
Lindvall K, Colstrup L, Wollter IM, et al. Compliance with treatment and understanding of 
own disease in patients with severe and moderate haemophilia. Haemophilia 
2006;12(1):4751.
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc 
fusion protein in severe hemophilia A. Blood 2014;123:31725.
Mair FS, May CR. Thinking about the burden of treatment. BMJ 2014;349:g6680.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic 
treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 
2007;357:53544.
Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, controlled, 
parallel-group trial of routine prophylaxis vs. on-demand treatment with 
sucrose-formulated recombinant factor VIII in adults with severe hemophilia A 
(SPINART). J Thromb Haemost 2013;11:111927. 
Mannucci PM, Tuddenham EG. The hemophiliasfrom royal genes to gene therapy. N 
Engl J Med 2001;344:17739.
Noone D, O'Mahony B, van Dijk JP, et al. A survey of the outcome of prophylaxis, 
on-demand treatment or combined treatment in 18-35-year old men with severe 
haemophilia in six countries. Haemophilia 2013;19(1):4450.
O’Donnell DE, Gebke KB. Activity restriction in mild COPD: a challenging clinical 
problem. Int J Chron Obstruc Pulmon Dis 2014;9:57788.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
107/Protocol BH30071, Version 4
O’Mahony B, Noone D, Giangrande LF, et al. Haemophilia care in Europea survey of 
35 countries. Haemophilia 2013;19:e23947.
Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations 
of current prophylactic regimens. Blood 2015;125(13):203844.
Oldenburg J, Brackmann HH. Prophylaxis in adult patients with severe haemophilia A. 
Thromb Res 2014;134(Suppl 1):S337.
Olivieri M, Kurnik K, Pfluger T, et al. Identification and long-term observation of early 
joint damage by magnetic resonance imaging in clinically asymptomatic joints in 
patients with haemophilia A or B despite prophylaxis. Haemophilia 
2012;18(3):36974.
Paschou SA, Anagnostis P, Karras S, et al. Bone mineral density in men and children 
with haemophilia A and B: a systematic review and meta-analysis. Osteoporos Int. 
2014;25(10):2399407.
Plug I and Mauser-Bunschoten EP, Brocker-Vriends AH, et al. Bleeding in carriers of 
hemophilia. Blood 2006;108:526.
Pollak E, Mühlan H, Von Mackensen S, et al. The Haemo-QoL Index: developing a short 
measure for health-related quality of life assessment in children and adolescents 
with haemophilia. Haemophilia 2006;12:38492.
Powell JS, Pasi JK, Ragni MV, et al. Phase 3 Study of Recombinant Factor IX Fc Fusion 
Protein in Hemophilia B. N Engl J Med 2013;369:231323.
Rabinovich RA, Louvaris Z, Raste Y, et al. Validity of physical activity monitors during 
daily life in patients with COPD. Eur Respir J 2013;42(5):120515.
Richards M, Altisent C, Batorova A, et al. Should prophylaxis be used in adolescent and 
adult patients with severe haemophilia? An European survey of practice and 
outcome data. Haemophilia 2007;13(5):4739.
Rodriguez V, Mancuso ME, Warad D, et al. Central venous access device (CVAD) 
complications in Haemophilia with inhibitors undergoing immune tolerance 
induction: Lessons from the international immune tolerance study. Haemophilia.
2015;21(5):e36974.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report—second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006;117:3917. 
Santagostino E, Lentz SR, Busk AK, et al. Assessment of the impact of treatment on 
quality of life of patients with haemophilia A at different ages: insights from two 
clinical trials on turoctocog alfa. Haemophilia 2014:20;52734.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
108/Protocol BH30071, Version 4
Schrijvers LH, Uitslager N, Schuurmans MJ, et al. Barriers and motivators of adherence 
to prophylactic treatment in haemophilia: a systematic review. Haemophilia 
2013;19:35561.
Shafer F, Smith L, Vendetti N, et al. Lack of seasonal variation in bleeding and 
patient-assessed pain patterns in patients with haemophilia B receiving 
on-demand therapy. Haemophilia 2014;20:34953.
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and 
tactical recommendations. AAPS J 2014;16:65873. 
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Am Soc 
Hematol Educ Program 2013;2013:3743. 
Skinner MW. WFH: closing the global gap—achieving optimal care. Haemophilia 
2012;18(Suppl 4):112.  
Stasyshyn O, Antunes S, Mamonov V, et al. Prophylaxis with anti-inhibitor coagulant 
complex improves health-related quality of life in haemophilia patients with 
inhibitors: results from FEIBA NF Prophylaxis Study. Haemophillia 
2014;20:64450.
Teal S, Brohan E, Hettema Y, et al. Development and psychometric evaluation of a 
novel tool for assessing patient perception and preference for haemophilia 
treatment (HaemoPREF). Haemophilia 2014;20(5):66673.
Troiano RP, Berrigan E, Dodd KW, et al. Physical activity in the United States measured 
by accelerometer. Med Sci Sports Exerc 2008;40(1):1818.
Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two 
prophylaxis regimens and a paired comparison of on-demand and prophylaxis 
treatments in hemophilia A management. J Thromb Haemost 2012;10:35967.
Van Remoortel H, Raste Y, Louvaris Z, et al.  Validity of six activity monitors in chronic 
obstructive pulmonary disease: a comparison with indirect calorimetry.  PLoS One 
2012;7:e39198. Doi:10.1371/journal.pone.0039198.
Vepsalainen K, Lassila R, Arola M, et al. Complications associated with central venous 
access device in children with haemophilia: a nationwide multicentre study in 
Finland. Haemophilia. 2015;21(6):74753.
von Mackensen S, Bullinger M. Development and testing of an instrument to assess the 
Quality of Life of Children with Haemophilia in Europe (Haemo-QoL). Haemophilia 
2004;10(Suppl 1):1725.
von Mackensen S, Czepa D, Herbsleb M, et al. Development and validation of a new 
questionnaire for the assessment of subjective physical performance in adult 
patients with haemophilia--the HEP-Test-Q. Haemophilia 2010;16(1):1708.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
109/Protocol BH30071, Version 4
von Mackensen S, Gringeri A. Health related quality of life in adult patients with 
haemophilia – assessment with a new disease-specific questionnaire [abstract]. J 
Thromb Haemost 2005;3:P0813.
von Mackensen S and Gringeri A. Quality of life in hemophilia. In: Preedy VR, Watson 
RR editors. Handbook of Disease Burdens and Quality of Life. Heidelberg: 
Springer, 2010:1896920.
Watz HF, Krippner A, Kirsten H, et al. Indacaterol improves lung hyperinflation and 
physical activity in patients with moderate chronic obstructive pulmonary disease-a 
randomized, multicenter, double-blind, placebo-controlled study. BMC Pulm Med 
2014;14:158.
Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of 
BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre 
phase I/III study in previously treated patients with severe (FIX level <1%) or 
moderately severe (FIX level 2%) haemophilia B. Haemophilia 2014;20:1524.
Wolin KY, Heil DP, Askew S, et al. Validation of the International Physical Activity 
Questionnaire-Short among Blacks. J Phys Act Health 2008;5(5):74660.
World Federation of Hemophilia. Annual Global Survey Data 2013 [resource on the 
Internet]. Accessed April 22, 2015. Available from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx.
[WHO] World Health Organization Toxicity Grading Scale For Determining The Severity 
Of Adverse Events.  Available from: 
http://www.icssc.org/Documents/Resources/AEManual2003Appendices 
February_06_2003%20final.pdf
[WHO] World Health Organization. Global recommendations on physical activity for 
health 2010. Available from: 
http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of 
life change using the Haem-A-QoL. Haemophilia 2015 Sep;21(5):57884. Epub 
2015 Mar 31. 
Yu CA, Rouse PC, Veldhuijzen JJ, et al. Subjective and objective levels of physical 
activity and their association with cardiorespiratory fitness in rheumatoid arthritis 
patients. Arthritis Res Ther 2015;17:59.
Zappa S, McDaniel M, Marandola J, et al. Treatment trends for haemophilia A and 
haemophilia B in the United States: results from the 2010 practice patterns survey. 
Haemophilia 2012;18(3):e14053.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
110/Protocol BH30071, Version 4
Appendix 1
Schedule of Assessments
Schedule of AssessmentsArms A, B, and D
Screen-
ing
Wk 
1 
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk 
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Every 
8 Wks 
from 
Wk 33
Wk 
49
Every 
12 Wks 
from 
Wk 61
Every 
24
Wks 
from 
Wk 
73
Daily/ 
weeklya
Study 
Com-
pletion/
ET 
Safety 
F/U 
Visit b
Informed consent c
x
Inclusion/exclusion criteria
x
Medical history and 
demographics d
x
Physical examination (including 
weight) e
x
x
x
x
x
x
x
x
x
Height 
x
x
x
Vital signs (including weight) f
x
x f
x
x
x
x
x
x
x
x
x
x f
x
x f
x
x
x f
x
HJHS g
x
x
Serum pregnancy test h
x
x
Concomitant medications i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG j
x
x j
x
x
x
Safety laboratory assessments h
x h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-FVIII antibodies k
x k
x
x
x
x
x
x
x
x
x
x
Anti-emicizumab antibodies l
x l
x
x l
x
x l
x
x l
x l
x l
x l
x l
x
x l
Bleed/medication questionnaire m
x
Bleed/medication data review n
x
x
x
x
x
x
x
x
x
x
x
x
x
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
111/Protocol BH30071, Version 4
Schedule of AssessmentsArms A, B, and D
Screen-
ing
Wk 
1 
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk 
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Every 
8 Wks 
from 
Wk 33
Wk 
49
Every 
12 Wks 
from 
Wk 61
Every 
24
Wks 
from 
Wk 
73
Daily/ 
weeklya
Study 
Com-
pletion/
ET 
Safety 
F/U 
Visit b
Adverse events o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IMP management p
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
x
HRQoL and health status 
(EQ-5D-5L) q
x
x
x
x
x q
x
PK assessment r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PD biomarkers s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bone biomarkers (fasted) t
x
x
x
x
x
x
Activity measure (optional) u
x
x
x
Patient preference survey
x
Patient satisfaction (SQ-ISHI) v
x
x
x
RCR blood DNA sample 
(optional) w
x w
x w
x w
x w
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
112/Protocol BH30071, Version 4
Schedule of AssessmentsArm C (Screening to Switch to Emicizumab)
Screen-
ing
Wk 1
Wk 5
Wk 9
Wk 13 Wk 17 Wk 21
Daily/ 
weekly a
Informed consent c
x
Inclusion/exclusion criteria
x
Medical history and demographics d
x
Physical examination (including weight) e
x
x
Vital signs (including weight) f
x
x f
x
x
x
x
x
Height
x
Serum pregnancy test h
x
HJHS g
x
Concomitant medications i
x
x
x
x
x
x
x
ECG j
x
x j
Safety laboratory assessments h
x h
x
Anti-FVIII antibodies k
x
Bleed/injection questionnaire m
x
Bleed/injection data review n
x
x
x
x
x
x
Adverse events o
x
x
x
x
x
x
HRQoL and health status q
x
x
Activity measure (optional) u
x
PD biomarkers assessment s
x
Bone biomarkers (fasted) t
x
RCR blood DNA sample (optional) w
x
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
113/Protocol BH30071, Version 4
Schedule of AssessmentsArm C (Continued, at Time of Switch to Emicizumab)
Wk 
25
Wk 
26
Wk 
27
Wk 
28
Wk 
29
Wk 
31
Wk 
33
Wk 
37
Wk 
41
Wk 
45
Wk 
49
Every 
8 Wks 
from 
Wk 57
Wk
73
Every 
12 Wks 
from 
Wk 85
Every 
24 
Wks 
from
Wk 
97
Daily/
weeklya
Study 
Compl-
etion/ 
ET
Safety 
F/U 
Visit b
Physical examination 
(including weight) e
x
x
x
x
x
x
x
x
Vital signs (including 
weight) f
x f
x
x
x
x
x
x
x
x
x
x f
x
x f
x
x
x f
x
Height
x
x
x
Serum pregnancy test h
x
HJHS g
x
x
x
Concomitant medications i
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG j
x
x j
x
x
Safety laboratory 
assessments h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-FVIII antibodies k
x 
x
x
x
x
x
x
x
x
x
Anti-emicizumab 
antibodies l
x l
x
x l
x
x l
x
x l
x
x l
x
x
x
x l
Bleed/medication 
questionnaire m
x
x
x
Bleed/medication data 
review n
x
x
x
x
x
x
x
x
x
x
x
x
x
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
114/Protocol BH30071, Version 4
Schedule of AssessmentsArm C (Continued, at Time of Switch to Emicizumab)
Wk 
25
Wk 
26
Wk 
27
Wk 
28
Wk 
29
Wk 
31
Wk 
33
Wk 
37
Wk 
41
Wk 
45
Wk 
49
Every 
8 Wks 
from 
Wk 57
Wk
73
Every 
12 Wks 
from 
Wk 85
Every 
24 
Wks 
from
Wk 
97
Daily/
weeklya
Study 
Compl-
etion/ 
ET
Safety 
F/U 
Visit b
Adverse events o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IMP management p
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HRQoL and health status q
x
x
x
x
x q
x
PK assessment r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PD biomarkers s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Bone biomarkers (fasted) t
x
x
x
x
x
x
Activity measure 
(optional)u
x
x
BMQbleed and medication questionnaire; eCRFelectronic Case Report Form; EQ-5D-5LEuroQoL Five-Dimension-Five Levels Questionnaire; ETearly termination; 
F/Ufollow-up; FVIIIfactor VIII; HRQoLhealth-related quality of life; HJHSHemophilia Joint Health Score; IMPinvestigational medicinal product, 
PDpharmacodynamic; PKpharmacokinetic; RCRRoche Clinical Repository; SQ-ISHISatisfaction QuestionnaireIntravenous Subcutaneous Hemophilia Injection; 
wk Week.
Notes:  The maximum allowable time between screening and enrollment is 6 weeks; if the elapsed time between screening and enrollment is more than 6 weeks, screening 
must be repeated.  All assessments should be performed within 2 days of the scheduled visit for the first 12 weeks and for Weeks 2537 for Arm C patients who switch over, 
then 7 days thereafter.  Clinic visits should coincide with the day of emicizumab dosing, and on those days the dose should be administered after blood draws and other 
assessments are conducted.  Unscheduled assessments may be performed at the discretion of the investigator and as clinically indicated.  Except for the bleed/injection 
questionnaire, HRQoL, and health status, all other patient data will be collected during office or nurse visits.  Evaluation at Weeks 25 or 49 will occur after a full 24 or 48 weeks 
in the study.  Study completion evaluation occurs when a patient discontinues emicizumab or transitions into another study.
a
Patients will complete the Bleed/Medication Questionnaire at least weekly and at the time of a bleed, or when they take a hemophilia-related medication (including 
emicizumab).  Arm B patients should indicate at least weekly whether or not they had a bleed. 
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
115/Protocol BH30071, Version 4
Schedule of AssessmentsArm C (Continued, at Time of Switch to Emicizumab)
Wk 
25
Wk 
26
Wk 
27
Wk 
28
Wk 
29
Wk 
31
Wk 
33
Wk 
37
Wk 
41
Wk 
45
Wk 
49
Every 
8 Wks 
from 
Wk 57
Wk
73
Every 
12 Wks 
from 
Wk 85
Every 
24 
Wks 
from
Wk 
97
Daily/
weeklya
Study 
Compl-
etion/ 
ET
Safety 
F/U 
Visit b
b
A safety follow-up visit will occur 24 weeks after discontinuing emicizumab, except for patients who have transferred to commercially available emicizumab.
c
Obtain written informed consent (or patient’s assent and legal representative written informed consent if patient is an adolescent) before distribution of BMQ handheld 
device and collection of any data.  Patients will be enrolled and randomized after giving informed consent and assent when appropriate. A patient who fulfills the inclusion 
and exclusion criteria should be enrolled and assigned to a treatment arm on the same day when the first dose of emicizumab is due (Week 1 visit).
d
Collected from patient medical records and documented in the eCRF, including information on target joint(s). 
e
Calculation of dose based on weight is required.  A complete physical examination will be performed at screening and at least a targeted physical examination will be 
performed at subsequent visits.  Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for bruises, hematomas, and injection-site reactions) 
as clinically indicated and/or with report of new or worsening adverse event.  HJHS will be done as part of physical examination between screening to Week 2, at Week 49, 
and annually.
f
Body temperature, blood pressure, pulse rate, and respiratory rate only to be used to monitor during and after injection for hypersensitivity reactions and not to be entered 
into eCRF, except at Weeks 1, 25, 49, at study completion/early termination, and at the safety follow-up visit (i.e., 24 weeks after discontinuing emicizumab for patients in 
Arms A, B, and D and at Week 73 for patients in Arm C).  If Screening and Week 1 occur on the same date, the vital signs should be measured only once.  If Screening and 
Week 1 occur on different dates, vital signs entry should be repeated for both assessments.  Height will be measured at screening and annually. 
g
See Appendix 8.  HJHS will be done as part of physical examination between screening to Week 2, at Week 49, and annually.
h
Laboratory data (performed locally) include:  complete blood count with differential (i.e., neutrophils, hemoglobin, platelet count), serum chemistries (including sodium, 
potassium, chloride, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, alanine aminotransferase, 
aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine phosphokinase, and uric acid). Laboratory assessments completed at the screening 
visit do not have to be repeated at Week 1, if the period between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by 
the investigator.  Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening (and within 7 days of study drug 
initiation, if applicable) and urine pregnancy tests performed at every clinic visit, with the exception of Weeks 24 and 7.  Patients in Arm C will have serum pregnancy test 
performed at Screening and before starting emicizumab (Week 25).
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
116/Protocol BH30071, Version 4
i
Concomitant medications (e.g., extra pain medication with bleed) will be asked about at the time of the monthly assessment, excluding treatments for bleeds (i.e., FVIII and 
other medications to treat bleeds), which will be collected on the bleeding questionnaire.  Hemostatic medications to treat or prevent bleeds in the week prior to starting 
emicizumab will also be collected and during Week 1 for patients in Arm D who continue their prior FVIII prophylaxis for the first week of the study.
j
Performed locally.  If screening ECG is abnormal, repeat at Week 1 (or Week 2 [or Week 5 for Arm C] if Screening and Week 1 occur on the same day), otherwise do not 
repeat.  ECGs will also be performed 48 and 24 weeks after starting emicizumab or dose escalation (up-titration), as well as at study completion/early termination.
k
Patient must have a documented local inhibitor test with negative result (0.6 BU) at screening or within the 8 weeks prior to enrollment.  Starting at Week 1, all subsequent 
anti-FVIII antibodies will be measured at a central laboratory using an aliquot of the citrate plasma collected for PD biomarker assessments, so a separate blood draw is not 
necessary.  Please consult the central laboratory services manual for details. 
l
Samples to detect anti-emicizumab antibodies will be collected prior to emicizumab administration at every clinic visit.  However, only samples from the following visits will be 
analyzed initially:  (Arms A, B, and D) immediately prior to the first injection at Week 1, every 8 weeks from Weeks 949, every 12 weeks starting from Week 61, and at the 
24-week post-emicizumab safety follow-up visit following initiation of emicizumab; Arm C immediately prior to the first injection at Week 25, every 8 weeks from Weeks 3373, 
every 12 weeks starting from Week 85, and at the 24-week post-emicizumab safety follow-up visit following initiation of emicizumab.  If any of these samples are positive 
and/or if there is suboptimal clinical response or low pharmacokinetic exposure, the remaining collected samples may be analyzed for anti-emicizumab antibodies.  
Anti-emicizumab antibodies may also be drawn at the time of systemic hypersensitivity events. 
m Reported by the patient, or the patient’s legally authorized representative, and includes:  start date and time, reason, type, location, and associated symptoms of each bleed, 
as well as start date and time, reason, type, number of injections, and dose of each hemophilia medication injection, including emicizumab. Patients who stop taking 
emicizumab should continue reporting bleeds and hemophilia medication administration on the handheld device until the safety follow-up visit.
n
At the Week 1 visit, patients will be trained on how to use and be provided their own handheld device.  At subsequent visits as marked, investigator review of patient-reported 
bleed/injection questionnaire information will be conducted for completeness and accuracy.
o
Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected worsening of the patient’s hemophilia in terms 
of severity (e.g., increased number of doses of FVIII to stop bleeds compared with before study entry), frequency of bleeds, or nature at any time during the study, this should 
be documented as an adverse event on the Adverse Event eCRF, conveying that the underlying condition has changed by including applicable descriptors (e.g., "increased 
clinical severity of hemophilia"). 
p
Drug accountability will not be performed at the first visit that includes emicizumab receipt.  Drug dispensation will not occur at the study completion/early termination visit. 
q
Haem-A-QoL questionnaire (age 18) and Haemo-QoL-Short Form (ages 1217), health status questionnaire EQ-5D-5L.  Patient-reported outcomes will be captured on-site 
by a device and transmitted to the database. After Week 49, HRQoLs will be captured every 24 weeks.
r
Emicizumab concentration.  Plasma samples for this assessment should be taken prior to injection.  Patients will be dosed at the clinics (self-administration) on days where 
trough plasma samples are to be collected
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 1
Schedule of Assessments (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
117/Protocol BH30071, Version 4
s
See Appendix 2 for detailed explanation of PD biomarker assessments (Sets 1 and 2).  Blood samples will be banked for 5 years for future exploratory PD biomarker 
analyses.  Blood samples may also be drawn to conduct biomarker assays at the central laboratory on an unscheduled basis (at the clinical judgment of the investigator) at 
any time. 
t
Serum and plasma for bone markers must be collected after fasting (no food or drink other than water for at least 8 hours prior to the blood draw).  Ideally these samples 
should be collected in the morning (before noon), to control for diurnal variation as well.
u Patients who consent to participate should receive ActiGraph device at Screening or Week 1 and on the visit prior to each assessment period.  Assessment periods occur
during Weeks 12, 2324, and 4748.  During activity assessment periods, patients wear the study device while awake for 2 consecutive weeks within the period between 
the distribution and collection of the device.
v
Only Arm D patients at baseline and on Week 21 or 25. 
w Sample for the RCR is optional and requires an additional consent.  This single sample may be drawn at Week 2, 3, 4, or 5 but is not drawn at Week 1 in order to avoid 
excessive blood draw.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
118/Protocol BH30071, Version 4
Appendix 2
Schedule of Pharmacodynamic Assessments
Sample
Visit a
Biomarker assays b
PD Set 1
Starting on emicizumab (Arms A, B, and D):
Every week during Weeks 14
Every 2 weeks during Weeks 57
Every 4 weeks during Weeks 925
Every 8 weeks during Weeks 3349
Every 12 weeks thereafter, while on emicizumab 
(Week 61 and beyond) 
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the 
investigator), while on emicizumab c
Starting on no prophylaxis, switch to emicizumab
after 24 weeks (Arm C):
Week 1
Every week during Weeks 2528
Every 2 weeks during Weeks 2932
Every 4 weeks during Weeks 3348  
Every 8 weeks during Weeks 4973
Every 12 weeks thereafter, while on emicizumab 
(Week 85 and beyond)
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the 
investigator), while on emicizumab c
Standard aPTT
Modified aPTT
PT
FVIII activity
Thrombin generation
D-dimer
Prothrombin fragment 1.2 
PD Set 2
Starting on emicizumab (Arms A, B and D):
Week 1
Week 25
Study Completion/Early Termination
Safety Follow-up Visit
Starting on no prophylaxis, switch to emicizumab
after 24 weeks (Arm C):
Week 1
Week 25
Week 49
Study Completion/Early Termination
Safety Follow-up Visit
FXIII activity e
VWF antigen
Fibrinogen
FVIIIfactor VIII; FXIIIfactor XIII; PDpharmacodynamic; RANK-LReceptor activator of 
nuclear factor kappa-B ligand; VWFvon Willebrand factor.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
119/Protocol BH30071, Version 4
Appendix 2
Schedule of Pharmacodynamic Assessments (cont.)
Sample
Visit a
Biomarker assays b
PD Set 3 d
(Bone 
Biomarkers)
Starting on emicizumab (Arms A, B and D):
Week 1
Week 13
Week 25
Week 49
Every 24 weeks thereafter, while on emicizumab 
(Week 73 and beyond)
Study Completion/Early Termination
Starting on no prophylaxis, switch to emicizumab 
after 24 weeks (Arm C):
Week 1
Week 25
Week 37
Week 49
Every 24 weeks thereafter, while on emicizumab 
(Week 73 and beyond)
Study Completion/Early Termination
CTX-1
OPG
P1NP
soluble RANK-L
CTX-1C-terminal telopeptide of collagen 1; CWAclot waveform analysis; P1NPprocollagen 
type 1 amino-terminal propeptide; OPG osteoprotegerin; PDpharmacodynamic; RANK-
LReceptor activator of nuclear factor kappa-B ligand.
a All samples are to be collected on Day 1 of the indicated week, prior to emicizumab injection (if 
applicable).  PD samples will be citrate plasma, EDTA plasma, or serum.  Refer to Appendix 1
for exact study visits.
b Biomarker assays will include, but are not limited to, those listed.  Additional samples will be 
frozen and banked for future exploratory research related to emicizumab, which may include 
coagulation tests such as CWA and others.  Blood volumes and processing procedures will be 
specified in the Central Laboratory Services Manual.
c Reasons for unscheduled visits may include evaluation or treatment for bleeds or 
hypersensitivity reactions.
d Serum and plasma for bone markers must be collected after fasting (no food or drink other 
than water for at least 8 hours prior to the blood draw).  Ideally these samples should be 
collected in the morning (before noon), to control for diurnal variation as well.  Please consult 
the Central Laboratory Services Manual for details.
e FXIII activity was tested only at Week 1 due to emicizumab interference with the FXIII 
assay.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
120/Protocol BH30071, Version 4
Appendix 3
Haemo-QoL-SF (United States/English)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
121/Protocol BH30071, Version 4
Appendix 3
Haemo-QoL-SF (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
122/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
123/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
124/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
125/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
126/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
127/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
128/Protocol BH30071, Version 4
Appendix 4
Haem-A-QoL (United States/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
129/Protocol BH30071, Version 4
Appendix 5
EQ-5D-5L (United Kingdom/English)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
130/Protocol BH30071, Version 4
Appendix 5
EQ-5D-5L (United Kingdom/English) (cont.)
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
131/Protocol BH30071, Version 4
Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
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 (APTT)
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
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
132/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
116 or mental status 
changes or seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
165 mEq/L or mental 
status changes or seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or 
intensive replacement 
Rx required or
hospitalization required.
2.0 mEq/L
or paresis or ileus or life-
threatening arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L
or life-threatening
arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental 
status changes or coma
Hyperglycemia (note if 
fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or 
ketoacidosis or seizures
Hypocalcemia (corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or 
life-threatening arrhythmia 
or tetany
Hypercalcemia (correct for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL
life-threatening arrhythmia
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
133/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CHEMISTRIES continued
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or 
life-threatening arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or
replacement Rx required
1.01.4 mg/dL intensive 
Rx or hospitalization
required
1.0 mg/dL or 
life-threatening arrhythmia
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
6ULN or required 
dialysis
URINALYSIS
Proteinuria
1or 0.3% or 3g/L
or 200 mg1 g loss/day
23or 0.31.0% or
310 g/L
12 g loss/day
4or 1.0% or 10 g/L
23.5 g loss/day
nephrotic syndrome or 
3.5 g loss/day
Hematuria
microscopic only
gross, no clots
gross clots
obstructive or required 
transfusion
CARDIAC DYSFUNCTION
Cardiac Rhythm
asymptomatic, transient
signs, no Rx required
recurrent/persistent; no 
Rx required
requires treatment
Hypertension
transient inc. 20 mm;
no Rx
recurrent, chronic, 
20 mm, Rx required
requires acute Rx; no
hospitalization
requires hospitalization
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
134/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CARDIAC DYSFUNCTION continued
Hypotension
transient orthostatic
hypotension, no Rx
symptoms correctable
with oral fluids Rx
requires IV fluids; no
hospitalization required
requires hospitalization
Pericarditis
minimal effusion
mild/moderate
asymptomatic effusion, 
no Rx
symptomatic effusion;
pain; EKG changes
tamponade;
pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
12 units transfused
massive blood loss;
3 units transfused
RESPIRATORY
Cough
transient; no Rx
treatment-associated
cough
local Rx
uncontrolled
Bronchospasm, Acute
transient; no Rx
70%79% FEV1
(or peak flow)
requires Rx normalizes 
with bronchodilator; FEV1
50%69%
(or peak Flow)
no normalization with
bronchodilator;
FEV1 25%49%
(or peak flow retractions)
cyanosis: FEV1
25%
(or peak flow) or intubated
GASTROINTESTINAL
Stomatitis
mild discomfort; no limits 
on activity
some limits on
eating/drinking
eating/talking very
limited
requires IV fluids
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
135/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
GASTROINTESTINAL continued
Nausea
mild discomfort;
maintains reasonable
intake
moderate discomfort;
intake decreased
significantly; some
activity limited
severe discomfort; no
significant intake;
activities limited
minimal fluid intake
Vomiting
transient emesis
occasional/moderate
vomiting
orthostatic hypotension 
or IV fluids required
hypotensive shock or 
hospitalization required for 
IV fluid therapy
Constipation
mild
moderate
severe
distensions w/vomiting
Diarrhea
transient 34 loose
stools/day
5-7 loose stools/day
orthostatic hypotension 
or
7 loose stools/day or
required IV fluids
hypotensive shock or 
hospitalization for IV fluid 
therapy required
NEURO AND NEUROMUSCULAR
Neuro-cerebellar
slight incoordination
dysdiadochokinesis
intention tremor,
dysmetria, slurred
speech; nystagmus
locomotor ataxia
incapacitated
Mood
mild anxiety or
depression
moderate anxiety or
depression and therapy 
required
severe anxiety or
depression or mania;
needs assistance
acute psychosis;
incapacitated, requires
hospitalization
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
136/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
NEURO AND NEUROMUSCULAR continued
Neuro control
(ADLactivities of daily 
living)
mild difficulty
concentrating; no Rx;
mild confusion/agitation;
ADL unaffected
moderate
confusion/agitation some 
limitation of ADL; minimal 
Rx
severe 
confusion/agitation
needs assistance for
ADL; therapy required
toxic psychosis;
hospitalization
Muscle strength
subjective weakness
no objective 
symptoms/signs
mild objective
signs/symptoms no 
decrease in function
objective weakness
function limited
paralysis
OTHER PARAMETERS
Fever: oral, 12 hours
37.738.5 C or
99.9101.3 F
38.639.5 C or
101.4103.1 F
39.640.5 C or
103.2104.9 F
40.5 C or
104.9 F
Headache
mild, no Rx therapy
transient, moderate; Rx
required
severe; responds to
initial narcotic therapy
intractable; required
repeated narcotic therapy
Fatigue
no decrease in ADL
normal activity decreased 
2550%
normal activity
decreased 50% can’t
work
unable to care for self
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria;
angioedema
anaphylaxis
Local Reaction
tenderness or erythema
induration 10 cm or
phlebitis or inflammation
Induration 10 cm or
ulceration
necrosis
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 6
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
137/Protocol BH30071, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
OTHER PARAMETERS continued
Mucocutaneous
erythema; pruritus
diffuse, maculopapular 
rash, dry desquamation
vesiculation, moist
desquamation, or
ulceration
exfoliative dermatitis, 
mucous membrane
involvement or erythema,
multiforme or suspected 
Stevens-Johnson or 
necrosis requiring surgery
NOTE:  For coding purposes, the following toxicity grades may be used interchangeably: 1mild; 2moderate; 3severe; 4life 
threatening.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
138/Protocol BH30071, Version 4
Appendix 7
Clinical Criteria for Diagnosing Anaphylaxis
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network.  Anaphylaxis is highly 
likely when any one of the following three criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips, 
tongue/uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia, syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours):

Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease in systolic blood pressure2

Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline
_____________________________________
1
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006;117:391–7.
2
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg [2 x age]) from 1 to 10 years, and less than 90 mmHg from 
11 to 17 years.
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
139/Protocol BH30071, Version 4
Appendix 8
Hemophilia Joint Health Score (HJHS)
Subject ID #:
Name of physiotherapist:
Assessment #: 
Date:
Time:
_
yyyy  /  mm  / dd
Hemophilia Joint Health Score 2.1 – Summary Score Sheet
Left Elbow
Right Elbow
Left Knee
Right Knee
Left Ankle
Right Ankle
Swelling
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Duration (swelling)
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Muscle Atrophy
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Crepitus on motion
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Flexion loss
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Extension loss
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Joint pain
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Strength
□ NE
□ NE
□ NE
□ NE
□ NE
□ NE
Joint Total
Sum of Joint Totals
NE=Non-Evaluable
Global Gait Score
(☐NE included in Gait items)
HJHS Total Score
Swelling
Crepitus on Motion
Strength (Using the Daniels & Worthingham’s scale)
0 = None
0 = None
Within available ROM
1 = Mild
1 = Mild
0 = Holds test position against gravity wi hin maximum resistance (gr. 5)
2 = Moderate
2 = Severe
1 = Holds test position against gravity within moderate resistance
3 = Severe
(but breaks with maximal resistance) (gr. 4)
2 = Holds test position with minimal resistance (gr. 3+)
Flexion Loss
or holds test position against gravity (gr. 3)
Duration
0 = < 5°
3 = Able to partially complete ROM against gravity (gr.3-/2+)
0 = No swelling
1 = 5° - 10°
Or able to move through ROM gravity eliminated (gr. 2)
Or < 6 months
2 = 11° - 20°
Or through partial ROM gravity eliminated (gr. 2-)
1 = ≥ 6 months
3 = > 20°
4 = Trace (gr.1) or no muscle contraction (gr. 0)
NE = Non-Evaluable
Muscle Atrophy
Extension Loss
0 = None
(from hyperextension)
Global Gate
1 = Mild
0 = < 5°
0 = All skills are within normal limits
2 = Severe
1 = 5° - 10°
1 = One skill is not within normal limits
2 = 11° - 20°
2 = Two skills are not within normal limits
3 = > 20°
3 = Three skills are not within normal limits
Joint Pain
4 = No skills are within normal limits
0 = No pain through active range of motion
NE = Non-Evaluable
1 = No pain through active range; only pain on
gentle overpressure or palpation
2 = Pain through active range
NOTE: there is an accompanying instruction manual and worksheets that are required when administering the HJHS
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
140/Protocol BH30071, Version 4
Appendix 8
Hemophilia Joint Health Score (HJHS) (cont.)
General comments:
The HJHS is designed for use by physiotherapists. In order to maintain the precision and validity of the tool 
(score), the developers of the tool strongly recommend that the tool be used by a physiotherapist/healthcare 
professionals who have hemophilia-related expertise/experience and have been trained in the use of clinical 
measures, musculoskeletal assessment and specifically administration of the HJHS.
It is essential for the physiotherapist to possess the requires expertise and skills necessary to use 
anthropometric measures such as muscle testing and range of motion /goniometry, as well as posture & gait 
assessment prior to performing the evaluation (HJHS).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
141/Protocol BH30071, Version 4
Appendix 9
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients on Emicizumab
The use of bypassing agents is not expected in hemophilia A patients without inhibitors.  
For completeness, this appendix includes guidelines provided for treatment of 
breakthrough bleeds in patients with inhibitors.  Careful consideration of the risks and 
potential benefits is advised when combining emicizumab, factor VIII (FVIII), and 
bypassing agent. 
Drugs intended to control bleeds, including bypassing agents, should be used at the 
lowest dose expected to achieve hemostasis.  Given that circulating emicizumab may 
increase patients’ coagulation potential, the doses required to achieve hemostasis may 
be lower than the FVIII or bypassing agent doses used prior to starting the study.
Caution should be taken for patients who are using recombinant activated factor VII 
(rFVIIa [e.g., consideration of using no more than 90 μg/kg of rFVIIa as an initial dose]).
Use of activated prothrombin complex concentrate (aPCC) in combination with 
emicizumab should be avoided completely in patients who have the option of using other 
bypassing agents to treat bleeds.  In the event that aPCC is the only available bypassing 
agent, the lowest dose expected to achieve hemostasis should be prescribed, with no 
more than 50 units/kg of aPCC to be administered as an initial dose.
Other bypassing agents (e.g., Byclot) should be avoided.  In cases where such agents 
are the only available bypassing agent, the lowest dose expected to achieve hemostasis 
should be prescribed, with no more than the lowest dose described in the prescribing 
information to be administered as an initial dose (e.g., no more than 60 g/kg of Byclot).
Exact dose and schedule of bypassing agents should be discussed with patients at the 
beginning and throughout the study.  Repeated dosing of rFVIIa, aPCC, or other 
bypassing agents should be performed only under medical supervision, which includes 
laboratory monitoring by additional local and central laboratory assessments, and 
consideration should be given to verifying bleeds prior to repeated dosing.
Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab.  The use of anti-fibrinolytics in conjunction with aPCC or Byclot
is prohibited.  
MONITORING:
In the event of a bleed treated with bypassing agents, the following local laboratory tests 
will be performed within 2448 hours of initial bypassing agent use so the investigator 
may monitor for of potential thromboembolic events and thrombotic microangiopathy:  
platelet count, serum creatinine, LDH, and peripheral blood smear analysis to evaluate 
for schistocytes.  A plasma sample should also be provided for local (first aliquot) and 
"Use of this document is governed by the terms of use on the first page of this document."


Appendix 9
Guidelines for Dosing and Monitoring Bypassing Agents for 
Patients on Emicizumab (cont.)
RO5534262—F. Hoffmann-La Roche Ltd
142/Protocol BH30071, Version 4
central (second aliquot) laboratory monitoring of prothrombin fragment 12, fibrinogen, 
and D-dimer.  If the test for prothrombin fragment 12 is not available at the site, the 
sample should be sent to the local reference laboratory, if available and if the results 
from the local reference laboratory can be obtained within a reasonable timeframe to 
allow for decision making.  For patients who require multiple doses of bypassing agents, 
laboratory monitoring should be performed every 2448 hours thereafter until 2448 
hours following the last dose of bypassing agents administered to treat a given bleed.  If 
applicable, laboratory results should be recorded in the unscheduled visit electronic 
Case Report Forms (eCRFs).
"Use of this document is governed by the terms of use on the first page of this document."


RO5534262—F. Hoffmann-La Roche Ltd
143/Protocol BH30071, Version 4
Appendix 10
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.
"Use of this document is governed by the terms of use on the first page of this document."

SAP_001.pdf: 
 
 
Official Title:  
 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF PROPHYLACTIC EMICIZUMAB 
VERSUS NO PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
WITHOUT INHIBITORS 
NCT Number: 
NCT02847637 
Document Date: 
STATISTICAL ANALYSIS PLAN 
Version 1: 20 June 2017 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.  
*Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan.  The specific details of 
the legal/regulatory entity within the relevant country are provided within the clinical trial 
agreement with the Investigator/Institution and the Clinical Trial Application with the Competent 
Authority. 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BH30071 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY 
AND PHARMACOKINETICS OF PROPHYLACTIC 
EMICIZUMAB VERSUS NO PROPHYLAXIS IN 
HEMOPHILIA A PATIENTS WITHOUT INHIBITORS 
PROTOCOL NUMBER: 
BH30071 
STUDY DRUG: 
Emicizumab (RO5534262) 
VERSION NUMBER: 
1 
IND NUMBER: 
122,954 
EUDRACT NUMBER: 
2016-000072-17 
SPONSOR: 
F. Hoffmann-La Roche Ltd and 
Chugai Pharmaceuticals Ltd.* 
PLAN PREPARED BY: 
  
DATE FINAL: 
See electronic date stamp below. 
Name
Reason for Signing
Date and Time
(UTC)
20-Jun-2017 16:41:18
Company Signatory (Clinical)


Emicizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan BH30071 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 9 
2.2 
Collection of Patient-Reported Data ........................................ 9 
2.2.1 
Collection of Bleed and Medication Data ................................. 9 
2.2.2 
Collection of Health-Related Quality-of-Life Data .................. 10 
2.2.3 
 ...................................................... 10 
2.3 
Endpoints ............................................................................... 11 
2.3.1 
Primary Efficacy Endpoint ...................................................... 11 
2.3.1.1 
Efficacy Period ....................................................................... 11 
2.3.1.2 
Treated Bleed ........................................................................ 12 
2.3.2 
Secondary Efficacy Endpoints ............................................... 12 
2.3.2.1 
All Bleeds ............................................................................... 12 
2.3.2.2 
Treated Spontaneous Bleeds ................................................ 13 
2.3.2.3 
Treated Joint Bleeds .............................................................. 13 
2.3.2.4 
Treated Target Joint Bleeds .................................................. 13 
2.3.2.5 
Intra-Patient Comparison ....................................................... 13 
2.3.2.6 
Haem-A-QoL at 24 Weeks ..................................................... 14 
2.3.2.7 
EQ-5D-5L at 24 Weeks.......................................................... 14 
2.3.3 
Exploratory Efficacy Endpoints .............................................. 14 
2.3.4 
Pharmacokinetic Endpoints ................................................... 14 
2.3.5 
Safety Endpoints ................................................................... 15 
2.3.6 
Exploratory Biomarker Endpoints .......................................... 15 
2.4 
Determination of Sample Size ............................................... 15 
2.5 
Analysis Timing ..................................................................... 16 
3. 
STUDY CONDUCT ..................................................................................... 16 
3.1 
Randomization Issues ........................................................... 16 
3.2 
Data Monitoring ..................................................................... 17 
4. 
STATISTICAL METHODS .......................................................................... 17 
4.1 
Output Layouts ...................................................................... 17 


Emicizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan BH30071 
4.2 
Analysis Populations ............................................................. 18 
4.2.1 
Randomized Population (ITT) ................................................ 18 
4.2.2 
All Patients ............................................................................. 18 
4.2.3 
All Emicizumab Patients ........................................................ 19 
4.2.4 
Pharmacokinetic-Evaluable Population ................................. 19 
4.2.5 
Safety Population .................................................................. 19 
4.2.6 
Up-Titrated Population ........................................................... 19 
4.2.7 
Non-Interventional Study (NIS) Population ............................ 19 
4.2.8 
 ................................................ 19 
4.3 
Analysis of Study Conduct ..................................................... 20 
4.4 
Analysis of Treatment Group Comparability .......................... 20 
4.5 
Efficacy Analysis .................................................................... 20 
4.5.1 
Primary Efficacy Endpoint ...................................................... 20 
4.5.2 
Secondary Efficacy Endpoints ............................................... 21 
4.5.2.1 
All Bleeds ............................................................................... 22 
4.5.2.2 
Treated Spontaneous Bleeds ................................................ 22 
4.5.2.3 
Treated Joint Bleeds .............................................................. 22 
4.5.2.4 
Intra-Patient ComparisonPrevious Prophylactic 
Patients .................................................................................. 22 
4.5.2.5 
Haem-A-QoL at 24 Weeks ..................................................... 22 
4.5.2.6 
Secondary Efficacy Endpoints Not Included in 
the Hierarchy ......................................................................... 22 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 23 
4.5.4 
Sensitivity Analyses ............................................................... 24 
4.5.5 
Subgroup Analyses ............................................................... 25 
4.6 
Pharmacokinetic Analyses ..................................................... 26 
4.7 
Safety Analyses ..................................................................... 26 
4.7.1 
Exposure to Study Medication ............................................... 26 
4.7.2 
Adverse Events ..................................................................... 26 
4.7.3 
Laboratory Data ..................................................................... 27 
4.7.4 
Vital Signs .............................................................................. 27 
4.7.5 
Electrocardiogram ................................................................. 27 
4.8 
Exploratory Biomarker Analyses ............................................ 27 
4.9 
Missing Data .......................................................................... 27 


Emicizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan BH30071 
4.10 
Interim Analyses .................................................................... 28 
5. 
REFERENCES ........................................................................................... 29 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema for Study BH30071 ............................................... 8 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 31 
Appendix 2 
Schedule of Assessments ........................................................... 42 


Emicizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan BH30071 
1. 
BACKGROUND 
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births. Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Mannucci and Tuddenham 2001; 
Franchini and Mannucci 2013). 
The absence or functional deficiency of FVIII leads to a lifelong bleeding tendency. 
Common clinical signs of hemophilia A include easy bruising; prolonged bleeding after 
trauma or surgery; spontaneous bleeding into joints, muscles, or soft tissues; and 
intracranial hemorrhage.  The severity of the disease roughly correlates with the residual 
endogenous level of FVIII activity. Approximately 68% of people with hemophilia A have 
moderate (25%) or severe (43%) forms, characterized by FVIII activity levels < 5% 
or < 1%, respectively, leading to frequent bleeding events with the sequelae of 
musculoskeletal complications (e.g., arthropathy), local functional deficits, hemorrhagic 
shock, neurocognitive defects, or even death (World Federation of Hemophilia 2013). 
Prophylactic FVIII replacement therapy (i.e., administered on a scheduled basis with the 
intent to prevent bleeds) has been proven to minimize bleeding events and 
complications (Manco-Johnson et al. 2007).  Since the 1990s, recombinant FVIII (rFVIII) 
concentrates have been standard-of-care treatment options for patients with 
hemophilia A (Kingdon and Lundblad 2002).  Current prophylactic regimens commonly 
use infusion therapy administered three times weekly; other regimens use every other 
day administration (Shapiro 2013). 
Prophylactic FVIII replacement therapy has been recognized as superior to episodic 
treatment of symptomatic bleeds for several decades (Khawaji et al. 2012) and was 
adopted by national and international organizations as the desired treatment approach.  
However, the burden of treatment (Eton et al. 2013, Mair and May 2014) is 
extraordinarily onerous, as adequate prophylaxis requires a lifetime of self-administered 
intravenous (IV) infusion of FVIII 3−4 times each week.  In addition to the obvious toll on 
the quality of patients’ life (Teal et al. 2014), this burden results in suboptimal care for 
many who elect to avoid routine prophylaxis, despite its medical advantage 
(Geraghty et al. 2006; Lindvall et al. 2006; De Moerloose et al. 2008; Collins et al. 2014; 
Oldenburg 2015).  Thus, episodic therapy is a standard-of-care for many patients with 
hemophilia in developed countries, where approximately one-third to one-half of the 
patients use FVIII on-demand and avoid continuous prophylaxis. 
Emicizumab (also known as ACE910 and RO5534262) is a humanized monoclonal 
modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure 
produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.  
Emicizumab bridges activated factor IX (FIXa) and factor X (FX) to restore the function 
of missing activated factor VIII (FVIIIa) that is needed for effective hemostasis.  In 


Emicizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan BH30071 
patients with hemophilia A, hemostasis can be restored irrespectively of the presence of 
FVIII inhibitors, as emicizumab shares no sequence homology with FVIII. 
In addition, emicizumab offers the possibility of subcutaneous (SC) administration, 
removing the need for venous access.  Finally, because the pharmacokinetic properties 
of this antibody are expected to enable marked extension of the dosing interval to once 
weekly, every other week, or even less frequently, this novel compound has the potential 
to dramatically change the treatment of patients with hemophilia A with or without FVIII 
inhibitors who are in need of effective, safe and low burden prophylactic therapy. 
Initial experience with emicizumab in humans was generated from one Phase I study 
(ACE001JP) and its ongoing extension, a Phase I/II study (ACE002JP).  See the 
RO5543262 [Emicizumab] Investigator's Brochure for additional details on clinical 
studies with emicizumab.  The results have also been published (Shima et al. 2016; 
Uchida et al. 2016).  Based on these compelling data, the Phase III development 
program in adult and pediatric patients with hemophilia A (both with and without FVIII 
inhibitors) was initiated.  Studies BH29884 (adults and adolescents) and BH29992 
(pediatric) in hemophilia A patients with FVIII inhibitors had a first data readout at the 
end of 2016 when this study was already ongoing. 
 
 
 
 
 
 
 
 
 
 
 
 Consequently it was decided 
that a minimum of 40 patients with prophylactic FVIII replacement therapy should come 
from a separate non-interventional study (NIS; BH29768) and have at least 6 months of 
data in the NIS before enrolling into Arm D of Study BH30071 (see Section 2).   
2. 
STUDY DESIGN 
Study BH30071 is a randomized, multicenter, open-label, Phase III clinical study will 
enroll patients aged 12 years or older with severe hemophilia A (intrinsic FVIII level < 1%) 


Emicizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan BH30071 
without inhibitors against FVIII.  Approximately 85 patients who received episodic 
treatment with FVIII prior to study entry and experience at least 5 bleeds over the prior 
24 weeks (annual bleed rate [ABR] ≥ 10) will be randomized in a 2:2:1 ratio to the 
following regimens: 
• 
Emicizumab prophylaxis at 3 mg/kg/week (wk) subcutaneously for 4 weeks, 
followed by 1.5 mg/kg/wk subcutaneously (Arm A)  
• 
Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
3 mg/kg/every 2 weeks (2wks) subcutaneously (Arm B), or 
• 
No prophylaxis control arm (Arm C) 
 
Randomization will be stratified according to the number of bleeds patients experienced 
over the last 24 weeks prior to study entry, < 9 versus ≥ 9 (or ABR 18), to ensure a 
balance of patients with lower versus higher number of bleeds in all arms.  All patients 
will continue usual episodic treatment with FVIII in case of a breakthrough bleeding 
event.   
In addition, 40−60 patients with severe hemophilia A who received FVIII prophylaxis 
prior to study entry will be enrolled and receive emicizumab prophylaxis at 3 mg/kg/wk 
subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk subcutaneously (Arm D).  To 
improve the validity of historical comparison in this group, at least 40 patients will be 
observed on FVIII prophylaxis in NIS BH29768 for a period of at least 24 weeks before 
enrolling in Arm D of this study. 
The study schema is shown Figure 1. 


(PLFL]XPDE²)+RIIPDQQ/D5RFKH/WG
6WDWLVWLFDO$QDO\VLV3ODQ%+
)LJXUH 6WXG\6FKHPDIRU6WXG\%+
Severe 
hemophilia A
Arm B emicizumab
3 mg/kg/2wks maintenance a
N=34
Arm A emicizumab
1.5 mg/kg/wk maintenance a
N=34
Arm C  
No prophylaxis b
N=17
ϲŵŽZшϱĨŽƌpatients 
receiving episodic FVIII
Randomization 
ƐƚƌĂƚŝĨŝĞĚďĂƐĞĚŽŶ
ϲŵŽZфŽƌшϵ
II
Ŷ
Arm D emicizumab
1.5 mg/kg/wk maintenance a
N=min 40-60
24 weeks primary ĞĨĨŝĐĂĐǇanalysis
emicizumab
continuation b
Pre-study 
episodic FVIII
Pre-study FVIII
Prophylaxis
R
Phase III Non-Inhibitor Design

ZNV HYHU\ZHHNVPR%5 PRQWKVEOHHGUDWH%5 EOHHGUDWH)9,,, IDFWRU9,,,
PR PRQWK5 UDQGRPL]DWLRQZN  ZHHN
D $OOSDWLHQWVZLOOUHFHLYHORDGLQJZLWKIRXUZHHNO\GRVHVRIHPLFL]XPDEPJNJZNSULRUWR
VWDUWLQJPDLQWHQDQFH
E $UP&SDWLHQWVGXULQJWKHQRSURSK\OD[LVSHULRGDUHGHVLJQDWHG&FRQWUROZKHUHDVDIWHUVZLWFK
WRHPLFL]XPDEDOORZHGSHUSURWRFRODIWHUZHHNVWKH\DUHGHVLJQDWHG$UP&HPL
7KHSULPDU\HIILFDF\DQDO\VLVGHILQHGDVFRPSDULQJWKHQXPEHURIEOHHGVRYHUWLPHIRU
SDWLHQWVUDQGRPL]HGWRUHFHLYHSURSK\ODFWLFHPLFL]XPDEYHUVXVQRSURSK\OD[LVZLOOEH
FRQGXFWHGDIWHUUHDFKLQJWKHFOLQLFDOFXWRIIZKLFKRFFXUVDWWKHHDUOLHVWWLPHSRLQWZKHQ
DOOUDQGRPL]HGSDWLHQWV$UPV$%DQG&DQGDPLQLPXPRISDWLHQWVIURP$UP'
KDYHHLWKHUFRPSOHWHGZHHNVLQWKHVWXG\RUGLVFRQWLQXHGIURPWKHVWXG\
7RREWDLQDGGLWLRQDOVDIHW\DQGHIILFDF\GDWDRQHPLFL]XPDESDWLHQWVZKRDUH
UDQGRPL]HGWRWKHQRSURSK\OD[LVDUPFRQWURODUP$UP&FRQWUROZLOOKDYHWKHRSSRUWXQLW\
WRVZLWFKDIWHUZHHNVWRUHFHLYHHPLFL]XPDESURSK\OD[LVDWPJNJZNV
PDLQWHQDQFHGRVHDIWHUZHHNVRIPJNJZNORDGLQJGRVH)RUFODULW\$UP&SDWLHQWV
GXULQJWKHQRSURSK\OD[LVSHULRGDUHGHVLJQDWHG&FRQWUROZKHUHDVDIWHUVZLWFKWR
HPLFL]XPDEWKH\DUHGHVLJQDWHG$UP&HPL$IWHUFRPSOHWLQJDWOHDVWZHHNVRI
WUHDWPHQWZLWKSURSK\ODFWLFHPLFL]XPDESDWLHQWVZKRUHFHLYHHPLFL]XPDESURSK\OD[LV
$UPV$%'RU$UP&HPLDIWHUWUHDWPHQWVZLWFKDQGGHULYHFOLQLFDOEHQHILWZLOOEH
DOORZHGWRFRQWLQXHHPLFL]XPDEXQWLOPDUNHWLQJDXWKRUL]DWLRQDVSDUWRIWKLVVWXG\RUD


Emicizumab—F. Hoffmann-La Roche Ltd 
9/Statistical Analysis Plan BH30071 
separate extension study, as long as they continue to derive clinical benefit and 
emicizumab is still in clinical development.  
Patients may be allowed to up-titrate their emicizumab dose if they meet the 
pre-specified criteria as described in the protocol.  Patients in the randomized arms can 
escalate after at least 24 weeks on emicizumab prophylaxis, while dose increase is 
permitted at any time after the second qualifying bleed for patients in Arm D.   
 
.   
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1.  
2.2 
COLLECTION OF PATIENT-REPORTED DATA 
2.2.1 
Collection of Bleed and Medication Data 
Bleed and medication data are collected through an electronic bleed and medication 
questionnaire (BMQ), which was developed by the Sponsor given that no standard 
questionnaire for collection of these data exists.   
The BMQ was developed as a patient-reported measure of bleeding episodes (including 
cause, type, location, and symptoms of bleeds) and hemophilia-related medication use.  
The draft questions were developed following review of the hemophilia A literature and 
discussions with medical professionals regarding what information on related bleeds was 
most important to capture.  Prior to use in this study, qualitative interviews with patients 
with hemophilia A were conducted in order to evaluate the measure’s content validity 
and to test the understanding and usability of the BMQ on an electronic, handheld 
device.  Cognitive interviews were conducted in person with a total of 20 patients aged 
12 years and older with hemophilia A; the results demonstrated that the BMQ was 
comprehensive and relevant to patients’ experiences with bleeds and treatments. 
To capture bleed data, emicizumab use, and other hemophilia medication use during 
study treatment, patients will complete the BMQ on a handheld device that will be 
provided to them during the Week 1 visit at the study site.  This device will remain with 
the patient for the duration of the study to enter bleed and medication data weekly at a 
minimum.  In case a patient did not experience any bleeds or administer any treatments 
for a week, the patient is asked to log into the device and fill in the questionnaire to 
confirm this.  These weekly entries, in addition to the bleeds and medication entries, can 
also be used to assess compliance.  Of note, the patient is able to enter bleeds and 
medications for the past 8 days, including the day the entries are made.  This 
retrospective data entry window was considered acceptable in terms of recall bias and 
was added in order to optimize the completeness of data collection. 


Emicizumab—F. Hoffmann-La Roche Ltd 
10/Statistical Analysis Plan BH30071 
Patients who withdraw from emicizumab treatment will continue to record bleeds and 
hemophilia medication administration until they complete the safety follow-up visit.  
The patient is able to edit and delete bleeds and medications for 24 hours after they are 
entered.  Furthermore, the investigator and patient are instructed to review the data 
together at every clinic visit.  If the patient has been unable to enter data for any reason, 
the investigator is able to do so using a data clarification request (DCR; not subject to 
the previous 8-day data entry window).  Note, the symptoms of joint and muscle bleeds 
are not collected in this case because the patient may not be able to reliably remember 
them.  In addition, the investigator is able to request a change be made to the vendor’s 
database by submitting a DCR. 
Furthermore, the Sponsor’s data manager and Medical Monitor review the patient 
entered data for clear inconsistencies against data collected on the electronic Case 
Report Form (eCRF) or to identify obvious data points to be clarified (e.g., missing entry 
of the weekly emicizumab injection).  These requests are sent to the investigator, who 
reviews them with the patient and may enter the data via the site data entry system or 
request a change to be made in the vendor’s database via a DCR, if necessary. 
2.2.2 
Collection of Health-Related Quality-of-Life Data 
At specified visits, patients will complete health-related quality-of-life (HRQoL), health 
status, and satisfaction/preference questionnaires on a tablet device that will remain at 
study sites.  The instructions for completing the patient-reported outcome (PRO) 
questionnaires electronically will be provided by the investigator staff during the Week 1 
visit at the site.  The data will be transmitted automatically after entry to a centralized 
secure database at the vendor. 
2.2.3 
 
 
 
 
 
 
 
 
 
 
  
 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
11/Statistical Analysis Plan BH30071 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
ENDPOINTS 
2.3.1 
Primary Efficacy Endpoint 
Bleed rate is defined as the number of bleeds over the efficacy period.  A bleed is 
counted in the primary analysis if it was treated with coagulation factors and fulfills the 
adapted International Society on Thrombosis and Haemostasis (ISTH; 
Blanchette et al. 2014) criteria, as described in Section 4.5.8 of the protocol.  More 
specifically, the following rules as outlined in the sections below are applied. 
2.3.1.1 
Efficacy Period 
The start of the efficacy period for each individual patient is defined as the first day when 
there is data in the BMQ.  For patients starting the study on emicizumab (Arms A, B, and 
D) this is expected to coincide with the Week 1 visit, and the day of their first 
emicizumab dose.  For patients who do not start the study on emicizumab (Arm C), the 
start of the efficacy period should coincide with the Week 1 visit.   
Of note, the first day when there is data in the BMQ, includes the first day for which data 
is reported via the handheld device, a DCR, or the day of device activation. 
A second efficacy period is defined for patients in Arm C who switch to emicizumab 
starting on the day of their first emicizumab dose. 
For patients randomized or enrolled on emicizumab, the end of the efficacy period is 
defined as the date of the clinical cutoff or the date of withdrawal from the initial study 
period (i.e., treatment phase according to eCRF), whichever is earlier.  For patients 
randomized to no prophylaxis (Arm C), the end of the first efficacy period is defined as 
the day before the first emicizumab dose or the date of withdrawal from the initial study 
period (i.e., treatment phase according to eCRF) or the date of the clinical cutoff if 


Emicizumab—F. Hoffmann-La Roche Ltd 
12/Statistical Analysis Plan BH30071 
neither of the aforementioned events has taken place.  For patients whose dose is 
up-titrated, the efficacy period on the initial dose (the initial period for patients 
randomized/enrolled to Arms A, B, and D; the second efficacy period, starting at first 
emicizumab dose for patients randomized to Arm C) ends 1 day prior to the first day on 
the up-titrated dose. 
For patients who withdraw from the study before reaching the Week 1 visit, the duration 
of the efficacy period is set to 1 day, and it starts and ends on the day of 
randomization/enrollment. 
For patients whose dose is up-titrated, the bleeds on the up-titrated dose are analyzed 
separately.  The efficacy period on a given up-titrated dose (second efficacy period for 
patients randomized/enrolled to Arms A, B, and D; third efficacy period for patient 
randomized to Arm C) starts with the first day on this dose and ends on the day of the 
clinical cutoff or the date of withdrawal. 
2.3.1.2 
Treated Bleed 
A bleed is considered to be a “treated bleed” if it is directly followed (i.e., there is not an 
intervening bleed) by a hemophilia medication reported to be a “treatment for bleed,” 
irrespective of the time between the treatment and the preceding bleed.  A bleed and the 
first treatment thereafter are considered to be pairs (i.e., one treatment belongs to one 
bleed only), with the following exception:  if multiple bleeds occur on the same calendar 
day, the subsequent treatment is considered to apply for each of these multiple bleeds 
(which are, however, counted as separate bleeds). 
Bleeds due to surgery/procedure are not included in the primary analysis.  Only 
treatments that were recorded as “treatment for bleed” are included in the determination 
of a treated bleed. 
72-Hour Rule 
Two bleeds of the same type (e.g., “joint,” “muscle,” or “other”) and at the same 
anatomical location are considered to be one bleed if the second occurs within 72 hours 
from the last treatment for the first bleed.  The last treatment is defined as the last 
treatment before a new bleed occurs, either in the same or in a different location.  This is 
in-line with the above definition that bleeds and treatments are considered to be pairs. 
2.3.2 
Secondary Efficacy Endpoints 
The same definition of the efficacy period applies to all bleed-related secondary efficacy 
endpoints. 
2.3.2.1 
All Bleeds 
“All bleeds” comprises both treated and non-treated bleeds.  In this definition, all bleeds 
are included, irrespective of treatment with coagulation factors, with the following 
exception:  bleeds due to surgery/procedure are excluded as for the primary analysis.  


Emicizumab—F. Hoffmann-La Roche Ltd 
13/Statistical Analysis Plan BH30071 
The endpoint of all bleeds fulfills the adapted ISTH criteria, as described in the protocol 
for the primary endpoint and the 72-hour rule, in particular.  For treated bleeds, it is 
implemented exactly as defined for the primary endpoint.  For non-treated bleeds (not 
followed by any treatments with coagulation factors before the recording of a subsequent 
bleed), it is implemented by calculating a treatment-free period of 72 hours from the 
bleed itself. 
2.3.2.2 
Treated Spontaneous Bleeds 
In the analysis of spontaneous bleeds, only treated bleeds that fulfill the 72-hour rule are 
included.  
Bleeds are classified as “spontaneous” if there is no other known contributing factor such 
as trauma or procedure/surgery. 
2.3.2.3 
Treated Joint Bleeds 
In the analysis of joint bleeds, only treated bleeds that fulfill the 72-hour rule are included.  
Bleeds due to procedure/surgery are again excluded. 
Joint bleeds are defined as bleeds where the bleed type is “joint” as reported in the BMQ 
and is reported with at least one of the following symptoms:  increasing swelling or 
warmth of the skin over the joint; and/or increasing pain, decreased range of motion, or 
difficulty using the joint compared with baseline. 
2.3.2.4 
Treated Target Joint Bleeds 
Target joints are joints into which repeated bleeds occur (i.e., ≥ 3 bleeds into the same 
joint over the last 24 weeks prior to study entry).  The target joints prior to study entry are 
identified through the eCRF.  The bleeds in target joints during the efficacy period are 
defined by first selecting the bleeds that fulfill the definition of a treated joint bleed and 
then counting how many of these occurred in a target joint as defined prior to study entry.  
The locations to be taken into account are shoulder, elbow, wrist, fingers/thumb, hip, 
knee, ankle, sole/heel, and toes.  Left and right sides of the same joint type are 
considered to be separate joints. 
2.3.2.5 
Intra-Patient Comparison 
In the intra-patient comparison (on All Bleeds and on Treated Bleeds as defined in 
Section 2.3.2.1 and Section 2.3.2.2, respectively), only patients who participated in 
NIS BH29768 are included.  This is because it is possible to apply the detailed bleed 
definitions only if the data are collected with the same granularity for both time periods.  
Of note, for some episodic patients who participated in NIS BH29768, the total time in 
that study prior to enrollment in Study BH30071 may be less than 24 weeks. 
The efficacy period in NIS BH29768 is defined as the time from the first entry on the 
electronic, handheld device or site data entry system to the day the patient completed 
the study, which may occur between 1 day and a few days prior to 


Emicizumab—F. Hoffmann-La Roche Ltd 
14/Statistical Analysis Plan BH30071 
enrollment/randomization in Study BH30071.  Usually, the date of the first BMQ entry in 
NIS BH29768 is the date the Training Module on the electronic, handheld device is 
completed.  The end of the efficacy period in NIS BH29768 is defined as the date of 
withdrawal or date of study completion or on the day of the clinical cutoff, whichever 
occurs earlier. 
2.3.2.6 
Haem-A-QoL at 24 Weeks 
The Haem-A-QoL and the Haemo-QoL-SF will be used to measure HRQoL in adults and 
adolescents, respectively.  Therefore, all calculations and analyses will be conducted 
separately for these two measures.  Total score and physical health subscale score for 
the Haem-A-QoL will be evaluated at 24 weeks in the study and formally analyzed as 
described in the efficacy analysis section.  However, only the physical health subscale 
will be part of the hierarchical testing procedure highlighted in this analysis section.  
Other subscale scores will be analyzed in a descriptive way. 
The number of adolescent patients in the randomized portion of the study will be too 
small to provide meaningful statistical analyses of the Haemo-QoL-SF and therefore the 
analysis of this endpoint will be descriptive.  
2.3.2.7 
EQ-5D-5L at 24 Weeks 
The European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) index utility score using 
the U.K. value set and visual analogue scale (VAS) will be evaluated at 24 weeks in the 
study.  These two endpoints will be analyzed as described in the efficacy analysis 
section but will not be part of the hierarchical testing procedure.  
2.3.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are as follows: 
• 
Patient satisfaction with treatment 
 
 
• 
Treatment preference for emicizumab prophylaxis versus FVIII prophylaxis or 
episodic therapy according to the preference survey 
• 
Number of days away from school/work 
• 
Number of days hospitalized 
• 
 
 
2.3.4 
Pharmacokinetic Endpoints 
The pharmacokinetic (PK) endpoint for this study is the exposure (trough plasma 
concentration) to emicizumab at the following timepoints: 
• 
Every week during Weeks 1−4 on emicizumab 
• 
Every 2 weeks during weeks 5−8 on emicizumab 
• 
Every 4 weeks during weeks 9−24 on emicizumab 
• 
Every 8 weeks during weeks 25−48 on emicizumab 


Emicizumab—F. Hoffmann-La Roche Ltd 
15/Statistical Analysis Plan BH30071 
• 
Every 12 weeks thereafter while on emicizumab until the end of the study 
 
2.3.5 
Safety Endpoints 
Safety parameters to be measured include exposure, adverse events (including serious 
adverse events, adverse events of special interest, adverse events leading to drug 
discontinuation, and deaths), clinical laboratory results (hematology, chemistry, anti-FVIII 
and anti-emicizumab antibodies), vital signs, ECG, and concomitant medication use.  
2.3.6 
Exploratory Biomarker Endpoints 
Exploratory biomarker endpoints include  
• 
Pharmacodynamic (PD) biomarkers of emicizumab, including but not limited to 
aPTT, thrombin generation, and FVIII activity 
• 
 
 
2.4 
DETERMINATION OF SAMPLE SIZE 
The sample size for this study is based on clinical rather than statistical considerations, 
taking into account the limited number of patients with hemophilia A without inhibitors 
available for participation in clinical studies and in an effort to collect sufficient data to 
assess the safety and efficacy of emicizumab. 
The sample size calculation is based on the evaluation of the primary efficacy endpoint, 
defined as the number of bleeds over time (i.e., bleed rate) with emicizumab (treatment 
group, λt) versus no prophylaxis (control group, λc), which are said to follow a negative 
binomial (NB) distribution.  With consideration of enrollment feasibility, a sample size of 
75 patients, assuming an allocation ratio of 2:2:1 (30 patients in each randomized 
treatment group and 15 patients in control group), will achieve a power of more than 
90% assuming a mean ABR of 4 and 14 bleeds (with variances = mean × 10) for the 
emicizumab treatment and control arms respectively, representing an expected 71% 
reduction in the ABR compared to the control arm.  Initial sample size calculations were 
performed with East, Version 6 (Cytel, Cambridge, MA), assuming the patients from 
each treatment group are followed up to 0.5 units of time (i.e., 24 weeks). 
However, the above approach to sample size calculation assumes similar follow-up for 
each patient.  Because this is unlikely to be seen in the study, power was also estimated 
by simulation to account for different follow-up times among patients.  Conducting 
simulations on the basis of an NB regression model including an offset variable to 
account for variable follow-up times, with all other assumptions remaining the same as 
previously described, the sample size is projected to have greater than 90% power at 
the 2-sided 0.05 level of significance. 
The analysis will include all enrolled patients regardless of their length of follow-up.  
Therefore, to ensure the analysis is based on sufficient follow-up data and with 2:2:1 
treatment to control randomization, approximately 34 patients in each randomized 


Emicizumab—F. Hoffmann-La Roche Ltd 
16/Statistical Analysis Plan BH30071 
emicizumab treatment arm (68 in total) and 17 patients in the control arm (approximately 
85 patients in total) will be enrolled. 
With a minimum of 40 and a maximum of 60 patients enrolled in the open-label 
prophylactic emicizumab arm, and assuming a mean ABR of 4 and variance of 4 × 10, 
this number is considered sufficiently powered to evaluate the efficacy endpoint in this 
cohort; the treatment will be considered to provide adequate control if the upper limit of 
the one sided 97.5% CI around the mean ABR is less than or equal to 6. 
The primary safety consideration in determining the sample size was the ability to 
sufficiently evaluate the safety profile of emicizumab as assessed by adverse events.  
Under the assumption that the occurrence of an adverse event can be adequately 
modeled using the binomial distribution, the planned sample size of 108−128 patients in 
the emicizumab treatment groups allows observation of adverse events having a true 
incidence rate of 1% with a probability of 0.66−0.72. 
No sample size re-assessment of the initially specified sample size will be performed. 
 
 
 
 
 
 
2.5 
ANALYSIS TIMING 
The primary efficacy analysis to assess the effect of emicizumab on bleed rate reduction 
will be performed at the earliest timepoint when all randomized patients (Arms A, B, and 
C) and a minimum of 40 patients from Arm D have either completed 24 weeks of study 
treatment or discontinued from the study.   
The final analysis will occur at the end of the study, as defined in the protocol.  No 
interim analysis is planned for the study. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Patients who received episodic treatment with FVIII prior to study entry will be 
randomized in a 2:2:1 ratio to receive either emicizumab prophylaxis at 3 mg/kg/wk 
subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk (Arm A) or 3 mg/kg/2wks (Arm B) 
subcutaneously, or to the control arm (no prophylaxis; Arm C).  The time between 
screening and enrollment of eligible patients should be ≤ 6 weeks; otherwise, patients 
must be re-screened to determine if they continue to meet the inclusion and exclusion 
criteria.  A central randomization procedure will be used for all patients who fulfill the 


Emicizumab—F. Hoffmann-La Roche Ltd 
17/Statistical Analysis Plan BH30071 
entry criteria at screening.  A block based randomization method will be used, stratified 
by the number of bleeds in the last 24 weeks (< 9 or ≥ 9).  The proposed randomization 
method is designed to balance treatment group assignment within the prognostic 
stratification factor. 
Patients on FVIII prophylaxis prior to study entry will be enrolled in a separate 
therapeutic arm to receive emicizumab prophylaxis (Arm D). 
3.2 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) has been assembled to review the 
safety data collected during the study.  The iDMC members consist of, at a minimum, 
independent hemostasis/thrombosis experts and a statistician, none of whom are 
otherwise involved in the conduct of study.  All analyses for review by the iDMC are 
prepared by an independent Data Coordinating Committee (iDCC) that is independent of 
the Sponsor.   
An iDCC performs unblinded analyses and provides tables and listings to support the 
iDMC reviews of safety data.  The safety data include demographic data, adverse events, 
serious adverse events, and laboratory abnormalities (coagulation, hematology, and 
chemistry).  Further information will be given by the iDCC to the iDMC on request.   
Following each meeting, the iDMC will recommend to the Sponsor whether the study 
should continue according to the protocol or may suggest changes to the protocol based 
on the outcome of the data review.  In exceptional cases, the iDMC may recommend 
stopping the study or closing a treatment arm for safety reasons.  The iDMC will monitor 
the incidence of the anticipated adverse events, as well as the overall safety of patients, 
during the study.  
The first safety review was conducted after 25 episodic patients (i.e., randomized to 
Arms A, B, or C) had been in the study for at least 2 months, and the iDMC 
recommended to continue.  Thereafter, the iDMC will meet at a frequency determined by 
the iDMC and the Sponsor according to the emerging safety profile. 
Further details are provided in a separate iDMC Charter. 
4. 
STATISTICAL METHODS 
4.1 
OUTPUT LAYOUTS 
The key output layouts are designed to address the study objectives in a flexible manner 
and provide an overall view of the efficacy and safety of emicizumab.  In particular, 
patients in Arm C are allowed to switch to receive emicizumab after the first 24 weeks in 
the study, yielding two “study periods” (i.e., when they receive no prophylaxis for the first 
24 weeks [no prophylaxis period, designated Arm Ccontrol] and emicizumab prophylaxis 
thereafter [emicizumab period, designated Arm Cemi]).  These two periods are analyzed 


Emicizumab—F. Hoffmann-La Roche Ltd 
18/Statistical Analysis Plan BH30071 
separately, and either period can be displayed on outputs together with the other 
treatment arms. 
The four key output layouts are: 
• 
Randomized patients: comparison of either emicizumab 1.5 mg/kg/wk (Arm A) 
versus no prophylaxis (control arm [Arm Ccontrol] prior to switch to emicizumab) or 
emicizumab 3 mg/kg/2wks (Arm B) versus no prophylaxis (Arm Ccontrol), within a 
single output produced for all comparisons involving arms A, B, and C prior to switch 
(Arm A versus Arm Ccontrol and Arm B versus Arm Ccontrol); these outputs form the 
core set of the efficacy comparisons and will be supported by a corresponding 
safety analysis 
• 
All patients: these outputs will be used to describe the baseline characteristics and 
study conduct 
• 
All emicizumab patients: these outputs will provide an overall view of all data 
collected under emicizumab prophylaxis (including control arm patients after switch 
[Arm Cemi]) and will include analyses of safety and descriptive efficacy   
• 
Intra-patient comparisons: Arm D is displayed separately with its own historical 
control (for Arms A and B, the patients are combined; see Section 4.5.2.6); for 
evaluations of the secondary endpoint with intra-patient comparisons, only patients 
who participated in the NIS BH29768 are included 
 
Of note, patients may be allowed to up-titrate their emicizumab dose as described in 
Section 2.  The data under the new, higher dose are analyzed and reported separately.  
Additional summaries will be produced for key safety and exposure on all data (i.e., data 
before and after up-titration).  Note, with longer follow-up or in case up-titration occurs 
more frequently than expected, outputs on all data may form the core analysis and 
additional summaries will be produced by dose. 
4.2 
ANALYSIS POPULATIONS 
4.2.1 
Randomized Population (ITT) 
The randomized population (intent-to-treat [ITT]) is defined as all randomized patients.  
The ITT population will be the primary analysis population for efficacy.  Patients are 
analyzed according to their randomized treatment arm.  Note that this population only 
includes patients in Arms A, B, and C. 
4.2.2 
All Patients 
The All Patients population includes all patients in their originally assigned treatment 
arms (including patients in Arm D previously treated with prophylactic FVIII), according 
to the interactive voice or Web Response System (IxRS). 


Emicizumab—F. Hoffmann-La Roche Ltd 
19/Statistical Analysis Plan BH30071 
4.2.3 
All Emicizumab Patients 
The All Emicizumab Patients population is the same as the All Patients population for 
Arms A, B, and D.  For Arm C, only patients who switch to receive emicizumab are 
included.   
4.2.4 
Pharmacokinetic-Evaluable Population 
The PK-Evaluable population includes all patients who have received at least one dose 
of emicizumab and have at least one post-baseline emicizumab concentration result. 
4.2.5 
Safety Population 
Two safety analysis populations are defined below: 
• 
Safety Population 1 (SAF1) includes all patients in Arms A, B, and D who received 
at least one dose of emicizumab and patients in Arm C who started the study period, 
defined as having a Week 1 visit.  For safety analysis of randomized patients, a 
subset of the SAF1 population (SAF1ND) will be used, which excludes patients in 
Arm D. 
• 
Safety Population 2 (SAF2) is exactly the same as SAF1 for patients in Arms A, B, 
and D.  For patients in Arm C, SAF2 includes all patients who switched to 
emicizumab and received at least one dose of emicizumab. 
 
4.2.6 
Up-titrated Population 
The Up-Titrated population (UPT) includes patients whose emicizumab dose was 
up-titrated to 3 mg/kg/wk. 
4.2.7 
Non-Interventional Study (NIS) Population 
The NIS population includes all patients who participated in NIS BH29768 prior 
enrollment to this study.  The NIS population includes two subpopulations: 
• 
The NISE population consisting in all the above NIS population previously treated 
with episodic FVIII 
• 
The NISP population consisting in all the above NIS population previously treated 
with prophylactic FVIII 
 
4.2.8 
 
 
 
 
   
 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
20/Statistical Analysis Plan BH30071 
4.3 
ANALYSIS OF STUDY CONDUCT 
Flow of patients through the study will be displayed in a “CONSORT” diagram.  A clear 
account of all patients who entered the study, who were enrolled and randomized, and 
who entered and completed each phase of the study will be displayed.  In addition, 
reasons for premature discontinuations from study treatment and reasons for 
withdrawing from the study (e.g., during follow-up) will be described. 
Major protocol deviations will be summarized. 
Observation time and duration of follow-up, as well as adherence to planned scheduled 
assessments and compliance with data entry into the electronic handheld device will 
also be evaluated. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Comparisons between the treatment arms of demographic data (e.g. age, sex, 
race/ethnicity, weight, and height) and baseline disease characteristics (e.g., number of 
bleeds in the past 24 weeks, previous hemophilia treatments, and number of target joints) 
will be conducted to establish if any observed differences between the treatment arms 
are not due to imbalances in patient characteristics at baseline.  Only descriptive 
analyses are planned, and no formal statistical tests will be applied. 
4.5 
EFFICACY ANALYSIS 
The primary and secondary efficacy analyses will be based on the All Patients 
population (see section 4.2.2).   
4.5.1 
Primary Efficacy Endpoint 
The primary efficacy objective is to evaluate the clinical effect of prophylactic 
emicizumab compared with no prophylaxis on the number of bleeds over time.  The 
definition of a bleed is described in Section 2.3.1.  The primary endpoint is based on 
treated bleeds. 
The comparison of the number of bleeds over time between the randomized treatment 
arms will be performed using an NB regression model, which accounts for different 
follow-up times, with the patient’s number of bleeds as a function of randomization and 
the time that each patient stays in the study (the length of the efficacy period) included 
as an offset in the model.  The model also includes the number of bleeds (< 9 or ≥ 9 
according to the eCRF data) in the last 24 weeks prior to study entry as a stratification 
factor.  This analytic model estimates the rate ratio, λt/λc, which quantifies the risk of 
bleeding associated with prophylactic emicizumab (λt) in comparison to no prophylaxis 
(λc).  Statistical significance is controlled at the 2-sided, 0.05 alpha (α) level.   
Of note, hierarchical testing is used to account for multiple testing and the first test to be 
included in the hierarchy is the emicizumab 1.5 mg/kg/wk maintenance dose versus 


Emicizumab—F. Hoffmann-La Roche Ltd 
21/Statistical Analysis Plan BH30071 
control.  The second test will be 3 mg/kg/2wks maintenance dose versus control.  A 
global approach using a model statement (within GENMOD) with a 3-level categorical 
effect for treatment (“1.5 mg/kg/wk,” “3 mg/kg/2wks,” or “no prophylaxis”) and an 
appropriate contrast statement will allow both tests to be performed via the following 
hypothesis  
H0 (null hypothesis): Rate Ratio = 1 versus H1 (alternative hypothesis): Rate Ratio ≠ 1. 
 
Statistical significance at the prespecified α level will be based on a Wald testing 
procedure.  Bleed rates for prophylactic emicizumab and no prophylaxis and the rate 
ratio will be presented and include 95% CIs. 
The number of bleeds can also be annualized for each patient using the following 
formula:   
ABR = (Number of bleeds/Total number of days during the efficacy period) × 365.25. 
 
Both the model-based method (estimated ABR from the NB model) and the method 
using the above formula (calculated ABR) will be used to describe the study results. 
If the NB model converges, the Van Elteren test to compare the mean ABR between the 
randomized arms will be provided as a sensitivity analysis.  However, if the convergence 
of the NB model is not achieved or is questionable or no bleeds at all were observed in 
one of the treatment arms, the primary efficacy analysis will be based on the Van Elteren 
test of ABR, according to the above formula. 
Of note, the Van Elteren test will be applied separately for the Arm A versus Arm Ccontrol 
(using only patients randomized to Arms A and Ccontrol) and for the Arm B versus 
Arm Ccontrol comparisons. 
4.5.2 
Secondary Efficacy Endpoints 
Type I error for secondary endpoints is controlled through a hierarchical testing 
framework. The α level is 0.05.  Following the two statistical comparisons described in 
Section 4.5.1 for the primary endpoint (Arm A versus Arm Ccontrol and Arm B versus 
Arm Ccontrol) the secondary endpoints are included in the hierarchy in the following order: 
• 
A versus C randomized comparison: all bleeds 
• 
B versus C randomized comparison: all bleeds 
• 
A versus C randomized comparison: treated joint bleeds 
• 
B versus C randomized comparison: treated joint bleeds 
• 
A versus C randomized comparison: treated spontaneous bleeds 
• 
B versus C randomized comparison: treated spontaneous bleeds 
• 
D intra-patient: all bleeds 
• 
D intra-patient: treated bleeds 


Emicizumab—F. Hoffmann-La Roche Ltd 
22/Statistical Analysis Plan BH30071 
 
A versus C randomized comparison: Haem-A-QoL physical health at 24 weeks 
 
B versus C randomized comparison: Haem-A-QoL physical health at 24 weeks  
 
4.5.2.1 
All Bleeds 
The definition of all bleeds is described in Section 2.3.2.1.  The analysis methodology is 
the NB regression model or the Van Elteren test, as described for the primary endpoint 
in Section 4.5.1. 
4.5.2.2 
Treated Spontaneous Bleeds 
The definition of treated spontaneous bleeds is described in Section 2.3.2.2.  The 
analysis methodology is the NB regression model or the Van Elteren test, the same as 
for the primary endpoint. 
4.5.2.3 
Treated Joint Bleeds 
The definition of treated joint bleeds is described in Section 2.3.2.3.  The analysis 
methodology is the NB regression model or the Van Elteren test, the same as for the 
primary endpoint. 
4.5.2.4 
Intra-Patient ComparisonPrevious Prophylactic Patients 
The definition of treated bleeds and all bleeds for the intra-patient comparison 
(Section 4.1) is the same as described for the primary and secondary endpoints.  The 
analysis methodology will be applied for Arm D (previous prophylactic patients) using the 
same NB regression model as for the primary endpoint with the exception that the SAS 
GENMOD procedure will include a REPEATED statement, to account for the 
intra-patient comparison.  For intra-patient analysis of Arms A and B, see Section 4.5.2.6. 
4.5.2.5 
Haem-A-QoL at 24 Weeks 
The physical health subscore of the Haem-A-QoL at 24 weeks will be analyzed using 
analysis of variance (ANOVA).  The model will include the treatment group together with 
the baseline score and treatment by baseline interaction as covariates.  As for the 
primary analysis, a global approach with a 3-level categorical effect for treatment 
(1.5 mg/kg/wk, 3 mg/kg/2wks, or no prophylaxis) will be produced for the comparisons of 
Arm A versus Arm C and Arm B versus Arm C.   
4.5.2.6 
Secondary Efficacy Endpoints Not Included in the Hierarchy 
Treated target joint bleeds (defined according to Section 2.3.2.4) on emicizumab will be 
compared with no prophylaxis and will be analyzed using the same methodology as for 
the primary endpoint (i.e., using the NB regression model or the Van Elteren test). 
 
 
 
 
 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
23/Statistical Analysis Plan BH30071 
 
     
The Haem-A-QoL total score, the EQ-5D-5L index utility score based on the U.K. value 
set, and the VAS at 24 weeks will be analyzed using the same analysis methodology as 
the Haem-A-QoL physical health subscore (i.e., via ANOVA). 
The same analysis methodology for the intra-patient comparison within Arm D for treated 
bleeds and all bleeds will be applied for the pooled Arms A and B (episodic patients 
randomized to emicizumab).  Of note: given the small number of NIS episodic patients 
that were randomized to either Arm A or B, it was considered that a pooled analysis was 
considered as more appropriate than two separate analyses. 
Only a descriptive summary of the Haemo-QoL-SF will be provided because of the small 
number of adolescents randomized to the study. 
4.5.3 
Exploratory Efficacy Endpoints 
All bleeds will be characterized descriptively, including the type, location, and cause of 
bleed (surgery/procedure, traumatic, spontaneous).  Bleed rates for spontaneous and 
traumatic bleeds will be calculated. 
For EQ-5D-5L, Haem-A-QoL, and Haemo-QoL-SF, exploratory analyses include 
descriptive analyses of change from baseline and between group comparisons over time 
for each individual subscale and the overall score.  In addition, a paired t-test will be 
conducted to compare the 24-week with the baseline score for the EQ-5D-5L and 
Haem-A-QoL questionnaires by treatment arm separately.  Due to the limited number of 
adolescent patients, paired t-tests will not be conducted on the Haemo-QoL-SF scales.  
For EQ-5D-5L and Haem-A-QoL, the number of patients who reported a clinically 
meaningful change from baseline to Week 24 will be reported.  For EQ-VAS, a 
meaningful change is 7 points and for the index scale it is 0.07 points 
(Walters et al. 2005; Pickard et al. 2007).  For Haem-A-QoL a meaningful change is 
7 points for the total score and 10 points for the physical health score 
(Wyrwich et al. 2015). 
The number of days away from school/work and days hospitalized will be presented by 
treatment arm using descriptive statistics and 95% CIs. 
 
 
 
 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
24/Statistical Analysis Plan BH30071 
 
 
Regarding the preference survey that is given to patients in Arms A, B, and D at 
Week 17, the proportion of patients preferring the older hemophilia IV treatment prior to 
enrollment in the study, emicizumab, and without treatment preference will be computed 
along with 95% CIs.  For patients who have a preference to emicizumab, the factors 
influencing the preference will be treated like ordered categorical variables (e.g., from 
“had no influence in my treatment preference” to “was the most important factor in my 
treatment preference”) and will be summarized accordingly.  The same approach will be 
applied for patients who have a preference to the old hemophilia treatment.  Bar charts 
by preference factors may be produced to characterize the preference profile of each 
treatment (“emicizumab” or “old hemophilia treatment”).    
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
4.5.4 
Sensitivity Analyses 
The sensitivity analyses will include different methods to define bleeds or eligible bleed 
data and different statistical models. 


Emicizumab—F. Hoffmann-La Roche Ltd 
25/Statistical Analysis Plan BH30071 
Different ways to define bleeds or eligible bleed data for A versus C and B versus C 
randomized comparisons: 
• 
Include all bleeds recorded by patients in the electronic patient-reported outcomes 
device (i.e., without the 72-hour rule)  
• 
Include treated joint bleeds defined as treated bleeds where the bleed type is “joint,” 
regardless whether any symptoms have been observed 
• 
Include only patients who received at least 12 weeks of emicizumab treatment (if 
needed) 
• 
Count days when treatment for bleeds was administered instead of the bleeds 
themselves 
• 
Include only the first 24 weeks of efficacy period in the analysis.  Patients who 
withdraw from study treatment are included up to the point of study treatment 
withdrawal.  
 
Different ways to analyze secondary endpoints with intra-patient comparison: 
• 
D intra-patient: include also period after up-titration 
• 
A intra-patient and B intra-patient: provide also analyses separately by arm (i.e., 
without grouping Arm A and Arm B) 
 
Different statistical models for the bleed rate: 
• 
An alternative NB modeling approach (using the GENMOD procedure) for the 
primary endpoint in which the A versus C and B versus C randomized comparisons 
are tested using separate models, including in the first model only the data for 
patients randomized into arms A and C and in the second model only the data for 
patients randomized into arms B and C. 
• 
Analysis of variance (ANOVA) 
• 
Van Elteren test (calculated ABR) 
 
4.5.5 
Subgroup Analyses 
Comparative subgroup analyses describing the primary endpoint, treated bleed rate, will 
be conducted for the randomized portion of the study.  In addition, estimated ABR 
including 95% CI will be calculated for all treatment arms in each subgroup.  Note, due 
to the small sample size, all subgroup analyses will be highly sensitive to variability 
caused by individual patients and need to be interpreted with caution.  No p-values will 
be calculated. 
The pre-specified subgroups are: 
• 
Age: < 18, ≥ 18 
• 
Age: < 65, ≥ 65 
• 
Race: Asian, Black or African American, White, Other 
• 
Number of bleeds during 24 weeks prior to study entry: ≤ 9, > 9 


Emicizumab—F. Hoffmann-La Roche Ltd 
26/Statistical Analysis Plan BH30071 
• 
Number of target joints: no target joint, any target joint 
 
Subgroup analyses are subject to having sufficient patients in a subgroup to provide 
meaningful results. 
In addition, region- and/or country-specific analyses will be performed to support 
regulatory submissions as needed. 
4.6 
PHARMACOKINETIC ANALYSES 
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be 
presented descriptively by treatment arm, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation. 
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various 
covariates, such as age, and body weight, on these parameters will be investigated 
graphically.  Secondary PK parameters, such as area under the concentration-time 
curve (AUC), will be derived from individual post-hoc predictions.  Data may be pooled 
with data from other studies.  These analyses will be reported in a dedicated report. 
In addition, region- and/or country-specific analyses will be performed to support 
regulatory submission as needed. 
4.7 
SAFETY ANALYSES 
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry and hematology, including complete blood count with 
differential), ECGs, vital signs, and antibodies to emicizumab and FVIII. 
4.7.1 
Exposure to Study Medication 
Information on study drug administration will be summarized by duration and cumulative 
dose.  In addition, treatment exposure will be summarized, including delays and 
interruptions.  The number of patients whose dose was up-titrated will be summarized. 
Patient withdrawals from study treatment will be reported in patient listings and summary 
tables. 
4.7.2 
Adverse Events 
Adverse events will be summarized and presented by System Organ Class mapped 
term, appropriate thesaurus level, and toxicity grade (WHO Criteria) for each treatment 
arm.  All adverse events will be coded using the current version of MedDRA at time of 
database closure.  The total number and percentage of patients with at least one 
adverse event and total number of adverse events will be summarized.  Separate 


Emicizumab—F. Hoffmann-La Roche Ltd 
27/Statistical Analysis Plan BH30071 
adverse event summaries for serious adverse events, adverse events of special interest, 
severity, relatedness, and discontinuation/modification will be provided. 
4.7.3 
Laboratory Data 
For clinical laboratory data that were collected from local laboratories, summary statistics 
in International System of Units (SI) will be presented by treatment arm.  Laboratory data 
not collected in SI units will be converted to SI units as applicable.  In addition, shift 
tables describing changes from baseline will be presented using the WHO toxicity 
grading scale. 
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or clinical pharmacology and pharmacokinetics will be summarized using standard 
language/terminology (Shankar et al. 2014). 
4.7.4 
Vital Signs 
Vital signs will be summarized by treatment arm using mean change from baseline 
tables over time.  Measurements consist of heart and respiratory rate, temperature, and 
systolic and diastolic blood pressures. 
4.7.5 
Electrocardiogram 
ECG results and corresponding changes from baseline will be summarized by treatment 
arm and visit for QT, RR, HR, QTcB, QTcF, PR, and QRS and T- and U-wave 
morphology. 
4.8 
EXPLORATORY BIOMARKER ANALYSES 
PD parameters (e.g., aPTT, parameters derived from thrombin generation, FVIII activity) 
 will be presented using summary statistics 
over time, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation.  Summary and individual patient plots will also 
be produced, if applicable.  
 
 
. 
4.9 
MISSING DATA 
On the electronic handheld devices, including the tablet on which the HRQoL endpoints 
are reported, it is not possible to leave questions unanswered or to enter partial data. 
Therefore the data for the primary and secondary bleed related endpoints and the 
HRQoL questionnaires are considered complete. 
In the site data entry system, the symptoms of joint and muscle bleed are not collected.  
Therefore, bleeds with an anatomical location in a joint are considered joint bleeds. 


Emicizumab—F. Hoffmann-La Roche Ltd 
28/Statistical Analysis Plan BH30071 
4.10 
INTERIM ANALYSES 
No efficacy interim analyses are planned. 


Emicizumab—F. Hoffmann-La Roche Ltd 
29/Statistical Analysis Plan BH30071 
5. 
REFERENCES 
 
 
Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from 
the SSC of the ISTH. J Thromb Haemost 2014;12:1935−9. 
Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX 
in hemophilia B: a multinational randomized phase 3 trial. Blood 
2014;124(26):3880−6. 
De Moerloose P, Urbancik W, Van Den Berg HM, et al. A survey of adherence to 
haemophilia therapy in six European countries: results and recommendations. 
Haemophilia 2008;14(5):931−8. 
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, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:179−84. 
Geraghty S, Dunkley T, Harrington C, et al. Practice patterns in haemophilia A 
therapyglobal progress towards optimal care. Haemophilia 2006;12(1):75−81. 
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult 
patients with severe haemophilia: a beneficial effect on orthopaedic outcome and 
quality of life. Eur J Haematol 2012;88(4):329−35. 
Kingdon HS, Lundblad RL. An adventure in biotechnology: the development of 
haemophilia A therapeuticsfrom whole-blood transfusion to recombinant DNA to 
gene therapy. Biotechnol Appl Biochem 2002;35:141−8. 
Lindvall K, Colstrup L, Wollter IM, et al. Compliance with treatment and understanding of 
own disease in patients with severe and moderate haemophilia. Haemophilia 
2006;12(1):47−51. 
Mair FS, 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, Tuddenham EG. The hemophiliasfrom royal genes to gene therapy. N 
Engl J Med 2001;344:1773−9. 
Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations 
of current prophylactic regimens. Blood 2015;125(13):2038−44. 


Emicizumab—F. Hoffmann-La Roche Ltd 
30/Statistical Analysis Plan BH30071 
Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health Qual Life Outcomes 2007;5:70. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and 
tactical recommendations. AAPS J 2014;16:658−73.  
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Am Soc 
Hematol Educ Program 2013;2013:37−43.  
Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized 
bispecific antibody in hemophilia A. N. Engl J Med 2016;374:2044−53. 
Teal S, Brohan E, Hettema Y, et al. Development and psychometric evaluation of a 
novel tool for assessing patient perception and preference for haemophilia 
treatment (HaemoPREF). Haemophilia 2014;20(5):666−73. 
 
Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a 
novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016:1−38. 
Walters SJ, Brazier JE. Comparison of the minimally important difference for two health 
state utility measures: EQ-5D and SF-6D. Qual Life Res 2005;14:1523−32. 
World Federation of Hemophilia. Annual Global Survey Data 2013 [resource on the 
Internet]. Accessed April 22, 2015. Available from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx. 
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of 
life change using the Haem-A-QoL. Haemophilia. 2015:21:578−84. 
 


 
Emicizumab—F. Hoffmann-La Roche Ltd 
31/Statistical Analysis Plan BH30071 
Appendix 1  
Protocol Synopsis 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF PROPHYLACTIC EMICIZUMAB 
VERSUS NO PROPHYLAXIS IN HEMOPHILIA A PATIENTS 
WITHOUT INHIBITORS 
PROTOCOL NUMBER: 
BH30071 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2016-000072-17 
IND NUMBER: 
122,954 
TEST PRODUCT: 
Emicizumab (RO5534262) 
PHASE: 
Phase III 
INDICATION: 
Hemophilia A without inhibitors 
SPONSOR: 
F. Hoffmann-La Roche Ltd and Chugai Pharmaceutical Co. Ltd. 
 
Objectives and Endpoints 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of prophylactic 
emicizumab (i.e., administered on a scheduled basis with the intent to prevent bleeds) 
compared with no prophylaxis in patients with hemophilia A without factor VIII (FVIII) inhibitors 
on the basis of the following endpoint: 
• 
The number of bleeds over time (i.e., bleed rate) 
 
The endpoint will be analyzed separately for the two emicizumab arms:  1.5 mg/kg/week (wk) 
and 3 mg/kg/every 2 weeks (2wks).  The primary endpoint is based on treated bleeds. 
Secondary Efficacy Objective 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of prophylactic emicizumab (in each individual emicizumab arms) 
on the basis of the following endpoint: 
Change in the number of bleeds over time compared with the patient’s historical bleed 
rate * 
• 
To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk or 
3 mg/kg/2wks subcutaneously compared with no prophylaxis for patients previously treated 
with episodic FVIII on the basis of the following endpoints: 
All bleeds over time 
Spontaneous bleeds over time (spontaneous bleed rate) 
Joint bleeds over time  


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
32/Statistical Analysis Plan BH30071 
Target joint bleeds over time (target joints are defined as joints with ≥ 3 bleeds 
occurring in the same joint over the last 24 weeks prior to study entry) 
HRQoL of patients according to Haem-A-QoL (aged ≥ 18) or Haemo-QoL-Short Form 
(aged 12−17) scores after 24 weeks 
Health status of patients according to EuroQoL Five-Dimension-Five Levels 
Questionnaire (EQ-5D-5L) scores after 24 weeks 
• 
To evaluate the efficacy of prophylactic emicizumab administered at 1.5 mg/kg/wk 
subcutaneously for patients previously treated with prophylactic FVIII on the basis of the 
following endpoint: 
Maintaining adequate control of bleeding by evaluation of the bleed rate * 
 
* Analyses will be performed for treated bleeds and all bleeds. 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To assess satisfaction regarding treatment with emicizumab prophylaxis
 
 
• 
To assess treatment preference for emicizumab prophylaxis versus FVIII prophylaxis or 
episodic therapy according to the preference survey  
• 
To assess changes in number of days away from school/work during treatment with 
prophylactic emicizumab compared with no prophylaxis 
• 
To assess changes in number of hospitalization days during treatment with prophylactic 
emicizumab compared with no prophylaxis  
• 
To assess potential pharmacodynamic (PD) biomarkers of emicizumab, including but not 
limited to aPTT, thrombin generation, and FVIII activity  
• 
 
• 
 
  
• 
 
 
 
Safety Objective 
The safety objective for this study is to evaluate the overall safety of prophylactic emicizumab 
compared with no prophylaxis in patients with hemophilia A without inhibitors on the basis of the 
following endpoints: 
• 
Incidence and severity of adverse events 
• 
Incidence and severity of thromboembolic events 
• 
Changes in physical examination findings and vital signs  
• 
Incidence of laboratory abnormalities  
• 
Incidence and severity of injection-site reactions  
• 
Incidence of adverse events leading to drug discontinuation  
• 
Incidence of severe hypersensitivity, anaphylaxis, or anaphylactoid reactions 
• 
Incidence and severity of thrombotic microangiopathy 
• 
Incidence and clinical significance of anti-emicizumab antibodies 
• 
Incidence of de novo development of FVIII inhibitors in patients receiving emicizumab 
prophylaxis 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan BH30071 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the exposure (trough 
plasma concentration) to emicizumab in patients treated on weekly or every 2 weeks dosing 
schedule at the following timepoints: 
• 
Every week during Weeks 1−4 on emicizumab 
• 
Every 2 weeks during Weeks 5−8 on emicizumab 
• 
Every 4 weeks during Weeks 9−24 on emicizumab 
• 
Every 8 weeks during Weeks 25−48 on emicizumab 
• 
Every 12 weeks thereafter while on emicizumab, until the end of the study 
 
Study Design 
Description of Study 
This randomized, multicenter, open-label, Phase III clinical study will enroll patients aged 
12 years or older with severe hemophilia A (intrinsic FVIII level < 1%) without inhibitors against 
FVIII.  Eighty-five patients who received episodic treatment with FVIII prior to study entry and 
experience at least 5 bleeds over the prior 24 weeks (annual bleed rate [ABR] ≥ 10) will be 
randomized in a 2:2:1 ratio (see protocol) to the following regimens: 
• 
Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
1.5 mg/kg/wk subcutaneously (Arm A),  
• 
Emicizumab prophylaxis at 3 mg/kg/wk subcutaneously for 4 weeks, followed by 
3 mg/kg/2wks subcutaneously (Arm B), or  
• 
No prophylaxis control arm (Arm C).  
 
Randomization will be stratified according to the number of bleeds patients experienced over 
the last 24 weeks prior to study entry—less than versus greater than or equal to 9 (or ABR 
18)—to ensure a balance of patients with lower versus higher number of bleeds in all arms.  All 
patients will use episodic treatment with FVIII at the lowest expected dose to achieve hemostasis 
in case of a breakthrough bleeding event (see below).    
In addition, 40−60 patients with severe hemophilia A who received FVIII prophylaxis prior to 
study entry will be enrolled and will receive emicizumab prophylaxis at 3 mg/kg/wk 
subcutaneously for 4 weeks, followed by 1.5 mg/kg/wk subcutaneously (Arm D; see protocol).  
A minimum of 40 patients in this group will complete at least 24 weeks of observation in an 
ongoing non-interventional study (BH29768) prior to enrollment in this study.  Eligibility for all 
patients in Arm D will be based on investigator’s attestation of adequate prophylaxis regimen in 
the 24 weeks prior to study entry. 
To avoid bleeds before adequate emicizumab plasma concentration is reached, these patients 
will continue their regular FVIII prophylaxis until the second emicizumab loading dose.  At the 
end of the first week of treatment, 95% of patients are expected to achieve emicizumab level of 
8 μg/mL, which is projected to have FVIII activity equivalent to approximately > 2%.  Thrombotic 
events were not found in the Japanese Phase I/II study where doses of FVIII were administered 
to treat breakthrough bleeds while patients had higher emicizumab steady-state level, 
supporting the safety of this approach.  Importantly, routine prophylaxis will be prohibited for all 
patients enrolled in Arms A, B, or C and for patients in Arm D immediately after the second 
emicizumab dose. 
Study enrollment will take place at the Week 1 visit.  A patient who fulfills the inclusion and 
exclusion criteria should be enrolled and assigned to a treatment arm at the Week 1 visit, the 
same day when the first dose of emicizumab is due for patients in Arms A, B, and D. 
Emicizumab is intended for prophylactic use only (i.e., not to treat bleeds that have already 
occurred).  The primary efficacy analysis, defined as comparing the number of bleeds over time 
for patients randomized to receive prophylactic emicizumab versus no prophylaxis will be 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
34/Statistical Analysis Plan BH30071 
conducted at the earliest timepoint when all randomized patients (Arms A, B, or C) and a 
minimum of 40 patients from Arm D have either completed 24 weeks in the study or 
discontinued from the study.  Therefore, there will be a range of observation periods from 6 to 
approximately 12 months, or longer.  Study patients will be enrolled globally from the Americas, 
Europe, Africa, and Asia-Pacific region. 
To obtain additional safety and efficacy data on emicizumab, patients who are randomized to 
the no prophylaxis arm (control arm, Arm C) will be expected to switch after 24 weeks to receive 
emicizumab prophylaxis at 3 mg/kg/2wks maintenance dose after 4 weeks of 3 mg/kg/wk 
loading dose.  This dose was chosen to enhance the safety and efficacy data obtained with 
Arm B patients. 
After completing at least 24 weeks of treatment with prophylactic emicizumab, patients who 
receive emicizumab prophylaxis (Arms A, B, D, or Arm C after treatment switch) and derive 
clinical benefit will be allowed to continue emicizumab until marketing authorization as part of 
this study or a separate extension study, as long as they continue to derive clinical benefit and 
emicizumab is still in clinical development (see protocol).  Those who are well controlled 
(ABR < 4) will continue treatment on their assigned emicizumab regimen; whereas, patients in 
Arms A, B, or C (after 24 weeks on emicizumab) who experience suboptimal control (ABR ≥ 4) 
will be offered the option to escalate to 3 mg/kg/wk after approval from the Medical Monitor.  
Patients in Arm D who experience suboptimal control while on emicizumab prophylaxis at the 
maintenance dose, will have the opportunity to escalate to 3 mg/kg/wk immediately after the 
second qualifying bleed.  Criteria and details of dose escalation are described in the protocol. 
During the study, individual bleeds will be captured as they occur, while HRQoL, health status, 
patient safety, patient preference and satisfaction, 
, and days of school or work 
missed will be assessed as outlined in the schedule of assessments.  Patients (or their 
caregiver) will be asked to record on an electronic, handheld device their bleeds (i.e., start date 
and time, reason, type, location, and associated symptoms of each bleed) and 
hemophilia-related medication use (i.e., start date and time, reason, type, dose of injection, and 
number of doses) at least weekly, when a bleed occurs, or when a hemophilia medication was 
taken at home or in the clinic. 
Throughout the study, biomarkers related to thromboembolism (e.g., D-dimer, prothrombin 
1.2 fragment) and emicizumab trough concentrations will be collected as per the schedule of 
assessments.  Immunologic biomarkers (i.e., anti-emicizumab antibodies and anti-FVIII 
antibodies) will also be measured as per the schedule of assessments (see protocol). 
Exploratory PD biomarkers (e.g., aPTT, FVIII activity, thrombin generation assay) will be 
collected as per the schedule of assessments.  As values for some of these tests are 
normalized by low plasma concentrations of emicizumab, a variety of assay formats (one stage, 
chromogenic) and modifications (predilution of patient plasma) will be investigated for 
assessment of PD response at higher emicizumab plasma concentrations. 
 
 
 In addition, FIX and FX antigen levels will be measured.   
Physical examinations, 
, vital 
signs assessments, ECGs, and laboratory assessments will be collected as per the schedule of 
assessments and will be the same for all patients, with the exception that emicizumab PK and 
ADAs will not be measured in patients in Arm C prior to the switch to emicizumab treatment.  
Adverse events will be captured as they occur for the duration of the study. 
All patients who receive emicizumab in the study will undergo PK assessments.  A washout 
period from FVIII therapy is not required prior to inclusion because FVIII replacement does not 
interfere with emicizumab PK assessments, and some patients with hemophilia A require 
frequent dosing with FVIII to treat bleeds or for prophylaxis. 
An independent Data Monitoring Committee (iDMC) composed of at minimum 
hemostasis/thrombosis experts and a statistician will be in place for the duration of the study 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
35/Statistical Analysis Plan BH30071 
and will monitor patient safety at pre-specified intervals and ad hoc as needed throughout the 
study (to be described in the iDMC charter).    
Breakthrough bleeds for patients receiving emicizumab will be treated with FVIII at the lowest 
FVIII dose expected to achieve hemostasis and captured as they occur on the handheld device.  
Patients (or their caregiver) will report bleed information, including site of bleed, type of bleed, 
category of bleed, time of each individual bleed (day, start time), symptoms of bleed, and 
treatment for bleed.  During the study patients will enter bleed and medication data at least 
weekly.  Of note, the clinical experience in the ongoing Phase I and I/II clinical studies includes 
the treatment of breakthrough bleeds with FVIII or bypassing agents in patients receiving 
emicizumab (over 
 bleeds treated) without any related safety concerns reported.  However, 
in the ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A 
with FVIII inhibitors), 2 events of TMA and 2 thromboembolic events were observed in 
patients on emicizumab who concomitantly used repeated doses of aPCC for the treatment of 
breakthrough bleeds (see protocol).  Although FVIII and aPCC are fundamentally different in 
their potential interaction with emicizumab, investigators should keep in mind that 
circulating emicizumab increases patients’ coagulation potential.  Therefore, it is 
recommended that: 
• 
Breakthrough bleeds should be treated with the lowest FVIII dose expected to achieve 
hemostasis, which may be lower than the patients’ prior FVIII dose.  Investigators should 
review with patients the dose to be used to treat breakthrough bleeds. 
• 
If breakthrough bleeding does not resolve after the first dose of FVIII, patients should be 
instructed to contact the treatment center before infusing multiple FVIII doses. 
• 
Investigators and patients should consider objective verification of bleeds. 
 
Investigators will contact the Medical Monitor in the event of suspected lack or loss of efficacy 
of emicizumab in order to discuss potential laboratory evaluations (e.g., anti-emicizumab 
antibodies, coagulation tests) to be performed as well as to re-evaluate their patient’s 
benefit-risk of continued treatment. 
The reason for the use of FVIII products will be documented (e.g., bleeding, one time 
prophylaxis, etc.).  A thorough documentation of the treatments for bleeds will be required, 
including agent, start time, dose, route of administration, and number of infusions needed to 
treat the bleed.   
A non-interventional study (BH29768) has been initiated to document the number and types of 
bleeds and current treatment with episodic or prophylactic FVIII agents, as well as to collect 
information on HRQoL, health status, and safety in patients with hemophilia A.  The 
assessments in the non-interventional study will mitigate the risk of underreporting of bleeds 
that likely occurs in the real world, and the resulting data will serve as a source of comparator 
information for some analyses conducted in the Phase III clinical studies, including this study.  
In addition, the non-interventional study will enable earlier identification and confirmation of 
patients who may qualify for the Phase III clinical study.  It is anticipated that a significant 
number of patients participating in Study BH29768 will enroll in this study, as long as they meet 
the inclusion and exclusion criteria and are able to enroll at a participating site while the study is 
open for enrollment. 
 
 
 
 
 
 
 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
36/Statistical Analysis Plan BH30071 
Number of Patients 
A total of 125−145 patients with severe hemophilia A will be enrolled, including 85 patients who 
received episodic treatment with FVIII and 40−60 who received FVIII prophylaxis prior to study 
entry. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form by the patient or a legal guardian 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the completion of patient-reported outcome 
questionnaires and bleed and medication diary through the use of an electronic device 
• 
Aged 12 years or older at the time of informed consent 
• 
Body weight ≥ 40 kg at the time of screening  
• 
Diagnosis of severe congenital hemophilia A (intrinsic FVIII level < 1%)  
• 
A negative test for inhibitor (i.e., < 0.6 BU) within 8 weeks of enrollment 
• 
No documented inhibitor (i.e., < 0.6 BU), FVIII half-life < 6 hours, or FVIII recovery < 66% in 
the last 5 years 
• 
Patients who completed successful immune tolerance induction (ITI) at least 5 years before 
screening are eligible, provided they have had no evidence of inhibitor recurrence 
(permanent or temporary) as may be indicated by detection of an inhibitor, FVIII half-life 
< 6 hours, or FVIII recovery < 66% since completing ITI. 
• 
Documentation of the details of prophylactic or episodic FVIII treatment and of number of 
bleeding episodes for at least the last 24 weeks 
• 
For patients on no prophylaxis (episodic treatment) pre-study, ≥ 5 bleeds in the last 
24 weeks prior to study entry.  
• 
Patients who were on FVIII prophylaxis for at least the last 24 weeks, can be enrolled 
regardless of the number of bleeds during this period.  Eligibility will be based on 
investigator’s attestation of adequate prophylaxis regimen. 
• 
At least 40 patients who were on FVIII prophylaxis pre-enrollment will have been enrolled 
for a minimum of 24 weeks in Study BH29768 (non-interventional) 
• 
Adequate hematologic function, defined as platelet count ≥ 100,000/µL and hemoglobin 
≥ 8 g/dL (4.97 mmol/L) at the time of screening 
• 
Adequate hepatic function, defined as total bilirubin ≤ 1.5 × the upper limit of normal (ULN) 
(excluding Gilbert’s syndrome) and both AST and ALT ≤ 3 × ULN at the time of screening; 
no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis  
• 
Adequate renal function, defined as serum creatinine ≤ 2.5 × ULN and creatinine clearance 
by Cockcroft-Gault formula ≥ 30 mL/min 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% 
per year and are approved by local health authorities and ethics committees during the 
treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of 
study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 1 year of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization (removal of ovaries 
and/or uterus). 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
37/Statistical Analysis Plan BH30071 
Examples of highly effective contraceptive methods with a failure rate of < 1% per year 
include proper use of combined oral or injected hormonal contraceptives, bilateral tubal 
ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.   
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.   
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Inherited or acquired bleeding disorder other than hemophilia A 
• 
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the 
investigator’s judgment 
• 
Previous (in the past 12 months) or current treatment for thromboembolic disease (with the 
exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is 
not currently ongoing) or signs of thromboembolic disease  
• 
Other conditions (e.g., certain autoimmune diseases) that may increase risk of bleeding or 
thrombosis  
• 
History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection 
• 
Known HIV infection with CD4 count < 200 cells/µL within 24 weeks prior to screening.  
Patients with HIV infection who has CD4 > 200 and meet all other criteria are eligible. 
• 
Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy 
• 
Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment. 
• 
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study, may pose additional risk, or would, in the opinion of the 
investigator, preclude the patient’s safe participation in and completion of the study 
• 
Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 
• 
Receipt of: 
Emicizumab in a prior investigational study 
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration 
A non-hemophilia-related investigational drug concurrently, within last 30 days or 
5 half-lives, whichever is shorter 
• 
Inability to comply with the study protocol in the opinion of the investigator 
• 
Pregnant or lactating, or intending to become pregnant during the study 
• 
Women who are not postmenopausal (≥ 48 weeks of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 7 days prior to 
initiation of study drug. 
 
End of Study 
The primary analysis will take place at the earliest timepoint when all randomized patients 
(Arms A, B, and C) and a minimum of 40 patients from Arm D have either completed 24 weeks 
of treatment or discontinued from the study. 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
38/Statistical Analysis Plan BH30071 
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., LPLV), as defined below: 
• 
Completed 24 weeks of emicizumab and either transferred to a separate extension study to 
receive further emicizumab as per Roche Global Policy on Continued Access to 
Investigational Medicinal Products or to commercial product 
OR 
• 
Completed the end of study safety follow-up visit 24 weeks after discontinuing emicizumab 
OR 
• 
Consent has been withdrawn 
OR 
• 
Lost to follow-up 
 
Length of Study 
The approximate length of the entire study from the first patient enrolled to the last patient last 
visit (LPLV [last patient, last visit]; see below) is 2 years. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Emicizumab, the only investigational medicinal product (IMP) in Study BH30071, is required for 
completion of this study and will be provided by the Sponsor, and accountability for each vial is 
required throughout the study.  The study site will acknowledge receipt of IMPs using the 
interactive voice or Web response system (IxRS) to confirm the shipment condition and content.  
Any damaged shipments will be replaced. 
Used and unused IMP vials will be returned by study patients to the site and appropriately 
accounted for.  Used vials will then be disposed of at the study site according to the study site’s 
institutional standard operating procedure.  Instructions regarding how to handle unused vials 
should be obtained from the Sponsor.  The site's method of IMP destruction must be agreed to 
by the Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Inventory Log. 
Non-Investigational Medicinal Products 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening to the study completion/discontinuation visit.  In addition, use of long-acting 
medications taken infrequently (e.g., zoledronic acid, Denosumab) will be recorded as well.  All 
such medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Concomitant use of the following drugs and therapies will be permitted: 
• 
To avoid bleeds before adequate emicizumab level is reached, patients in Arm D will 
continue their regular FVIII prophylaxis until the second emicizumab loading dose.  
Concomitant routine FVIII prophylaxis is not permissible otherwise during the study.  
• 
Drugs intended to control bleeds, including FVIII as standard of care/episodic treatment.  
Specific dosages of FVIII will not be mandated in the study but rather should be 
administered according to the respective prescribing information or as previously used per 
each individual patient (for information on the formulation, packaging, and handling of 
agents, see the local prescribing information for the marketed drug in question). 
• 
Drugs and therapies to treat adverse events and use of topical antiseptics, anesthetics, eye 
drops, etc., that are not considered to result in systemic exposure 
 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
39/Statistical Analysis Plan BH30071 
Statistical Methods 
Efficacy Analysis 
The primary and secondary efficacy analyses to evaluate the clinical effect of prophylactic 
emicizumab compared with no prophylaxis will include all randomized patients, with patients 
grouped according to the treatment assigned at randomization.  For patients previously treated 
with prophylactic FVIII, the efficacy analysis will include all enrolled patients.   
Safety Analysis 
The safety analyses population will be based on all enrolled patients grouped according to the 
actual treatment received.  For Arm C patients, all safety data reported up to the day prior to 
switching will be included in the ‘control arm’ safety summaries, and all safety data reported on 
or after the date of switching to active treatment will be reported separately. 
Safety will be assessed through descriptive summaries of adverse events, laboratory test 
results (serum chemistry and hematology, including complete blood count with differential), 
ECGs, vital signs, and antibodies to emicizumab and FVIII. 
To evaluate the overall safety of prophylactic emicizumab compared to no prophylaxis, the 
incidence of adverse events will be summarized and presented by System Organ Class 
mapped term, appropriate thesaurus level, and toxicity grade for each treatment arm.   
For clinical laboratory data, summary statistics will be presented by treatment arm.  In addition, 
shift tables describing changes from baseline will be presented using the WHO toxicity grading 
scale. 
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, and/or 
clinical pharmacology and PK will be summarized adopting standard language/terminology. 
Pharmacokinetic Analyses 
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be presented 
descriptively by treatment group, including arithmetic and geometric means, median, range, 
standard deviations, and coefficients of variation. 
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
gender, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as AUC, will be derived from individual post-hoc predictions.  Data may be 
pooled with data from other studies.  These analyses will be reported in a dedicated report. 
Exploratory Analyses 
Summary statistics of the number of work/school days missed and days hospitalized will be 
presented by treatment arm.  Summary statistics will also be presented for the 
 
emicizumab Preference Survey.  PD parameters (e.g., aPTT, parameters derived from thrombin 
generation, FVIII activity) 
 will be presented using 
summary statistics, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
40/Statistical Analysis Plan BH30071 
  
 
 
 
 
 
Determination of Sample Size   
The sample size for this study is based on clinical rather than statistical considerations, taking 
into account the limited number of patients with hemophilia A without inhibitors available for 
participation in clinical studies and in an effort to collect sufficient data to assess the safety and 
efficacy of emicizumab. 
The sample size calculation is based on the evaluation of the primary efficacy endpoint, defined 
as the number of bleeds over time (i.e., bleed rate) with emicizumab (treatment group, λt) 
versus no prophylaxis (control group, λc), which are said to follow a negative binomial (NB) 
distribution.  With consideration of enrollment feasibility, a sample size of 75 patients, assuming 
an allocation ratio of 2:2:1 (30 patients in each randomized treatment group and 15 patients in 
control group), will achieve a power of more than 90% assuming a mean ABR of 4 and 
14 bleeds (with variances = mean × 10) for the emicizumab treatment and control arms 
respectively, representing an expected 71% reduction in the ABR compared to the control arm.  
Initial sample size calculations were performed with East®, Version 6 (Cytel, Cambridge, MA), 
assuming the patients from each treatment group are followed up to 0.5 units of time 
(i.e., 24 weeks). 
However, the above approach to sample size calculation assumes similar follow-up for each 
patient.  Because this is unlikely to be seen in the study, power was also estimated by 
simulation to account for different follow-up times among patients.  Conducting simulations on 
the basis of an NB regression model including an offset variable to account for variable 
follow-up times, with all other assumptions remaining the same as previously described, the 
sample size is projected to have greater than 90% power at the 2-sided 0.05 level of 
significance. 
The analysis will include all enrolled patients regardless of their length of follow-up.  Therefore, 
to ensure the analysis is based on sufficient follow-up data and with 2:2:1 treatment to control 
randomization, approximately 34 patients in each randomized emicizumab treatment arm (68 in 
total) and 17 patients in the control arm (approximately 85 patients in total) will be enrolled. 
With a minimum of 40 and a maximum of 60 patients enrolled in the open-label prophylactic 
emicizumab arm, and assuming a mean ABR of 4 and variance of 4 × 10, this number is 
considered sufficiently powered to evaluate the efficacy endpoint in this cohort; the treatment 
will be considered to provide adequate control if the upper limit of the one-sided 97.5% CI 
around the mean ABR is less than or equal to 6. 
The primary safety consideration in determining the sample size was the ability to sufficiently 
evaluate the safety profile of emicizumab as assessed by adverse events.  Under the 
assumption that the occurrence of an adverse event can be adequately modeled using the 
binomial distribution, the planned sample size of 108−128 patients in the emicizumab treatment 
groups allows observation of adverse events having a true incidence rate of 1% with a 
probability of 0.66−0.72. 
During the study, a re-assessment of the initially specified sample size based on aggregated 
(not by treatment arm) data to-date (and potentially from the non-interventional study [BH29768] 
findings) may be performed.  This may result in an increase in sample size, if necessary, to 
maintain adequate power without affecting the type 1 error rate.  Study integrity will be upheld, 
as access to information via aggregated analyses and their results will be minimized to limit 
operational bias. 


Appendix 1  
Protocol Synopsis (cont.)  
Emicizumab—F. Hoffmann-La Roche Ltd 
41/Statistical Analysis Plan BH30071 
 
 
 
 
 
 
 
Interim Analyses  
No interim analysis for efficacy is planned. 
 


 
Emicizumab—F. Hoffmann-La Roche Ltd 
42/Statistical Analysis Plan BH30071 
Appendix 2  
Schedule of Assessments 
 
Schedule of Assessments−Arms A, B, and D 
 
Screen-
ing 
Wk 
1  
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Every 
8 Wks 
from 
Wk 33 
Wk 
49 
Every 
12 Wks 
from 
Wk 61 
Wk 
73 
Daily/ 
weeklya 
Study 
Com-
pletion/ 
ET  
Safety  
F/U 
Visit b 
Informed consent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (including 
weight) e 
x 
x 
 
 
 
x 
 
 
 
 
 
x 
 
x 
x 
x 
 
x 
x 
Height  
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
Vital signs (including weight) f 
x 
x f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
x 
x f 
x 
x 
 
x f 
x 
Serum pregnancy test h 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications i 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECG j 
x 
x j 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Safety laboratory assessments h 
x h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Anti-FVIII antibodies k 
x k 
x 
 
x 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
x 
x 
Anti-emicizumab antibodies l 
 
x l 
 
 
 
x 
 
x l 
x 
x l 
x 
x l 
x l 
x l 
x l 
x l 
 
x 
x l 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
43/Statistical Analysis Plan BH30071 
Schedule of Assessments−Arms A, B, and D 
 
Screen-
ing 
Wk 
1  
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Every 
8 Wks 
from 
Wk 33 
Wk 
49 
Every 
12 Wks 
from 
Wk 61 
Wk 
73 
Daily/ 
weeklya 
Study 
Com-
pletion/ 
ET  
Safety  
F/U 
Visit b 
Bleed/medication questionnaire m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bleed/medication data review n 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Adverse events o 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
IMP management p 
 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
HRQoL and health status 
(EQ-5D-5L) q 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
x 
 
x q 
 
x 
 
PK assessment r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
PD biomarkers s 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Patient preference survey 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
RCR blood DNA sample 
(optional) w 
 
 
x w 
x w 
x w 
x w 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
44/Statistical Analysis Plan BH30071 
Schedule of Assessments−Arm C (Screening to Switch to Emicizumab) 
 
Screen-
ing 
Wk 1 
Wk 5 
Wk 9 Wk 13  Wk 17  Wk 21 
Daily/ 
weekly a 
Informed consent c 
x 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
Medical history and demographics d 
x 
 
 
 
 
 
 
 
Physical examination (including weight) e 
x 
x 
 
 
 
 
 
 
Vital signs (including weight) f 
x 
x f 
x 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
Serum pregnancy test h 
x 
 
 
 
 
 
 
 
Concomitant medications i 
x 
x 
x 
x 
x 
x 
x 
 
ECG j 
x 
x j 
 
 
 
 
 
 
Safety laboratory assessments h 
x h 
x 
 
 
 
 
 
 
Anti-FVIII antibodies k 
x 
 
 
 
 
 
 
 
Bleed/injection questionnaire m 
 
 
 
 
 
 
 
x 
Bleed/injection data review n 
 
x 
x 
x 
x 
x 
x 
 
Adverse events o 
 
x 
x 
x 
x 
x 
x 
 
HRQoL and health status q 
 
x 
 
 
x 
 
 
 
PD biomarkers assessment s 
 
x 
 
 
 
 
 
 
RCR blood DNA sample (optional) w 
 
 
x 
 
 
 
 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
45/Statistical Analysis Plan BH30071 
Schedule of Assessments−Arm C (Continued, at Time of Switch to Emicizumab) 
 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
29 
Wk 
31 
Wk 
33 
Wk 
37  
Wk 
41  
Wk 
45 
Wk 
49 
Every 
8 Wks 
from 
Wk 57 
Wk 
73 
Every 
12 Wks 
from 
Wk 85 
Wk 
97 
Daily/ 
weeklya 
Study 
Compl-
etion/ 
ET 
Safety 
F/U 
Visit b 
Physical examination 
(including weight) e 
x 
 
 
 
x 
 
 
 
 
 
x 
 
x 
x 
x 
 
x 
x 
Vital signs (including 
weight) f 
x f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
x 
x f 
x 
x 
 
x f 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
Serum pregnancy test h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications i 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ECG j 
x 
 
 
 
x j 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Safety laboratory 
assessments h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Anti-FVIII antibodies k 
x  
 
x 
 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
x 
x 
Anti-emicizumab 
antibodies l 
x l 
 
 
 
x 
 
x l 
x 
x l 
x 
x l 
x 
x l 
x 
x 
 
x 
x l 
Bleed/medication 
questionnaire m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Bleed/medication data 
review n 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
46/Statistical Analysis Plan BH30071 
Schedule of Assessments−Arm C (Continued, at Time of Switch to Emicizumab) 
 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
29 
Wk 
31 
Wk 
33 
Wk 
37  
Wk 
41  
Wk 
45 
Wk 
49 
Every 
8 Wks 
from 
Wk 57 
Wk 
73 
Every 
12 Wks 
from 
Wk 85 
Wk 
97 
Daily/ 
weeklya 
Study 
Compl-
etion/ 
ET 
Safety 
F/U 
Visit b 
Adverse events o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
IMP management p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
HRQoL and health status q 
x 
 
 
 
 
 
 
x 
 
 
x 
 
x 
 
x q 
 
x 
 
PK assessment r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
PD biomarkers s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
BMQ = bleed and medication questionnaire; eCRF = electronic Case Report Form; EQ-5D-5L = EuroQoL Five-Dimension-Five Levels Questionnaire; ET = early termination; 
F/U = follow-up; FVIII = factor VIII; HRQoL = health-related quality of life; 
; IMP = investigational medicinal product, 
PD = pharmacodynamic; PK = pharmacokinetic; RCR = Roche Clinical Repository; 
; 
wk = Week. 
Notes:  The maximum allowable time between screening and enrollment is 6 weeks; if the elapsed time between screening and enrollment is more than 6 weeks, screening 
must be repeated.  All assessments should be performed within ± 2 days of the scheduled visit for the first 12 weeks and for Weeks 25−37 for Arm C patients who switch 
over, then ± 7 days thereafter.  Clinic visits should coincide with the day of emicizumab dosing, and on those days the dose should be administered after blood draws and 
other assessments are conducted.  Unscheduled assessments may be performed at the discretion of the investigator and as clinically indicated.  Except for the bleed/injection 
questionnaire, HRQoL, and health status, all other patient data will be collected during office or nurse visits.  Evaluation at Weeks 25 or 49 will occur after a full 24 or 48 weeks 
in the study.  Study completion evaluation occurs when a patient discontinues emicizumab or transitions into another study. 
a Patients will complete the Bleed/Medication Questionnaire at least weekly and at the time of a bleed, or when they take a hemophilia-related medication (including 
emicizumab).  Arm B patients should indicate at least weekly whether or not they had a bleed.  
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
47/Statistical Analysis Plan BH30071 
b A safety follow-up visit will occur 24 weeks after discontinuing emicizumab. 
c Obtain written informed consent (or patient’s assent and legal representative written informed consent if patient is an adolescent) before distribution of BMQ handheld device 
and collection of any data.  Patients will be enrolled and randomized after giving informed consent and assent when appropriate.  A patient who fulfills the inclusion and 
exclusion criteria should be enrolled and assigned to a treatment arm on the same day when the first dose of emicizumab is due (Week 1 visit). 
d Collected from patient medical records and documented in the eCRF, including information on target joint(s). 
e Calculation of dose based on weight is required.  A complete physical examination will be performed at screening and at least a targeted physical examination will be 
performed at subsequent visits.  Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for bruises, hematomas, and injection-site reactions) 
as clinically indicated and/or with report of new or worsening adverse event.  
 
 
f 
Body temperature, blood pressure, pulse rate, and respiratory rate only to be used to monitor during and after injection for hypersensitivity reactions and not to be entered into 
eCRF, except at Weeks 1, 25, 49, at study completion/early termination, and at the safety follow-up visit (i.e., 24 weeks after discontinuing emicizumab for patients in Arms A, 
B, and D and at Week 73 for patients in Arm C).  If Screening and Week 1 occur on the same date, the vital signs should be measured only once.  If Screening and Week 1 
occur on different dates, vital signs entry should be repeated for both assessments.  Height will be measured at screening and annually.  
g See protocol. 
h Laboratory data (performed locally) include:  complete blood count with differential (i.e., neutrophils, hemoglobin, platelet count), serum chemistries (including sodium, 
potassium, chloride, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, alanine aminotransferase, 
aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine phosphokinase, and uric acid).  Laboratory assessments completed at the screening visit 
do not have to be repeated at Week 1, if the period between Screening and Week 1 is 5 days or less and there has been no change in health status as assessed by the 
investigator.  Female patients with childbearing potential will be required to have a negative serum pregnancy test result at Screening (and within 7 days of study drug 
initiation, if applicable) and urine pregnancy tests performed at every clinic visit, with the exception of Weeks 24 and 7.  Patients in Arm C will have serum pregnancy test 
performed at Screening and before starting emicizumab (Week 25). 
i 
Concomitant medications (e.g., extra pain medication with bleed) will be asked about at the time of the monthly assessment, excluding treatments for bleeds (i.e., FVIII and 
other medications to treat bleeds), which will be collected on the bleeding questionnaire.  Hemostatic medications to treat or prevent bleeds in the week prior to starting 
emicizumab will also be collected and during Week 1 for patients in Arm D who continue their prior FVIII prophylaxis for the first week of the study. 
j 
Performed locally.  If screening ECG is abnormal, repeat at Week 1 (or Week 2 [or Week 5 for Arm C] if Screening and Week 1 occur on the same day), otherwise do not 
repeat.  ECGs will also be performed 48 and 24 weeks after starting emicizumab or dose escalation (up-titration), as well as at study completion/early termination. 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
48/Statistical Analysis Plan BH30071 
k Patient must have a documented local inhibitor test with negative result (< 0.6 BU) at screening or within the 8 weeks prior to enrollment.  Starting at Week 1, all subsequent 
anti-FVIII antibodies will be measured at a central laboratory using an aliquot of the citrate plasma collected for PD biomarker assessments, so a separate blood draw is not 
necessary.  Please consult the central laboratory services manual for details.  
l 
Samples to detect anti-emicizumab antibodies will be collected prior to emicizumab administration at every clinic visit.  However, only samples from the following visits will be 
analyzed initially:  (Arms A, B, and D) immediately prior to the first injection at Week 1, every 8 weeks from Weeks 9−49, every 12 weeks starting from Week 61, and at the 
24-week post-emicizumab safety follow-up visit following initiation of emicizumab; Arm C immediately prior to the first injection at Week 25, every 8 weeks from Weeks 33−73, 
every 12 weeks starting from Week 85, and at the 24-week post-emicizumab safety follow-up visit following initiation of emicizumab.  If any of these samples are positive 
and/or if there is suboptimal clinical response or low pharmacokinetic exposure, the remaining collected samples may be analyzed for anti-emicizumab antibodies.  
Anti-emicizumab antibodies may also be drawn at the time of systemic hypersensitivity events.  
m Reported by the patient, or the patient’s legally authorized representative, and includes:  start date and time, reason, type, location, and associated symptoms of each bleed, 
as well as start date and time, reason, type, number of injections, and dose of each hemophilia medication injection, including emicizumab.  Patients who stop taking 
emicizumab should continue reporting bleeds and hemophilia medication administration on the handheld device until the safety follow-up visit.  
n At the Week 1 visit, patients will be trained on how to use and be provided their own handheld device.  At subsequent visits as marked, investigator review of patient-reported 
bleed/injection questionnaire information will be conducted for completeness and accuracy. 
o Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected worsening of the patient’s hemophilia in terms 
of severity (e.g., increased number of doses of FVIII to stop bleeds compared with before study entry), frequency of bleeds, or nature at any time during the study, this should 
be documented as an adverse event on the Adverse Event eCRF, conveying that the underlying condition has changed by including applicable descriptors (e.g., "increased 
clinical severity of hemophilia").  
p Drug accountability will not be performed at the first visit that includes emicizumab receipt.  Drug dispensation will not occur at the study completion/early termination visit.  
q Haem-A-QoL questionnaire (age ≥ 18) and Haemo-QoL-Short Form (ages 12−17), health status questionnaire EQ-5D-5L.  Patient-reported outcomes will be captured on-site 
by a device and transmitted to the database.  After Week 49, HRQoLs will be captured every 24 weeks. 
r Emicizumab concentration.  Plasma samples for this assessment should be taken prior to injection.  Patients will be dosed at the clinics (self-administration) on days where 
trough plasma samples are to be collected 
s See protocol for detailed explanation of PD biomarker assessments (Sets 1 and 2).  Blood samples will be banked for 5 years for future exploratory PD biomarker analyses.  
Blood samples may also be drawn to conduct biomarker assays at the central laboratory on an unscheduled basis (at the clinical judgment of the investigator) at any time.  
t 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
49/Statistical Analysis Plan BH30071 
u 
 
 
 
 
v 
  
w Sample for the RCR is optional and requires an additional consent.  This single sample may be drawn at Week 2, 3, 4, or 5 but is not drawn at Week 1 in order to avoid 
excessive blood draw. 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
50/Statistical Analysis Plan BH30071 
SCHEDULE OF PHARMACODYNAMIC ASSESSMENTS 
Sample 
Visit a 
Biomarker assays b 
PD Set 1 
Starting on emicizumab (Arms A, B, and D): 
Every week during Weeks 1−4 
Every 2 weeks during Weeks 5−7 
Every 4 weeks during Weeks 9−25 
Every 8 weeks during Weeks 33−49 
Every 12 weeks thereafter, while on emicizumab 
(Week 61 and beyond)  
Study Completion/Early Termination 
Safety Follow-up Visit 
Unscheduled visit (at the discretion of the 
investigator), while on emicizumab c 
 
Starting on no prophylaxis, switch to 
emicizumab after 24 weeks (Arm C): 
Week 1 
Every week during Weeks 25−28 
Every 2 weeks during Weeks 29−32 
Every 4 weeks during Weeks 33−48   
Every 8 weeks during Weeks 49−73 
Every 12 weeks thereafter, while on emicizumab 
(Week 85 and beyond) 
Study Completion/Early Termination 
Safety Follow-up Visit 
Unscheduled visit (at the discretion of the 
investigator), while on emicizumab c 
Standard aPTT 
Modified aPTT 
PT 
FVIII activity 
Thrombin generation 
FIX antigen 
FX antigen 
D-dimer 
Prothrombin fragment 1.2  


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
51/Statistical Analysis Plan BH30071 
SCHEDULE OF PHARMACODYNAMIC ASSESSMENTS 
Sample 
Visit a 
Biomarker assays b 
PD Set 2 
Starting on emicizumab (Arms A, B and D): 
Week 1 
Week 25 
Study Completion/Early Termination 
Safety Follow-up Visit 
 
Starting on no prophylaxis, switch to 
emicizumab after 24 weeks (Arm C): 
Week 1 
Week 25 
Week 49 
Study Completion/Early Termination 
Safety Follow-up Visit 
FXIII activity 
VWF antigen 
Fibrinogen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
52/Statistical Analysis Plan BH30071 
SCHEDULE OF PHARMACODYNAMIC ASSESSMENTS 
Sample 
Visit a 
Biomarker assays b 
 
 
 
 
 
 
 
 
 


Appendix 2  
Schedule of Assessments (cont.) 
 
Emicizumab—F. Hoffmann-La Roche Ltd 
53/Statistical Analysis Plan BH30071 
 
; 
; FVIII = factor VIII; FIX = factor IX; 
FX = factor X; 
; 
 
 
; 
PD = pharmacodynamic; 
; VWF = von Willebrand 
factor.  
a All samples are to be collected on Day 1 of the indicated week, prior to emicizumab injection (if applicable).  
PD samples will be citrate plasma, EDTA plasma, or serum.  Refer to protocol for exact study visits. 
b Biomarker assays will include, but are not limited to, those listed.  
 
 
 Blood volumes and processing procedures will be specified in the Central Laboratory 
Services Manual. 
c Reasons for unscheduled visits may include evaluation or treatment for bleeds or hypersensitivity 
reactions. 
d 
 
 
.