Conditions: Hemophilia A
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This Phase IV, multicenter study will evaluate whether participants with Hemophilia A (PwHA) with or without inhibitors receiving emicizumab prophylaxis can safely undergo minor surgical procedures without additional prophylactic bypassing agents (BPA; for participants with inhibitors) or factor VIII (FVIII; for participants without inhibitors).

Detailed description:

Arms:
arm 1: This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled but did not have surgery. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. arm 2: This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled and had surgery for central venous access device (CVAD) removal. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. arm 3: This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled and had surgery for simple dental extraction. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. arm 4: This cohort included participants with Hemophilia A (PwHA) without inhibitors that were enrolled and had surgery for central venous access device (CVAD) removal. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. arm 5: This cohort included participants with Hemophilia A (PwHA) without inhibitors that were enrolled and had surgery for simple dental extraction. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery.

Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY 
OF EMICIZUMAB PROPHYLAXIS IN PATIENTS WITH HEMOPHILIA 
A WITH OR WITHOUT INHIBITORS UNDERGOING MINOR 
SURGICAL PROCEDURES 
NCT Number: NCT03361137 
Document Date: Protocol Version 4: 15-March-2019 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Emicizumab—Genentech, Inc.
Protocol ML39791, Version 4
PROTOCOL
TITLE:
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY OF EMICIZUMAB PROPHYLAXIS IN
PATIENTS WITH HEMOPHILIA A WITH OR WITHOUT
INHIBITORS UNDERGOING MINOR SURGICAL 
PROCEDURES
PROTOCOL NUMBER:
ML39791
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (HEMLIBRA)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  22 June 2017
DATE AMENDED:
Version 2:  16 August 2017
Version 3:  15 June 2018
Version 4:  See electronic date stamp below.
 
15-Mar-2019 16:05:27
Title
Approver's Name
Date and Time (UTC)


Emicizumab—Genentech, Inc.
2/Protocol ML39791, Version 4
PROTOCOL AMENDMENT, VERSION 4
RATIONALE
Protocol ML39791 has been amended primarily to add an additional cohort of patients 
with hemophilia A (PwHA) without inhibitors, but has also been modified for clarification. 
Changes to the protocol and the rationale are summarized below:

Emicizumab has been approved for routine prophylaxis to prevent or reduce the 
frequency of bleeding episodes in adult and pediatric patients ages newborn and 
older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII 
inhibitors.  Because of this label change, the following updates have been made:
–
An additional cohort of PwHA without inhibitors has been added, as 
investigators would like prospectively collected data surrounding minor surgical 
procedures in this population. The Phase III trials were not designed to 
determine surgical outcomes from procedures that may have occurred. The 
study design, including the total length of the study, has been updated to reflect 
the addition of PwHA without inhibitors (Sections 1.3, 2, 3.1, 3.2, 4.1, 6, 9.4).  
–
The inclusion and exclusion criteria have been updated to reflect the additional 
cohort and label change (4.1.1 and 4.1.2).
–
Background and other general language have been updated to reflect the label 
change (Section 1.2 and throughout protocol).

The length of study has been corrected to begin at the time the first patient is 
enrolled (Section 3.1).

Contraception requirements have been updated to align with the Phase III HAVEN 
studies (Section 4.1.1).

The timing for HIV testing has been updated to within 24 weeks of enrollment 
(Section 4.1.2).

The time window for concomitant therapy has been updated to 28 days before 
enrollment until Study Day 28 (Section 4.4).

Height is no longer listed as a necessary assessment in Section 4.5.4, as it is not 
required per protocol.

It has been clarified that biological samples will be destroyed no later than 5 years 
after the final study results have been reported (Section 4.5.6).

The Background and Safety sections of the protocol have been updated with recent 
clinical data to align with the most recent United States Package Insert (USPI; 
Sections 1.2, 5.1.1.1, 5.1.1.2, 5.1.1.3).  

A section on immunogenicity has been added to align with the USPI 
(Section 5.1.1.5).

For adverse event reporting purposes, it has been clarified that a protocol-mandated 
intervention may include additional surgical procedures unrelated to the primary 
surgery (Section 5.2.1). 


Emicizumab—Genentech, Inc.
3/Protocol ML39791, Version 4

It has been clarified that the consent date will be considered the date of enrollment 
(Appendix 1).  

Timing for standard-of-care tests or examinations performed prior to obtaining 
informed consent has been clarified (Appendix 1).

The list of minor surgical procedures that are acceptable for entry into this study has 
been updated to include lysis of penile adhesions (Appendix 3).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Emicizumab—Genentech, Inc.
4/Protocol ML39791, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 16
1.1
Background on Hemophilia A with and Without 
Inhibitors................................................................................ 16
1.2
Background on Emicizumab (Hemlibra) ................................ 18
1.3
Study Rationale and Benefit-Risk Assessment...................... 21
2.
OBJECTIVES AND ENDPOINTS ............................................................... 21
3.
STUDY DESIGN......................................................................................... 23
3.1
Description of the Study......................................................... 23
3.2
End of Study and Length of Study......................................... 24
3.3
Rationale for Study Design.................................................... 24
3.3.1
Rationale for Emicizumab Dose and Schedule...................... 24
3.3.2
Rationale for Biomarker Assessments................................... 25
4.
MATERIALS AND METHODS .................................................................... 25
4.1
Patients.................................................................................. 25
4.1.1
Inclusion Criteria.................................................................... 25
4.1.2
Exclusion Criteria................................................................... 26
4.2
Method of Treatment Assignment and Blinding..................... 27
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 27
4.3.1
Study Treatment.................................................................... 27
4.3.1.1
Emicizumab........................................................................... 27
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 27
4.3.3
Continued Access to Emicizumab ......................................... 28
4.4
Concomitant Therapy ............................................................ 28
4.4.1
Permitted Therapy................................................................. 28
4.4.2
Prohibited Therapy ................................................................ 29
4.5
Study Assessments ............................................................... 29
4.5.1
Informed Consent Forms and Screening Log........................ 29


Emicizumab—Genentech, Inc.
5/Protocol ML39791, Version 4
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 30
4.5.3
Physical Examinations........................................................... 30
4.5.4
Vital Signs.............................................................................. 30
4.5.5
Bleed and Medications Diary................................................. 30
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 30
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 31
4.6.1
Study Discontinuation............................................................ 31
4.6.2
Patient Discontinuation from Study........................................ 31
4.6.3
Study Discontinuation............................................................ 32
4.6.4
Site Discontinuation............................................................... 32
5.
ASSESSMENT OF SAFETY....................................................................... 32
5.1
Safety Plan ............................................................................ 32
5.1.1
Risks Associated with Emicizumab ....................................... 33
5.1.1.1
Thromboembolic Events and Thrombotic 
Microangiopathy .................................................................... 33
5.1.1.2
Injection-Site Reactions......................................................... 33
5.1.1.3
Systemic Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid........................................................................ 34
5.1.1.4
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
in the Setting of Emicizumab ................................................. 34
5.1.1.5
Immunogenicity .................................................................... 34
5.1.2
Laboratory Coagulation Test Interference ............................. 35
5.2
Safety Parameters and Definitions ........................................ 36
5.2.1
Adverse Events ..................................................................... 36
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 37
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 38
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 38
5.3.1
Adverse Event Reporting Period ........................................... 38
5.3.2
Eliciting Adverse Event Information....................................... 39


Emicizumab—Genentech, Inc.
6/Protocol ML39791, Version 4
5.3.3
Assessment of Severity of Adverse Events ........................... 39
5.3.4
Assessment of Causality of Adverse Events ......................... 39
5.3.5
Procedures for Recording Adverse Events............................ 40
5.3.5.1
Injection Reactions ................................................................ 40
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 41
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 41
5.3.5.4
Persistent or Recurrent Adverse Events................................ 41
5.3.5.5
Abnormal Laboratory Values ................................................. 42
5.3.5.6
Abnormal Vital Sign Values ................................................... 42
5.3.5.7
Abnormal Liver Function Tests.............................................. 43
5.3.5.8
Deaths ................................................................................... 43
5.3.5.9
Preexisting Medical Conditions.............................................. 44
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic 
Bleeds.................................................................................... 44
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 44
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 45
5.4.1
Emergency Medical Contacts................................................ 46
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 46
5.4.3
Reporting Requirements for Pregnancies.............................. 46
5.4.3.1
Pregnancies in Female Patients............................................ 46
5.4.3.2
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 47
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 47
5.5
Follow-Up of Patients after Adverse Events .......................... 49
5.5.1
Investigator Follow-Up........................................................... 49
5.5.2
Sponsor Follow-Up ................................................................ 49
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 49
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 50


Emicizumab—Genentech, Inc.
7/Protocol ML39791, Version 4
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 50
6.1
Determination of Sample Size ............................................... 50
6.2
Summaries of Conduct of Study............................................ 51
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 51
6.4
Efficacy Analyses .................................................................. 51
6.5
Safety Analyses..................................................................... 51
6.6
Pharmacokinetic Analyses..................................................... 52
7.
DATA COLLECTION AND MANAGEMENT ............................................... 52
7.1
Data Quality Assurance......................................................... 52
7.2
Electronic Case Report Forms............................................... 52
7.3
Source Data Documentation.................................................. 52
7.4
Use of Computerized Systems .............................................. 53
7.5
Retention of Records............................................................. 53
8.
ETHICAL CONSIDERATIONS.................................................................... 54
8.1
Compliance with Laws and Regulations ................................ 54
8.2
Informed Consent.................................................................. 54
8.3
Institutional Review Board or Ethics Committee.................... 55
8.4
Confidentiality........................................................................ 55
8.5
Financial Disclosure .............................................................. 56
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 56
9.1
Study Documentation ............................................................ 56
9.2
Protocol Deviations................................................................ 56
9.3
Site Inspections ..................................................................... 57
9.4
Administrative Structure......................................................... 57
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 57
9.6
Protocol Amendments ........................................................... 58
10. REFERENCES ........................................................................................... 59


Emicizumab—Genentech, Inc.
8/Protocol ML39791, Version 4
LIST OF TABLES
Table 1
Objectives and Endpoints ........................................................... 22
Table 2
Coagulation Test Results Affected and Unaffected by 
Emicizumab (Hemlibra)............................................................... 35
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 39
Table 4
Causal Attribution Guidance ....................................................... 40
Table 5
Precision of the Study for a Binary Efficacy Endpoint 
(Illustrative Purposes) ................................................................. 51
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 24
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 63
Appendix 2
Assessment of Hemostatic Response for Surgical 
Procedures.................................................................................. 66
Appendix 3
Minor Surgical Procedures.......................................................... 67
Appendix 4
World Health Organization Toxicity Grading Scale for 
Determining the Severity of Laboratory Abnormalities and 
Adverse Events........................................................................... 68
Appendix 5
Clinical Criteria for Diagnosing Anaphylaxis................................ 73


Emicizumab—Genentech, Inc.
9/Protocol ML39791, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY OF EMICIZUMAB PROPHYLAXIS IN
PATIENTS WITH HEMOPHILIA A WITH OR WITHOUT 
INHIBITORS UNDERGOING MINOR SURGICAL 
PROCEDURES
PROTOCOL NUMBER:
ML39791
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (HEMLIBRA)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the contract research organization (CRO).


Emicizumab—Genentech, Inc.
10/Protocol ML39791, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-LABEL
STUDY OF EMICIZUMAB PROPHYLAXIS IN PATIENTS WITH 
HEMOPHILIA A WITH OR WITHOUT INHIBITORS
UNDERGOING MINOR SURGICAL PROCEDURES
PROTOCOL NUMBER:
ML39791
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (HEMLIBRA)
PHASE:
Phase IV
INDICATION:
Hemophilia A with or without inhibitors
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety and efficacy of emicizumab prophylaxis in patients with 
hemophilia A (PwHA; with or without inhibitors) that are undergoing minor surgical procedures
without additional prophylaxis with bypassing agents (BPA; for patients with inhibitors) or 
factor VIII (FVIII; for patients without inhibitors).  All endpoints will be measured and 
described separately for the inhibitor and non-inhibitor cohorts.  Pharmacokinetics will also be 
evaluated as exploratory objectives of the study.  For the purposes of this protocol, study 
treatment is not intended to imply that the Sponsor is providing the study drug; rather, 
emicizumab is required for all patients during the study per the inclusion and exclusion criteria.
Note: Throughout the protocol, all references to BPA will be specific for patients with 
inhibitors and all references to FVIII will be specific for patients without inhibitors, unless 
otherwise noted.  


Emicizumab—Genentech, Inc.
11/Protocol ML39791, Version 4
Primary Objective
Corresponding Endpoints
To evaluate the 
efficacy of 
emicizumab in 
preventing surgery-
related bleeding in 
PwHA with and
without inhibitors 
undergoing minor 
surgical procedures
Efficacy will be measured by:
Percentage of patients without excessive bleeding at surgical sites and 
did not require BPA/FVIII a use for bleeding related to the surgery, from 
the start of the surgery until the patient is discharged from the surgery.  
For the purposes of this endpoint, the absence of excessive bleeding and 
BPA/FVIII a use will be measured by a good to excellent rating using the 
hemostatic efficacy scale (ISTH SSC recommendations) and will be 
determined upon patient discharge by the healthcare professional 
performing the procedure.
Percentage of patients with excessive bleeding at surgical sites and 
required BPA/FVIII a use for bleeding related to the surgery, from the 
start of the surgery until the patient is discharged from the surgery. 
Bleeding and BPA/FVIII a use will be assessed using the hemostatic 
efficacy scale and measured by a rating of fair to poor, and will be 
determined upon patient discharge by the healthcare professional 
performing the procedure.
Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed for excessive bleeding 
at surgical sites will be summarized.
Percentage of patients who, after being discharged from surgery, 
experienced bleeds that were either related or unrelated to the surgery 
and also required BPA/FVIII a use 
–
Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed will be summarized 
Safety
Incidence and severity of all adverse events
–
Incidence and severity of serious adverse events
–
Incidence and severity of adverse events of special interest
Percentage of patients with surgical complications requiring 
hospitalization or return to surgery 
Percentage of patients who need blood/blood product transfusions (i.e., 
platelets, plasma, etc.) during surgery
Exploratory 
Objective
Exploratory Endpoints
To evaluate 
potential 
relationships 
between drug 
exposure and the 
efficacy and 
safety of 
emicizumab
Selected efficacy and safety endpoints will be descriptively summarized 
by plasma emicizumab concentration levels
To describe the 
incidence of
spontaneous 
bleeding in the 
post-operative 
period.
Percentage of patients with zero bleeds (regardless of treated or not)
after being discharged from surgery
BPAbypassing agent;ISTH SSCInternational Society on Thrombosis and Haemostasis
Scientific and Standardization Committee; FVIII factor VIII; PwHApatients with 
Hemophilia A.
a
BPA use is specific for patients with inhibitors and FVIII use is specific for patients 
without inhibitors.


Emicizumab—Genentech, Inc.
12/Protocol ML39791, Version 4
Study Design
Description of Study
This Phase IV, multicenter study will evaluate whether PwHA (with or without inhibitors)
receiving emicizumab prophylaxis can safely undergo minor surgical procedures without 
additional prophylaxis with BPA or FVIII (for patients with or without inhibitors, 
respectively).  The use of BPA/FVIII for excessive surgical bleeding will then be measured 
intra-operatively and post-operatively.  In addition, surgical complications from bleeding and 
blood product transfusions will be evaluated.  This study will assess emicizumab prophylaxis 
alone to control surgery-related bleeding in PwHA with or without inhibitors undergoing minor 
surgical procedures.  Each cohort (PwHA with inhibitors and PwHA without inhibitors) will 
be assessed separately.
Patients can be screened and enrolled up to 60 days prior to surgery.  They must have received 
a minimum of four loading doses of emicizumab prior to their surgical procedure, been adherent 
with emicizumab prophylaxis, and must not have received BPA/FVIII for at least 24 hours prior 
to surgery.  In addition, they must plan to continue emicizumab prophylaxis for at least 1 month 
after the surgical procedure.  Follow-up will be conducted by phone on Study Days 2 and 3 
(approximately 24 and 48 hours post-operation) to record any bypassing agent use or FVIII use 
and surgical bleeding within the first 48 hours, as well as treatment of any other bleeding 
unrelated to surgery.  BPA/FVIII should only be used for treatment of bleeding.  Follow-up will 
be conducted in person on Study Day 8 ( 2 days) to examine the patient for any post-surgical 
complications and to collect information on treatment of bleeding.  Lastly, follow-up will be 
conducted by phone on Study Day 28 ( 2 days) to record any surgical complications, bleeds, 
and/or use of BPA/FVIII.
Blood samples will also be collected in this study for observational purposes and will not be 
used to determine eligibility or treatment decisions.  Samples will be used to evaluate 
emicizumab concentration (PK) prior to surgery.
Safety follow-up will be conducted after signing the informed consent form.  Patients will be 
monitored for adverse events to evaluate the safety of emicizumab alone or in combination with 
BPA/FVIII.
Periodic Safety Review
In order to ensure that patients enrolled in this study are safely undergoing minor surgical 
procedures without additional pre-operative prophylaxis with BPAs/FVIII, periodic safety 
assessments are planned.  The study team will perform periodic data review of all available 
data.
Number of Patients
Approximately 4060 PwHA (approximately 2030 patients with inhibitors and 2030 
patients without inhibitors) will be enrolled and undergo a minor surgical procedure at 
approximately 20 sites in the United States.  An effort will be made to ensure enrollment 
between multiple surgery types.  A maximum of 9 patients in each cohort will be enrolled in any 
given surgery type.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent/Assent Form

Any age (newborn and older) 

Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of hemophilia A and current or history of an inhibitor (Bethesda 
titer 0.6 Bethesda units) and currently using BPA for breakthrough bleeds (for PwHA 
with inhibitors)

Diagnosis of hemophilia A and no history of an inhibitor (Bethesda titer 0.6 Bethesda 
units), or a history of an inhibitor that has been tolerized for >5 years and using FVIII for 
breakthrough bleeds (for PwHA without inhibitors)


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13/Protocol ML39791, Version 4

Plan to receive at least 4 loading doses of emicizumab and been adherent to emicizumab 
prophylaxis by the time of the surgery

Undergoing minor surgery within 60 days of study enrollment.  Other minor surgical 
procedures could be included upon consultation and approval of Medical Monitor, but 
examples include (see Appendix 3 for a full list):
–
Central venous catheter insertion/removal/replacement 
–
Simple dental extractions
–
Colonoscopy, cystoscopy, or endoscopy with biopsy
–
Excisional skin biopsy

Must plan to continue emicizumab prophylaxis for at least 1 month after surgery

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 during the study period
–
A woman is considered to be of childbearing potential if she is post-menarchal, has not 
reached a postmenopausal state (12 continuous months 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 contraceptive, 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 trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation 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:

Diagnosis of a bleeding disorder other than hemophilia A

Tolerized to Factor VIII products (for PwHA with inhibitors)

Using FVIII products to treat breakthrough bleeds(for PwHA with inhibitors)

Tolerized to FVIII products for <5 years (for PwHA without inhibitors)

Treatment with bypassing agents or FVIII within 24 hours prior to surgical procedure

Undergoing a major surgical procedure

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 current signs of thromboembolic disease

Other conditions (e.g., certain autoimmune diseases, including, but not limited to diseases 
such as systemic lupus erythematosus, inflammatory bowel disease, and antiphospholipid 
syndrome) that may increase the risk of bleeding or thrombosis

Patients who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous 
medical or family history of TMA), in the investigator’s judgment

Would refuse treatment with blood or blood products, if necessary.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

Pregnant or lactating, or intending to become pregnant during the study
–
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days before Study Day 1


Emicizumab—Genentech, Inc.
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
Treatment with any of the following:
–
An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives 
of last drug administration before Study Day 1
–
A non-hemophilia-related investigational drug within the last 30 days or 5 half-lives before 
Study Day 1, whichever is longer
–
An investigational drug concurrently

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 enrollment
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  The end of a patient’s participation in the study is 
expected to occur after Study Day 28.
Length of Study
The total length of the study, from enrollment of the first patient to the end of the study (last 
patient last visit), is expected to be approximately 2430 months.
Emicizumab
If a patient is prescribed emicizumab for prophylaxis, emicizumab is administered 3 mg/kg/week 
subcutaneously for the first 4 weeks when initiating treatment (loading doses), followed by 
1.5 mg/kg/week subcutaneously or by any other approved maintenance regimen.  Patients must 
have received all loading doses and been adherent to emicizumab prophylaxis prior to surgery 
and plan to continue emicizumab for a minimum of 1 month after surgery.   For the purposes of 
this protocol, study treatment is not intended to imply that the Sponsor is providing the study 
drug; rather, emicizumab is required for all patients during the study per the inclusion and 
exclusion criteria.
Statistical Methods
Analysis
This is an open-label, single-arm, multicenter study to evaluate emicizumab prophylaxis in 
PwHA without inhibitors and PwHA with inhibitors, who are undergoing minor surgical 
procedures.  Each cohort will be evaluated separately.  No statistical hypothesis will be tested.  
There are three populations that will be included in the analyses, which are defined as follows: 

All Enrolled Population: All patients who sign informed consent.

Safety Analysis Population: All enrolled patients who receive emicizumab

Efficacy Analysis Population: All enrolled patients who receive emicizumab and undergo a 
minor surgery.
Only descriptive summaries will be presented for data collected in this study.  Continuous 
variables will be summarized using means, standard deviations, medians, and ranges; 
categorical variables will be summarized using proportions, and 95% confidence intervals where 
applicable, as appropriate.  Additional details of the analyses will be presented in the statistical 
analysis plan.
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 inhibitor patients with a planned minor surgery available for 
participation in this study.  Table 5 illustrates the precision of this study for a binary efficacy 
endpoint assuming a total of approximately 2030 patients per cohort enrolled into this study, 
received emicizumab, and underwent a protocol-specified minor surgery.
During the study, a re-assessment of the initially specified sample size may be performed.  This 
may result in an increase in sample size, if necessary, to expand the safety database.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
annualized bleeding rate
aPCC
activated prothrombin complex concentrate 
BPA
bypassing agent
COX-2
cyclooxygenase-2
CVAD
central venous access device
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
FEIBA
Factor Eight Inhibitor Bypassing Activity
FIXa
activated factor IX
FVIII
factor VIII
FVIII
activated factor VIII
FX
factor X
HCP
healthcare provider
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
Health-Related Quality of Life
ICH
International Conference on Harmonisation
IgG4
immunoglobulin G4
IMP
investigational medicinal product
IRB
Institutional Review Board
LPLV
last patient last visit
NOAEL
no observed adverse effect level
PK
pharmacokinetic
PwHA
Patients with Hemophilia A
rFVIII
recombinant FVIII
rFVIIa
recombinant activated factor VII
TE
thrombotic events
TMA
thrombotic microangiopathy
USPI
US Package Insert


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1.
BACKGROUND
1.1
BACKGROUND ON HEMOPHILIA A WITH AND WITHOUT 
INHIBITORS
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 
1 in 5000 live male births.  Patients with hemophilia A (PwHA) have a deficiency or 
defect 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 male 
will transmit a normal Y chromosome to all his sons and an abnormal X chromosome to 
all his daughters, his sons will not be affected and all of his daughters will be carriers.  
For female carriers, with each birth there is a 50% chance to transmit the disorder to 
male infants and a 50% chance for female infants to be a carrier.  Women 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 PwHA 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 PwHA have moderate (25%) 
or severe (43%) hemophilia, characterized by FVIII activity levels of 1%5% or 1%,
respectively, leading to frequent bleeding events with the sequelae of musculoskeletal 
complications, such as arthropathy, local functional deficits, hemorrhagic shock, 
neurocognitive defects, or even death (World Federation of Hemophilia 2013).  These 
disease-related issues can have a significant impact on the health-related quality of life 
(HRQoL) of both adult and adolescent patients (Brown et al. 2009).
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 
concentrates have been standard-of-care treatment options for PwHA (Kingdon and 
Lundblad 2002).  Treatment regimens to achieve optimal prevention of bleeding events 
vary individually; some patients tolerate nadir 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 standard prophylactic regimens commonly use 


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infusion therapy administered three times weekly; other regimens can vary from every 
other day administration to less frequent dosing, depending on the patient’s needs and 
the FVIII product being used (Shapiro 2013; Croteau 2015).
The required adherence to demanding therapeutic regimens that include frequent 
infusions to achieve adequate hemostatic coverage during periods of highest activity 
makes these regimens less effective and compromises their cost-benefit ratio 
(Thornburg 2010).  Major issues with current regimens are the need for adequate 
venous access and patient/family compliance with regular prophylaxis, especially in the 
very young pediatric population, in whom central venous access devices (CVADs) have 
been used to overcome technical difficulties.  Although CVADs make prophylaxis 
feasible in young children, CVADs are associated with complications, including 
mechanical failure, dehiscence of the skin over the reservoir, infection, and thrombosis 
(Ewenstein et al. 2004).  In addition, significant healthcare provider efforts are required 
to manage optimal treatment solutions and to overcome identified issues 
(Schrijvers et al. 2013).  Thus, both the disease and its treatment have the potential to 
affect HRQoL, the latter through limitations on daily activities that treatment may impose. 
The development of inhibitory alloantibodies (inhibitors) occurs in approximately 20%30% 
of patients with severe hemophilia A and in 3%13% of those with moderate or mild 
disease (Franchini and Mannucci 2013).  Inhibitors neutralize the activity of endogenous 
FVIII as well as that of FVIII administered as replacement therapy.  For patients with a 
history of a high-titer (5 BU/mL) inhibitor following a re-challenge with FVIII 
administration (high-responding inhibitor), the only hemostatic options currently available 
are pro-thrombotic coagulation factors that augment other parts of the coagulation 
cascade (i.e., “bypassing agents”).  Bypassing agents (BPA) include Factor Eight 
Inhibitor Bypassing Activity (FEIBA), an activated prothrombin complex concentrate 
(aPCC; FEIBA will be referred to as aPCC throughout this document), and NovoSeven®
(recombinant activated human FVIIa [rFVIIa]; NovoSeven® will be referred to as rFVIIa 
throughout this document) (Srivastava et al. 2013).  Both have been used as prophylaxis 
to prevent bleeding in patients with inhibitors against FVIII (“inhibitor patients”); however, 
the only available product for this indication in most countries is the aPCC, FEIBA.  Of 
note, treatment of patients with congenital hemophilia A of any severity with high-titer 
inhibitors is similar, and their severity, as defined at diagnosis based on FVIII activity 
(mild, moderate, or severe), no longer is prognostic of their clinical phenotype and risk of 
bleeding. Both rFVIIa and aPCC have indications (Négrier 1997; Shapiro 1998) for use 
as prophylactic therapy for surgical procedures. Clinical response to BPAs may vary 
between patients. Surgery is a particular situation requiring effective hemostasis during 
the procedure and for several days postoperatively to obtain satisfactory wound healing.
However, the optimal dose of BPA in different surgical situations has not been clearly 
established.
The development of effective prophylactic treatment options with decreased 
immunogenicity and less frequent dosing requirements is a high, unmet medical need in 


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PwHA.  Reducing the time and burden associated with frequent intravenous dosing and 
the impact of the disease on aspects of physical health and other areas of function, while 
promoting increased efficacy, may further improve HRQoL.  In patients with inhibitors, 
data from a study showed that patients receiving prophylactic treatment with FEIBA had 
improved HRQoL compared to those who received episodic therapy (i.e., administered 
following bleeds) with FEIBA (Gringeri et al. 2013).  Therefore, despite major therapeutic 
advances in the treatment of hemophilia A, opportunities remain to optimize and 
transform therapy, in particular for patients with inhibitors.
APCCs may be associated with side effects, such as thromboembolic events,
hypersensitivity reactions, and disseminated intravascular coagulation, as well as 
anemia, diarrhea, hepatitis B surface antibody positive, nausea, and vomiting.  RFVIIA
side effects may include thrombosis and hypersensitivity, as well as fever, headache,
injection site reactions, dizziness, nausea, or vomiting.  Both aPCC and rFVIIa are 
administered intravenously, with aPCC prophylaxis requiring every other day dosing and 
rFVIIa requiring daily (or more frequent) dosing.
1.2
BACKGROUND ON EMICIZUMAB (HEMLIBRA)
Emicizumab (HEMLIBRA; ACE910; CH5534262; RO5534262) is a recombinant, 
humanized, bispecific immunoglobulin G4 (IgG4) monoclonal antibody that binds with 
moderate affinity to activated factor IX (FIXa) and factor X (FX), bridging the factors 
together to allow for activation of FX by FIXa.  Emicizumab is being developed for the 
treatment of hemophilia A. In the United States, emicizumab is indicated for routine 
prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and 
pediatric patients ages newborn and older with hemophilia A (congenital factor VIII 
deficiency) with or without factor VIII inhibitors.
In PwHA, hemostasis can be restored with emicizumab irrespective of the presence of 
FVIII inhibitors, as emicizumab shares no sequence homology with FVIII.  In addition, 
emicizumab can be administered via subcutaneous (SC) injection, alleviating the need 
for venous access.  Finally, due to the pharmacokinetic (PK) properties of therapeutic
antibodies, markedly extending the dosing interval to once weekly or less frequently is 
possible with this novel compound and provides an alternate treatment choice for PwHA
with and without FVIII inhibitors who are in need of effective, safe, and convenient 
prophylactic therapy.
The nonclinical and clinical data with emicizumab support a positive benefit-risk 
assessment, which has been validated with approval for use by various drug approval 
agencies. Evaluation of in vivo efficacy under spontaneous or local trauma-induced 
bleeding conditions in cynomolgus monkeys using a hemophilia A model demonstrated 
the ability of emicizumab to significantly reduce bleeding tendency under both sets of 
conditions.  In terms of safety, thrombus formation with emicizumab did not markedly 
exceed thrombus formation observed with FVIIa, aPCC, or FVIII in an in vivo
cynomolgus monkey venous stasis model.  No toxicologically relevant changes 


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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 no observed adverse 
effect level (NOAEL) was the highest tested dose in each toxicity study.  
Currently available experience with emicizumab in humans includes data from two 
completed Phase I studies (ACE001JP and JP29574), and an ongoing Phase I/II 
extension study (ACE002JP). ACE001JP was a single study conducted in three parts, 
including 48 healthy male volunteers (Parts A and B) and 18 PwHA (Part C) who 
received emicizumab.  Emicizumab was administered at doses of 0.3, 1, and 
3 mg/kg/week. Only PwHA received the 3 mg/kg dose.
In addition, the clinical program includes Phase III studies in patients with hemophilia A: 
HAVEN 1 evaluates emicizumab prophylaxis in people 12 years of age or older with 
hemophilia A and inhibitors to factor VIII who were previously treated with episodic or 
prophylactic bypassing agents. HAVEN 2 evaluates weekly, every other week, and 
every 4 weeks dosing in pediatric patients with inhibitors.  HAVEN 3 evaluates weekly 
and every other week dosing in adolescent and adult patients without inhibitors and 
HAVEN 4 evaluates every 4-week dosing in adolescent and adult patients with and 
without inhibitors.
The Phase I and I/II studies demonstrated promising results for emicizumab prophylaxis 
in reducing the annualized bleeding rate (ABR) in Japanese PwHA with and without 
inhibitors against FVIII.  After administration of emicizumab to PwHA, ABRs decreased 
in all patients compared to the pretreatment period, regardless of whether or not they 
had FVIII inhibitors, with the exception of 1 patient in the 3 mg/kg/week group who was 
previously treated with FVIII prophylaxis and had a baseline ABR of 0; in this patient, 
ABR was maintained at 0 while receiving emicizumab.  Among all patients, percentage 
reduction in ABRs based on initial dose cohort assignment ranged from 22.8% to 100% 
in the 0.3 mg/kg/week group, from 81.7% to 100% in the 1 mg/kg/week group, and from 
92.6% to 100% in the 3 mg/kg/week group.
In the Phase I/II studies, no thromboembolic or systemic hypersensitivity adverse events 
have been seen to date. The majority of adverse events were of a mild or moderate 
intensity.  The most common related adverse events were mild injection-site reactions.
A total of 150 adverse events were observed in the 18 PwHA in Study ACE0001JP.  The 
majority of adverse events were of mild intensity, except for 11 moderate adverse events 
(upper respiratory tract infection, bipolar disorder, contusion, enteritis infectious, 
impaired healing, musculoskeletal pain, calculus ureteric, hemophilia [i.e., left hip joint 
bleeding due to hemophilia], hand fracture, asthma, and headache) and two severe 
events (appendicitis and mesenteric hematoma), neither of which was deemed related to 
emicizumab.  Local injection site reactions were observed in 7 patients (38.9% of 
patients).


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In the Phase III study in adolescents and adults (HAVEN 1), patients previously treated 
with episodic BPA were randomized in a 2:1 ratio to receive either prophylactic 
emicizumab 3 mg/kg/week SC for 4 weeks, followed by 1.5 mg/kg/week SC thereafter 
(Arm A), or to the control arm (Arm B), which consists of no prophylaxis (i.e., only 
episodic bypassing agent treatment).  Patients previously treated with prophylactic BPA
were switched immediately to prophylactic emicizumab (Arm C).  Episodic treatment of 
breakthrough bleeds with bypassing agents was allowed per protocol.  The primary 
endpoint of the study is the number of treated bleeds over time with emicizumab 
prophylaxis (Arm A) versus no prophylaxis (Arm B).  The study showed a statistically 
significant reduction in the number of bleeds over time in people treated with 
emicizumab prophylaxis compared to those receiving no prophylactic treatment.  The 
study also met all secondary endpoints, including a statistically significant reduction in 
the number of bleeds over time with emicizumab prophylaxis treatment in an intra-
patient comparison in people who had received prior bypassing agent prophylaxis 
treatment.  
Interim results from the Phase III study evaluating emicizumab prophylaxis in children 
less than 12 years of age with hemophilia A and inhibitors to factor VIII (HAVEN 2) 
showed a clinically meaningful reduction in the number of bleeds over time after a 
median of 12 weeks of treatment.
Pooled data from two randomized trials in adult and adolescent patients (HAVEN 1 
and HAVEN 3), one single-arm trial in adult and adolescent patients (HAVEN 4), one 
single-arm trial in pediatric patients (HAVEN 2), and one dose-finding trial, in which 
a total of 391 male patients with hemophilia A received at least 1 dose of HEMLIBRA 
as routine prophylaxis showed that four patients (1%) withdrew from treatment due to 
adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial
thrombophlebitis, headache, and injection site reaction.
Additionally, there were 130 instances of aPCC treatment in 37 patients, of which 13 
instances (10%) consisted of on average a cumulative amount of 100 U/kg/24 hours of 
aPCC for 24 hours or more; 2 of the 13 were associated with thrombotic events and 3 of 
the 13 were associated with TMA.  Both patients with TE and 2 of 3 patients with TMA
have fully recovered.  One patient with TMA died from rectal hemorrhage (see 
Section 5.1.1).  
Two patients (1 patient with TMA and 1 patient with TE) restarted emicizumab in the 
HAVEN 1 trial without recurrence of TMA or TE.  No TE or TMA events have been 
observed during the interim analysis of the HAVEN 2 trial.
Results from HAVEN 3 and HAVEN 4 have demonstrated that emicizumab 
prophylaxis reduced bleeding events requiring treatment in patients without inhibitors 
on a once weekly or every 2 weeks dosing schedule and in patients with and without 


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inhibitors on an every 4 weeks dosing schedule (Genentech 2018; Mahlangu et al. 2018;
Young et al. 2018).
Note: Investigators are recommended to refer to US-Package Insert (USPI) of 
HEMLIBRA(emicizumab) (2018) for additional details on results of nonclinical and 
clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
PwHA with inhibitors routinely require treatment with BPA, to control perioperative 
bleeding, while PwHA without inhibitors routinely require treatment with FVIII to 
control perioperative bleeding.  They may receive doses pre-operatively, 
intra-operatively, and post-operatively depending on the extent of the surgical procedure 
and likelihood of bleeding.  This study will investigate whether or not patients with 
hemophilia A with and without inhibitors who are on emicizumab prophylaxis can 
undergo minor surgical procedures without the need for additional prophylaxis with BPA
or FVIII, respectively, to prevent excessive surgical bleeding.  
All consensus guidelines regarding treatment of bleeding for patients with hemophilia A 
with and without inhibitors undergoing surgical procedures recommend treatment with 
BPA/FVIII (Giangrande et al. 2009; Teitel et al. 2009; Shapiro and Cooper 2012; 
National Hemophilia Foundation 2017; Collins et al. 2018).  Treatment with hemostatic 
agents (BPA/FVIII for patients with and without inhibitors, respectively) is at the 
discretion of the physician based on the duration, complexity, and risk of bleeding with 
the procedure.  However, with emicizumab prophylaxis, it is believed that patients will 
have enough hemostatic ability to forgo the need for additional pre-operative prophylaxis 
with BPA/FVIII when undergoing minor surgical procedures. There has been some 
experience and case reports of patients who have undergone minor surgical procedures 
while on emicizumab prophylaxis, though there has not been a uniform approach to 
these procedures and management was left to the discretion of the treating physician
(Kruse-Jarres et al. 2017a; Kruse-Jarres et al. 2017b). In this study, all patients will
preoperatively be treated only with emicizumab prophylaxis, and intra-operative or post-
operative treatment with BPA/FVIII will only be administered for excessive bleeding (or 
new breakthrough bleeds) at the discretion of the treating physician.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety and efficacy of emicizumab prophylaxis in PwHA with 
and without inhibitors undergoing minor surgical procedures.  All endpoints will be 
measured and described separately for the inhibitor and non-inhibitor cohorts.  
Pharmacokinetics will also be evaluated as exploratory objectives of the study.  For the
purposes of this protocol, study treatment is not intended to imply that the Sponsor is 
providing the study drug; rather, emicizumab is required for all patients during the study
per the inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2).


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Table 1
Objectives and Endpoints
Primary Objective
Corresponding Endpoints
To evaluate the 
efficacy of 
emicizumab in 
preventing surgery-
related bleeding in 
PwHA with and
without inhibitors
undergoing minor 
surgical procedures
Efficacy will be measured by:
Percentage of patients without excessive bleeding at surgical sites and did 
not require BPA/FVIII a use for bleeding related to the surgery, from the 
start of the surgery until the patient is discharged from the surgery. For the 
purposes of this endpoint, the absence of excessive bleeding and 
BPA/FVIII a use will be measured by a good to excellent rating using the 
hemostatic efficacy scale (ISTH SSC recommendations, see Appendix 2) 
and will be determined upon patient discharge by the healthcare 
professional performing the procedure.
Percentage of patients with excessive bleeding at surgical sites and required
BPA/FVIII a use for bleeding related to the surgery, from the start of the 
surgery until the patient is discharged from the surgery. Bleeding and BPA
/FVIII a use will be assessed using the hemostatic efficacy scale and 
measured by a rating of fair to poor, and will be determined upon patient
discharge by the healthcare professional performing the procedure.
Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed for excessive bleeding at 
surgical sites will be summarized.
Percentage of patients who, after being discharged from surgery, 
experienced bleeds that were either related or unrelated to the surgery and 
also required BPA/FVIII a use
–
Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed will be summarized
Safety
Incidence and severity of all adverse events
–
Incidence and severity of serious adverse events
–
Incidence and severity of adverse events of special interest
Percentage of patients with surgical complications requiring hospitalization 
or return to surgery 
Percentage of patients who need blood/blood product transfusions (i.e., 
platelets, plasma, etc.) during surgery
Exploratory 
Objective
Exploratory Endpoints
To evaluate 
potential 
relationships 
between drug 
exposure and the 
efficacy and safety 
of emicizumab
Selected efficacy and safety endpoints will be descriptively summarized by 
plasma emicizumab concentration levels
To describe the 
incidence of
spontaneous
bleeding in the 
post-operative 
period.
Percentage of patients with zero bleeds (regardless of treated or not) after 
being discharged from surgery
BPAbypassing agent;ISTH SSCInternational Society on Thrombosis and Haemostasis Scientific 
and Standardization Committee; FVIII factor VIII; PwHApatients with Hemophilia A.
a
BPA use is specific for patients with inhibitors and FVIII use is specific for patients without 
inhibitors.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This Phase IV, multicenter study will evaluate whether PwHA (with or without inhibitors) 
receiving emicizumab prophylaxis can safely undergo minor surgical procedures without
additional prophylaxis with BPA (for patients with inhibitors) or FVIII (for patients 
without inhibitors). Note:  Throughout the protocol, unless otherwise noted, all 
references to BPA will be specific for patients with inhibitors and all references to FVIII 
will be specific for patients without inhibitors.  
The use of BPA/FVIII for excessive surgical bleeding will then be measured 
intra-operatively and post-operatively.  In addition, surgical complications from bleeding 
and blood product transfusions will be evaluated. This study will assess emicizumab 
prophylaxis alone to control surgery-related bleeding in PwHA with and without 
inhibitors undergoing minor surgical procedures.  Each cohort (PwHA with inhibitors 
and PwHA without inhibitors) will be assessed separately.
Patients can be screened and enrolled up to 60 days prior to surgery.  They must have 
received a minimum of four loading doses of emicizumab prior to their surgical 
procedure, been adherent with emicizumab prophylaxis, and must not have received 
BPA/FVIII for at least 24 hours prior to surgery.  In addition, they must plan to continue 
emicizumab prophylaxis for at least 1 month after the surgical procedure.  Follow-up will 
be conducted by phone on Study Days 2 and 3 (approximately 24 and 48 hours 
post-operation) to record any bypassing agent use or FVIII use and surgical bleeding 
within the first 48 hours, as well as treatment of any other bleeding unrelated to surgery.  
BPA/FVIII should only be used for treatment of bleeding.  Follow-up will be conducted 
in person on Study Day 8 (2 days) to examine the patient for any post-surgical
complications and to collect information on treatment of bleeding.  Lastly, follow-up will 
be conducted by phone on Study Day 28 (2 days) to record any surgical complications, 
bleeds, and/or use of BPA/FVIII (see Appendix 1).
Blood samples will also be collected in this study for observational purposes and will not 
be used to determine eligibility or treatment decisions.  Samples will be used to evaluate 
emicizumab concentration (PK) prior to surgery.
Safety follow-up will be conducted after signing the informed consent form. Patients will 
be monitored for adverse events to evaluate the safety of emicizumab alone or in 
combination with BPA/FVIII.  
Periodic Safety Review
In order to ensure that patients enrolled in this study are safely undergoing minor 
surgical procedures without additional pre-operative prophylaxis with BPAs/FVIII,
periodic safety assessments are planned.  The study team will perform periodic data 
review of all available data.


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Figure 1
Study Schema
FVIIIfactor VIII; USUnited States.
a A maximum of 9 patients in each cohort will undergo any surgery type
b Undergoing minor surgery within 60 days of enrollment.  Must have received all loading doses 
of emicizumab prior to surgery.
c 2 days if Study Day 2 or 3 falls on a weekend.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  The end of a patient’s 
participation in the study is expected to occur after Study Day 28.
The total length of the study, from enrollment of the first patient to the end of the study 
(last patient last visit), is expected to be approximately 2430 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Emicizumab Dose and Schedule
Emicizumab is given at a loading dose of 3 mg/kg SC once weekly for the first 4 weeks 
followed by 1.5 mg/kg SC once weekly or by any other FDA-approved maintenance 
regimen.  


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Note: Investigators are recommended to refer to US-Package Insert (USPI) of 
HEMLIBRA(emicizumab) (2018) for additional details on emicizumab dose and
schedule.
3.3.2
Rationale for Biomarker Assessments
Emicizumab plasma concentration has been shown to vary among patients (data on file)
and patients receive similar benefits at various levels. Emicizumab plasma 
concentration will be collected prior to surgery and assessed in an effort to identify any 
relationship to efficacy or safety.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 4060 PwHA (2030 patients with inhibitors and 2030 patients 
without inhibitors) will be enrolled and undergo a minor surgical procedure at 
approximately 20 sites in the United States.  An effort will be made to ensure enrollment 
between multiple surgery types. A maximum of 9 patients in each cohort will be enrolled 
in any given surgery type.  The list of surgery types is provided in Appendix 3.
4.1.1
Inclusion Criteria

Signed Informed Consent/Assent Form

Any age (newborn and older)

Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of hemophilia A and current or history of an inhibitor (Bethesda 
titer 0.6 Bethesda units) and currently using BPA for breakthrough bleed (for 
PwHA with inhibitors)

Diagnosis of hemophilia A and no history of an inhibitor (Bethesda 
titer 0.6 Bethesda units), or a history of an inhibitor that has been tolerized 
for >5 years and using FVIII for breakthrough bleeds (for PwHA without 
inhibitors)

Plan to receive at least 4 loading doses of emicizumab and been adherent to
emicizumab prophylaxis by the time of the surgery

Undergoing minor surgery within 60 days of study enrollment.  Other minor surgical 
procedures could be included upon consultation and approval of Medical Monitor, 
but examples include (see Appendix 3 for a full list):
–
Central venous catheter insertion/removal/replacement
–
Simple dental extractions
–
Colonoscopy, cystoscopy, or endoscopy with biopsy
–
Excisional skin biopsy

Must plan to continue emicizumab prophylaxis for at least 1 month after surgery


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
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 during the study period
–
A woman is considered to be of childbearing potential if she is post-menarchal, 
has not reached a postmenopausal state (12 continuous months 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 
contraceptive, 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 trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
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:

Diagnosis of a bleeding disorder other than hemophilia A

Patients who have been tolerized to Factor VIII products (for PwHA with inhibitors)

Tolerized to FVIII products for <5 years (for PwHA without inhibitors)

Using FVIII products to treat breakthrough bleeds (for PwHA with inhibitors)

Treatment with bypassing agents or FVIII within 24 hours prior to surgical 
procedure

Undergoing a major surgical procedure

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 current signs of thromboembolic 
disease

Other conditions (e.g., certain autoimmune diseases, including, but not limited to 
diseases such as systemic lupus erythematosus, inflammatory bowel disease, and 
antiphospholipid syndrome) that may increase the risk of bleeding or thrombosis

Patients who are at high risk for thrombotic microangiopathy (TMA; e.g., have a 
previous medical or family history of TMA), in the investigator’s judgment

Would refuse treatment with blood or blood products, if necessary.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study


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
Pregnant or lactating, or intending to become pregnant during the study
–
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days before Study Day 1

Treatment with any of the following:
–
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration before Study Day 1
–
A non-hemophilia-related investigational drug within the last 30 days or 
5 half-lives before Study Day 1, whichever is longer
–
An investigational drug concurrently

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 
enrollment
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label, single-arm study in which all enrolled patients are receiving 
emicizumab.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
4.3.1
Study Treatment
4.3.1.1
Emicizumab
If a patient is prescribed emicizumab for prophylaxis, emicizumab is administered 
3 mg/kg/week subcutaneously for the first 4 weeks when initiating treatment (loading 
doses), followed by 1.5 mg/kg/week subcutaneously or by any other approved 
maintenance regimen.  Patients must have received all loading doses and been 
adherent to emicizumab prophylaxis prior to surgery and plan to continue emicizumab 
for a minimum of 1 month after surgery.   For the purposes of this protocol, study 
treatment is not intended to imply that the Sponsor is providing the study drug; rather, 
emicizumab is required for all patients during the study per the inclusion and exclusion 
criteria (see Sections 4.1.1 and 4.1.2). 
4.3.2
Study Treatment Dosage, Administration, and Compliance
All eligible patients receive emicizumab via SC injection at a loading dose 3 mg/kg once 
weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other 
approved maintenance regimen, as long as they continue to derive sufficient benefit.  
Patients must have received all loading doses prior to surgery and plan to continue 
emicizumab for a minimum of 1 month after surgery.  Dosing should be adjusted if the 
patient has a significant change in body weight.
Note: Investigators are recommended to refer to the USPI of HEMLIBRA(emicizumab)
(2018) for additional details on emicizumab dose and administration.


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4.3.3
Continued Access to Emicizumab
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Sponsor study drug (emicizumab) or any other study treatments or 
interventions to patients during the study or to patients who have completed the study. 
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 28 days before enrollment until Study Day 28.  Hemostatic medications to 
treat or prevent bleeds in the week prior to starting emicizumab will also be collected.  All 
medications, including treatments for bleeds (i.e., BPA/FVIII and other medications to 
treat bleeds) should be reported to the investigator at each contact with their Healthcare 
Provider and will be captured in the eCRF. 
4.4.1
Permitted Therapy
Concomitant use of the following drugs and therapies will be permitted:

Drugs intended to treat bleeds, including BPA/FVIII (for PwHA with and without 
inhibitors, respectively) as standard-of-care treatment
–
Emicizumab increases coagulation potential.  If a bypassing agent is indicated in 
a patient receiving emicizumab prophylaxis, the bypassing agent dose required 
may be lower than that used without emicizumab prophylaxis. The dose and 
duration of treatment with bypassing agents will depend on the location and 
extent of bleeding and the patient’s clinical condition. 
–
Avoid use of aPCC unless no other treatment options are available.  If aPCC is 
indicated in a patient receiving emicizumab prophylaxis, the initial dose should 
not exceed 50 U/kg.  If bleeding is not controlled with the initial dose of aPCC up 
to 50 U/kg, then additional doses of aPCC should be administered under medical 
guidance or supervision, and the total aPCC dose should not exceed 100 U/kg 
over 24 hours of treatment.  Weigh the risk of TMA and thromboembolism 
against the risk of bleeding when considering aPCC treatment beyond the initial 
100 U/kg over 24 hours. Continue following this bypassing agent dosing 
guidance for at least 6 months after discontinuation of emicizumab prophylaxis

Anti-fibrinolytics will be allowed pre-operatively and use can be continued in the 
peri-operative and post-operative periods

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

Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.
Note: Investigators are recommended to refer to the USPI of HEMLIBRA(emicizumab)
(2018) for additional details on emicizumab dose and administration.


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4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 4 weeks 
prior to study start unless otherwise noted:

Drugs that would affect hemostasis (e.g., aspirin, non-steroidal anti-inflammatory 
drugs that are not selective or preferential cyclooxygenase-2 [COX-2] inhibitors, or 
anticoagulants [other than to flush, dwell, or de-clot a CVAD]) but excluding drugs 
intended to control bleeding episodes or used in the context of minor surgery (e.g., 
tooth extraction) or injuries (e.g., concussion) to prevent deterioration

Systemic immunomodulators (e.g., rituximab, interferon) other than antiretroviral 
therapy from enrollment to last observation

FVIII or BPA for prophylaxis or for the treatment of a breakthrough bleed within 
24 hours prior to surgery

Other investigational drugs from enrollment to last observation
If prohibited therapy is administered for any reason, it should be recorded on the eCRF.  
If prohibited treatment is prescribed or considered medically necessary, the medical 
monitor should be consulted to discuss any changes in the benefit/risk and determine 
whether the patient should continue on the study.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations). Children 
and adolescents (18 years of age) will complete an Assent Form when capable and 
their parents or legally authorized representatives will also complete an Informed 
Consent Form. Informed Consent Forms for enrolled patients and for patients who are 
not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
If the screening period extends beyond the 60-day window allowed by the protocol for 
any reason, the patient should be re-consented prior to the expiration of the original 60-
day screening window.  The complete screening evaluations should also be repeated 
and documented following the re-consent.  Only one extension of the screening period 
with proper re-consent will be allowed for a patient. 


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4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history includes hemophilia-related history, 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 prior 
immune tolerance induction, anaphylaxis, or known thrombophilia.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 28 days prior 
to Study Day 1 will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A limited physical examination will include evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, respiratory, gastrointestinal, and dermatologic systems.  
Focused examination of the musculoskeletal, genitourinary, and neurological systems
should be performed as related to the surgical procedure.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.  At 
subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.
4.5.4
Vital Signs
Vital sign assessments will include measurements of body temperature, systolic and 
diastolic blood pressure, pulse rate, respiratory rate, and weight, as indicated in the 
schedule of assessments (see Appendix 1).  
4.5.5
Bleed and Medications Diary
Patients (or patient’s legally authorized representative) will complete the 
bleed/medication diary; one diary card per week for 4 weeks after being discharged from 
surgery.  Information obtained will include start date and time, reason, type, location of 
each bleed, as well as start date and time, reason, type, and dose of each injection, if 
any, including emicizumab. Diary entries for events should be completed on the cards 
as soon as events occur.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (complete blood count with differential [i.e., neutrophils, hemoglobin, 
platelet count])

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, and creatine phosphokinase)


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
Pregnancy test:  Women of childbearing potential must have a negative serum 
pregnancy test result within 7 days before Study Day 1
Samples for the following laboratory tests will be sent to a central laboratory for analysis.  
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.

Serum samples for pharmacokinetic analysis
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  Samples 
collected for study-related analyses will be destroyed no later than 5 years after the final 
study results have been reported.
Data arising from sample analysis including data on germline mutations will be subject to 
the confidentiality standards described in Section 8.4.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Discontinuation
Patients must permanently discontinue the study if they experience any of the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue the study prematurely will not be replaced.
4.6.2
Patient Discontinuation from Study
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  
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 


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appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Emicizumab is being developed for the treatment of hemophilia A, and is FDA approved 
for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult 
and pediatric patients with hemophilia A (congenital factor VIII deficiency) with or
without factor VIII inhibitors.  The safety plan for this study is designed to ensure patient 
safety and will include specific eligibility criteria and monitoring assessments as detailed 
below. Refer to the HEMLIBRA(emicizumab) USPI for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this
study. Eligibility criteria have been designed to exclude patients at higher risk for
toxicities. Patients will undergo safety monitoring during the study, including
assessment of the nature, frequency, and severity of adverse events. In addition, 
guidelines for managing adverse events, including criteria for dosage modification and
treatment interruption or discontinuation, are provided below.


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5.1.1
Risks Associated with Emicizumab
5.1.1.1
Thromboembolic Events and Thrombotic Microangiopathy
Thrombotic Microangiopathy Associated with Emicizumab and aPCC
Cases of thrombotic microangiopathy (TMA) were reported from clinical trials when on 
average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex 
concentrate (aPCC) was administered for 24 hours or more to patients receiving 
emicizumab prophylaxis. In clinical trials, thrombotic microangiopathy was reported in 
0.8% of patients (3 of 391) and in 9.7% of patients (3 of 37) who received at least one 
dose of aPCC.  Patients presented with thrombocytopenia, microangiopathic hemolytic 
anemia, and acute kidney injury, without severe deficiencies in a disintegrin and 
metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity. 
Evidence of improvement was seen within one week following discontinuation of aPCC. 
One patient resumed emicizumab following resolution of TMA. 
Consider the benefits and risks if aPCC must be used in a patient receiving emicizumab 
prophylaxis. Monitor for the development of TMA when administering aPCC. 
Immediately discontinue aPCC and interrupt emicizumab prophylaxis if clinical 
symptoms and/or laboratory findings consistent with TMA occur, and manage as 
clinically indicated. Consider the benefits and risks of resuming emicizumab prophylaxis 
following complete resolution of TMA on a case-by-case basis.
Thromboembolism Associated with Emicizumab and aPCC
Thrombotic events were reported from clinical trials when on average a cumulative 
amount of >100 U/kg/24 hours of aPCC was administered for 24 hours or more to 
patients receiving emicizumab prophylaxis. In clinical trials, thrombotic events were 
reported in 0.5% of patients (2 of 391) and in 5.4% of patients (2 of 37) who received at 
least one dose of aPCC. 
No thrombotic event required anticoagulation therapy. Evidence of improvement or 
resolution was seen within one month following discontinuation of aPCC. One patient 
resumed emicizumab following resolution of thrombotic event.
Consider the benefits and risks if aPCC must be used in a patient receiving emicizumab 
prophylaxis. Monitor for the development of thromboembolism when administering 
aPCC. Immediately discontinue aPCC and interrupt emicizumab prophylaxis if clinical 
symptoms, imaging, or laboratory findings consistent with thromboembolism occur, and 
manage as clinically indicated. Consider the benefits and risks of resuming emicizumab
prophylaxis following complete resolution of thrombotic events on a case-by-case basis.
5.1.1.2
Injection-Site Reactions
In total, 85 patients (22%) reported injection site reactions (ISRs).  All ISRs observed in
emicizumab clinical trials were reported as mild to moderate intensity.  Most ISRs (93%)


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resolved without treatment.  The most commonly reported ISR symptoms were injection
site erythema (11%), injection site pain (4%), and injection site pruritus (4%).
Note: Investigators are recommended to refer to the USPI of HEMLIBRA(emicizumab)
(2018) for additional details on ISRs observed in PwHA while on emicizumab prophylaxis.
5.1.1.3
Systemic Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, 
including anaphylaxis and anaphylactic reactions, may occur.  As of October 2018, in 
completed and ongoing clinical studies of emicizumab, no serious adverse events 
consistent with systemic hypersensitivity, anaphylactic, or anaphylactoid 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 should instruct patients how to recognize the signs and symptoms of systemic 
hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an HCP or 
seek emergency care in case of any such occurrence. 
5.1.1.4
Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays in the Setting of 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII activity, 
and FVIII inhibitor measurement by Bethesda assay) are not reliable and do not 
accurately reflect the patient’s underlying hemostatic status while receiving emicizumab 
prophylaxis (see Section 5.1.2). Due to the long t1/2 of emicizumab, these effects on 
coagulation assays may persist for up to 6 months after the last dose.
There is a risk of life-threatening bleeding due to unreliable standard coagulation tests 
and inhibitor assays in the setting of emicizumab, which may be observed by 
practitioners, particularly emergency care practitioners.
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 April 2017, no instances of under-treatment of bleeding events due to 
unreliable standard coagulation tests and inhibitor assays in the setting of emicizumab 
were observed.
5.1.1.5
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection 
of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody positivity in an assay may be 
influenced by several factors, including assay methodology, sample handling, timing of 
sample collection, concomitant medication, and underlying disease. For these reasons, 


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comparison of the incidence of antibodies to emicizumab-kxwh in the studies described 
below with the incidence of antibodies in other studies or to other products may be 
misleading.
The immunogenicity of emicizumab was evaluated using an enzyme-linked 
immunosorbent assay (ELISA) or an electrochemiluminescence (ECL) assay. In the 
dose-finding trial (n 18), four patients tested positive for anti-emicizumab antibodies. 
In the pooled HAVEN clinical trials, 3.5% of patients (14/398) tested positive for 
anti-emicizumab antibodies and <1% of patients (3/398) developed anti-emicizumab
antibodies with neutralizing potential (based on declining pharmacokinetics). One 
patient from HAVEN 2, who developed an anti-emicizumab neutralizing antibody, 
experienced loss of efficacy after 5 weeks of treatment. 
There was no clinically apparent impact of the presence of anti-emicizumab-kxwh 
antibodies on safety.
5.1.2
Laboratory Coagulation Test Interference
Emicizumab affects intrinsic pathway clotting-based laboratory tests, including activated 
clotting time (ACT), aPTT, and all assays based on aPTT, such as one-stage FVIII
activity (Table 2). Therefore, intrinsic pathway clotting-based laboratory test results in 
patients treated with emicizumab should not be used to monitor emicizumab activity, 
determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor 
titers.  Laboratory tests affected and unaffected by emicizumab are shown in Table 2.  
Table 2
Coagulation Test Results Affected and Unaffected by 
Emicizumab (HEMLIBRA)
Results Affected by Emicizumab
Results Unaffected by Emicizumab
Activated partial thromboplastin time (aPTT)
Thrombin Time (TT)
Activated clotting time (ACT)
One-stage, PT-based, single factor assays
One–stage, aPTT-based, single factor assays
Chromogenic-based single-factor assays 
other than FVIII*
aPTT-based Activated Protein C Resistance 
(APC-R)
Immuno-based assays (i.e., ELISA, 
turbidometric methods)
Bethesda assays(clotting-based) for FVIII inhibiter 
titers
Bethesda assays (bovine chromogenic) for 
FVIII inhibitor titers
Genetic tests of coagulation factors (e.g., 
Factor V Leiden, Prothrombin 20210)
Effects of Emicizumab on Coagulation Test Results
Emicizumab restores the tenase cofactor activity of activated factor VIII (FVIIIa).  
Coagulation laboratory tests based on intrinsic clotting (i.e., aPTT) measure the total 
clotting time including time needed for activation of FVIII to FVIIIa by thrombin.  Such 
intrinsic pathway-based tests will yield overly shortened clotting times with emicizumab, 
which does not require activation by thrombin.  The overly shortened intrinsic clotting 
time will then disturb all single-factor assays based on aPTT, such as the one-stage 


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FVIII activity assay.  However, single-factor assays utilizing chromogenic or immuno-
based methods are not affected by emicizumab and may be used to monitor coagulation 
parameters during treatment, with specific considerations for FVIII chromogenic activity 
assays as described below.
Chromogenic FVIII activity tests may be manufactured with either human or bovine 
coagulation proteins.  Assays containing human coagulation factors are responsive to 
emicizumab but may overestimate the clinical hemostatic potential of emicizumab.  In 
contrast, assays containing bovine coagulation factors are insensitive to emicizumab (no 
activity measured) and can be used to monitor endogenous or infused FVIII activity, or to 
measure anti-FVIII inhibitors.
Emicizumab remains active in the presence of inhibitors against FVIII and so will 
produce a false-negative result in clotting-based Bethesda assays for functional 
inhibition of FVIII.  Instead, a chromogenic Bethesda assay utilizing a bovine-based FVIII 
chromogenic test that is insensitive to emicizumab may be used.
Due to the long half-life of emicizumab, these effects on coagulation assays may persist 
for up to 6 months after the last dose.
Note: Investigators are recommended to refer to the USPI of HEMLIBRA(emicizumab) 
(2018) 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.
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 
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
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 Study Day 1 (e.g., screening invasive procedures such as 
biopsies, or additional surgical procedures unrelated to the primary surgery)
All bleeds will be recorded on the bleed/medication diary.  Bleeds meeting the criteria of 
serious adverse events (as per Section 5.2.2) should be reported on the appropriate
adverse event eCRF page regardless of whether the bleeds are consistent with patients’
pre-study disease state. New, non-serious bleeds consistent with patients’ pre-study 
disease state will not be considered adverse events.
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 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.


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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 include either 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.

Anaphylactic, anaphylactoid, and severe systemic hypersensitivity reactions (see 
Sampson’s Criteria in Appendix 5)

Thromboembolic events

Thrombotic microangiopathy
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 Section5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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After informed consent has been obtained, all adverse events will be reported until 
Study Day 28).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The World Health Organization (WHO) toxicity grading scale (see Appendix 4) will be
used for assessing adverse event severity.  Table 3 will be used for assessing severity 
for adverse events that are not specifically listed in the WHO toxicity grading scale.
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 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 (see also    
Table 4):

Temporal relationship of event onset to the initiation of study drug


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
Course of the event, with special consideration of the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged by the investigator to be related to study drug injection should be captured as 
a diagnosis (e.g., "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 Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same administration of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF. Only for local 
injection-site reactions should the dedicated Injection-Site Reaction eCRF be used to 
capture the individual signs/symptoms.


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5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection 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.
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.


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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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
For concerns about laboratory findings on coagulation-related tests in patients receiving 
emicizumab, refer to Section 5.1.2 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)


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
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 cause of hyperbilirubinemia
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.2.3).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  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 


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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of hemophilia "hemophilia progression" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6
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 severity (e.g., increased number of coagulation factor doses 
required to stop bleeds with emicizumab, in the absence of neutralizing anti-emicizumab 
antibodies, compared with before study entry) or frequency of bleeds or changed in 
nature at any time during the study.  When recording an unanticipated worsening of 
hemophilia on the Adverse Event eCRF, it is important to convey the concept that the 
condition has changed by including applicable descriptors (e.g., "increased clinical 
severity of hemophilia").
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
outside of observation post-operatively or prolonged hospitalization (defined as 
hospitalization for additional nights (more than 1 night) post-operatively) 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. 


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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The 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
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; (see Section 5.4.2 for
further details)

Pregnancies (see Section 5.4.3 for further details)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for
details on reporting requirements)
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


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information:
Medical Monitors:
, M.D.
Telephone Nos.:
(United States)
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
Serious Adverse Events and Adverse Events of Special Interest should be reported after 
informed consent has been obtained, until Study Day 28.  Investigators should record all 
case details that can be gathered immediately (i.e., within 24 hours after learning of the 
event) on the Adverse Event eCRF and submit the report via the electronic data capture 
(EDC) system.  The Adverse Event eCRF should be completed and submitted via the 
EDC system.  A report will be generated and sent to Safety Risk Management by the 
EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur greater than 28 days after 
surgery 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 emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue emicizumab
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 


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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
Congenital Anomalies/Birth Defects and Abortions
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).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher
than the assigned dose

Medication error:  accidental deviation in the administration of a drug
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or
dependence, physical harm, and/or psychological harm}

Drug misuse:  intentional deviation in the administration of a drug that does not
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with emicizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug
administered and a description of the error (e.g., wrong dose administered, wrong


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dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental
overdose" as the event term.  Check the "Accidental overdose" and "Medication
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication
error" as the event term.  Check the "Medication error" box.  Enter a description of
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse"
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse"
boxes.

Drug administered to someone other than the patient:  Enter the drug name and
"patient supplied drug to third party" as the event term.  Check the "Drug misuse"
box.
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the
"Intentional overdose" and "Drug abuse" boxes.


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
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check
the "Intentional overdose" and "Drug misuse" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after surgery) if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  The 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

US-Package Insert (PI) of HEMLIBRA (emicizumab)® (2018)
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is an open-label, single-arm, multicenter study to evaluate emicizumab prophylaxis 
in PwHA without inhibitors and PwHA with inhibitors, who are undergoing minor 
surgical procedures.  Each cohort will be evaluated separately.  No statistical hypothesis 
will be tested. There are three populations that will be included in the analyses, which 
are defined as follows: 

All Enrolled Population: All patients who sign informed consent.

Safety Analysis Population: All enrolled patients who receive emicizumab

Efficacy Analysis Population: All enrolled patients who receive emicizumab and
undergo a minor surgery
Only descriptive summaries will be presented for data collected in this study.  
Continuous variables will be summarized using means, standard deviations, medians, 
and ranges; categorical variables will be summarized using proportions, and 95% 
confidence intervals where applicable, as appropriate.  Additional details of the analyses 
will be presented in the statistical 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 inhibitor patients with a planned minor surgery 
available for participation in this study.  Table 5 illustrates the precision of this study for a 
binary efficacy endpoint assuming a total of approximately 2030 patients per cohort 


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enrolled into this study, received emicizumab, and underwent a protocol-specified minor 
surgery.
During the study, a re-assessment of the initially specified sample size may be 
performed.  This may result in an increase in sample size, if necessary, to expand the 
safety database.
Table 5
Precision of the Study for a Binary Efficacy Endpoint (Illustrative 
Purposes)
Sample 
Size
Count of 
Events a
Estimate of 
Proportion
Lower Limit of 
95% CI b
Upper Limit of 
95% CI b
20
2
0.1
0.012
0.317
20
6
0.3
0.119
0.543
20
10
0.5
0.272
0.728
30
3
0.1
0.021
0.265
30
9
0.3
0.147
0.494
30
15
0.5
0.313
0.687
a This is the assumed observed count of events of interest.
b Calculated using exact test procedure based on the Clopper-Pearson method.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized overall and by type of surgery.  Reasons for premature study withdrawal will 
be listed and summarized.  Enrollment and major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate.  Summaries will be presented overall and by type of surgery.
6.4
EFFICACY ANALYSES
Descriptive statistics along with 95% confidence intervals will be used to provide point
estimates and precision related to efficacy outcomes.
6.5
SAFETY ANALYSES
Safety will be assessed through descriptive summaries of safety endpoints, adverse 
events, and vital signs.
All adverse events occurring after informed consent is obtained will be coded. 
Treatment emergent events will be summarized by severity, and tabulated by body 


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system and preferred term for individual events within each system organ class. In 
addition, serious adverse events, adverse events of special interest (AESIs), and 
adverse events leading to study discontinuation will be summarized. All serious adverse 
events and deaths will be listed. 
6.6
PHARMACOKINETIC ANALYSES
Individual and mean emicizumab concentrations will be tabulated. Additional analyses 
will be conducted as appropriate.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
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
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 


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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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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 laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
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 


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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.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of 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 (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.


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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 trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring.
Approximately 40-60 patients (approximately 2030 patients with inhibitors and 2030 
patients without inhibitors) will be enrolled and undergo a minor surgical procedure at 
approximately 20 sites in the United States.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.


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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities
Study Day
(Window)
Screening a
Surgery b
Post-Operative 
Follow-Up Call c
Post-Operative 
Follow-Up Call d
Post-Operative 
Follow-Up Visit e
Post-Operative 
Follow-Up Call/
Study 
Completion f
60 to 1
1
2
3
8
(2 days)
28
(2 days)
Informed consent g
x
Demographic data
x
Medical history and baseline 
conditions
x
Vital signs
x
x
x
Weight h
x
x
Limited physical examination i,j
x
xk
x
Hematology l
x
Chemistry m
x
Serum pregnancy test
x
Plasma pharmacokinetic sample
xn
Concomitant medications o
x
x
x
x
x
x
Adverse events p
x
x
x
x
x
x
Bleed and Medication Diary q
x
x
x
x
x


Appendix 1
Schedule of Activities (cont’d)
Emicizumab—Genentech, Inc.
64/Protocol ML39791, Version 4
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 60 days prior to Study Day 1 may be 
used and do not need to be repeated for enrollment. Patients can be re-consented if surgery is delayed or if they lose and regain eligibility. 
b All assessments should be completed within 24 hours before surgery except adverse event assessment (peri-operative) and bleed/medication 
diary.
c The clinician is to call the patient on Study Day 2, which is post-operative Day 1 (approximately 24 hours post-operation), for follow-up.  The call 
can be made up to 2 days after Study Day 2 if it falls on a weekend or holiday.  This assumes that the patient was discharged and did not remain 
inpatient (e.g., for observation).
d The clinician is to call the patient on Study Day 3, which is post-operative Day 2 (approximately 48 hours post-operation), for follow-up.  The call 
can be made up to 2 days after Study Day 3 if it falls on a weekend or holiday.  This assumes that the patient was discharged and did not remain 
inpatient (e.g., for observation).
e The patient is to return to the clinic on Study Day 8 (2 days) for follow-up.
f
The clinician is to call the patient on Study Day 28 (2 days) for follow-up.  After this call, the patient will have completed the study.
g Informed consent must be documented before any study-specific (nonstandard of care) screening procedure is performed, and may be 
obtained up to 60 days before enrollment in the study.  Consent date will be considered the date of enrollment. 
h Weight is used to calculate emicizumab dose (based on weight).
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, respiratory, gastrointestinal, and dermatologic systems.
Focused examination of the musculoskeletal, genitourinary, and neurological systems should be performed as related to the surgical procedure.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
j
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
k Site must document that patient was clinically stable and not actively bleeding prior to discharge.
l
Hematology includes complete blood count with differential (i.e., neutrophils, hemoglobin, platelet count).
m Chemistry panel includes 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, and 
creatine phosphokinase).
n PK sample must be obtained at the study site 24 hours before surgery.
o Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 28 days prior to surgery until Study Day 28.


Appendix 1
Schedule of Activities (cont’d)
Emicizumab—Genentech, Inc.
65/Protocol ML39791, Version 4
p After informed consent has been obtained, all adverse events will be reported until Study Day 28.  After this period, adverse events should be 
reported per routine reporting requirements.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to prior study drug treatment. The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until 
a final outcome can be reported.
q Patients (or patient’s legally authorized representative) will complete the bleed/medication diary and will include start date and time, reason, type, 
location of each bleed, as well as start date and time, reason, type, and dose of bypassing agent, if any, excluding emicizumab.


Emicizumab—Genentech, Inc.
66/Protocol ML39791, Version 4
Appendix 2
Assessment of Hemostatic Response for Surgical Procedures
Source:  Blanchette et al. 2014.


Emicizumab—Genentech, Inc.
67/Protocol ML39791, Version 4
Appendix 3
Minor Surgical Procedures
The below procedures meet the definition of minor for the purposes of this study:

Abdominal hernia repair

Botulinum toxin injections

Central venous catheter insertion/removal/replacement

Circumcision

Colonoscopy, cystoscopy, or endoscopy with biopsy

Simple dental extractions (not oral surgery)

Excision of nevi

Excisional skin biopsy

Hardware (e.g. external fixation, pins, etc.) removal

Intra-articular injections

Lysis of penile adhesions

Nail removal

Tendon lengthening

Wound debridement

Other (surgeries not listed here may be included after consultation and approval by 
the Genentech Medical Monitor)


Emicizumab—Genentech, Inc.
68/Protocol ML39791, Version 4
Appendix 4
World Health Organization Toxicity Grading Scale for Determining the Severity of Laboratory 
Abnormalities and Adverse Events
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
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
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
CHEMISTRIES (cont.)
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


Appendix 4
World Health Organization Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse 
Events (cont.)
Emicizumab—Genentech, Inc.
69/Protocol ML39791, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L or life-threatening
arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental status
changes or coma
Hyperglycemia (note if 
fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or ketoacidosis or 
seizures
Hypocalcemia (corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or life-threatening
arrhythmia or tetany
Hypercalcemia (correct for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL life-threatening
arrhythmia
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or life-threatening
arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or
replacement Rx required
1.01.4 mg/dL intensive Rx 
or hospitalization required
1.0 mg/dL or life-threatening
arrhythmia
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
6ULN or required dialysis
URINALYSIS
Proteinuria
1or 0.3% or 3g/L
or 200 mg1 g loss/day
23or 0.31.0% or 
310 g/L
12 g loss/day
4or 1.0 % or 10 g/L
23.5 g loss/day
nephrotic syndrome or 
3.5 g loss/day
Hematuria
microscopic only
gross, no clots
gross clots
obstructive or required transfusion


Appendix 4
World Health Organization Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse 
Events (cont.)
Emicizumab—Genentech, Inc.
70/Protocol ML39791, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CARDIAC DYSFUNCTION
Cardiac Rhythm
asymptomatic, transient
signs, no Rx required
recurrent/persistent; no Rx 
required
requires treatment
Hypertension
transient, inc. 20 mm;
no Rx
recurrent, chronic, 
20 mm, Rx required
requires acute Rx; no
hospitalization
requires hospitalization
Hypotension
transient orthostatic
hypotension, no Rx
symptoms correctable
with oral fluids Rx
requires IV fluids; no
hospitalization required
requires hospitalization
Pericarditis
minimal effusion
mild/moderate
asymptomatic effusion, 
no Rx
symptomatic effusion; pain; 
EKG changes
tamponade; pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
12 units transfused
massive blood loss;
3 units transfused
RESPIRATORY
Cough
transient; no Rx
treatment-associated
cough
local Rx
uncontrolled
Bronchospasm, Acute
transient; no Rx
70%79% FEV1
(or peak flow)
requires Rx normalizes 
with bronchodilator;
FEV1 50%69%
(or peak flow)
no normalization with
bronchodilator;
FEV1 25%49%
(or peak flow retractions)
cyanosis:  FEV1 25%
(or peak flow) or intubated
GASTROINTESTINAL
Stomatitis
mild discomfort; no
limits on activity
some limits on
eating/drinking
eating/talking very limited
requires IV fluids
Nausea
mild discomfort;
maintains reasonable
intake
moderate discomfort;
intake decreased
significantly; some
severe discomfort; no
significant intake; activities 
limited
minimal fluid intake


Appendix 4
World Health Organization Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse 
Events (cont.)
Emicizumab—Genentech, Inc.
71/Protocol ML39791, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
activity limited
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


Appendix 4
World Health Organization Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse 
Events (cont.)
Emicizumab—Genentech, Inc.
72/Protocol ML39791, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
NEURO AND NEUROMUSCULAR (cont.)
Neuro control
(ADLactivities of daily 
living)
mild difficulty
concentrating; no Rx;
mild confusion/agitation;
ADL unaffected
moderate confusion/ 
agitation; some limitation 
of ADL; minimal Rx
severe confusion/agitation;
needs assistance for ADL;
therapy required
toxic psychosis; hospitalization
Muscle strength
subjective weakness
no objective 
symptoms/signs
mild objective
signs/symptoms no 
decrease in function
objective weakness function 
limited
paralysis
OTHER PARAMETERS
Fever: oral, 12 hours
37.738.5 C or
99.9101.3 F
38.639.5 C or
101.4103.1 F
39.640.5 C or
103.2104.9 F
40.5 C or
104.9 F
Headache
mild, no Rx therapy
transient, moderate; Rx
required
severe; responds to initial 
narcotic therapy
intractable; required repeated 
narcotic therapy
Fatigue
no decrease in ADL
normal activity
decreased 2550%
normal activity decreased
50% can’t work
unable to care for self
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria;
angioedema
anaphylaxis
Local Reaction
tenderness or erythema
induration 10 cm or
phlebitis or inflammation
Induration 10 cm or
ulceration
necrosis
Mucocutaneous
erythema; pruritus
diffuse, maculopapular 
rash, dry desquamation
vesiculation, moist
desquamation, or ulceration
exfoliative dermatitis, mucous
membrane involvement or
erythema multiforme or suspected 
Stevens-Johnson or necrosis
requiring surgery
For coding purposes, the following toxicity grades may be used interchangeably: 1mild; 2moderate; 3severe; 4life threatening.


Emicizumab—Genentech, Inc.
73/Protocol ML39791, Version 4
Appendix 5
Clinical Criteria for Diagnosing Anaphylaxis
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network.1 Anaphylaxis is highly 
likely when any one of the following three criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips, 
tongue/uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia, syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours):

Infants and children: low systolic blood pressure (age specific) or greater than 
30% decrease in systolic blood pressure 2

Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline
_____________________________________
1
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006; 117: 391–7.
2
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg [2 x age]) from 1 to 10 years, and less than 90 mmHg from 
11 to 17 years.

SAP_001.pdf: 
 
Official Title: 
 
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY 
OF EMICIZUMAB PROPHYLAXIS IN PATIENTS WITH HEMOPHILIA 
A WITH OR WITHOUT INHIBITORS UNDERGOING MINOR 
SURGICAL PROCEDURES 
NCT Number: NCT03361137 
Document Date: SAP Version 1: 26-May-2020 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is a Genentech, Inc. document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc.
Emicizumab—Genentech, Inc.
Statistical Analysis Plan ML39791
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-LABEL 
STUDY OF EMICIZUMAB PROPHYLAXIS IN PATIENTS 
WITH HEMOPHILIA A WITH OR WITHOUT INHIBITORS 
UNDERGOING MINOR SURGICAL PROCEDURES
PROTOCOL NUMBER:
ML39791
STUDY DRUG:
Emicizumab (HEMLIBRA®)
VERSION NUMBER:
1.0
IND NUMBER:
122954
EUDRACT NUMBER:
Not applicable
Date and Time(UTC)        Reason for Signing                              Name
26-May-2020 17:07:39
Company Signatory


Emicizumab—Genentech, Inc.
2/Statistical Analysis Plan ML39791
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 4
2.
STUDY DESIGN........................................................................................... 4
2.1
PROTOCOL SYNOPSIS ......................................................... 5
2.2
ENDPOINTS............................................................................ 5
2.2.1
Primary Efficacy Endpoints...................................................... 5
2.2.2
Secondary Efficacy Endpoints................................................. 6
2.2.3
Exploratory Efficacy Endpoints................................................ 6
2.2.4
Pharmacokinetic Endpoints ..................................................... 6
2.2.5
Safety Endpoints ..................................................................... 6
2.3
Determination of Sample Size ................................................. 7
2.4
Analysis Timing ....................................................................... 7
3.
STUDY CONDUCT....................................................................................... 8
3.1
Randomization Issues ............................................................. 8
3.2
Independent Review Facility.................................................... 8
3.3
Data Monitoring ....................................................................... 8
4.
STATISTICAL METHODS ............................................................................ 8
4.1
Analysis Populations ............................................................... 8
4.1.1
All Enrolled Population............................................................. 8
4.1.2
Efficacy Analysis Population.................................................... 8
4.2
Analysis of Study Conduct....................................................... 8
4.3
Analysis of Demographics, Baseline 
Characteristics, and Medical History ....................................... 9
4.4
Efficacy Analysis...................................................................... 9
4.4.1
Primary Efficacy Endpoint........................................................ 9
4.4.2
Secondary Efficacy Endpoints............................................... 10
4.4.3
Exploratory Efficacy Endpoints.............................................. 10
4.4.4
Sensitivity Analyses............................................................... 10
4.4.5
Subgroup Analyses ............................................................... 10
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 10
4.6
Safety Analyses..................................................................... 10


Emicizumab—Genentech, Inc.
3/Statistical Analysis Plan ML39791
4.6.1
Exposure of Study Medication............................................... 10
4.6.2
Adverse Events ..................................................................... 10
4.6.3
Laboratory Data..................................................................... 11
4.6.4
Vital Signs.............................................................................. 11
4.7
Missing Data.......................................................................... 11
4.8
Interim Analyses .................................................................... 11
5.
REFERENCES ........................................................................................... 12
LIST OF TABLES
Table 1
Precision of the Study for a Binary Efficacy Endpoint 
(Illustrative Purposes) ................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 13
Appendix 2
Schedule of Activities................................................................. 18


Emicizumab—Genentech, Inc.
4/Statistical Analysis Plan ML39791
1.
BACKGROUND
This study will evaluate the safety and efficacy of emicizumab prophylaxis in patients 
with hemophilia A (PwHA; with and without inhibitors) that are undergoing minor surgical
procedures without additional prophylaxis with bypassing agents (BPA; for patients with 
inhibitors) or factor VIII (FVIII; for patients without inhibitors).  Pharmacokinetics will also 
be evaluated as exploratory objectives of the study.  For the purposes of this protocol, 
study treatment is not intended to imply that the Sponsor is providing the study drug; 
rather, emicizumab is required for all patients during the study per the inclusion and 
exclusion criteria.
2.
STUDY DESIGN
This Phase IV, multicenter study will evaluate whether PwHA receiving emicizumab 
prophylaxis can safely undergo minor surgical procedures without additional prophylaxis 
with BPAs for patients with inhibitors or FVIII for patients without inhibitors.  Current 
guidelines recommend a pre-operative dose of BPA/FVIII as surgical prophylaxis, but in 
patients on emicizumab prophylaxis in this study, additional pre-operative prophylaxis 
with BPA/FVIII will not be used.  The use of BPA/FVIII for excessive surgical bleeding 
will be measured intraoperatively and postoperatively.  In addition, surgical 
complications from bleeding and blood product transfusions will be evaluated.  This 
study will assess emicizumab prophylaxis alone to control surgery-related bleeding in 
PwHA undergoing minor surgical procedures.
Patients can be screened and enrolled up to 60 days prior to surgery.  They must have 
received a minimum of four loading doses of emicizumab prior to their surgical 
procedure, been adherent with emicizumab prophylaxis, and must not have received 
BPA/FVIII for at least 24 hours prior to surgery.  In addition, they must plan to continue 
emicizumab prophylaxis for at least 1 month after the surgical procedure.  Follow-up will 
be conducted by phone on Study Days 2 and 3 (approximately 24 and 48 hours post 
operation) to record any BPA/FVIII use and surgical bleeding within the first 48 hours, 
as well as treatment of any other bleeding unrelated to surgery.  BPA/FVIII should only 
be used for treatment of bleeding.  Follow-up will be conducted in person on Study Day 
8 (± 2 days) to examine the patient for any postsurgical complications and to collect 
information on treatment of bleeding.  Lastly, follow-up will be conducted by phone on
Study Day 28 (± 2 days) to record any surgical complications, bleeds, and/or use of 
BPA/FVIII (see Appendix 2).
Blood samples will also be collected in this study for observational purposes and will not 
be used to determine eligibility or treatment decisions.  Samples will be used to evaluate 
emicizumab concentration (PK) prior to surgery.
Safety follow-up will be conducted after signing the informed consent form and patients 
will be monitored for adverse events as noted above to evaluate the safety of 
emicizumab alone or in combination with BPA/FVIII.


Emicizumab—Genentech, Inc.
5/Statistical Analysis Plan ML39791
Figure 1 shows the study schema. 
Figure 1
Study Schema
FVIIIfactor VIII; USUnited States.
a A maximum of 9 patients in each cohort will undergo any surgery type
b Undergoing minor surgery within 60 days of enrollment.  Must have received all loading doses 
of emicizumab prior to surgery.
c 2 days if Study Day 2 or 3 falls on a weekend.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
ENDPOINTS
All endpoints will be measured and described separately for the inhibitor and non-
inhibitor cohorts.  For all endpoints in this section, BPA use is specific for patients with 
inhibitors and FVIII use is specific for patients without inhibitors.
2.2.1
Primary Efficacy Endpoints

Percentage of patients without excessive bleeding at surgical sites and did not 
require BPA/FVIII use for bleeding related to the surgery, from the start of the 
surgery until the patient is discharged from the surgery.  For the purposes of this 
endpoint, the absence of excessive bleeding and BPA/FVIII use will be measured by 
a good to excellent rating using the hemostatic efficacy scale (ISTH SSC 
recommendations, see References) and will be determined upon patient discharge 
by the healthcare professional performing the procedure.


Emicizumab—Genentech, Inc.
6/Statistical Analysis Plan ML39791

Percentage of patients with excessive bleeding at surgical sites and required 
BPA/FVIII use for bleeding related to the surgery, from the start of the surgery until 
the patient is discharged from the surgery. Bleeding and BPA/FVIII use will be 
assessed using the hemostatic efficacy scale and measured by a rating of fair to 
poor, and will be determined upon patient discharge by the healthcare professional 
performing the procedure.
-
Dose and schedule (including number of doses, total dose, and frequency) of 
BPAs/FVIII used per bleed for excessive bleeding at surgical sites will be 
summarized.
Percentage of patients who, after being discharged from surgery, experienced bleeds 
that were either related or unrelated to the surgery and also required BPA/FVIII use 
-
Dose and schedule (including number of doses, total dose, and frequency) of 
BPAs/FVIII used per bleed will be summarized.
Bleeding events and self-administered BPA/FVIII use in the third endpoint above are
self-reported on the Bleeding and Medication Diary CRF page by patients who undergo
the surgical procedure in the study. BPA/FVIII, whenever administered by the health
care provider, will be obtained and reported by the PI on the Concomitant Medication 
CRF page.
2.2.2
Secondary Efficacy Endpoints
Not applicable.
2.2.3
Exploratory Efficacy Endpoints

In the original protocol, select efficacy endpoints were to be summarized 
descriptively by plasma emicizumab concentration levels. Given that this study is 
being terminated early with limited sample sizes, these will no longer be performed.

Percentage of patients with zero bleeds (regardless of treated or not) after being 
discharged from surgery.
2.2.4
Pharmacokinetic Endpoints

Emicizumab plasma concentrations on the day of the surgery will be summarized 
descriptively.
2.2.5
Safety Endpoints

Incidence and severity of all adverse events
Incidence and severity of serious adverse events
Incidence and severity of adverse events of special interest


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
Percentage of patients with surgical complications requiring hospitalization or return 
to surgery

Percentage of patients who need blood/blood product transfusions (i.e., platelets, 
plasma, etc.) during surgery

In the original protocol, selected safety endpoints were to be descriptively 
summarized by plasma emicizumab concentration levels.  Given the early 
termination of this study and limited sample sizes, these will no longer be 
performed.
2.3
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 a planned minor surgery available 
for participation in this study.  Table 5 illustrates the precision of this study for a binary 
efficacy endpoint assuming a total of approximately 20-30 patients per cohort enrolled 
into this study, receiving emicizumab, and undergoing a protocol-specified minor 
surgery.
During the study, a re-assessment of the initially specified sample size was allowed but 
never needed to be performed.  
Table 1
Precision of the Study for a Binary Efficacy Endpoint (Illustrative 
Purposes)
a This is the assumed observed count of events of interest.
b Calculated using exact test procedure based on the Clopper-Pearson method (Clopper 
et al. 1934).
2.4
ANALYSIS TIMING
Only one analysis is planned at the end of the study after the database is cleaned and 
locked.


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3.
STUDY CONDUCT
Patients are considered to be enrolled into the study once they sign the informed 
consent form. Safety follow-up will be conducted after the informed consent form is 
signed.
3.1
RANDOMIZATION ISSUES
Not applicable.
3.2
INDEPENDENT REVIEW FACILITY
Not applicable.
3.3
DATA MONITORING
Not applicable.
4.
STATISTICAL METHODS
This is an open-label, single-arm, multicenter study.  No statistical hypothesis will be 
tested.
Only descriptive summaries will be presented for data collected in this study and the 
data will be summarized separately for the inhibitor and non-inhibitor cohorts.  
Continuous variables will be summarized using means, standard deviations, medians, 
and ranges; categorical variables will be summarized using proportions, and 95% 
confidence intervals, where applicable.  In the event that sample sizes are too small or 
data too sparse given the early termination of this study, summaries will be relegated to 
simple listings.
4.1
ANALYSIS POPULATIONS
4.1.1
All Enrolled Population
All patients who sign informed consent.
4.1.2
Efficacy Analysis Population
All enrolled patients who receive emicizumab and undergo a minor surgery.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who enroll, discontinue, or complete the study will be analyzed
separately for each inhibitor and non-inhibitor cohort and will be summarized overall and 
by type of surgery for the all enrolled population.  Reasons for premature study 
withdrawal will be listed and summarized.  Enrollment and major protocol deviations will 
be listed and evaluated for their potential effects on the interpretation of study results.


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4.3
ANALYSIS OF DEMOGRAPHICS, BASELINE 
CHARACTERISTICS, AND MEDICAL HISTORY
Demographic, baseline characteristics, and medical history will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented
separately for the inhibitor and non-inhibitor cohorts and will be displayed overall and by 
type of surgery for the all enrolled population.
4.4
EFFICACY ANALYSIS
Descriptive statistics along with 95% Clopper Pearson confidence intervals will be used 
to provide point estimates and precision related to efficacy outcomes. All efficacy 
analyses will be performed on the efficacy analysis population.
4.4.1
Primary Efficacy Endpoint
The first 2 primary endpoints listed under section 2.2.1 are composite endpoints from 
data points collected on the “On-study Targeted Surgery and Procedure Log” CRF page: 
“Intraoperative and/or postoperative blood loss increased over expectation for the non-
hemophilic patient determined at the time of discharge” and “Did the patient use any 
BPA/FVIII for the surgery before the discharge?”.
Primary endpoint 1 is met when response to “Intraoperative and/or postoperative blood 
loss increased over expectation for the non-hemophilic patient determined at the time of 
discharge” is “0 to <10%” or “10% to < 25%” AND response to “Did the patient use any 
BPA/FVIII for the surgery before the discharge?” is “No”.
Primary endpoint 2 is met when response to “Intraoperative and/or postoperative blood 
loss increased over expectation for the non-hemophilic patient determined at the time of 
discharge” is “25% to <50%” or “>=50%” AND response to “Did the patient use any 
BPA/FVIII for the surgery before the discharge?” is “Yes”.
For the purposes of summarizing the dose and schedule of BPA use per bleed as it 
relates to primary endpoint 2, BPAs/FVIII used for excessive bleeding at surgical sites 
are reported by the investigator and captured in “Concomitant Medications” CRF.
Primary endpoint 3 is also a composite endpoint based on information collected in 
“Bleed and Medication Diary” and “Concomitant Medications” CRFs.
For primary endpoint 3, bleeding information is self-reported by patients (or patient’s 
legally authorized representative) on the “Bleed and Medication Diary” and transcribed 
into the “Bleed and Medication Diary” CRF page. BPAs/FVIII used to treat excessive 
bleeding are also self-reported by patients if they are administered by the patients. 
BPAs/FVIII administered by the investigators to treat the bleeding will be reported on 
the “Concomitant Medications” CRF page.


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4.4.2
Secondary Efficacy Endpoints
Not applicable.
4.4.3
Exploratory Efficacy Endpoints
As an exploratory efficacy endpoint, the percentage of patients with zero bleeds 
(regardless of treated or not) after being discharged from surgery will be summarized 
separately for the inhibitor and non-inhibitor cohorts and will be displayed overall and by 
surgery type.   
4.4.4
Sensitivity Analyses
A descriptive summary of additional post-surgery bleeds requiring BPA/FVIII use beyond 
the first treated bleed will be presented without any formal statistical testing in order to 
observe how additional treated bleeds after discharge from the surgery were distributed 
in the study. Specifically, the percentage of patients with 0 bleeds, 1 bleed, 2 bleeds, 3 
bleeds and >3 bleeds will be summarized separately for each of the inhibitor and non-
inhibitor cohort and will be displayed overall and by surgery type.
4.4.5
Subgroup Analyses
Not applicable.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Mean and median emicizumab concentrations at the beginning of the surgery will be 
summarized separately for each of the inhibitor and non-inhibitor cohorts and will be 
displayed overall and by surgery type.
4.6
SAFETY ANALYSES
Safety will be assessed through descriptive summaries of safety endpoints, adverse 
events, and vital signs.
4.6.1
Exposure of Study Medication
Information on emicizumab administration after discharge from surgery will be collected 
on the Bleed and Medication Diary and summarized by presenting the percentage of 
patients who took their emicizumab as prescribed at each visit as well as the 
mean/median dose taken. These analyses will be performed separately for the inhibitor 
and non-inhibitor cohorts and will be displayed overall and by surgery type.
4.6.2
Adverse Events
All adverse events occurring after informed consent is obtained will be coded.  
Treatment emergent events will be summarized by severity, and tabulated by body 
system and preferred term for individual events within each system organ class.  In 
addition, serious adverse events, adverse events of special interest (AESIs), and 
adverse events leading to study discontinuation will be summarized.  All serious adverse 
events and deaths will be listed.


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Non-treatment-emergent events will be identified through two entries on the “Adverse 
Events” CRF page: response to “Action taken with emicizumab due to SAE/AE” is “Not 
applicable” AND response to “Date of most recent dose of Emicizumab prior to AE 
onset” is missing. These events will not be included in the treatment emergent safety 
analysis, but will be included in Adverse Event listing with an appropriate flag.
The safety endpoint, “Percentage of patients with surgical complications requiring 
hospitalization or return to surgery”, is a composite endpoint. Surgical complications are
entered as adverse events on the “Adverse Events” CRF page with “Other suspected 
causes” marked as “Study Surgery or Procedure”. This endpoint is met when response 
to "It required or prolonged inpatient hospitalization” is checked OR response to 
response to “Was procedure/surgery performed?” is “Yes”.
4.6.3
Laboratory Data
For clinical laboratory data which are collected from local laboratories, summary 
statistics will be presented.
4.6.4
Vital Signs
Vital signs will be summarized using mean change from baseline tables over time.  
Measurements consist of heart and respiratory rate, temperature, and systolic and 
diastolic blood pressures.
4.7
MISSING DATA
Incomplete dates for AEs, concomitant medication and laboratory data are handled as 
described in the Roche data analysis standards (GDSR). 
Diary cards are used to collect bleeding information post study surgery, either related or 
unrelated to the study surgery, as well as BPA//FVIII use for any bleeds. Missing 
information on bleeds are handled as follows:

If, on a given day, the treatment time is partial and the bleed time complete, the 
partial time is assumed to be the same as the complete time. In cases of 
multiple events per day, the last complete time is used.

All bleeds with an anatomical location in a joint are considered joint bleeds

All bleeds with missing cause are included as spontaneous bleeds
4.8
INTERIM ANALYSES
Not applicable.


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5.
REFERENCES
Clopper, C.; Pearson, E. S. "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika 1934. 26: 404–413. doi:10.1093/biomet/26.4.404
In-text citation: (Clopper et al. 1934)


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE IV, MULTICENTER, SINGLE-ARM, OPEN-LABEL 
STUDY OF EMICIZUMAB PROPHYLAXIS IN PATIENTS WITH 
HEMOPHILIA A WITH OR WITHOUT INHIBITORS
UNDERGOING MINOR SURGICAL PROCEDURES
PROTOCOL NUMBER:
ML39791
VERSION NUMBER:
4
EUDRACT NUMBER:
Not applicable
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (HEMLIBRA)
PHASE:
Phase IV
INDICATION:
Hemophilia A with or without inhibitors
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety and efficacy of emicizumab prophylaxis in patients with 
hemophilia A (PwHA; with or without inhibitors) that are undergoing minor surgical procedures
without additional prophylaxis with bypassing agents (BPA; for patients with inhibitors) or 
factor VIII (FVIII; for patients without inhibitors).  All endpoints will be measured and 
described separately for the inhibitor and non-inhibitor cohorts.  Pharmacokinetics will also be 
evaluated as exploratory objectives of the study.  For the purposes of this protocol, study 
treatment is not intended to imply that the Sponsor is providing the study drug; rather, 
emicizumab is required for all patients during the study per the inclusion and exclusion criteria.
Note: Throughout the protocol, all references to BPA will be specific for patients with 
inhibitors and all references to FVIII will be specific for patients without inhibitors, unless 
otherwise noted.  


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Primary Objective
Corresponding Endpoints
To evaluate the 
efficacy of 
emicizumab in 
preventing surgery-
related bleeding in 
PwHA with and 
without inhibitors 
undergoing minor 
surgical 
procedures
Efficacy will be measured by:
Percentage of patients without excessive bleeding at surgical sites and 
did not require BPA/FVIII a use for bleeding related to the surgery, from 
the start of the surgery until the patient is discharged from the surgery.  
For the purposes of this endpoint, the absence of excessive bleeding 
and BPA/FVIII a use will be measured by a good to excellent rating 
using the hemostatic efficacy scale (ISTH SSC recommendations) and 
will be determined upon patient discharge by the healthcare 
professional performing the procedure.
Percentage of patients with excessive bleeding at surgical sites and 
required BPA/FVIII a use for bleeding related to the surgery, from the 
start of the surgery until the patient is discharged from the surgery. 
Bleeding and BPA/FVIII a use will be assessed using the hemostatic 
efficacy scale and measured by a rating of fair to poor, and will be 
determined upon patient discharge by the healthcare professional 
performing the procedure.
Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed for excessive 
bleeding at surgical sites will be summarized.
Percentage of patients who, after being discharged from surgery, 
experienced bleeds that were either related or unrelated to the surgery 
and also required BPA/FVIII a use 
– Dose and schedule (including number of doses, total dose, and 
frequency) of BPAs/FVIII a used per bleed will be summarized 
Safety
Incidence and severity of all adverse events
– Incidence and severity of serious adverse events
– Incidence and severity of adverse events of special interest
Percentage of patients with surgical complications requiring 
hospitalization or return to surgery 
Percentage of patients who need blood/blood product transfusions (i.e., 
platelets, plasma, etc.) during surgery
Exploratory 
Objective
Exploratory Endpoints
To evaluate 
potential 
relationships 
between drug 
exposure and the 
efficacy and 
safety of 
emicizumab
Selected efficacy and safety endpoints will be descriptively 
summarized by plasma emicizumab concentration levels
To describe the 
incidence of
spontaneous 
bleeding in the 
post-operative 
period.
Percentage of patients with zero bleeds (regardless of treated or not)
after being discharged from surgery
BPAbypassing agent;ISTH SSCInternational Society on Thrombosis and Haemostasis
Scientific and Standardization Committee; FVIII factor VIII; PwHApatients with 
Hemophilia A.
a
BPA use is specific for patients with inhibitors and FVIII use is specific for patients 
without inhibitors.


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Study Design
Description of Study
This Phase IV, multicenter study will evaluate whether PwHA (with or without inhibitors)
receiving emicizumab prophylaxis can safely undergo minor surgical procedures without 
additional prophylaxis with BPA or FVIII (for patients with or without inhibitors, 
respectively).  The use of BPA/FVIII for excessive surgical bleeding will then be measured 
intra-operatively and post-operatively.  In addition, surgical complications from bleeding and 
blood product transfusions will be evaluated.  This study will assess emicizumab prophylaxis 
alone to control surgery-related bleeding in PwHA with or without inhibitors undergoing minor 
surgical procedures.  Each cohort (PwHA with inhibitors and PwHA without inhibitors) will 
be assessed separately.
Patients can be screened and enrolled up to 60 days prior to surgery.  They must have received 
a minimum of four loading doses of emicizumab prior to their surgical procedure, been adherent 
with emicizumab prophylaxis, and must not have received BPA/FVIII for at least 24 hours prior 
to surgery.  In addition, they must plan to continue emicizumab prophylaxis for at least 1 month 
after the surgical procedure.  Follow-up will be conducted by phone on Study Days 2 and 3 
(approximately 24 and 48 hours post-operation) to record any bypassing agent use or FVIII use 
and surgical bleeding within the first 48 hours, as well as treatment of any other bleeding 
unrelated to surgery.  BPA/FVIII should only be used for treatment of bleeding.  Follow-up will 
be conducted in person on Study Day 8 ( 2 days) to examine the patient for any post-surgical 
complications and to collect information on treatment of bleeding.  Lastly, follow-up will be 
conducted by phone on Study Day 28 ( 2 days) to record any surgical complications, bleeds, 
and/or use of BPA/FVIII.
Blood samples will also be collected in this study for observational purposes and will not be 
used to determine eligibility or treatment decisions.  Samples will be used to evaluate 
emicizumab concentration (PK) prior to surgery.
Safety follow-up will be conducted after signing the informed consent form.  Patients will be 
monitored for adverse events to evaluate the safety of emicizumab alone or in combination with 
BPA/FVIII.
Periodic Safety Review
In order to ensure that patients enrolled in this study are safely undergoing minor surgical 
procedures without additional pre-operative prophylaxis with BPAs/FVIII, periodic safety 
assessments are planned.  The study team will perform periodic data review of all available 
data.
Number of Patients
Approximately 4060 PwHA (approximately 2030 patients with inhibitors and 2030 
patients without inhibitors) will be enrolled and undergo a minor surgical procedure at 
approximately 20 sites in the United States.  An effort will be made to ensure enrollment 
between multiple surgery types.  A maximum of 9 patients in each cohort will be enrolled in any
given surgery type.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent/Assent Form

Any age (newborn and older) 

Ability to comply with the study protocol, in the investigator’s judgment

Diagnosis of hemophilia A and current or history of an inhibitor (Bethesda 
titer 0.6 Bethesda units) and currently using BPA for breakthrough bleeds (for PwHA 
with inhibitors)

Diagnosis of hemophilia A and no history of an inhibitor (Bethesda titer 0.6 Bethesda 
units), or a history of an inhibitor that has been tolerized for >5 years and using FVIII for 
breakthrough bleeds (for PwHA without inhibitors)


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
Plan to receive at least 4 loading doses of emicizumab and been adherent to emicizumab 
prophylaxis by the time of the surgery

Undergoing minor surgery within 60 days of study enrollment.  Other minor surgical 
procedures could be included upon consultation and approval of Medical Monitor, but 
examples include (see Appendix 3 for a full list):
–
Central venous catheter insertion/removal/replacement 
–
Simple dental extractions
–
Colonoscopy, cystoscopy, or endoscopy with biopsy
–
Excisional skin biopsy

Must plan to continue emicizumab prophylaxis for at least 1 month after surgery

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 during the study period
–
A woman is considered to be of childbearing potential if she is post-menarchal, has not 
reached a postmenopausal state (12 continuous months 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 contraceptive, 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 trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post-ovulation 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:

Diagnosis of a bleeding disorder other than hemophilia A

Tolerized to Factor VIII products (for PwHA with inhibitors)

Using FVIII products to treat breakthrough bleeds(for PwHA with inhibitors)

Tolerized to FVIII products for <5 years (for PwHA without inhibitors)

Treatment with bypassing agents or FVIII within 24 hours prior to surgical procedure

Undergoing a major surgical procedure

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 current signs of thromboembolic disease

Other conditions (e.g., certain autoimmune diseases, including, but not limited to diseases 
such as systemic lupus erythematosus, inflammatory bowel disease, and antiphospholipid 
syndrome) that may increase the risk of bleeding or thrombosis

Patients who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous 
medical or family history of TMA), in the investigator’s judgment

Would refuse treatment with blood or blood products, if necessary.

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

Pregnant or lactating, or intending to become pregnant during the study
–
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days before Study Day 1


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
Treatment with any of the following:
–
An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives 
of last drug administration before Study Day 1
–
A non-hemophilia-related investigational drug within the last 30 days or 5 half-lives before 
Study Day 1, whichever is longer
–
An investigational drug concurrently

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 enrollment
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  The end of a patient’s participation in the study is 
expected to occur after Study Day 28.
Length of Study
The total length of the study, from enrollment of the first patient to the end of the study (last 
patient last visit), is expected to be approximately 2430 months.
Emicizumab
If a patient is prescribed emicizumab for prophylaxis, emicizumab is administered 3 mg/kg/week 
subcutaneously for the first 4 weeks when initiating treatment (loading doses), followed by 
1.5 mg/kg/week subcutaneously or by any other approved maintenance regimen.  Patients must 
have received all loading doses and been adherent to emicizumab prophylaxis prior to surgery 
and plan to continue emicizumab for a minimum of 1 month after surgery.   For the purposes of 
this protocol, study treatment is not intended to imply that the Sponsor is providing the study 
drug; rather, emicizumab is required for all patients during the study per the inclusion and 
exclusion criteria.
Statistical Methods
Analysis
This is an open-label, single-arm, multicenter study to evaluate emicizumab prophylaxis in 
PwHA without inhibitors and PwHA with inhibitors, who are undergoing minor surgical 
procedures.  Each cohort will be evaluated separately.  No statistical hypothesis will be tested.  
There are three populations that will be included in the analyses, which are defined as follows: 

All Enrolled Population: All patients who sign informed consent.

Safety Analysis Population: All enrolled patients who receive emicizumab

Efficacy Analysis Population: All enrolled patients who receive emicizumab and undergo a 
minor surgery.
Only descriptive summaries will be presented for data collected in this study.  Continuous 
variables will be summarized using means, standard deviations, medians, and ranges; 
categorical variables will be summarized using proportions, and 95% confidence intervals where 
applicable, as appropriate.  Additional details of the analyses will be presented in the statistical 
analysis plan.
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 inhibitor patients with a planned minor surgery available for 
participation in this study.  Table 5 illustrates the precision of this study for a binary efficacy 
endpoint assuming a total of approximately 2030 patients per cohort enrolled into this study, 
received emicizumab, and underwent a protocol-specified minor surgery.
During the study, a re-assessment of the initially specified sample size may be performed.  This 
may result in an increase in sample size, if necessary, to expand the safety database.


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Appendix 2
Schedule of Activities
Study Day
(Window)
Screening a
Surgery b
Post-Operative 
Follow-Up 
Call c
Post-Operative 
Follow-Up Call d
Post-Operative 
Follow-Up Visit e
Post-Operative 
Follow-Up Call/
Study 
Completion f
60 to 1
1
2
3
8
(2 days)
28
(2 days)
Informed consent g
x
Demographic data
x
Medical history and baseline 
conditions
x
Vital signs
x
x
x
Weight h
x
x
Limited physical examination i,j
x
xk
x
Hematology l
x
Chemistry m
x
Serum pregnancy test
x
Plasma pharmacokinetic sample
xn
Concomitant medications o
x
x
x
x
x
x
Adverse events p
x
x
x
x
x
x
Bleed and Medication Diary q
x
x
x
x
x


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a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 60 days prior to Study Day 1 may be 
used and do not need to be repeated for enrollment.  Patients can be re-consented if surgery is delayed or if they lose and regain eligibility. 
b All assessments should be completed within 24 hours before surgery except adverse event assessment (peri-operative) and bleed/medication 
diary.
c The clinician is to call the patient on Study Day 2, which is post-operative Day 1 (approximately 24 hours post-operation), for follow-up.  The call 
can be made up to 2 days after Study Day 2 if it falls on a weekend or holiday.  This assumes that the patient was discharged and did not remain 
inpatient (e.g., for observation).
d The clinician is to call the patient on Study Day 3, which is post-operative Day 2 (approximately 48 hours post-operation), for follow-up.  The call 
can be made up to 2 days after Study Day 3 if it falls on a weekend or holiday.  This assumes that the patient was discharged and did not remain 
inpatient (e.g., for observation).
e The patient is to return to the clinic on Study Day 8 (2 days) for follow-up.
f
The clinician is to call the patient on Study Day 28 (2 days) for follow-up.  After this call, the patient will have completed the study.
g Informed consent must be documented before any study-specific (nonstandard of care) screening procedure is performed, and may be 
obtained up to 60 days before enrollment in the study.  Consent date will be considered the date of enrollment. 
h Weight is used to calculate emicizumab dose (based on weight).
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, respiratory, gastrointestinal, and dermatologic systems.  
Focused examination of the musculoskeletal, genitourinary, and neurological systems should be performed as related to the surgical procedure.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
j
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
k Site must document that patient was clinically stable and not actively bleeding prior to discharge.
l
Hematology includes complete blood count with differential (i.e., neutrophils, hemoglobin, platelet count).
m Chemistry panel includes 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, and 
creatine phosphokinase).
n PK sample must be obtained at the study site 24 hours before surgery.
o Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 28 days prior to surgery until Study Day 28.


Emicizumab—Genentech, Inc.
20/Statistical Analysis Plan ML39791
p After informed consent has been obtained, all adverse events will be reported until Study Day 28.  After this period, adverse events should be 
reported per routine reporting requirements.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to prior study drug treatment. The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until 
a final outcome can be reported.
q Patients (or patient’s legally authorized representative) will complete the bleed/medication diary and will include start date and time, reason, type, 
location of each bleed, as well as start date and time, reason, type, and dose of bypassing agent, if any, excluding emicizumab.