Conditions: Hemophilia A
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
This non-randomized, multicenter, open-label, Phase III clinical study will evaluate the efficacy, safety, and pharmacokinetics of emicizumab administered subcutaneously initially once weekly (QW) in pediatric participants with hemophilia A with FVIII inhibitors. This study will open two additional non-randomized cohorts to investigate once every 2 weeks (Q2W) and once every 4 weeks (Q4W) regimens in pediatric participants.

Detailed description:

Arms:
arm 1: Participants will receive emicizumab at a loading dose of 3 milligrams per kilogram (mg/kg) QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg QW SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first. arm 2: Participants will receive emicizumab at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 3 mg/kg every 2 weeks (Q2W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first. arm 3: Participants will receive emicizumab at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks (Q4W) SC for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria set forth in the protocol, whichever occurs first.

Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: Emicizumab will be administered as per the schedule specified in the respective arm.

Protocol document:
Prot_000.pdf: 
 
 
Official Title:  
 
A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO 
EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN 
HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS 
NCT Number: 
NCT02795767 
Document: 
Version & Date:  
PROTOCOL 
Version 4: 01 September 2017 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
F. Hoffmann-La Roche Ltd of Basel, Switzerland, and Chugai Pharmaceutical Co. Ltd.* of Tokyo, Japan, will 
act as co-sponsors of this global study. However, it may be implemented in individual countries by Roche’s 
local affiliates, including Genentech, Inc. in the United States, or Chugai Pharmaceutical Co. Ltd.* in South 
Korea, Taiwan, and Japan. The information contained in this document, especially any unpublished data, is 
the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence 
as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics 
Committee or Institutional Review Board. It is understood that this information will not be disclosed to others 
without written authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered.
*Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan. The specific details of the 
legal/regulatory entity within the relevant country are provided within the clinical trial agreement with the 
Investigator/Institution and the Clinical Trial Application with the Competent Authority.
Emicizumab—F. Hoffmann-La Roche Ltd
Protocol BH29992, Version 4
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III 
CLINICAL TRIAL TO EVALUATE THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF 
SUBCUTANEOUS ADMINISTRATION OF 
EMICIZUMAB IN HEMOPHILIA A PEDIATRIC 
PATIENTS WITH INHIBITORS
PROTOCOL NUMBER:
BH29992
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000073-21
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd and
Chugai Pharmaceutical Co. Ltd.
DATE FINAL:
20 January 2016
DATES AMENDMED:
Version 2:  12 July 2016
Version 3:  8 December 2016
Version 4:  See electronic date stamp below.
 
01-Sep-2017 18:27:12
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Emicizumab—F. Hoffmann-La Roche Ltd
2/Protocol BH29992, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol BH29992 has been primarily amended to evaluate additional emicizumab 
dosing schedules and to update safety information. Changes to the protocol, along with 
a rationale for each change, are summarized below:

Two cohorts (designated as Cohorts B and C; patients 211 years of age) have 
been added to the study to investigate additional less frequent emicizumab dosing 
schedules (every 2 weeks [Q2W] and every 4 weeks [Q4W]), which would allow the 
option to select a preferred schedule, while still delivering the same cumulative dose
(Sections 1.3, 3.3.1, 3.3.1.1, and 6.9.1.1). The addition of these cohorts is reflected 
throughout the protocol (Sections 16).

Recent safety findings of thrombotic microangiopathy (TMA) observed in 
Study BH29884 have been added (Sections 1.2, 3.1, and 5.1.1.4).

Clarification regarding laboratory monitoring of coagulation status after any 
bypassing agent use has been added.  Laboratory monitoring is to be done after 
any use of a bypassing agent, and not only after use of a bypassing agent to treat 
breakthrough bleeds (Section 5.1.2).

An exclusion criterion has been added for patients who are unable to or unwilling to 
receive blood or blood products (or any standard-of-care treatment for a 
life-threatening condition). This criterion has been added in context of a fatal 
outcome from a life-threatening rectal hemorrhage in Study BH29884 in a patient 
who declined receipt of blood and blood products (Sections 4.3 and 5.1.1.4).

The up-titration schema has been modified with removal of the 2.25-mg/kg once 
weekly (QW) dosing level.  This is based on an interim data review characterizing 
exposure at 1.5 mg/kg QW in patients 212 years of age to be similar to 
adolescent/adult patients (Section 4.5.2). As such, the up-titration dose will be the 
same used in adolescent/adult patients (3 mg/kg QW).

A new safety risk associated with emicizumab has been added as follows:
Life-threatening bleeding due to unreliable standard coagulation tests and 
inhibitors 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 are impacted by the presence of emicizumab and, therefore, are not 
reflecting the patient’s underlying hemostatic status accurately (Section 5.1.1.5).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

Event reporting for hospitalization has been clarified (Section 5.3.5.11).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).


Emicizumab—F. Hoffmann-La Roche Ltd
3/Protocol BH29992, Version 4
Additional minor changes have been made to improve clarity, consistency, and 
alignment with the other emicizumab protocols.  Substantive new information appears in 
italics.  This amendment represents cumulative changes to the original protocol.


Emicizumab—F. Hoffmann-La Roche Ltd
4/Protocol BH29992, Version 4
PROTOCOL AMENDMENT, VERSION 4:
SUMMARY OF CHANGES
PROTOCOL TITLE
The protocol title has been revised as follows:
A SINGLE-ARM, MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL 
TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
ONCE WEEKLY SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN 
HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable.
SECTION 1.2:  BACKGROUND ON EMICIZUMAB
Clinical Studies
… Two severe adverse events were observed:  appendicitis and mesenteric hematoma.  
Both events were considered to be serious adverse events and not related to 
emicizumab administration. In the Phase I/II Studies ACE001JP and ACE002JP, no 
thrombotic microangiopathy (TMA), thromboembolic adverse events, or systemic 
hypersensitivity reactions have been reported in any dosing cohort thus far, including 
those patients who required concomitant FVIII concentrates or bypassing agent therapy
to treat bleeds.
In the ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia 
A with FVIII inhibitors), as of November April 20176, TMA thrombotic 
microangiopathy (TMA; atypical hemolytic uremic syndrome [aHUS]) was observed in 32
patients receiving emicizumab and bypassing agents; and 32 cases of serious 
thromboembolic events were observed in 2 patients receiving emicizumab and 
bypassing agents. For more details refer to Sections 5.1.1.3 and 5.1.1.4.
SECTION 1.3:  STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
… In these studies, no thromboembolic or systemic hypersensitivity adverse events 
were observed; however, in the ongoing Phase III Study BH29884,32 cases of TMA 
(aHUS) and 2 3 serious thromboembolic events were observed in patients on 
emicizumab who received bypassing agents for the treatment of breakthrough bleeds.  
Three Four out of these 54 patients have fully recovered and the fourth patient’s 
condition has improved, and 1 patient died due to severe rectal bleeding (see 
Sections 5.1.1.3 and 5.1.1.4).
This current study is designed to evaluate the efficacy, safety, and pharmacokinetics of 
emicizumab administered subcutaneously initially once weekly (QW) in pediatric 
patients with hemophilia A with FVIII inhibitors.  Following review of data in adult 
and adolescent patients with hemophilia A from two ongoing Phase III studies 


Emicizumab—F. Hoffmann-La Roche Ltd
5/Protocol BH29992, Version 4
evaluating emicizumab at 3 mg/kg every 2 weeks (Q2W; BH30071) and 6 mg/kg every 
4 weeks (Q4W; BO39182), this study will open two additional non-randomized cohorts 
to investigate Q2W and Q4W regimens in pediatric patients (see Section 3.3.1).
SECTION 2:  OBJECTIVES AND ENDPOINTS
The objectives of the study are to investigate (with no formal hypothesis testing) the 
efficacy, safety, and pharmacokinetics of once weekly SC administration of emicizumab 
administered at 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W in pediatric patients 
with hemophilia A and FVIII inhibitors who are currently receiving treatment with 
bypassing agents.  A total of approximately 80 patients are planned:  approximately 
60 patients in Cohort A (1.5 mg/kg QW) and approximately 10 patients each in 
Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W).  At least 20 pPatients younger 
than 12 years old of age and up to 60 patients are planned for enrollment, with allowance 
of patients 1217 years of age who weigh 40 kg at the time of informed consent to 
further evaluate dosing of emicizumab in patients 40 kg.  Of note, enrollment in 
Cohort A may be left open exclusively for patients 2 years of age until approximately 
5 such patients have been enrolled.
SECTION 2.1:  EFFICACY OBJECTIVES
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as 
appropriate.
The efficacy objectives for this study are as follows: 

To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds 
over time (i.e., bleed rate) *

To evaluate the efficacy in reducing the number of bleeds over time compared with 
the patient's historical bleed rate (intra-patient comparison, Cohort A only, as 
patients enrolled in Cohorts B and C will not have previously participated in the 
non-interventional study) *

To characterize the efficacy of up-titration on an both an intra-patient and 
population level, also based on the basis of the number of bleeds over time *

To evaluate the HRQoL of children 817 years of age according to 
Haemo-QoL-Short Form (SF) (completed by patients)

To evaluate proxy-reported HRQoL and aspects of caregiver burden using the 
Adapted InhibQoL Including Aspects of Caregiver Burden questionnaire for all 
children (completed by caregivers)

To assess the number of days missed from daycare/school and days hospitalized
* Analyses will be performed for:  treated bleeds, all bleeds, treated spontaneous bleeds, 
treated joint bleeds, and treated target joint bleeds.  


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6/Protocol BH29992, Version 4
SECTION 2.2:  SAFETY OBJECTIVE
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as 
appropriate.
SECTION 2.3:  PHARMACOKINETIC OBJECTIVE
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W).
The PK objective for this study is to characterize the exposure (Ctrough) of emicizumab in 
patients receiving 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W prior to drug 
administration on Day 1 and at the following timepoints: …
SECTION 3.1:  DESCRIPTION OF THE STUDY
This single-arm, non-randomized, multicenter, open-label, Phase III clinical study will 
enroll children with hemophilia A who have inhibitors against FVIII.  Children with 
hemophilia A and documented historical FVIII inhibitor titer (5 BU) must currently be 
receiving treatment with bypassing agents.  At least 2040 patients younger than 
12 years of age and up to approximately 8060 patients are planned for enrollment, with 
allowance of patients 1217 years of age who weigh 40 kg at the time of informed 
consent.  Patients will receive weekly SC doses of emicizumab at 1.5 mg/kg QW 
(Cohort A) for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation 
from the study due to any cause, or other criteria set forth in the protocol, whichever 
occurs first (see Figure 1).  After 52 weeks of treatment, an individual patient who 
continues to derive clinical benefit may continue receiving prophylactic emicizumab as 
part of this study or a future separate emicizumab extension study.
Because of the uncertainty of the dosing regimen needed in patients 12 years of age or 
40 kg to achieve similar exposure as in adults and adolescents, this study will first 
evaluate the appropriate dosing regimen in children by starting with the same weekly
dosing regimen (1.5 mg/kg QW) being evaluated in the Phase III study (BH29884) in 
adult/adolescent patients with hemophilia A with inhibitors (see Section 3.3.1 for details). 
Emicizumab will be administered with a weekly loading dose of 3.0 mg/kg QW for the 
first 4 weeks (Day 1 of each week) followed by a maintenance dose of 1.5 mg/kg/week 
(Day 1 of each week) QW (Cohort A) for the remainder of the treatment period.  During 
the 52-week treatment period, individual patients may have their dose up-titrated if they 
experience suboptimal bleeding control on emicizumab .  Investigators will monitor 
patients regularly with the guidance of an up-titration algorithm (see Section 4.5.2). 
Should patients meet protocol-defined criteria for efficacy-guided up-titration, the 
investigator will contact the Medical Monitor to initiate a discussion about possible 
up-titration (see Section 4.5.2).  
In a first interim data review, the appropriateness of the initial dosing regimen will be 
evaluated (maintenance dose of 1.5 mg/kg QW/week) after the first 35 patients (2 to 
12 years of age) have been dosed for a minimum of 12 weeks. …


Emicizumab—F. Hoffmann-La Roche Ltd
7/Protocol BH29992, Version 4
Furthermore, should patient recruitment be faster than anticipated, enrollment will be 
placed on a temporary hold following the first 20 patients until the JMC releases its 
recommendations on the appropriateness of the maintenance dose (Cohort A).  After 
the JMC recommendations are released following both interim data reviews, the study 
will continue to enroll in Cohort A up to a maximum of approximately 60 patients.
Once 1) the exposure at 1.5 mg/kg QW has been characterized in this pediatric 
population; 2) Cohort A is fully enrolled; and 3) review of data in adults and 
adolescents from two ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W 
(BH30071) and 6 mg/kg Q4W (BO39182) identifies no safety concerns, this study will 
open two additional non-randomized cohorts to investigate Q2W and Q4W regimens in 
pediatric patients.  Recruitment to Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg 
Q4W) will occur in parallel with alternate cohort allocation via IxRS, for a total of 
approximately 10 patients per cohort.  Of note, enrollment to Cohorts B and C will be 
limited to patients 211 years of age.  Emicizumab will be administered with a loading 
dose of 3 mg/kg QW for the first 4 weeks followed by a maintenance dose of 3 mg/kg 
Q2W (Cohort B) and 6mg/kg Q4W (Cohort C) for a minimum of 52 weeks, or until 
unacceptable toxicity, discontinuation from the study due to any cause, or other criteria 
set forth in the protocol, whichever occurs first (see Figure 1).  During the 52-week 
treatment period, individual patients may have their dose up-titrated if they experience 
suboptimal bleeding control on emicizumab.
The entire study will enroll up to approximately 80 patients with allowance for 
additional patients 2 years of age in Cohort A.
A patient who fulfills the inclusion and exclusion criteria should be enrolled at the Week 1 
visit.  Prophylactic use of bypassing agents should be discontinued by the timethe day 
before the first dose of emicizumab is given. 
FIGURE 1:  Study Schema
Figure 1 has been revised to reflect changes made to the study design.
The primary analysis for all cohorts will be performed 52 weeks after the last all patients
in the primary cohort population of Cohort A has have been enrolled or withdrawn 
prematurely, whichever occurs first.  The primary population of cCohort A consists of all 
patients enrolled prior to the close of enrollment for patients 2 years of age (up to 
approximately 60 patients) and is used to define the timing of the primary analysis of 
Cohorts A, B, and C.  If no patients 2 years of age are included in the primary 
population of cCohort A, the primary analysis will still occur at the specified time; 
however, enrollment in the study to Cohort A may be left open exclusively for patients 
2 years of age in order to enroll up to approximately 5 such patients.  Note that these 
patients will be included in the primary analysis of cCohort A regardless of their 
follow-up time. Additionally, all available data from patients enrolled in Cohorts B and 
C (efficacy period approximately 6 months) will be included in the primary analysis of 


Emicizumab—F. Hoffmann-La Roche Ltd
8/Protocol BH29992, Version 4
Cohort A. Additionally, the protocol may be amended at a future date in order to study 
alternative dosing regimens (e.g., every 2 weeks, every 4 weeks) in pediatric patients.
During the study, caregivers will be asked to enter any individual bleeds, 
hemophilia-related medications, and emicizumab treatments that occur on an electronic, 
handheld device.  Entries should be made at least weekly to document emicizumab 
dosing, or and also at any time a bleed occurs or a hemophilia medication, including 
emicizumab, is administered. …
Emicizumab is intended in this study for prophylactic use only (i.e., not to treat bleeds 
that have already occurred).  Therefore, in this study all patients maywill continue to 
receive episodic treatment for breakthrough bleeds as needed. …  
… However, in the ongoing Phase III Study BH29884 (adolescent and adult patients with 
hemophilia A with FVIII inhibitors), 32 events of TMA and 32 serious thromboembolic 
events were observed in patients who concomitantly used repeated doses of aPCC
100 U/kg/day of aPCC on average for 24 hours for the treatment of breakthrough 
bleeds (see Sections 1.2, 1.3, 5.1.1.3, and 5.1.1.4). …
… Pediatric patients who are enrolled in the non-interventional Study BH29768 are 
eligible to enroll in this study, as long as they meet the inclusion and exclusion criteria 
and are able to enroll at a participating site while the study is open for enrollment. All 
patients who participated in the non-interventional study will be enrolled in Cohort A.
SECTION 3.2:  END OF STUDY AND LENGTH OF STUDY
LENGTH OF STUDY
The length of the entire study from screening of the first patient to the last patient 
completing 52 weeks in the study and/or the end of study follow-up visit (24 weeks after 
discontinuing emicizumab) will be approximately 128152 weeks.
END OF STUDY
The primary analysis will take place at the same time for Cohorts A, B, and C.  It will 
occur after all patients in the primary population of Cohort A have completed 52 weeks 
of treatment, or have withdrawn prematurely, whichever occurs first.  All data from 
patients enrolled in Cohorts B and C will be included regardless of follow-up time.
SECTION 3.3:  RATIONALE FOR STUDY DESIGN
… The Sponsor has chosen a similar approach utilizing a single-arm, non-randomized,
descriptive study to investigate the pharmacokinetics, safety, and efficacy of emicizumab 
in pediatric hemophilia A patients with FVIII inhibitors. …
… The proposed study, BH29992, will therefore evaluate the use of prophylactic 
emicizumab, in children with inhibitors to FVIII previously treated with bypassing agents 
in a non-randomized, single-arm, multicenter, open-label study.  


Emicizumab—F. Hoffmann-La Roche Ltd
9/Protocol BH29992, Version 4
SECTION 3.3.1:  Rationale for Emicizumab Dose and Schedule
Once weekly lLoading doses of 3 mg/kg QW emicizumab for 4 weeks will be, followed 
by a maintenance dose of 1.5 mg/kg once weekly QW will be the initial dosing regimen 
in pediatric for patients enrolled in Cohort A.  Subsequent dose adaptation will be made 
as required based on efficacy and exposure, as detailed below.
… In light of the opposing effect of body weight and clearance maturation on the 
emicizumab exposure, and the uncertainty associated with the effect of clearance 
maturation, there is a possibility that the same dosing regimen in adolescent/adult and 
pediatric patients (i.e., once-weekly loading doses of 3 mg/kg QW for 4 weeks, followed 
by a maintenance dose of 1.5 mg/kg QW once weekly) provides the same efficacy 
trough of 45 μg/mL.  Thus, Study BH29992 will evaluate the appropriate dosing regimen 
in children by starting with the same dosing regimen as the adult and adolescent study, 
BH29884.
Individual pediatric patients may have their dose up-titrated after 12 weeks if they 
experience suboptimal control of bleeding on emicizumab (see Section 4.5.2). …
SECTION 3.3.1.1:  Interim Analysis, JMC Recommendations, and 
Rationale for Enrollment of Q2W/Q4W in Pediatric Patients
The initial maintenance dose of 1.5 mg/kg QW was evaluated by the Study BH29992 
JMC during an interim data review (clinical cutoff date:  28 October 2016).  As 
enrollment occurred faster than anticipated, the two planned data review meetings were 
combined into one.  All available data (including safety, efficacy, and pharmacokinetics) 
from the first 20 patients enrolled in Cohort A was assessed by the JMC to determine 
the appropriateness of the starting maintenance dose, as well as to decide whether the 
study could begin enrolling patients 2 years of age.  On 7 December 2016, the JMC 
recommended continuing enrollment of patients in Cohort A at the maintenance dose of 
1.5 mg/kg QW, as well as to open enrollment to patients 2 years of age at that same 
maintenance dose.  Since exposure at 1.5 mg/kg QW was similar between patients 312
years of age and adolescent/adult patients, the up-titration scheme for children has been 
modified to be the same as the one used in adolescent/adult patients, that is, individual 
up-titration to 3 mg/kg QW should they experience suboptimal control of bleeding on 
emicizumab (see Section 4.5.2).
Furthermore, two Phase III studies investigating 3 mg/kg Q2W (BH30071) and 
6 mg/kg Q4W (BO39182) have been initiated in adolescent/adult patients with 
hemophilia A without inhibitors (BH30071) and with and without inhibitors 
(BO39182).  All three dosing regimens are predicted to achieve similar exposure (in 
terms of steady-state average concentration, Cavg,ss; see Table 2), and despite higher peak 
concentrations and lower trough concentrations with less frequent dosing regimens, all 
are expected to result in similar treatment response (all three dosing regimens provide 
similar predicted ABR distribution) and safety profiles.  Of note, the exposures 
achieved with these three dosing regimens remain well below the safe and well-tolerated 


Emicizumab—F. Hoffmann-La Roche Ltd
10/Protocol BH29992, Version 4
one achieved with the highest dose of 3 mg/kg QW (observed trough concentration of 
120 26.8 g/mL).  Ultimately, these three dosing regimens will provide the option for 
patients to receive emicizumab at different scheduled intervals, while still delivering 
the same cumulative dose.
TABLE 2:  Simulated Median Pharmacokinetic Parameters
Table 2 has been added. Subsequent tables have been renumbered accordingly.
An independent Data Monitoring Committee (iDMC) conducted a scheduled review of 
the safety data in Study BH30071, which detected no unforeseen safety signals in 
adult/adolescent patients treated with emicizumab at 3 mg/kg Q2W.  Meanwhile, an 
interim analysis of 6 mg/kg Q4W in a run-in cohort of 7 adolescent/adult patients in 
Study BO39182 indicated that observed PK parameters at 6 mg/kg Q4W were as 
expected, in line with earlier simulations.  This study is ongoing with no safety 
concerns raised by the iDMC to date.  Therefore in this current study, following 
completion of accrual to Cohort A (1.5mg/kg QW), enrollment to Cohorts B (3 mg/kg 
Q2W) and C (6 mg/kg Q4W) can commence.
The emicizumab regimens to be evaluated in this study consist of a loading dose of 
3 mg/kg weekly for 4 weeks, followed by a maintenance dose administered either 
1.5 mg/kg QW, 3 mg/kg every Q2W, or 6 mg/kg Q4W.  Of note, a maintenance dose of 
3 mg/kg QW may also be evaluated in the setting of patients who have their dose 
up-titrated.
SECTION 3.3.2:  Rationale for Patient Population
… However, due to the current uncertainty of dosing in patients 40 kg (with some 
patients 12 years of age falling into this category), patients 1217 years of age who 
weigh 40 kg will also be allowed to enroll (in Cohort A).
… Finally, pediatric patients 2 years of age with inhibitors treated with bypassing 
agents, and determined by investigator to be at high risk of bleed, will also be allowed to 
enroll (in Cohort A).
SECTION 3.3.3:  Rationale for the Efficacy Analyses
The objective of the efficacy analysis is to evaluate the clinical effect of prophylactic 
emicizumab on the number of bleeds over time (i.e., bleed rate). Another efficacy 
analysis will also characterize the efficacy of up-titration on an intra-patient and 
population level.  As mentioned in Section 3.1, the primary efficacy analysis will be 
performed 52 weeks after the last patient from the primary population of cCohort A has 
been enrolled or withdrawn prematurely, whichever occurs first.  Primary efficacy 
analyses for Cohorts B and C will occur at the time of the primary analysis for 
Cohort A.  Additional efficacy analyses will be performed at the end of the study and as 
needed to support regulatory interactions. 


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11/Protocol BH29992, Version 4
SECTION 4.1:  PATIENTS
Approximately 80 The target population will be children 12 years of age with 
hemophilia A and with FVIII inhibitors who have beenpreviously treated with bypassing 
agents to control or prevent bleedswill be enrolled in the study (approximately 60 
patients in Cohort A, 10 patients in Cohort B, and 10 patients in Cohort C).  In addition 
to this primary population of children 12 years of age, patients 1217 years of age who 
weigh 40 kg at the time of informed consent will also be eligible to enroll. These 
patients, as well as those 2 years of age at the time of informed consent, will only be 
eligible to enroll in Cohort A.  Of note, enrollment in Cohort A may be left open 
exclusively for patients 2 years of age until approximately 510 such patients have 
been enrolled prior to the closure of Cohorts B and C, whichever occurs first.   
SECTION 4.2:  INCLUSION CRITERIA

Children 12 years of age at time of informed consent with allowance for the 
following:
Patients 1217 years of age and who weigh 40 kg at the time of informed 
consent (Cohort A only)
Patients 2 years of age will be allowed to participate only after the 
protocol-defined interim data review criteria are met (Cohort A only)

For patients 2 years of age (Cohort A only): determined by investigator to be in
high unmet medical need
SECTION 4.3:  EXCLUSION CRITERIA

Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood 
products (or any standard-of-care treatment for a life-threatening condition) 
SECTION 4.4:  METHOD OF TREATMENT ASSIGNMENT
The study is an a non-randomized, open-label, Phase III, multicenter , single-arm study 
of emicizumab in pediatric patients 12 years of age and 1217 years of age who weigh 
40 kg with hemophilia A with inhibitors. 
The study consists of three cohorts.  Patients will receive an initial loading dose of 
3 mg/kg QW for the first 4 weeks followed by a maintenance dose of either 1.5 mg/kg 
QW (Cohort A), 3 mg/kg Q2W (Cohort B), or 6 mg Q4W (Cohort C).  The study will 
begin by recruiting patients in Cohort A.  Once 1) the exposure at 1.5 mg/kg QW has 
been characterized in this pediatric population; 2) Cohort A is fully enrolled; and 3) 
review of data in adults and adolescents from two ongoing Phase III studies evaluating 
emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg Q4W (BO39182) identifies no 
safety concerns, this study will open two additional non-randomized cohorts to 
investigate Q2W and Q4W regimens in pediatric patients.  Recruitment to Cohort B 
(3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W) will occur in parallel with alternate 
cohort allocation via IxRS.    


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The time between screening and enrollment of eligible patients should be ≤ 28 days; 
otherwise, patients must be re-screened to determine if they continue to meet the 
inclusion and exclusion criteria. Emicizumab will be administered with a weekly loading 
dose of 3.0 mg/kg for the first 4 weeks (Day 1 of each week) followed by a maintenance 
dose of 1.5 mg/kg/week (Day 1 of each week).  During the 52-week treatment period, 
individual patients may have their dose up-titrated if they experience suboptimal 
bleeding control on emicizumab (see Section 4.5.2).
SECTION 4.5.2:  Dosage, Administration, and Compliance
Emicizumab treatment will begin with will be administered subcutaneously at a weekly 
a loading dose of 3.0 mg/kg QW for the first 4 weeks (Day 1 of each week) followed on 
Week 5 by a starting maintenance dose of either 1.5 mg/kg QW/week (Cohort A), 
3 mg/kg Q2W (Cohort B), or 6 mg/kg Q4W (Cohort C).  Note that the cumulative dose 
studied in all three cohorts is identical, but the dose administration schedule differs 
between cohorts. (Day 1 of each week).  Patients will receive weekly SC doses 
ofprophylactic emicizumab for a minimum of 52 weeks, or until unacceptable toxicity or 
discontinuation from the study due to any cause. The initial dosing regimen may be 
adapted if the maintenance dose of 1.5 mg/kg/week in the first few 35 patients 2 to 
12 years of age fails to achieve optimal control of bleeds after the first 12 weeks of 
treatment.  This decision will be determined following a first interim data review of all 
available data (e.g., safety, efficacy, and pharmacokinetics) by the JMC (as detailed in 
the JMC Agreement).  All patients enrolled following the first interim data review will
receive the starting maintenance dose selected by the JMC.  In a second interim data 
review, all cumulative data (e.g., safety, efficacy, and pharmacokinetics) will be 
evaluated by the JMC to provide recommendations for enrollment of children 2 years of
age, as well as on any additional adaptations of the maintenance dose if necessary. 
Should patient recruitment be faster than anticipated, enrollment will be placed on a 
temporary hold following the first 20 patients until the JMC releases its recommendations 
on the appropriateness of the maintenance dose.  After the JMC recommendations are 
released following both interim data reviews, the study will continue to enroll up to a 
maximum of approximately 60 patients (to maximize the safety database).
On 7 December 2016, the JMC recommended continued enrollment to Cohort A at the 
original starting maintenance dose of 1.5 mg/kg QW, and to open enrollment to 
patients 2 years of age at that same maintenance dose.  Moreover, review of data in 
adults and adolescents from two ongoing Phase III studies evaluating emicizumab at 
3 mg/kg Q2W (BH30071) and 6 mg/kg Q4W (BO39182) has identified no safety 
concerns to date.  See Section 3.3.1.1 for details.
During the 52-week treatment period, individual patients may have their dose up-titrated 
if they experience suboptimal bleeding control on emicizumab. Patients in Cohorts A, B, 
or C with 2 qualifying bleeds within a 12-week interval may have the opportunity to 
have their maintenance emicizumab dose increased to 3 mg/kg QW starting on Week 17, 
if they receive approval from the Medical Monitor.  Of note, for patients from Cohorts 


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B or C who have a dose up-titration, their dosing regimen will change from Q2W or 
Q4W to QW. Qualifying bleeds are defined as spontaneous and clinically significant, 
physician verified (e.g., with diagnostic imaging, clinical examination, photograph), 
and occurring while on prophylactic emicizumab at steady-state on the maintenance 
dose (after Week 5). Investigators will monitor patients regularly with the guidance of an 
up-titration algorithm (see Figure 3 and Table 2).  Should patients meet protocol-defined 
criteria for efficacy-guided up-titration, the investigator will contact the Medical Monitor to 
initiate a discussion about possible up-titration. Ultimately, the decision for up-titration 
will be based on meeting protocol-defined criteria and approval from the Medical Monitor.  
In the case ofUpon up-titration to thea new maintenance dose of 3 mg/kg QW, the 
patient’s schedule of assessments will reset to Week 1, and the next five weekly up-
titrated dosesvisits must be administered at thetake place at the site during a patient’s 
visit.
On the basis of three predefined maintenance doses (1.5, 2.25, and 3.0 mg/kg/week; 
see Section 3.3.1), efficacy-guided up-titration will be possible from 1.5 to 
2.25 mg/kg/week and subsequently to 3.0 mg/kg/week (see Figure 3 and Table 2).  An 
individual patient is eligible for up-titration after a minimum of 12 weeks of treatment on a 
respective dose following protocol-defined criteria as described below.  Bleeding events 
qualifying for up-titration must be spontaneous and clinically significant, with a minimum 
of two being physician verified (e.g., with diagnostic imaging, clinical examination, 
photograph).  Following the initial 12 weeks of treatment at a specific dose, patients 
should be assessed regularly for bleeds meeting criteria for up-titration.  Of note, all 
available cumulative data for the individual patient (i.e., including safety and 
pharmacokinetics) may also be considered in the decision making process for 
efficacy-guided up-titration.

After completing the first 12 weeks (i.e., week 13), including 8 weeks at 
1.5 mg/kg/week, up-titration to 2.25 mg/kg/week may occur if the patient has 
developed 2 bleeds in the last 8 weeks.  From 12 weeks onward, a patient may be 
eligible for up-titration to 2.25 mg/kg/week if the patient has developed 2 bleeds in 
any given period of 12 weeks starting from week 5 at the 1.5 mg/kg dose level.

After completing 12 weeks (i.e., up-titration 1, week 13) at 2.25 mg/kg/week, 
up-titration to 3.0 mg/kg/week may occur if the patient has developed 2 bleeds in 
the last 4 weeks.  From 12 weeks onward at 2.25 mg/kg/week, a patient may be 
eligible for up-titration to 3.0 mg/kg/week if the patient develops 2 bleeds in any 
given period of 12 weeks starting from week 9 at the 2.25 mg/kg dose level.

After completing 12 weeks (i.e., up-titration 2, week 13) at 3.0 mg/kg/week, further 
up-titration may be considered if the patient has developed 2 bleeds in the last 
4 weeks.  From 12 weeks onward at 3.0 mg/kg/week, further up-titration may be 
considered if the patient has developed 2 bleeds in any given period of 12 weeks 
starting from week 9 at the 3.0 mg/kg dose level. 


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
If the investigator believes that a specific patient warrants dose up-titration based on 
a different reason, they must discuss the case with the Medical Monitor for 
consideration and potential approval.
Based on ongoing evaluation of efficacy, safety, and PK data, including interim analyses, 
the Sponsor and/or the JMC may recommend a dose higher than 3.0 mg/kg QW/week
for a patient or a patient population.  Dosing above 3.0 mg/kg QW/week (not higher than 
6.0 mg/kg QW/week) may, therefore, occur while ensuring that the exposure will not 
exceed the exposure achieved with the safe and well tolerated highest dosing regimen 
tested in clinic. 
FIGURE 3:  Efficacy-Guided Up-Titration Algorithm
Figure 3 (previous version) has been removed.
TABLE 2:  Efficacy-Guided Up-Titration
Table 2 (previous version) has been removed. Subsequent tables have been 
renumbered accordingly.
Study site healthcare providers (HCPs) will be trained on how to properly prepare the 
study medication and administer the correct calculated dose subcutaneously as 
described in the IFU document.  Patients/caregivers will in turn be trained by an HCP on 
study medication preparation and self-administration/administration at the recommended 
sites of injection as detailed in the IFU.  The HCP is to inform the patient/caregiver of the 
volumetric dose to be administered and dosing frequency.  Note that during the course 
of the study, should the patient’s body weight change to affect the dose (e.g., 10%), 
the new volumetric dose to be administered must be communicated to the 
patient/caregiver.
In order to minimize the number of injections for pediatric patients in certain high weight 
categories, the administration per single injection of up to 2 mL of drug product solution 
may be permitted, pending approval from the Sponsor, individual countries, and 
participating sites.  This will require combining emicizumab drug product solution from 
more than 1 vial of a given concentration (i.e., vial pooling) into a single syringe using a 
new transfer needle for each vial.  Upon Sponsor approval, tThe detailed procedure for 
vial pooling will beis described in the IFU.  Vials of different emicizumab concentrations 
must not be combined.
Details on the devices to be used for study medication withdrawal from the vial and SC 
injection are provided in the Pharmacy Manual.
Emicizumab will be administered as a SC injection in the home setting, with one dose 
every week, after a period of in-clinic administration and training. …


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Study medication should be administered on the scheduled dosing day.  On days when 
trough plasma PK samples are to be collected, patients will be dosed after those samples 
are drawn. 

For patients in Cohort A (QW dosing), iIf the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, the study medication 
should be administered as soon as possible within a window of 3 days from the 
scheduled dosing date.  If more than 3 days has passed, the missed dose should be 
skipped, and the patient/caregiver should administer his or her next dose at the next 
scheduled time (with the study medication dosing resumed in accordance with the 
original dosing schedule).

For patients in Cohort B (Q2W dosing), if the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, study medication should 
be administered as soon as possible within a window of 7 days from the scheduled 
dosing date.  If more than 7 days have passed, the patient/caregiver should take his 
or her next dose at the next scheduled time with the study medication dosing 
resumed in accordance with the original dosing schedule.

For patients in Cohort C (Q4W dosing), if the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, study medication should 
be administered as soon as possible within a window of 14 days from the scheduled 
dosing date.  If more than 14 days have passed, the patient/caregiver should take 
his or her next dose at the next scheduled time with the study medication dosing 
resumed in accordance with the original dosing schedule.
SECTION 4.6.2:  Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 4 weeks 
prior to initiation of study treatment unless otherwise specified:

Use of aPCC or Byclotas concomitant prophylactic treatment, including for short-
term prophylaxis (note:  this criterion does not apply to the 4 weeks prior to 
initiation of study treatment)

Use of anti-fibrinolytics in conjunction with aPCC or Byclot

Use of concomitant prophylactic regimen with FVIII or rFVIIa  (note:  this criterion 
does not apply to the 4 weeks prior to initiation of study treatment)
Intermittent doses or short-term prophylaxis (e.g., around the time of surgery), 
however, are permitted
…
SECTION 4.7.1:  Informed Consent Forms and Screening Log
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomizationenrollment. …


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SECTION 4.7.5:  Laboratory, Biomarker, and Other Biological Samples

In patients who receive bypassing agents, …  
If applicable, laboratory results should be recorded in the unscheduled visit eCRFs 
“Local Lab Following Treatment with Bypassing Agents” eCRF page.
SECTION 5.1.1.3:  Hypercoagulation and Thromboembolic Events
As of November 2016April 2017, there have been 2 3 serious thromboembolic events 
reported in 2 patients with hemophilia A with inhibitorswho were treated with bypassing 
agents while receiving emicizumab prophylaxis in Study BH29884.  
 
 
 
 
 
 
 
 
 
 For more details please refer to the Emicizumab Investigator’s 
Brochure.
These events should be reported as Serious Adverse Events or Adverse Events of 
Special Interest as described in Section 5.2.3.  HCPs should educate patients/caregivers 
to recognize signs and symptoms of potential thromboembolism or thrombosis (i.e., 
dyspnea, chest pain, leg pain or swelling; or if in the head, headache, numbness in the 
face, eye pain or swelling, or vision impairment; or if in the skin, blackening and 
associated pain) and ensure that they understand the importance of seeking appropriate 
medical attention.  Patients and/or caregivers will also receive two alert cards to remind 
them of this information and these instructions should thromboembolism be suspected.
SECTION 5.1.1.4:  Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) is used to describe a group of disorders with clinical 
features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage 
that can include the kidneys, gastrointestinal system, or central nervous system, and so.  
As of November April 20162017, 32 cases of TMA, diagnosed as aHUS, were observed 
in Study BH29884 involving patients with hemophilia A with inhibitors who were treated 
with bypassing agents while receiving emicizumab.  
 
 
 
 


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  For more details please refer to the Emicizumab 
Investigator’s Brochure.
SECTION 5.1.1.5:  Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays in the Setting of Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII 
activity, and FVIII inhibitor measurement by Bethesda assay) are not reliable and do 
not accurately reflect the patient’s underlying hemostatic status while receiving 
emicizumab prophylaxis (see Section 5.1.3 and the Emicizumab Investigator’s 
Brochure).  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 if a patient is treated by a practitioner 
other than the emicizumab-prescribing practitioner in settings such as an emergency 
room or in an acute-care setting.
Emicizumab’s mechanism of action and resulting interference were clearly 
demonstrated in a wide variety of coagulation laboratory tests approved for in vitro 
diagnostic use.  Clinical trials also demonstrated the effects of emicizumab on 


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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.
SECTION 5.1.2:  Management of Specific Adverse Events
TABLE 3:  Guidelines for Management of Specific Adverse Events
Table 3 has been revised to reflect the changes to the protocol.
SECTION 5.1.3:  Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab
… Emicizumab activity cannot be detected by chromogenic assays using purified bovine 
coagulation proteins and can only be detected using an assay composed of human 
proteins.  Table 4 summarizes the coagulation tests affected and unaffected by 
emicizumab. See the Emicizumab Investigator's Brochure for additional details on which 
tests can be used and how the test results can be interpreted.
TABLE 4:  Coagulation Test Results Affected and Unaffected by 
Emicizumab
Table 4 has been added.  Subsequent tables have been renumbered accordingly.
SECTION 5.3.5.8:  Deaths
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.  The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization
The following hospitalization scenarios are not considered to be adverse events:An 
event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol (e.g., for study drug administration)

Hospitalization for respite care


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
Hospitalization for a preexisting condition, provided that all of the following criteria
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
The following hospitalization scenarios are not considered to be serious adverse events 
but should be reported as adverse events instead: 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
SECTION 5.4.1:  Emergency Medical Contacts
Medical Monitor:
, M.D. (secondary)
Telephone No.:
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
No formal hypothesis testing is planned in the study.  All the analyses will be descriptive 
and be performed for each cohort separately.
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited 
number of pediatric patients with hemophilia A with inhibitors available for participation in 
this study.  Hence, at least 2040 children younger than 12 years of age and up to 
8060 patients with hemophilia A and FVIII inhibitors who are currently receiving 
treatment with bypassing agents will be enrolled in this study: approximately 60 patients 
in Cohort A , with allowance of patients 1217 years of age who weigh 40 kg at the 
time of informed consent and approximately 10 patients each in Cohort B and Cohort C.
SECTION 6.2:  SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study in each cohort will 
be summarized. …
SECTION 6.3:  SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, weight etc.) 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 cohort dosing regimen (i.e., Cohort A:  1.5 mg/kg QW; 
Cohort B:  3 mg/kg Q2W; Cohort C:  6 mg/kg Q4W) and overall as 
appropriate(maintenance dose 1.5, 2.25, or 3.0 mg/kg/week).


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SECTION 6.4:  EFFICACY ANALYSES
The efficacy analyses are to evaluate the clinical effect of prophylactic emicizumab on 
the number of bleeds over time (i.e., bleed rate), and to characterize the efficacy of 
up-titration on an intra-patient and population level.  These analyses will be conducted 
using different bleed definitions such as treated bleeds, all bleeds, treated spontaneous 
bleeds, treated joint bleeds, and treated target joint bleeds. 
The primary analysis will be performed 52 weeks after the last patient in the primary 
population of cCohort A has been enrolled or withdrawn prematurely, whichever occurs 
first.  The primary populationcohort consists of all patients enrolled in Cohort A prior to 
the close of enrollment for patients 2 years of age (up to approximately 60 patients), 
and is used to define the timing of the primary analysis. The primary analysis will also 
include all available data from patients enrolled in Cohorts B and C, regardless of their 
follow-up time.  If no patients 2 years of age are included in the primary cohort, the 
primary analysis will still occur at the specified time; however, eEnrollment in the study 
Cohort A may be left open exclusively for patients 2 years of age in order to enroll up 
toapproximately 510 such patients.  Note that these patients will be included in the 
primary population analysiscohort regardless of their follow-up time.  Further analyses 
will may be conducted while the study is ongoing (see Section 6.9).  
SECTION 6.4.1:  Efficacy Endpoints
One efficacy objective is to evaluate the clinical effect of prophylactic emicizumab on the 
number of bleeds over time. This analysis will be performed for each cohort separately 
as well as overall as appropriate. Another objective is to characterize the efficacy up-
titration on an intra-patient and population level.  The comparison between historical and 
on-study treatment period for bleeds over time will also be evaluated for patients who 
were previously enrolled in Study BH29768.  These patients will enroll exclusively in 
Cohort A, therefore this intra-patient analysis will be conducted only in patients 
receiving the 1.5 mg/kg QW maintenance dose.  The definition of a bleed is described in 
Section 4.7.8.  All definitions (i.e., treated bleeds, all bleeds, treated spontaneous bleeds, 
treated joint bleeds, treated target joint bleeds) will be evaluated for each of the efficacy 
objectives. 
Characterizing the effect of emicizumab on-study treatment period for bleed over time as 
well as analyses of up-titration and the comparison between historical and on study 
treatment period for bleed over time will be performed for Cohort A and for the overall 
analysis using a negative binomial regression model, which accounts for different follow-
up times, with the patient’s number of bleeds as a function of the time that each patient 
stays in the study included as an offset in the model. 
The number of bleeds will be also annualized (Annualized Bleeding RateABR) for 
Cohorts B and C as well as for each patient using the following formula: 
…


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Efficacy endpoints will be analyzed separately by cohort (i.e., Cohort A:  1.5 mg/kg 
QW; Cohort B:  3 mg/kg Q2W; Cohort C:  6 mg/kg Q4W) and overall as appropriate. 
Patients who require up-titration will be reported in their original maintenance dose 
group, and a listing based on their up-titration period will be provided. A detailed
description of the statistical methods that will be used for the efficacy analyses will be 
provided in the SAP.
SECTION 6.4.2:  Exploratory Efficacy Endpoints
Summary statistics of the number of daycare/school and days hospitalized will be 
presented for each cohort separately.
SECTION 6.5:  SAFETY ANALYSES
Safety analyses will be performed for each cohort separately and overall as appropriate.
SECTION 6.6:  PHARMACOKINETIC ANALYSES
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be 
presented descriptively by dose groups (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W, 
3 mg/kg QW in case of up-titration), including arithmetic and geometric means, median, 
range, standard deviations, and coefficients of variation.
SECTION 6.7:  PATIENT-REPORTED OUTCOME ANALYSES
Scale scores for the Haemo-QoL-SF and the Adapted InhibQoL Including Aspects of 
Caregiver Burden will be calculated for each assessment, with change scores being 
examined for the assessments over the course of the study.  These will be summarized 
descriptively by cohort.  A descriptive summary of the number of daycare/school days 
missed and days hospitalized will also be presented by cohort.
SECTION 6.8:  PHARMACODYNAMIC BIOMARKER ANALYSES
PD parameters (e.g., aPTT, FVIII activity) will be presented using summary statistics by 
dose groups, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation. These analyses will be presented by cohort.
SECTION 6.9.1.1:  JMC Recommendations and Enrollment of Q2W/Q4W 
in Pediatric Patients
On 7 December 2016, based on a combined interim analysis of the first 20 patients 
enrolled, the JMC recommended to continue enrolling patients to Cohort A at the 
maintenance dose of 1.5 mg/kg QW, and to begin enrollment of patients 2 years of 
age.  See Section 3.3.1.1 for details. 
After the JMC recommendations are were released following both interim data 
reviewsthis interim analysis, the study will continued to enroll up to a maximum of 
approximately 60 patients (to maximize the safety database). up to approximately 
60 patients in Cohort A. Upon completion of recruitment to Cohort A, and following 
review of data in adults and adolescents from two ongoing Phase III studies evaluating 
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safety concerns, recruitment with alternating allocation of patients to Cohorts B and C 
via IxRS could begin up to a maximum of approximately 10 patients in each cohort.  
See Section 3.3.1.1 for details. 
SECTION 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.
SECTION 9.6:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
… 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: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf.
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
APPENDIX 1:  Schedule of Assessments
The schedule of assessments has been revised to reflect the changes to the protocol.
SAMPLE INFORMED CONSENT FORM AND ASSENTS
The sample Informed Consent Form and Assents have been revised to reflect the 
changes to the protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 29
PROTOCOL SYNOPSIS .................................................................................... 30
1.
BACKGROUND .......................................................................................... 41
1.1
Background on Pediatric Hemophilia A with 
Inhibitors................................................................................ 41
1.2
Background on Emicizumab.................................................. 44
1.3
Study Rationale and Benefit–Risk Assessment..................... 49
2.
OBJECTIVES AND ENDPOINTS ............................................................... 51
2.1
Efficacy Objectives ................................................................ 51
2.2
Safety Objective .................................................................... 52
2.3
Pharmacokinetic Objective .................................................... 53
2.4
Pharmacodynamic Biomarker Objective................................ 53
3.
STUDY DESIGN......................................................................................... 53
3.1
Description of the Study......................................................... 53
3.2
End of Study and Length of Study......................................... 57
3.3
Rationale for Study Design.................................................... 58
3.3.1
Rationale for Emicizumab Dose and Schedule...................... 59
3.3.1.1
Interim Analysis, JMC Recommendations, and 
Rationale for Enrollment of Q2W/Q4W in 
Pediatric Patients................................................................... 62
3.3.2
Rationale for Patient Population ............................................ 63
3.3.3
Rationale for the Efficacy Analyses ....................................... 64
3.3.4
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 65
3.3.5
Rationale for Biomarker Assessments................................... 66
3.3.6
Rationale for Pharmacokinetic Sample Schedule.................. 67
4.
MATERIALS AND METHODS .................................................................... 67
4.1
Patients.................................................................................. 67
4.2
Inclusion Criteria.................................................................... 67
4.3
Exclusion Criteria................................................................... 68
4.4
Method of Treatment Assignment.......................................... 69


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4.5
Study Treatment.................................................................... 70
4.5.1
Formulation, Packaging, and Handling.................................. 70
4.5.1.1
Emicizumab........................................................................... 70
4.5.2
Dosage, Administration, and Compliance.............................. 70
4.5.3
Investigational Medicinal Product Accountability ................... 73
4.5.4
Post-Study Access to Emicizumab........................................ 74
4.6
Concomitant and Rescue Therapy ........................................ 75
4.6.1
Permitted Therapy................................................................. 75
4.6.2
Prohibited Therapy ................................................................ 76
4.7
Study Assessments ............................................................... 76
4.7.1
Informed Consent Forms and Screening Log........................ 76
4.7.2
Medical History and Demographic Data ................................ 77
4.7.3
Physical Examinations........................................................... 77
4.7.4
Vital Signs.............................................................................. 77
4.7.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 77
4.7.6
Electrocardiograms................................................................ 79
4.7.7
Electronic Patient-Reported Outcomes.................................. 79
4.7.8
Bleed Definitions.................................................................... 80
4.8
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 82
4.8.1
Patient Discontinuation.......................................................... 82
4.8.2
Study Treatment Discontinuation........................................... 82
4.8.3
Study and Site Discontinuation.............................................. 83
5.
ASSESSMENT OF SAFETY....................................................................... 83
5.1
Safety Plan ............................................................................ 83
5.1.1
Risks Associated with Emicizumab ....................................... 83
5.1.1.1
Injection-Site Reactions......................................................... 83
5.1.1.2
Hypersensitivity Reaction, Anaphylaxis, 
Anaphylactoid Reaction......................................................... 84
5.1.1.3
Hypercoagulation and Thromboembolic Events .................... 84
5.1.1.4
Thrombotic Microangiopathy ................................................. 85


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5.1.1.5
Life-Threatening Bleeding Due to Unreliable 
Standard Coagulation Tests and Inhibitor Assays 
in the Setting of Emicizumab ................................................. 86
5.1.2
Management of Specific Adverse Events .............................. 87
5.1.3
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab .......................................................... 88
5.2
Safety Parameters and Definitions ........................................ 89
5.2.1
Adverse Events ..................................................................... 89
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 90
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 91
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91
5.3.1
Adverse Event Reporting Period ........................................... 91
5.3.2
Eliciting Adverse Event Information....................................... 92
5.3.3
Assessment of Severity of Adverse Events ........................... 92
5.3.4
Assessment of Causality of Adverse Events ......................... 93
5.3.5
Procedures for Recording Adverse Events............................ 93
5.3.5.1
Injection-Site Reactions......................................................... 93
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 93
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 94
5.3.5.4
Persistent or Recurrent Adverse Events................................ 94
5.3.5.5
Abnormal Laboratory Values ................................................. 95
5.3.5.6
Abnormal Vital Sign Values ................................................... 95
5.3.5.7
Abnormal Liver Function Tests.............................................. 96
5.3.5.8
Deaths ................................................................................... 96
5.3.5.9
Preexisting Medical Conditions.............................................. 97
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic 
Bleeds.................................................................................... 97
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 97
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 98
5.3.5.13
Patient-Reported Outcome Data ........................................... 98


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5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 98
5.4.1
Emergency Medical Contacts................................................ 99
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 99
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 99
5.4.2.2
Events That Occur after Study Drug Initiation...................... 100
5.4.3
Reporting Requirements for Pregnancies............................ 100
5.4.3.1
Pregnancies in Female Patients.......................................... 100
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 100
5.4.3.3
Abortions ............................................................................. 101
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 101
5.5
Follow-Up of Patients after Adverse Events ........................ 101
5.5.1
Investigator Follow-Up......................................................... 101
5.5.2
Sponsor Follow-Up .............................................................. 101
5.6
Post-Study Adverse Events................................................. 101
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 102
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 102
6.1
Determination of Sample Size ............................................. 102
6.2
Summaries of Conduct of Study.......................................... 103
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 103
6.4
Efficacy Analyses ................................................................ 103
6.4.1
Efficacy Endpoints............................................................... 103
6.4.2
Exploratory Efficacy Endpoints............................................ 104
6.5
Safety Analyses................................................................... 105
6.6
Pharmacokinetic Analyses................................................... 105
6.7
Patient-Reported Outcome Analyses .................................. 105
6.8
Pharmacodynamic Biomarker Analyses .............................. 106
6.9
Interim Data Review ............................................................ 106
6.9.1
Planned Interim Data Review .............................................. 106


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6.9.1.1
JMC Recommendations and Enrollment of 
Q2W/Q4W in Pediatric Patients........................................... 106
7.
DATA COLLECTION AND MANAGEMENT ............................................. 107
7.1
Data Quality Assurance....................................................... 107
7.2
Electronic Case Report Forms............................................. 107
7.3
Patient-Reported Outcome Data ......................................... 107
7.4
Source Data Documentation................................................ 108
7.5
Use of Computerized Systems ............................................ 108
7.6
Retention of Records........................................................... 109
8.
ETHICAL CONSIDERATIONS.................................................................. 109
8.1
Compliance with Laws and Regulations .............................. 109
8.2
Informed Consent................................................................ 109
8.3
Institutional Review Board or Ethics Committee.................. 111
8.4
Confidentiality...................................................................... 111
8.5
Financial Disclosure ............................................................ 112
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 112
9.1
Study Documentation .......................................................... 112
9.2
Protocol Deviations.............................................................. 112
9.3
Site Inspections ................................................................... 112
9.4
Administrative Structure....................................................... 112
9.5
Joint Monitoring Committee................................................. 113
9.6
Publication of Data and Protection of Trade 
Secrets ................................................................................ 113
9.7
Protocol Amendments ......................................................... 114
10. REFERENCES ......................................................................................... 115
LIST OF TABLES
Table 1
Mean Reduction (%) of Annualized Bleeding Rates in 
Inhibitor and Non-Inhibitor Patients Enrolled in 
ACE001JP/ACE002JP................................................................ 59
Table 2
Simulated Median Pharmacokinetic Parameters ........................ 63


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Table 3
Guidelines for Management of Specific Adverse Events ............ 87
Table 4
Coagulation Test Results Affected and Unaffected by 
Emicizumab ................................................................................ 89
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 92
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 55
Figure 2
Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event............................................................................ 60
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 121
Appendix 2
Schedule of PD Assessments................................................... 127
Appendix 3
Haemo-QoL-SF (United States/English) ................................... 128
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden 
(United States/English) ............................................................. 130
Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of 
Laboratory Abnormalities and Adverse Events ......................... 136
Appendix 6
Clinical Criteria for Diagnosing Anaphylaxis.............................. 143


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III
CLINICAL TRIAL TO EVALUATE THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF 
SUBCUTANEOUS ADMINISTRATION OF 
EMICIZUMAB IN HEMOPHILIA A PEDIATRIC 
PATIENTS WITH INHIBITORS
PROTOCOL NUMBER:
BH29992
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000073-21
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (RO5534262)
MEDICAL MONITOR:
 M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd and
Chugai Pharmaceutical Co. Ltd.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor.


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PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO 
EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF SUBCUTANEOUS ADMINISTRATION 
OF EMICIZUMAB IN HEMOPHILIA A PEDIATRIC PATIENTS WITH 
INHIBITORS
PROTOCOL NUMBER:
BH29992
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000073-21
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase III
INDICATION:
Hemophilia A
SPONSOR:
F. Hoffmann-La Roche Ltd and
Chugai Pharmaceutical Co. Ltd.
Objectives and Endpoints
The objectives of the study are to investigate (with no formal hypothesis testing) the efficacy, 
safety, and pharmacokinetics of SC emicizumab administered at 1.5 mg/kg QW, 3 mg/kg Q2W, 
and 6 mg/kg Q4W in pediatric patients with hemophilia A and factor VIII (FVIII) inhibitors who 
are currently receiving treatment with bypassing agents.  A total of approximately 80 patients 
are planned:  approximately 60 patients in Cohort A (1.5 mg/kg QW) and approximately 
10 patients each in Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W).  Patients younger 
than 12 years of age are planned for enrollment, with allowance of patients 1217 years of age 
who weigh 40 kg at the time of informed consent to further evaluate dosing of emicizumab in 
patients 40 kg. Of note, enrollment in Cohort A may be left open exclusively for patients 
2 years of age until approximately 5 such patients have been enrolled.
Efficacy Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as appropriate.
The efficacy objectives for this study are as follows:

To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds over 
time (i.e., bleed rate) *

To evaluate the efficacy in reducing the number of bleeds  over time compared with the 
patient's historical bleed rate (intra-patient comparison, Cohort A only, as patients enrolled 
in Cohorts B and C will not have previously participated in the non-interventional 
study) *

To characterize the efficacy of up-titration on an intra-patient level, based on the basis of the
number of bleeds over time *

To evaluate the health-related quality of life (HRQoL) of children 817 years of age 
according to Haemo-QoL-Short Form (SF) (completed by patients)

To evaluate proxy-reported HRQoL and aspects of caregiver burden using the Adapted 
InhibQoL Including Aspects of Caregiver Burden questionnaire for all children (completed 
by caregivers)


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
To assess the number of days missed from daycare/school and days hospitalized
* Analyses will be performed for:  treated bleeds, all bleeds, treated spontaneous bleeds, 
treated joint bleeds, and treated target joint bleeds.
Safety Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as appropriate.
The safety objective for this study is to evaluate the overall safety of emicizumab in pediatric 
patients with hemophilia A and inhibitors on the basis of the following endpoints:

Incidence and severity of adverse events

Incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs 

Incidence of laboratory abnormalities 

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to drug discontinuation 

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 

Incidence and severity of thrombotic microangiopathy

Incidence and clinical significance of anti-emicizumab antibodies
Pharmacokinetic Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W).
The pharmacokinetic (PK) objective for this study is to characterize the exposure (Ctrough) of 
emicizumab in patients receiving 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W prior to 
drug administration on Day 1 and at the following timepoints:

Every week during Weeks 14 on emicizumab

Every 2 weeks during Weeks 59 on emicizumab

Every 4 weeks during Weeks 1337 on emicizumab

Every 8 weeks during Weeks 4149 on emicizumab

Every 12 weeks from Week 57 thereafter while continuing on emicizumab, until the end of 
the study

Additional PK samples will be taken in patients who require up-titration (see schedule of 
assessments in the protocol)
Pharmacodynamic Biomarker Objective
The pharmacodynamic (PD) biomarker objective for this study is as follows:

To assess potential PD biomarkers of emicizumab, including but not limited to aPTT and 
FVIII activity, at designated timepoints throughout the study.
Study Design
Description of Study
This non-randomized, multicenter, open-label, Phase III clinical study will enroll children with 
hemophilia A who have inhibitors against FVIII.  Children with hemophilia A and documented 
historical FVIII inhibitor titer (5 BU) must currently be receiving treatment with bypassing 
agents.  At least 40 patients younger than 12 years age and up to approximately 80 patients 
are planned for enrollment, with allowance of patients 1217 years of age who weigh 40 kg at 
the time of informed consent.  Patients will receive SC doses of emicizumab at 1.5 mg/kg QW 
(Cohort A)for a minimum of 52 weeks or until unacceptable toxicity, discontinuation from the 
study due to any cause, or other criteria set forth in the protocol, whichever occurs first.  After 
52 weeks of treatment, an individual patient who continues to derive clinical benefit may


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continue receiving prophylactic emicizumab as part of this study or a future separate 
emicizumab extension study.
Because of the uncertainty of the dosing regimen needed in patients 12 years of age or
40 kg to achieve similar exposure as in adults and adolescents, this study will first evaluate 
the appropriate dosing regimen in children by starting with the same weekly dosing regimen 
(1.5 mg/kg QW) being evaluated in the Phase III study (BH29884) in adult/adolescent patients 
with hemophilia A with inhibitors (see protocol for details).  Emicizumab will be administered 
with a weekly dose of 3 mg/kg QW for the first 4 weeks followed by a maintenance dose of 
1.5 mg/kg QW (Cohort A) for the remainder of the treatment period.  During the 52-week 
treatment period, individual patients may have their dose up-titrated if they experience 
suboptimal bleeding control on emicizumab (see protocol).
In a first interim data review, the appropriateness of the initial dosing regimen will be evaluated 
(maintenance dose of 1.5 mg/kg QW) after the first 35 patients (2 to 12 years of age) have
been dosed for a minimum of 12 weeks.  A Joint Monitoring Committee (JMC; see protocol) will 
review all cumulative data (e.g., safety, efficacy, and pharmacokinetics) to provide 
recommendations on increasing the starting maintenance dose (if necessary) to target a similar 
plasma emicizumab trough concentration as the one being targeted in adolescents and adults 
(i.e., 45 µg/mL).  All patients enrolled following the first interim data review will receive the 
starting maintenance dose selected by the JMC.  Those patients enrolled prior to the first 
interim data review who had not had their dose up-titrated will remain on their current 
maintenance dose, unless they meet eligibility for up-titration based on protocol-defined criteria 
(see protocol).
In order to include and safely treat the youngest patients (birth to 2 years of age), this study 
will include a staggered approach to enrollment by age.  Patients 2 to 12 years of age and 
patients 1217 years of age who weigh 40 kg will enroll first.  A second interim data review will 
occur once at least 10 patients between 2 and 12 years of age have been dosed for a 
minimum of 12 weeks, at which time all cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) will be evaluated to provide recommendations for enrollment of children 
2 years of age, as well as on any additional adaptations of the maintenance dose if necessary.
Furthermore, should patient recruitment be faster than anticipated, enrollment will be placed on
a temporary hold following the first 20 patients until the JMC releases its recommendations on 
the appropriateness of the maintenance dose (Cohort A).  After the JMC recommendations are 
released following both interim data reviews, the study will continue to enroll in Cohort A up to 
approximately 60 patients.
Once 1) the exposure at 1.5 mg/kg QW has been characterized in this pediatric population; 
2) Cohort A is fully enrolled; and 3) review of data in adults and adolescents from two 
ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg 
Q4W (BO39182) identifies no safety concerns, this study will open two additional 
non-randomized cohorts to investigate Q2W and Q4W regimens in pediatric patients.  
Recruitment to Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W) will occur in parallel 
with alternate cohort allocation via IxRS, for a total of approximately 10 patients per cohort.  
Of note, enrollment to Cohorts B and C will be limited to patients 211 years of age.  
Emicizumab will be administered with a loading dose of 3 mg/kg QW for the first 4 weeks 
followed by a maintenance dose of 3 mg/kg Q2W (Cohort B) and 6mg/kg Q4W (Cohort C) for 
a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to 
any cause, or other criteria set forth in the protocol, whichever occurs first (see protocol).  
During the 52-week treatment period, individual patients may have their dose up-titrated if 
they experience suboptimal bleeding control on emicizumab.
The entire study will enroll up to approximately 80 patients with allowance for additional 
patients 2 years of age in Cohort A.
A patient who fulfills the inclusion and exclusion criteria should be enrolled at the Week 1 visit.  
Prophylactic use of bypassing agents should be discontinued the day before the first dose of 
emicizumab is given. 
The primary analysis for all cohorts will be performed 52 weeks after all patients in the primary
population of Cohort A have been enrolled or withdrawn prematurely, whichever occurs first.  
The primary population of Cohort A consists of all patients enrolled prior to the close of 
enrollment for patients 2 years of age (up to approximately 60 patients) and is used to define


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the timing of the primary analysis of Cohorts A, B, and C.  If no patients 2 years of age are 
included in the primary population of Cohort A, the primary analysis will still occur at the 
specified time; however, enrollment to Cohort A may be left open exclusively for patients 
2 years of age in order to enroll approximately 5 such patients.  Note that these patients will 
be included in the primary analysis of Cohort A regardless of their follow-up time.  Additionally, 
all available data from patients enrolled in Cohorts B and C (efficacy period approximately 6 
months) will be included in the primary analysis of Cohort A.
During the study, caregivers will be asked to enter any individual bleeds, hemophilia-related 
medications, and emicizumab treatments that occur on an electronic, handheld device.  Entries 
should be made at least weekly, and also at any time a bleed occurs or a hemophilia medication, 
including emicizumab, is administered.  Detailed information about bleeds (type, location, 
date/time) will be captured.  Detailed information about hemophilia medications (agent, dose,
reason for administration, date/time) and emicizumab dosing (total volume, date/time) will also 
be captured.  In addition, HRQoL using the Haemo-QoL-SF (completed by children 8 years of 
age and older), proxy-reported HRQoL and aspects of caregiver burden using Adapted 
InhibQoL (completed by caregivers of all children) and missed daycare/school will be collected 
on a separate electronic, handheld device during a patient’s visit prior to emicizumab injection at 
Week 1 and every 12 weeks thereafter, as outlined in the schedule of assessments (see
protocol).  The number of days the child was hospitalized, if applicable, will be derived from data 
collected on eCRF.
Emicizumab is intended in this study for prophylactic use only (i.e., not to treat bleeds that have 
already occurred).  Therefore, in this study all patients will continue to receive episodic 
treatment for breakthrough bleeds as needed.  Breakthrough bleeds should preferably be 
treated with rFVIIa at the lowest expected dose to achieve hemostasis and captured as they 
occur on the electronic, handheld device.  There is clinical experience in the ongoing Phase I/II 
clinical studies with the treatment of over 80 breakthrough bleeds in patients receiving 
emicizumab with either FVIII or bypassing agents.  FVIII, aPCC, and rFVIIa do not interfere with 
emicizumab PK assessments, and no safety signals have been observed when breakthrough
bleeds were treated with standard-of-care regimens during Phase I/II studies.  However, in the 
ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with FVIII 
inhibitors), 3 events of TMA and 3 serious thromboembolic events were observed in patients 
who concomitantly used 100 U/kg/day of aPCC on average for 24 hours for the treatment of 
breakthrough bleeds (see protocol).  Therefore, it is recommended that breakthrough bleeds are
treated with rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should 
be avoided or limited (see protocol).  Also, local and central laboratory assessments are 
required to monitor the risk for thromboembolic events or TMA as per the schedule of 
assessments (see protocol).  Investigators will be asked to contact the Medical Monitor in the 
event of suspected lack or loss of efficacy of emicizumab in order to discuss potential laboratory 
evaluations (e.g., anti-emicizumab antibodies, coagulation tests) to be performed as well as to 
re-evaluate the patient’s benefit-risk of continued treatment.
Physical examinations, vital sign assessments, ECG, and safety laboratory assessments will be 
collected as per the schedule of assessments (see protocol).  Adverse events will be captured 
on an ongoing basis as they occur during the study.  All patients in this study will undergo PK 
assessments.  Blood samples will also be collected to assess the PD properties of emicizumab
(i.e., aPTT, FVIII activity), as well as to assess immunogenicity (i.e., anti-emicizumab antibodies 
and anti-FVIII antibodies).  A detailed list is provided in the schedule of assessments (see 
protocol).
Of note, a non-interventional study (Study BH29768) has been initiated to document the number 
and types of bleeds and current treatment with episodic or prophylactic bypassing agents, as 
well as collect information on HRQoL, health status, and safety in patients with hemophilia A 
(including children 12 years of age).  The assessments in the non-interventional study will 
mitigate the risk of inaccurate reporting of bleeds that may occur with historical data collection 
and may provide data collected prospectively for over 24 weeks.  Pediatric patients who are 
enrolled in the non-interventional Study BH29768 are eligible to enroll in this study, as long as 
they meet the inclusion and exclusion criteria and are able to enroll at a participating site while 
the study is open for enrollment.  All patients who participated in the non-interventional 
study will be enrolled in Cohort A.


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Number of Patients
At least 40 children younger than 12 years of age and up to 80 patients with hemophilia A and 
FVIII inhibitors who are currently receiving treatment with bypassing agents will be enrolled in 
this study: approximately 60 patients in Cohort A with allowance of patients 1217 years of 
age who weigh 40 kg at the time of informed consent and approximately 10 patients each in 
Cohort B and Cohort C.
Target Population
Approximately 80 children 12 years of age with hemophilia A and with FVIII inhibitors 
previously treated with bypassing agents will be enrolled in the study (approximately 60 
patients in Cohort A, 10 patients in Cohort B, and 10 patients in Cohort C).  In addition to this 
primary population of children 12 years of age, patients 1217 years of age who weigh 40 kg 
at the time of informed consent will also be eligible to enroll.  These patients, as well as those 
2 years of age at the time of informed consent, will only be eligible to enroll in Cohort A.  
Of note, enrollment in Cohort A may be left open exclusively for patients 2 years of age 
until approximately 510 such patients have been enrolled prior to the closure of Cohorts B 
and C, whichever occurs first.
Inclusion Criteria
Children must meet the following criteria for study entry:

Written informed consent must be obtained from parent/legally acceptable representative 
and an assent from the child when applicable (latest approved version by the Independent 
Ethics Committee [IEC]/Institutional Review Board [IRB]) prior to any of the study-specific 
assessments and procedures being performed.

Children 12 years of age at time of informed consent with allowance for the following:
Patients 1217 years of age and who weigh 40 kg at the time of informed consent 
(Cohort A only)
Patients 2 years of age will be allowed to participate only after the protocol-defined 
interim data review criteria are met (Cohort A only)

Body weight 3 kg at time of informed consent

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures including the completion of applicable patient-reported outcome 
(PRO) questionnaires 

Caregivers of all children must have the willingness and ability to comply with all study 
procedures including the completion of the bleed/medication questionnaire and applicable 
HRQoL questionnaires 

Diagnosis of congenital hemophilia A of any severity and documented history of high-titer 
inhibitor (i.e., 5 BU)

Requires treatment with bypassing agents

For patients 2 years of age: 
If on an episodic bypassing agent regimen: ABR of 6 (3 bleeds in the last 24 weeks) 
OR 
If on a prophylactic bypassing agent regimen: inadequately controlled (e.g., 2 bleeds 
since starting prophylaxis or 1 life-threatening bleed) or central venous access device 
(CVAD) placement medically not feasible or deemed unsafe by investigator

For patients 2 years of age (Cohort A only): determined by investigator to be in high
unmet medical need

Adequate hematologic function, defined as platelet count of 100 109 cells/L and 
hemoglobin 8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5 age adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT 3 age adapted ULN 
at the time of screening


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
Adequate renal function: serum creatinine must be 1.5 ULN for age.  When the serum 
creatinine is 1.5 ULN, creatinine clearance by Bedside Schwartz formula must be 
70 mL/min/1.73m2

At screening, in the rare cases of hemophilia in female patients who are of childbearing 
potential, patients will be required to have a negative serum pregnancy test result (with 
urine pregnancy tests performed at subsequent specified visits) and will have to agree to 
remain abstinent or use single or combined highly effective contraceptive methods that 
result in a failure rate of 1% per year and are approved by local health authorities and 
ethics committees during the treatment period and for at least 5 elimination half-lives 
(24 weeks) after the last dose of study drug.
Exclusion Criteria
Children who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy or 
prophylaxis treatment with FVIII  
Patients awaiting initiation of ITI will be eligible 
Patients in whom ITI has failed will be eligible with a 72-hour washout period prior to the 
first emicizumab administration.

Previous (in the past 12 months) or current treatment for thromboembolic disease (with the
exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is 
not currently ongoing) or signs of thromboembolic disease 

Other diseases (i.e., certain autoimmune disease [e.g., systemic lupus erythematosus], 
cardiovascular disease) that may increase risk of bleeding or thrombosis

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Known infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) 

Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment

Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrollment or 
planned use during the study period

Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study

Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood 
products (or any standard-of-care treatment for a life-threatening condition) 

Receipt of:
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter
An investigational drug concurrently

Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study or that would, in the opinion of the investigator or Sponsor, 
preclude the patient’s safe participation in and completion of the study or interpretation of 
the study results
End of Study
The primary analysis will take place at the same time for Cohorts A, B, and C.  It will occur 
after all patients in the primary population of Cohort A have completed 52 weeks of treatment, 
or have withdrawn prematurely, whichever occurs first.  All data from patients enrolled in 
Cohorts B and C will be included regardless of follow-up time.


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After 52 weeks of treatment, an individual patient who continues to derive clinical benefit may 
continue receiving prophylactic emicizumab as part of this study or a future separate 
emicizumab extension study.  Patients who discontinue emicizumab will have a safety follow-up 
visit at 24 weeks after the last emicizumab dose.
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., LPLV), as defined below:

Completed 52 weeks of emicizumab and either transferred to a separate extension study to 
receive further emicizumab as per Roche Global Policy on Continued Access to 
Investigational Medicinal Products or to commercial product
OR

Completed the end of study safety follow-up visit 24 weeks after discontinuing emicizumab
OR

Consent has been withdrawn
OR

Lost to follow-up
Length of Study
The length of the entire study from screening of the first patient to the last patient completing 
52 weeks in the study and/or the end-of-study follow-up visit (24 weeks after discontinuing 
emicizumab) will be approximately 152 weeks.
Investigational Medicinal Product
Test Product (Investigational Drug)
Emicizumab treatment will begin with a loading dose of 3 mg/kg QW for the first 4 weeks 
(Day 1 of each week) followed on Week 5 by a maintenance dose of either 1.5 mg/kg QW 
(Cohort A), 3 mg/kg Q2W (Cohort B), or 6 mg/kg Q4W (Cohort C).  Note that the cumulative 
dose studied in all three cohorts is identical, but the dose administration schedule differs 
between cohorts.  Patients will receive prophylactic emicizumab for a minimum of 52 weeks or 
until unacceptable toxicity or discontinuation from the study due to any cause.  See protocol for 
treatment details.
Emicizumab will be administered as a SC injection in the home setting after a period of in-clinic 
administration and training.  The first five drug administrations must be performed in a 
monitored setting such as an infusion center, clinic, or hospital, with a 60-minute observation 
period following each of the first three doses.  For patients with a previous history of a clinically 
significant hypersensitivity reaction, additional precautions should be considered (see protocol).  
The fourth and fifth scheduled study drug administrations must also be performed in the 
monitored setting, and the patient/caregiver will be trained and have the opportunity to ask any 
questions to the HCP before the scheduled start of home administration.  The patient (7 years 
of age)/caregiver will observe at least one SC injection performed by the HCP and successfully 
administer at least one SC injection while being observed by the HCP prior to starting home 
administration.  Each site will have the discretion to provide additional training if deemed 
appropriate.  If, despite additional training, the investigator determines that the patient/caregiver 
is unable to inject emicizumab correctly, then arrangements may be made to identify a trained 
caregiver or HCP to administer the SC injections.
Non-Investigational Medicinal Products
None.
Statistical Methods
Efficacy Analyses
The efficacy analyses are to evaluate the clinical effect of prophylactic emicizumab on the 
number of bleeds over time (i.e., bleed rate), and to characterize the efficacy of up-titration on 
an intra-patient level.  These analyses will be conducted using different bleed definitions such 
as treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated 
target joint bleeds.


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The primary analysis will be performed 52 weeks after the last patient in the primary population 
of Cohort A has been enrolled or withdrawn prematurely, whichever occurs first.  The 
primary population consists of all patients enrolled in Cohort A prior to the close of enrollment 
for patients 2 years of age (up to approximately 60 patients) and is used to define the timing 
of the primary analysis.  The primary analysis will also include all available data from patients 
enrolled in Cohorts B and C, regardless of their follow-up time.  Enrollment in Cohort A may 
be left open exclusively for patients 2 years of age in order to enroll approximately 510 such 
patients.  Note that these patients will be included in the primary population analysis regardless 
of their follow-up time.  Further analyses may be conducted while the study is ongoing (see 
protocol).
Safety Analyses
Safety analyses will be performed for each cohort separately and overall as appropriate.
The safety analyses population will be based on all patients who received at least one
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including complete 
blood count with differential and platelet counts), ECGs, vital signs, and anti-emicizumab 
antibodies.
To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate thesaurus level, 
and toxicity grade.   
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading scale.
Data on the impact of immunogenicity (anti-emicizumab antibodies and anti-FVIII antibodies) on 
safety, efficacy, and/or pharmacodynamics and pharmacokinetics will be summarized using 
standard language/terminology.
Pharmacokinetic Analyses
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be presented 
descriptively by dose groups (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W, 3 mg/kg QW in 
case of up-titration), including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
sex, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as area under the curve, will be derived from individual post-hoc predictions.  
Data may be pooled with data from previous Phase I/II studies and Phase III Studies.  These 
analyses will be reported in a dedicated report.
Patient-Reported Outcome Analyses
Scale scores for the Haemo-QoL-SF and the Adapted InhibQoL Including Aspects of Caregiver 
Burden will be calculated for each assessment, with change scores being examined for the 
assessments over the course of the study.  These will be summarized descriptively by cohort.  
A descriptive summary of the number of daycare/school days missed and days hospitalized will 
also be presented by cohort.
Pharmacodynamic Biomarker Analyses
PD parameters (e.g., aPTT, FVIII activity) will be presented using summary statistics by dose 
groups, including arithmetic and geometric means, median, range, standard deviations, and 
coefficients of variation. These analyses will be presented by cohort.
Interim Data Review
In a first interim data review, the appropriateness of the initial dosing regimen will be evaluated 
(maintenance dose of 1.5 mg/kg/week).  This dosing regimen may be adapted following 
analysis of all available data (e.g., safety, efficacy, pharmacokinetics) by the JMC (see protocol) 
if a majority of the first 35 patients (aged 2 to 12 years of age) fail to achieve optimal control 
of bleeds after the first 12 weeks of treatment; or if their plasma emicizumab concentration 
trough level is lower than the one being targeted in adolescents and adults (i.e., 45 µg/mL).  


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Should patients 12 years of age and 40 kg be enrolled at the time of this first interim data 
review, available data from these patients will also be included.
A second interim data review will occur once at least 10 patients between 2 and 12 years of age 
have been dosed for a minimum of 12 weeks.  All available cumulative data (e.g., safety, 
efficacy, pharmacokinetics) will be evaluated by the JMC to provide recommendations for the 
enrollment of children 2 years of age, as well as on any further adaptations of the 
maintenance dose if necessary.  Again, should patients 12 years of age and 40 kg be 
enrolled at the time of this second interim data review, available data from these patients will 
also be included.
Should patient recruitment be faster than anticipated, enrollment will be placed on a temporary 
hold following the first 20 patients until the JMC releases its recommendations on the 
appropriateness of the maintenance dose.  
JMC Recommendations and Enrollment of Q2W/Q4W in Pediatric Patients
On 7 December 2016, based on a combined interim analysis of the first 20 patients enrolled, 
the JMC recommended to continue enrolling patients to Cohort A at the maintenance dose of 
1.5 mg/kg QW, and to begin enrollment of patients 2 years of age.  See protocol for details. 
After the JMC recommendations were released following this interim analysis, the study 
continued to enroll up to approximately 60 patients in Cohort A. Upon completion of 
recruitment to Cohort A, and following review of data in adults and adolescents from two 
ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg 
Q4W (BO39182) identifying no safety concerns, recruitment with alternating allocation of 
patients to Cohorts B and C via IxRS could begin up to a maximum of approximately 10 
patients in each cohort.  See protocol for details.
Additional interim data reviews will be prespecified in the Statistical Analysis Plan; other 
analyses may be conducted at various timepoints to support regulatory submissions.
Determination of Sample Size  
The sample size for this study is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited number of 
pediatric patients with hemophilia A with inhibitors available for participation in this study.  
Hence, at least 40 children younger than 12 years of age and up to 80 patients with hemophilia 
A and FVIII inhibitors who are currently receiving treatment with bypassing agents will be 
enrolled in this study: approximately 60 patients in Cohort A with allowance of patients 
1217 years of age who weigh 40 kg at the time of informed consent and approximately 
10 patients each in Cohort B and Cohort C.  
During the study, a re-assessment of the initially specified sample size based on enrollment 
consideration 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
ADA
anti-drug antibody
aHUS
atypical hemolytic uremic syndrome
aPCC
activated prothrombin complex concentrate 
AUC
area under the curve
BA
bioavailability
BU
Bethesda unit
Cmax
maximum plasma concentration
CVAD
central venous access device
cyFcγR
cynomolgus monkey Fcγ receptor
cyFcRn
cynomolgus monkey neonatal Fc receptor
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome
FDA
U.S. Food and Drug Administration
FEIBA
Factor Eight Inhibitor Bypassing Activity
FIX
factor IX
FIX:Ag
factor IX antigen
FIXa
activated factor IX
FVIII
factor VIII
FVIIIa
activated factor VIII
FX
factor X
FX:Ag
factor X antigen
HBV
hepatitis B virus
HCP
healthcare provider
HCV
hepatitis C virus
hFcγR 
human Fcγ receptor
hFcRn 
human neonatal Fc receptor
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
Health-Related Quality of Life
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFU
Instructions For Use


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Abbreviation
Definition
IgG4
immunoglobulin G4
ISTH
International Society on Thrombosis and Haemostasis
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITI
immune tolerance induction
IV
intravenous
IxRS
interactive voice or Web Response System
JMC
Joint Monitoring Committee
LPLV
last patient, last visit
MAA
Marketing Authorization Application
MAD
multiple ascending dose
NOAEL
no observed adverse effect level
PD
pharmacodynamic
PK
pharmacokinetic
PRO
patient-reported outcome
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected using Fridericia’s formula
QW
once weekly
rFVIII
recombinant FVIII
rFVIIa
recombinant activated factor VII
SAD
single ascending dose
SAP
Statistical Analysis Plan
SC
subcutaneous
t1/2
half-life
tmax
time to maximum plasma concentration
TMA
thrombotic microangiopathy
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON PEDIATRIC HEMOPHILIA A WITH 
INHIBITORS
Hemophilia A is a bleeding disorder characterized by congenital underproduction of or 
dysfunction of factor VIII (FVIII), an essential protein in promoting clot formation.  The 
gene that encodes FVIII is located on the long arm of the X chromosome.  Genetic 
aberrations causing this disease are transmitted via X-linked recessive inheritance, from 
mothers with one affected FVIII gene (“carriers”), to half of their newborn sons.  An 
estimated 400,000 people worldwide are living with hemophilia (WFH 2012a), with an 
incidence of approximately 1 in 5,000 live male births.  Hemophilia A affects 
approximately 320 newborns each year in the United States (CDC 2014; NIH 2014; 
Franchini and Mannucci 2013; WFH 2013a).  In the European Union, this would equate 
to around 415 newborns with hemophilia A in 2014.  No racial differences have been 
reported in the distribution of patients with hemophilia and the number of patients with 
hemophilia A registered in 2013, in various regions across the world, including
4,761 individuals in Japan; 15,963 in North America; and 19,397 in the five major 
European nations (United Kingdom, France, Germany, Italy, and Spain [Spain estimate 
from 2012]) (WFH 2013a).
The absence or functional deficiency of FVIII leads to a lifelong bleeding tendency.  
Common clinical signs of hemophilia A include easy bruising; prolonged bleeding after 
trauma or surgery; spontaneous bleeding into joints, muscles, or soft tissues; and 
intracranial hemorrhage.  The severity of the disease roughly correlates with the residual 
endogenous level of FVIII activity.  Approximately 68% of people with hemophilia A have 
moderate (25%) or severe (43%) forms, characterized by FVIII activity levels 5% or 
1%, respectively, leading to frequent bleeding events with the sequelae of 
musculoskeletal complications, such as arthropathy, local functional deficits, 
hemorrhagic shock, neurocognitive defects, or even death (WFH 2013a).  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).
Treatments for hemophilia A can be broadly categorized into two types: episodic (or 
“on-demand”), in which treatments are administered in response to the occurrence of 
bleeding symptoms; and prophylactic, in which treatments are administered on a 
scheduled basis to prevent the onset of bleeding.  
The standard treatment, for patients with hemophilia A without inhibitors, is intravenous 
(IV) FVIII replacement therapy with recombinant FVIII (rFVIII) or plasma-derived FVIII 
concentrates.  Prophylaxis has been shown to markedly reduce the bleeding rate in 
adults with severe hemophilia A (Valentino et al. 2012; Manco-Johnson et al. 2013).  In 
children, the current standard-of-care is primary prophylaxis with regular FVIII infusions 
(starting from the first joint bleed onward or earlier; Valentino et al. 2012), focusing on 
joint preservation with, optimally, no bleeds and the prevention of long-term 


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consequences such as joint damage. The overall goal is to enable normal psychosocial
development without overprotection (Coppola et al. 2010).  Early prophylaxis has been 
shown to lead to better long-term outcomes (Kreuz et al. 1999; 
Manco-Johnson et al. 2007; Gouw et al. 2013).  Adolescents and adult patients are more 
likely to have arthropathy with target joints (Gruppo et al. 2013) and the treatment goal of 
secondary prophylaxis (after the second joint bleed) or tertiary prophylaxis (after onset of 
joint disease) is to enable normal activities of daily life and physical exercise, as well as 
reduce progression of arthropathy and disability (Tagliaferri et al. 2008).  
Unfortunately, up to 30% of patients with hemophilia A develop neutralizing 
alloantibodies (inhibitors) against FVIII (Franchini et al. 2012). Inhibitors neutralize the 
activity of endogenous FVIII as well as of FVIII administered as replacement therapy. 
For patients with high titer inhibitor (5 Bethesda units [BU]/mL), FVIII replacement 
therapy is rendered ineffective, precluding the use of a safe and effective 
standard-of-care and markedly increasing the risk of morbidity and mortality due to 
bleeding complications (Franchini et al. 2012). The overall incidence of inhibitors among 
patients with hemophilia A is 20%30% (Franchini et al. 2012); but because inhibitors 
can develop very early during the course of FVIII therapy (within 1050 exposure days), 
with half of all cases occurring before the age of 5 years, pediatric patients represent the 
population at highest risk of developing inhibitors (Kreuz et al. 1995; 
Wight and Paisley 2003; Kempton and White 2009; Hay and DiMichele 2012). 
For patients who develop inhibitors against FVIII, immune tolerance induction (ITI) may 
help restore a patient’s clinical response to FVIII concentrates.  Permanent eradication 
of FVIII inhibitors is the ultimate goal of ITI, and it is successful in approximately 60%80% 
of adults and children with inhibitors (Santagostino et al. 2009; Hay and DiMichele 
2012;).  Most physicians delay the start of ITI for up to 1 year from the time the inhibitor 
is first diagnosed to allow very high titers of inhibitors to fall because a pre-ITI inhibitor 
titer measuring 10 BU/mL is the most powerful predictor of ITI success 
(Mariani and Kroner 1999; DiMichele and Kroner 2002). Regimens that delay treatment 
until the inhibitor has fallen below 10 BU/mL positively affect both the likelihood of 
success (79%87% success rate) and the time required to achieve tolerance
(Mauser-Bunschoten et al. 1995; Kroner 1999; Rocino and de Biasi 1999; 
Smith et al. 1999). Furthermore, the rate of response to ITI does not decline until ITI has
been delayed beyond 5 years from the time of diagnosis (Brackmann et al. 1996; 
Mauser-Bunschoten et al. 1995; Kroner 1999; DiMichele and Kroner, 2002). However, 
an optimal regimen for ITI remains to be defined (although a recent study suggested 
superior safety outcomes using high-dose regimens administered daily 
[Hay and DiMichele 2012]), and the length of treatment is dictated by individual 
responses, ranging from months to years.  Because uninterrupted and uncomplicated 
venous access is essential in children undergoing ITI, this process is particularly 
burdensome in the pediatric patient population, who require frequent visits to hemophilia 


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centers for regular infusion of FVIII concentrate through central venous access devices 
(CVADs). 
Long-term CVAD use requires considerable commitment from caregivers and patients, 
and serious complications can occur, including thrombosis, bleeding, mechanical 
dysfunction, and most commonly, infection. A recent prospective study in pediatric 
hemophilia A patients with inhibitors reported that 183 lines were implanted in 
99 patients, with 41% of patients having at least one documented infection. The median 
time to line removal was 483 days [IQR (143-1071)] (Rodriguez et al. 2015).  A Finnish 
retrospective study similarly reported that 47% of 106 catheters implanted in 58 patients 
had to be removed because of a complication (Vepsalainen et al. 2015). CVAD-related 
bacteremia and sepsis pose potentially lethal problems for patients with hemophilia and 
result in a substantial proportion of emergency room visits for children.  A retrospective 
study of pediatric emergency department management of children with hemophilia 
showed that of 536 visits from 84 male patients (median age 4 years), 12% were due to 
suspected CVAD infection (Ozgonenel et al. 2013). Indeed, infection occurs more 
frequently in hemophilia patients with inhibitors (Bollard et al. 2000; Valentino et al. 2004; 
van Dijk et al. 2004), with rates being highest among patients with inhibitors undergoing 
ITI, ranging from 50%83% (van den Berg et al. 1998).  If ITI is unsuccessful, inhibition 
of FVIII concentrate treatment may persist throughout the patient’s life.  Additionally, the 
use of ITI treatment is not viewed as a viable option for patient management in many 
countries, owing to its high cost, lack of availability of FVIII concentrates, and daily 
administrations.  These disadvantages are compounded in the young pediatric 
population due to the necessity for central venous access and related complications, as 
well as the psychological stress of this treatment on patients and their families.  
For patients with a history of a high-titer (5 BU/mL) inhibitor who are unable to 
eradicate their inhibitors or are not candidates for ITI, the only hemostatic options 
currently available are coagulation factors that augment other parts of the coagulation 
cascade (i.e., bypassing agents).  Bypassing products include Factor Eight Inhibitor 
Bypassing Activity (FEIBA), an activated prothrombin complex concentrate (aPCC), 
and NovoSeven, a recombinant activated human FVII (rFVIIa) (Srivastava et al. 2013).  
Unfortunately, the hemostatic effect of bypassing agents in patients with inhibitors is 
suboptimal, leading to a higher number of bleeds (annualized bleeding rate [ABR] of 
810 with FEIBA[Leissinger et al. 2011; Antunes et al. 2014] and 23 bleeds/month 
with NovoSeven[Konkle et al. 2007] compared with that of FVIII concentrates in 
non-inhibitor patients who achieve a median ABR of approximately 02 with optimal 
prophylaxis (Manco-Johnson et al. 2013).  In addition, as opposed to the 812-hour 
half-life and 1520-minute infusion time of FVIII, NovoSevenhas a short half-life of only 
23 hours, and FEIBArequires 2550 minutes to infuse (with a half-life of 47 hours), 
requiring frequent and extended IV infusions, respectively.
Recent investigations into prophylactic therapy in adults and children with bypassing 
agents NovoSeven(Konkle et al. 2007) and FEIBA(Leissinger et al. 2011; 


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Antunes et al. 2014) have shown that these products lead to reductions in bleed rates
compared with episodic treatment with these same products. However, as detailed 
above, this efficacy is suboptimal and does not approach the level of hemophilia control
that can be achieved with FVIII concentrates in non-inhibitor patients. Following 
scientific consultations that the Sponsor conducted with pediatric hematology experts in 
the European Union, United States, and Japan, no consensus was apparent regarding 
whether NovoSevenor FEIBAshould be the standard-of-care therapy for children with 
inhibitors to FVIII. Furthermore, both prophylactic and episodic regimens with bypassing 
agents are proposed as appropriate for children with inhibitors to FVIII.  
Despite prophylactic regimens being standard-of-care for hemophilia patients without 
inhibitors in many countries, a large proportion of hemophilia patients with FVIII inhibitors 
currently are treated with episodic regimens, partly because of the treatment burden of 
these prophylaxis regimens.  A recent survey of hemophilia centers across 14 countries 
suggested that 41% of pediatric hemophilia patients with inhibitors were on ITI alone, 17% 
were on both ITI and prophylactic bypassing agents, 16% were on prophylactic 
bypassing agents alone, and 26% were on neither ITI nor prophylactic bypassing agents
(Carcao et al. 2015).
Because current available therapies are suboptimal, there is a need to develop 
alternative therapeutic options for pediatric patients with hemophilia A and FVIII 
inhibitors (Gringeri et al. 2013).  Limitations of bypassing agents include an increased 
risk of thrombosis, suboptimal efficacy, and lack of administration convenience that 
collectively increase the likelihood of severe bleeds and the associated complications 
that impair HRQoL (Hedner 2011).  Given the significant management challenges in 
children with hemophilia, there is a need for development of effective prophylactic 
treatment options that demonstrate more reliable efficacy, decreased immunogenicity, 
and less treatment burden to prevent bleeding and minimize long-term morbidity of 
children with hemophilia.
1.2
BACKGROUND ON EMICIZUMAB
Description of the Molecule
Emicizumab (also referred to as RO5534262 or ACE910) is a recombinant, humanized, 
bispecific, immunoglobulin G4 (IgG4) monoclonal antibody that binds with moderate 
affinity to activated factor IX (FIX) and factor X (FX), mimicking the co-factor function of 
FVIII. 
Mechanism of Action
FVIII is a glycoprotein found in plasma that, in its activated form, serves as a cofactor for 
FIXa and FX, facilitating the reaction, whereby FX is catalyzed to FXa (Mann et al. 1990).  
After coagulation is initiated by the complex of exposed tissue factor and activated 
factor VII (FVIIa) in plasma and a small amount of thrombin is produced, FVIII 
undergoes enzymatic cleavage by thrombin and is converted into activated FVIII (FVIIIa).  
Because it enhances the FIXainduced FX activation reaction by 200,000-fold, FVIIIa 


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plays a critical role in accelerating the explosive burst of thrombin production in the 
propagation phase of the coagulation reaction process (van Dieijen et al. 1981).
Emicizumab binds with moderate affinity (in the low µM range) to FIXa and FX, and has 
cofactor activity that substitutes for FVIII.  Emicizumab mimics FVIII and, therefore, is 
capable of promoting the activation of FX by FIXa and downstream hemostasis at the 
site of bleeding in patients with hemophilia A who have decreased or no circulating 
levels of FVIII, irrespective of the presence of FVIII inhibitors (Sampei et al. 2013).  
Furthermore, as emicizumab has no structural relationship to FVIII or other coagulation 
factors, emicizumab is not expected to induce or enhance the development of direct 
inhibitors to FVIII or other coagulation factors.  Due to the favorable pharmacokinetic (PK)
properties of this antibody with the possibility of less frequent SC administration of 
emicizumab compared with IV FVIII therapies, this novel compound may have the 
potential to significantly change the treatment of patients with hemophilia A with and 
without FVIII inhibitors.
Nonclinical Studies
Binding studies of emicizumab to cynomolgus monkey FIX and FX showed a similar 
affinity as to the human factors.  Mechanistic in vitro studies were conducted in human 
and cynomolgus FVIII-neutralized plasma and in various coagulation factor-specific 
assay testing systems, which revealed that emicizumab shortened aPTT and promoted 
thrombin generation.  Emicizumab bound to human Fcγ receptor (hFcγR), cynomolgus 
monkey Fcγ receptor (cyFcγR), human neonatal Fc receptor (hFcRn), and cynomolgus 
monkey neonatal Fc receptor (cyFcRn) with similar affinities as a human IgG4 antibody, 
natalizumab.
In vivo pharmacology experiments in cynomolgus monkeys were conducted in a model 
of hemophilia A where endogenous FVIII levels were neutralized by an anti-FVIII specific 
monoclonal antibody.  This model mimics essential characteristics of patients with 
hemophilia A and was used to test in vivo pharmacodynamics and efficacy under 
spontaneous or local trauma-induced bleeding conditions.  In summary, emicizumab
demonstrated the ability to significantly reduce bleeding tendency under both sets of 
conditions.
Potential prothrombotic risks associated with emicizumab-induced FVIII mimetic activity 
were further explored in an in vivo cynomolgus monkey venous stasis model.  In this 
model, thrombus formation in the presence of emicizumab was compared with that in the 
presence of FVIII or bypassing agents FVIIa or aPCC.  Thrombus formation with 
emicizumab did not markedly exceed formation observed with rFVIIa, aPCC, or FVIII.
The pharmacokinetics/toxicokinetics of emicizumab were assessed in cynomolgus 
monkeys after single and multiple doses were administered IV and via the intended 
clinical SC route.  After a single IV dose of 6 mg/kg emicizumab in male cynomolgus 
monkeys, the plasma clearance was 3.62 mL/day/kg and the terminal plasma half-life 


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(t1/2) of emicizumab was 19.4 days.  The single SC administration study (dose levels: 
0.06, 0.6, and 6 mg/kg) indicated slow (time to maximum plasma concentration [tmax]: 
3.005.33 days) and complete absorption (bioavailability [BA]: 102% at 6 mg/kg).  The 
IV and SC multiple dosing studies (toxicokinetic monitoring) revealed a t1/2 in the range of 
14.930.8 days.  Overall, exposures in terms of maximum plasma concentration (Cmax) 
and area under the curve (AUC) increased in an approximately dose proportional 
manner.
A fraction of the cynomolgus monkeys treated with repeated doses of emicizumab
showed the formation of anti-emicizumab antibodies (which is expected with humanized 
monoclonal antibodies) with few animals also showing neutralizing antibodies.
Aspects of acute as well as repeated-dose toxicity including local tolerance assessment 
were evaluated in cynomolgus monkeys in 4-, 13-, and 26-week SC dose toxicity studies 
(at doses up to 30 mg/kg weekly), and a 4-week IV dose toxicity study (at doses up to 
100 mg/kg weekly).  No toxicologically relevant changes attributable to SC or IV 
administration of emicizumab were observed; the no observed adverse effect level 
(NOAEL) was the highest tested dose in each toxicity study.
The conducted in vitro and in vivo studies demonstrated the mode of action of 
emicizumab and provided supportive data on efficacious dose levels in a relevant 
hemophilia A disease model which were used for dose extrapolation to humans.  
See the Emicizumab Investigator's Brochure for additional details on nonclinical studies 
with emicizumab.
Clinical Studies
The experience with emicizumab in humans includes data from one completed Phase I 
study (Study ACE001JP, last patient, last visit [LPLV] on 17 April 2015) and its ongoing 
extension, a Phase I/II study (Study ACE002JP).  See the Emicizumab Investigator's 
Brochure for additional details on clinical studies with emicizumab.
Study ACE001JP was a single study conducted in 3 parts, including both healthy 
subjects (Part A and Part B) and patients with hemophilia A (Part C).  The objective of 
Parts A and B in healthy subjects was to investigate the tolerability, safety, PK, and 
pharmacodynamic (PD) response of SC administered emicizumab in adult Japanese 
and Caucasian males and to evaluate for racial differences, if any, in their PK and PD 
response.  Healthy male volunteers aged 2044 were eligible for enrollment.  A total of 
64 healthy volunteers were enrolled in Parts A and B from August 2012 to April 2013.  In 
Part C, the objective was to investigate the tolerability, safety, PK, and PD response of 
SC administered emicizumab in patients with hemophilia A.  Patients were eligible for 
enrollment if they were 1259 years of age, 40 kg in weight, had a diagnosis of severe 
congenital hemophilia A, and had documentation of bleeds and/or treatment with 
coagulation factor in the last 6 months.  For those with inhibitors, patients must have had 


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6 bleeds in the 6 months prior to enrollment, and for those without inhibitors, patients 
were required to have received 150 lifetime doses of FVIII replacement, including in the 
last 6 months.  A total of 18 patients with hemophilia A were enrolled from May 2013 to 
June 2014. 
In the SAD portion of Study ACE001JP, healthy volunteers (Japanese [Part A] and 
Caucasian [Part B]) received a single SC injection of emicizumab (48 patients) or 
placebo (16 patients), at dose levels ranging from 0.0011 mg/kg. Six subjects received 
emicizumab and 2 subjects received placebo at each dose level. In Part C (the MAD 
portion) of Study ACE001JP, a total of 18 patients with hemophilia A were enrolled in 
three cohorts of 6 patients each for each dose level (Cohort C-1: 1 mg/kg loading dose 
followed by weekly SC injections of 0.3 mg/kg [0.3 mg/kg/week group]; 
Cohort C-2: 3 mg/kg loading dose followed by weekly SC injections of 1 mg/kg 
[1 mg/kg/week group]; Cohort C-3: 3 mg/kg weekly SC injections [3 mg/kg/week group]).
Study ACE002JP is an extension study that allows for continued treatment with 
emicizumab of patients enrolled in Part C of Study ACE001JP.  In order to be eligible for 
the extension study, patients must have completed 12 weeks of assigned treatment in 
Study ACE001JP and had bleeds prior to study entry.  Study ACE002JP allows for dose 
escalation in patients who have an inadequate response to emicizumab—if the current 
dose is safe and well-tolerated, in such cases, his or her dose should be increased. 
Study ACE002JP will enable patients from Study ACE001JP to continue receiving 
emicizumab until the drug has received marketing approval or emicizumab development 
is discontinued, whichever is sooner.
Study ACE001JP has been completed (LPLV on 17 April 2015) and Study ACE002JP is 
currently ongoing.  Seventeen of 18 patients in Part C of Study ACE001JP completed 
the 12-week treatment period.  One patient moved to the follow-up period.  A total of 
16 of the 17 patients who completed the 12-week treatment period subsequently 
enrolled into extension Study ACE002JP and 1 of the 17 patients moved to the 
post-treatment follow-up period of Study ACE001JP.  In Cohort C, there were 
5 adolescent patients (12-18 years old): 1 patient (
 years old) in Cohort C-1; 
2 patients (
years old, 
years old) in Cohort C-2; and 2 patients (
years old, 
years old) in Cohort C-3.  There were 11 patients with inhibitors:  4 patients in 
Cohort C-1; 4 patients in Cohort C-2; and 3 patients in Cohort C-3.
The Phase I and I/II studies, have shown promising results for emicizumab prophylaxis 
in reducing the ABR in Japanese patients with hemophilia A with and without inhibitors 
against FVIII.  During the 6 months before study enrollment, patients without FVIII 
inhibitors had received FVIII prophylactic replacement therapy, while the patients with 
inhibitors had received episodic therapy and/or prophylactic therapy with bypassing 
agents. During the course of emicizumab administration, ABRs decreased in all patients 
compared with the pretreatment period, regardless of whether or not they had inhibitors, 
with the exception of one non-inhibitor patient previously on FVIII prophylaxis in the 


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3 mg/kg/week group who had a baseline ABR of 0 (in this patient, the ABR was 
maintained at 0 while receiving emicizumab).  Among all patients, (excluding those who 
had dose escalations), ABR reduction ranged from 22.8%100% in the 0.3 mg/kg/week 
group, from 78.9%100% in the 1 mg/kg/week group, and from 86.4%100% in the 
3 mg/kg/week group.  Three patients had dose escalations after starting 
Study ACE002JP.  The dose of emicizumab was escalated from 0.3 mg/kg/week to 
1 mg/kg/week and then to 3 mg/kg/week in 2 of 6 patients in Cohort C-1 who 
transitioned to Study ACE002JP.  In one of these patients, with inhibitors against FVIII, 
treatment with 0.3, 1, and 3 mg/kg/week resulted in 49.3%, 57.5%, and 84.7% 
reductions in ABR, respectively, compared with that of pre-dose.  In the other patient
without inhibitors against FVIII, treatment with 0.3, 1, and 3 mg/kg/week resulted in 
22.8%, 62.3%, and 97.5% reductions in ABR, respectively, compared with that of 
pre-dose.  One additional patient without inhibitors against FVIII in the 0.3 mg/kg/week 
group started an escalated dose of 1 mg/kg/week just before the data cutoff.
Emicizumab was safe and well-tolerated in these patients. Most adverse events were of 
mild intensity, except for five moderate adverse events (upper respiratory tract infection, 
bipolar I disorder, hemophilia [i.e., left hip joint bleeding due to hemophilia], headache, 
and asthma) and two severe adverse events (appendicitis and mesenteric hematoma).  
None of the moderate or severe adverse events were considered by investigators to be 
related to emicizumab. Local injection-site reactions were observed in 7 patients (38.9% 
of patients).  These local injection-site reactions included injection-site erythema 
(3 patients), injection-site hematoma (2 patients), injection-site pruritus (2 patients), 
injection-site rash (1 patient), injection-site pain (1 patient), and injection-site discomfort 
(1 patient).  All local injection-site reactions were of mild intensity and all resolved except 
for two cases: 1 patient, who started at the 0.3 mg/kg/week dose level and received an 
increased dose, reported a case of injection-site pruritus, which remained ongoing at the 
last data cutoff; and in another patient, a case of injection-site hematoma in the 
3 mg/kg/week group (considered to be not related to study therapy) remains unresolved.
Other adverse events reported in more than 20% of patients included nasopharyngitis 
(7 patients, 38.9%), dental caries (6 patients, 33.3%), pharyngitis (5 patients, 27.8%), 
excoriation (4 patients, 22.2%), and headache (4 patients, 22.2%). Two severe adverse 
events were observed: appendicitis and mesenteric hematoma.  Both events were 
considered to be serious adverse events and not related to emicizumab administration. 
In the Phase I/II Studies ACE001JP and ACE002JP, no thrombotic microangiopathy 
(TMA), thromboembolic adverse events, or systemic hypersensitivity reactions have 
been reported in any dosing cohort thus far, including those patients who required 
concomitant FVIII concentrates or bypassing agent therapy to treat bleeds.
In the ongoing Phase III Study BH29884 (adolescent and adult patients with 
hemophilia A with FVIII inhibitors), as of April 2017, TMA was observed in 3 patients 
receiving emicizumab and bypassing agents; and 3 cases of serious thromboembolic 


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events were observed in 2 patients receiving emicizumab and bypassing agents. For 
more details refer to Sections 5.1.1.3 and 5.1.1.4.
In terms of PK, emicizumab exhibited linear PK after single SC administration.  Following 
single SC injection, its mean elimination t½ (45 weeks) was similar to that of other 
human IgG antibodies.  Furthermore, comparison of PK profiles between Japanese and 
Caucasian patients did not reveal racial differences.  
In patients with hemophilia A, emicizumab trough plasma concentrations increased in a 
dose-dependent manner with weekly dosing to achieve a plateau (steady state) after 
approximately 12 weeks in the first two dosing groups, while they continued to increase 
in the highest dose group where no loading dose was administered and steady state 
was expected later.
In the Phase I/II Studies ACE001JP and ACE002JP, emicizumab has been administered 
to 48 healthy subjects and 18 patients with hemophilia A.  A total of 6 subjects/patients 
tested positive for anti-drug antibodies (ADAs) on at least one occasion. Four
subjects/patients presented with treatment emergent ADAs. Out of these 4
subjects/patients, 1 healthy subject had a neutralizing ADA (based on its PK and PD
profiles). Safety profiles in subjects/patients who tested positive for ADAs did 
not generally differ from those of subjects/patients who tested negative for 
ADAs. Likewise, the presence or absence of ADAs had no impact on efficacy profiles in 
patients with hemophilia A.
Based on these compelling Phase I/II data, a clinical development program in adult and 
pediatric patients with hemophilia A (both with and without FVIII inhibitors) has been
initiated.  See the Emicizumab Investigator's Brochure for additional details on clinical 
studies with emicizumab.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
For patients with hemophilia A who are diagnosed with inhibitors, permanent eradication 
of inhibitors is the ultimate goal.  This can be achieved by means of intensive FVIII 
administration over many months with ITI, which is successful in approximately 60%80% 
of treated inhibitor patients (Mariani et al. 2003; Santagostino et al. 2009;
Hay and DiMichele 2012).  However, hemostatic management may be challenging 
during the time interval required to achieve ITI success.  Furthermore, ITI is not viewed 
as a viable option for inhibitor patients in many countries, owing to its high cost, the 
scarce local supply of FVIII concentrates, practical issues and potential complications 
associated with CVADs, and psychological stress on patients and their families for this 
highly demanding therapeutic endeavor.  
Therefore, for those patients with inhibitors who are unable to eradicate their inhibitors or 
are not candidates for ITI, bypassing agents are required to treat or prevent bleeds.  
Unfortunately, the hemostatic effect of bypassing agents is unstable in comparison with 


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that of FVIII concentrates.  As opposed to the 812-hour half-life and 1520-minute 
infusion time of FVIII, NovoSeven has a short half-life of only 23 hours, and FEIBA
requires 2550 minutes to infuse (with a half-life of 47 hours), requiring frequent or 
extended IV infusions, respectively.  In practice, some inhibitor patients will have bleeds 
that respond better to NovoSeven while others will respond better to FEIBA.  Several 
recent publications evaluating the efficacy of prophylactic therapy in adults and children 
with the bypassing agents NovoSeven (Konkle et al. 2007) and FEIBA
(Leissinger et al. 2007; Ettingshausen et al. 2010; Leissinger et al. 2011; 
Antunes et al. 2014) showed decreased bleeding rates compared with episodic 
treatment.  
In the FEIBA prophylaxis pivotal study (PROOF study), patients with inhibitors on 
episodic bypassing agents were eligible for participation if they had a minimum historical 
ABR of 12. Thirty-six patients (age range 756) were enrolled, including 5 children of 
711 years of age and 4 children of 1215 years of age.  On prophylactic aPCC, their 
median ABR (interquartile range) decreased from 28.7 (32.3) to 7.9 (8.1) 
(Antunes et al. 2014), suggesting that while this treatment was partially efficacious for 
some, there still exists suboptimal control of bleeds and unmet medical need in this 
population.
Given the hemostatic management challenges in hemophilia A patients with inhibitors, 
there is an urgent need for therapeutics that have more reliable efficacy, an extended 
half-life, and reduced treatment burden to prevent bleeding for patients with hemophilia 
A with inhibitors.
The nonclinical and clinical data related to emicizumab to-date support a positive 
benefit-risk assessment.  As described in Section 1.2, evaluation of in vivo 
pharmacodynamics and efficacy in a cynomolgus monkey model of hemophilia A 
demonstrated the ability of emicizumab to significantly reduce bleeding tendency under 
both spontaneous and local trauma-induced bleeding conditions. No toxicologically 
relevant changes attributable to SC (at doses up to 30 mg/kg weekly) or IV (at doses up 
to 100 mg/kg weekly) administration of emicizumab were observed, and the NOAEL was 
the highest tested dose in each toxicity study. Due to the PK properties of emicizumab, 
with the possibility of less frequent SC administration compared with FVIII therapies, 
emicizumab may have the potential to significantly improve the treatment of 
hemophilia A adult, adolescent, and pediatric patients, both with and without FVIII 
inhibitors, who are in need of treatment to prevent bleeding episodes.  Furthermore, 
emicizumab has no structural relationship to FVIII and, therefore, is not expected to 
induce or enhance the development of direct inhibitors to FVIII or other coagulation 
factors.  
The positive benefit-risk assessment of emicizumab was corroborated in the Phase I/II 
studies, which included 5 adolescents (two 
-year-old patients, one 
year-old patient, 
and two 
-year-old patients), where clinically meaningful reductions in ABR at all dose 


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levels tested have been seen to-date along with a favorable risk-benefit profile.  
Emicizumab was well tolerated in the Phase I/II studies.  The majority of adverse events 
were of mild intensity. The majority of adverse events were not considered related to 
emicizumab.  In these studies, no thromboembolic or systemic hypersensitivity adverse 
events were observed; however, in the ongoing Phase III Study BH29884, 3 cases of 
TMA and 3 serious thromboembolic events were observed in patients on emicizumab 
who received bypassing agents for the treatment of breakthrough bleeds.  Four out of 
these 5 patients have fully recovered and 1 patient died due to severe rectal bleeding
(see Sections 5.1.1.3 and 5.1.1.4).
Given the significant unmet medical need among pediatric patients with hemophilia A 
with FVIII inhibitors and positive benefit-risk assessment for emicizumab, initiation of a 
pediatric Phase III study is appropriate.  See Section 3.3 for the details of the design and 
rationale for Study BH29992.
This current study is designed to evaluate the efficacy, safety, and pharmacokinetics of 
emicizumab administered subcutaneously initially once weekly (QW) in pediatric 
patients with hemophilia A with FVIII inhibitors. Following review of data in adult
and adolescent patients with hemophilia A from two ongoing Phase III studies 
evaluating emicizumab at 3 mg/kg every 2 weeks (Q2W; BH30071) and 6 mg/kg every 
4 weeks (Q4W; BO39182), this study will open two additional non-randomized cohorts 
to investigate Q2W and Q4W regimens in pediatric patients (see Section 3.3.1).
2.
OBJECTIVES AND ENDPOINTS
The objectives of the study are to investigate (with no formal hypothesis testing) the 
efficacy, safety, and pharmacokinetics of SC emicizumab administered at 1.5 mg/kg 
QW, 3 mg/kg Q2W, and 6 mg/kg Q4W in pediatric patients with hemophilia A and FVIII 
inhibitors who are currently receiving treatment with bypassing agents.  A total of 
approximately 80 patients are planned: approximately 60 patients in Cohort A 
(1.5 mg/kg QW) and approximately 10 patients each in Cohort B (3 mg/kg Q2W) and 
Cohort C (6 mg/kg Q4W).  Patients younger than 12 years of age are planned for 
enrollment, with allowance of patients 1217 years of age who weigh 40 kg at the time 
of informed consent to further evaluate dosing of emicizumab in patients 40 kg.  Of 
note, enrollment in Cohort A may be left open exclusively for patients 2 years of age 
until approximately 5 such patients have been enrolled.
2.1
EFFICACY OBJECTIVES
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as 
appropriate.


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The efficacy objectives for this study are as follows: 

To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds 
over time (i.e., bleed rate) *

To evaluate the efficacy in reducing the number of bleeds over time compared with 
the patient's historical bleed rate (intra-patient comparison, Cohort A only, as 
patients enrolled in Cohorts B and C will not have previously participated in the
non-interventional study) *

To characterize the efficacy of up-titration on an intra-patient level, based on the 
basis of the number of bleeds over time *

To evaluate the HRQoL of children 817 years of age according to 
Haemo-QoL-Short Form (SF) (completed by patients)

To evaluate proxy-reported HRQoL and aspects of caregiver burden using the 
Adapted InhibQoL Including Aspects of Caregiver Burden questionnaire for all 
children (completed by caregivers)

To assess the number of days missed from daycare/school and days hospitalized
* Analyses will be performed for:  treated bleeds, all bleeds, treated spontaneous bleeds, 
treated joint bleeds, and treated target joint bleeds.  
2.2
SAFETY OBJECTIVE
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as 
appropriate.
The safety objective for this study is to evaluate the overall safety of emicizumab in 
pediatric patients with hemophilia A and inhibitors on the basis of the following endpoints:

Incidence and severity of adverse events

Incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs 

Incidence of laboratory abnormalities 

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to drug discontinuation 

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 

Incidence and severity of TMA  

Incidence and clinical significance of anti-emicizumab antibodies


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2.3
PHARMACOKINETIC OBJECTIVE
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg 
QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W).
The PK objective for this study is to characterize the exposure (Ctrough) of emicizumab in 
patients receiving 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W prior to drug 
administration on Day 1 and at the following timepoints:

Every week during Weeks 14 on emicizumab

Every 2 weeks during Weeks 59 on emicizumab

Every 4 weeks during Weeks 1337 on emicizumab

Every 8 weeks during Weeks 4149 on emicizumab

Every 12 weeks from Week 57 thereafter while continuing on emicizumab, until the 
end of the study

Additional PK samples will be taken in patients who require up-titration (see 
schedule of assessments in Appendix 1)
2.4
PHARMACODYNAMIC BIOMARKER OBJECTIVE
The PD biomarker objective for this study is as follows:

To assess potential PD biomarkers of emicizumab, including but not limited to aPTT
and FVIII activity, at designated timepoints throughout the study.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This non-randomized, multicenter, open-label, Phase III clinical study will enroll children
with hemophilia A who have inhibitors against FVIII.  Children with hemophilia A and 
documented historical FVIII inhibitor titer (5 BU) must currently be receiving treatment 
with bypassing agents.  At least 40 patients younger than 12 years of age and up to 
approximately 80 patients are planned for enrollment, with allowance of patients 1217
years of age who weigh 40 kg at the time of informed consent.  Patients will receive SC 
doses of emicizumab at 1.5 mg/kg QW (Cohort A) for a minimum of 52 weeks, or until 
unacceptable toxicity, discontinuation from the study due to any cause, or other criteria 
set forth in the protocol, whichever occurs first (see Figure 1). After 52 weeks of 
treatment, an individual patient who continues to derive clinical benefit may continue 
receiving prophylactic emicizumab as part of this study or a future separate emicizumab 
extension study.
Because of the uncertainty of the dosing regimen needed in patients 12 years of age or 
40 kg to achieve similar exposure as in adults and adolescents, this study will first 
evaluate the appropriate dosing regimen in children by starting with the same weekly
dosing regimen (1.5 mg/kg QW) being evaluated in the Phase III study (BH29884) in 
adult/adolescent patients with hemophilia A with inhibitors (see Section 3.3.1 for details). 
Emicizumab will be administered with a loading dose of 3 mg/kg QW for the first 


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4 weeks followed by a maintenance dose of 1.5 mg/kg QW (Cohort A) for the 
remainder of the treatment period.  During the 52-week treatment period, individual 
patients may have their dose up-titrated if they experience suboptimal bleeding control 
on emicizumab (see Section 4.5.2).  
In a first interim data review, the appropriateness of the initial dosing regimen will be 
evaluated (maintenance dose of 1.5 mg/kg QW) after the first 35 patients (2 to
12 years of age) have been dosed for a minimum of 12 weeks.  A Joint Monitoring 
Committee (JMC; see Section 9.5) will review all cumulative data (e.g., safety, efficacy, 
and pharmacokinetics) to provide recommendations on increasing the starting 
maintenance dose (if necessary) to target a similar plasma emicizumab trough 
concentration as the one being targeted in adolescents and adults (i.e., 45 µg/mL).  All 
patients enrolled following the first interim data review will receive the starting 
maintenance dose selected by the JMC.  Those patients enrolled prior to the first interim 
data review who had not had their dose up-titrated will remain on their current 
maintenance dose, unless they meet eligibility for up-titration based on protocol-defined 
criteria (see Section 4.5.2).
In order to include and safely treat the youngest patients (birth to 2 years of age), this 
study will include a staggered approach to enrollment by age.  Patients 2 to 12 years 
of age and patients 1217 years of age who weigh 40 kg will enroll first.  A second 
interim data review will occur once at least 10 patients between 2 and 12 years of 
age have been dosed for a minimum of 12 weeks, at which time all cumulative data (e.g., 
safety, efficacy, and pharmacokinetics) will be evaluated to provide recommendations for 
enrollment of children 2 years of age, as well as on any additional adaptations of the 
maintenance dose if necessary.
Furthermore, should patient recruitment be faster than anticipated, enrollment will be 
placed on a temporary hold following the first 20 patients until the JMC releases its 
recommendations on the appropriateness of the maintenance dose (Cohort A).  After 
the JMC recommendations are released following both interim data reviews, the study 
will continue to enroll in Cohort A up to approximately 60 patients.
Once 1) the exposure at 1.5 mg/kg QW has been characterized in this pediatric 
population; 2) Cohort A is fully enrolled; and 3) review of data in adults and 
adolescents from two ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W 
(BH30071) and 6 mg/kg Q4W (BO39182) identifies no safety concerns, this study will 
open two additional non-randomized cohorts to investigate Q2W and Q4W regimens in 
pediatric patients. Recruitment to Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg 
Q4W) will occur in parallel with alternate cohort allocation via IxRS, for a total of 
approximately 10 patients per cohort. Of note, enrollment to Cohorts B and C will be 
limited to patients 211 years of age. Emicizumab will be administered with a loading 
dose of 3 mg/kg QW for the first 4 weeks followed by a maintenance dose of 3 mg/kg 
Q2W (Cohort B) and 6mg/kg Q4W (Cohort C) for a minimum of 52 weeks, or until 


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unacceptable toxicity, discontinuation from the study due to any cause, or other criteria 
set forth in the protocol, whichever occurs first (see Figure 1). During the 52-week 
treatment period, individual patients may have their dose up-titrated if they experience 
suboptimal bleeding control on emicizumab.
The entire study will enroll up to approximately 80 patients with allowance for 
additional patients 2 years of age in Cohort A.
A patient who fulfills the inclusion and exclusion criteria should be enrolled at the Week 1 
visit.  Prophylactic use of bypassing agents should be discontinued the day before the
first dose of emicizumab is given. 
Figure 1
Study Schema
JMCJoint Monitoring Committee; Q2W every 2 weeks; Q4W every 4 weeks; QW once 
weekly; Scrscreening.
*
In a first interim data review, the starting maintenance dose will be evaluated after the first
35 patients (2 to 12 years of age) have been dosed for a minimum of 12 weeks.  A JMC 
will review all cumulative data (e.g., safety, efficacy, and pharmacokinetics) to provide 
recommendations on increasing the starting maintenance dose.  A second interim data review
will occur by the JMC once at least 10 patients (2 to 12 years of age) have been dosed for a 
minimum of 12 weeks, at which time all available cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) will be evaluated to provide recommendations for the enrollment of children 
2 years of age, as well as on the maintenance dose. Should patient recruitment be faster 
than anticipated, enrollment will be placed on a temporary hold after the first 20 patients until 
the JMC releases its recommendations on the appropriateness of the maintenance dose.  After 
the JMC recommendations are released following both interim data reviews, the study will 
continue to enroll up to a maximum of approximately 60 patients in Cohort A. Subsequently, 
should no safety concerns arise from review of adult/adolescent data at Q2W (BH20071) and 
Q4W (BO39182) dosing, parallel enrollment with alternate cohort allocation to Cohorts B 
and C (up to approximately 10 patients per cohort, respectively) will commence.


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The primary analysis for all cohorts will be performed 52 weeks after all patients in the 
primary population of Cohort A have been enrolled or withdrawn prematurely, whichever 
occurs first.  The primary population of Cohort A consists of all patients enrolled prior to
the close of enrollment for patients 2 years of age (up to approximately 60 patients)
and is used to define the timing of the primary analysis of Cohorts A, B, and C.  If no 
patients 2 years of age are included in the primary population of Cohort A, the primary 
analysis will still occur at the specified time; however, enrollment to Cohort A may be left
open exclusively for patients 2 years of age in order to enroll approximately 5 such
patients.  Note that these patients will be included in the primary analysis of Cohort A
regardless of their follow-up time. Additionally, all available data from patients enrolled 
in Cohorts B and C (efficacy period approximately 6 months) will be included in the 
primary analysis of Cohort A.
During the study, caregivers will be asked to enter any individual bleeds, 
hemophilia-related medications, and emicizumab treatments that occur on an electronic, 
handheld device.  Entries should be made at least weekly, and also at any time a bleed 
occurs or a hemophilia medication, including emicizumab, is administered.  Detailed
information about bleeds (type, location, date/time) will be captured.  Detailed 
information about hemophilia medications (agent, dose, reason for administration, 
date/time) and emicizumab dosing (total volume, date/time) will also be captured.  In 
addition, HRQoL using the Haemo-QoL-SF (completed by children 8 years of age and 
older), proxy-reported HRQoL and aspects of caregiver burden using Adapted InhibQoL 
(completed by caregivers of all children) and missed daycare/school will be collected on 
a separate electronic, handheld device during a patient’s visit prior to emicizumab 
injection at Week 1 and every 12 weeks thereafter, as outlined in the schedule of 
assessments (see Appendix 1).  The number of days the child was hospitalized, if 
applicable, will be derived from data collected on eCRF.
Emicizumab is intended in this study for prophylactic use only (i.e., not to treat bleeds 
that have already occurred).  Therefore, in this study all patients may continue to receive 
episodic treatment for breakthrough bleeds as needed.  Breakthrough bleeds should 
preferably be treated with rFVIIa at the lowest expected dose to achieve hemostasis and 
captured as they occur on the electronic, handheld device.  There is clinical experience 
in the ongoing Phase I/II clinical studies with the treatment of over 80 breakthrough 
bleeds in patients receiving emicizumab with either FVIII or bypassing agents.  FVIII,
aPCC, and rFVIIa do not interfere with emicizumab PK assessments, and no safety 
signals have been observed when breakthrough bleeds were treated with standard-of-
care regimens during Phase I/II studies.  However, in the ongoing Phase III Study 
BH29884 (adolescent and adult patients with hemophilia A with FVIII inhibitors), 
3 events of TMA and 3 serious thromboembolic events were observed in patients who 
concomitantly used 100 U/kg/day of aPCC on average for 24 hours for the treatment
of breakthrough bleeds (see Sections 1.2, 1.3, 5.1.1.3, and 5.1.1.4). Therefore, it is 
recommended that breakthrough bleeds are treated with rFVIIa only, if possible, and that 


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the use of aPCC or other bypassing agents should be avoided or limited (see 
Sections 4.6.1 and 4.6.2).  Also, local and central laboratory assessments are required 
to monitor the risk for thromboembolic events or TMA as per the schedule of 
assessments (see Appendix 1 and Appendix 2).  Investigators will be asked to contact 
the Medical Monitor in the event of suspected lack or loss of efficacy of emicizumab in 
order to discuss potential laboratory evaluations (e.g., anti-emicizumab antibodies, 
coagulation tests) to be performed as well as to re-evaluate the patient’s benefit-risk of 
continued treatment.
Physical examinations, vital sign assessments, ECG, and safety laboratory assessments 
will be collected as per the schedule of assessments (see Appendix 1).  Adverse events 
will be captured on an ongoing basis as they occur during the study.  All patients in this 
study will undergo PK assessments.  Blood samples will also be collected to assess the 
PD properties of emicizumab (i.e., aPTT, FVIII activity), as well as to assess 
immunogenicity (i.e., anti-emicizumab antibodies and anti-FVIII antibodies).  A detailed 
list is provided in the schedule of assessments (see Appendix 1).
Of note, a non-interventional study (Study BH29768) has been initiated to document the 
number and types of bleeds and current treatment with episodic or prophylactic 
bypassing agents, as well as collect information on HRQoL, health status, and safety in 
patients with hemophilia A (including children 12 years of age).  The assessments in 
the non-interventional study will mitigate the risk of inaccurate reporting of bleeds that 
may occur with historical data collection and may provide data collected prospectively for 
over 24 weeks.  Pediatric patients who are enrolled in the non-interventional Study 
BH29768 are eligible to enroll in this study, as long as they meet the inclusion and 
exclusion criteria and are able to enroll at a participating site while the study is open for 
enrollment. All patients who participated in the non-interventional study will be 
enrolled in Cohort A.
3.2
END OF STUDY AND LENGTH OF STUDY
LENGTH OF STUDY
The length of the entire study from screening of the first patient to the last patient 
completing 52 weeks in the study and/or the end of study follow-up visit (24 weeks after 
discontinuing emicizumab) will be approximately 152 weeks.
END OF STUDY
The primary analysis will take place at the same time for Cohorts A, B, and C. It will 
occur after all patients in the primary population of Cohort A have completed 52 weeks 
of treatment, or have withdrawn prematurely, whichever occurs first. All data from 
patients enrolled in Cohorts B and C will be included regardless of follow-up time.
After 52 weeks of treatment, an individual patient who continues to derive clinical benefit 
may continue receiving prophylactic emicizumab as part of this study or a future 


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separate emicizumab extension study.  Patients who discontinue emicizumab will have a 
safety follow-up visit at 24 weeks after the last emicizumab dose.
The end of this study is defined as the date when the last remaining patient has 
completed the last visit (i.e., LPLV), as defined below:

Completed 52 weeks of emicizumab and either transferred to a separate extension 
study to receive further emicizumab as per Roche Global Policy on Continued 
Access to Investigational Medicinal Products or to commercial product
OR

Completed the end of study safety follow-up visit 24 weeks after discontinuing 
emicizumab
OR

Consent has been withdrawn
OR

Lost to follow-up
3.3
RATIONALE FOR STUDY DESIGN
Regulatory Agencies introduced the concept of extrapolation of efficacy from adult to 
pediatric patients in the European Union with the Guidelines, ’’Concept paper on 
extrapolation of efficacy and safety in medicine development’’ (EMA 2013) and in the 
United States with 1994 Final Regulation on Pediatric Labeling.  Indeed, recent 
registration studies of clotting factor concentrates (Eloctate SBA, Novoeight SBA, 
Advate SBA), for children with hemophilia A, have defined pharmacokinetics and safety 
in pediatric patients with extrapolation of efficacy data from adults and adolescents.  The 
Sponsor has chosen a similar approach utilizing a non-randomized, descriptive study to 
investigate the pharmacokinetics, safety, and efficacy of emicizumab in pediatric 
hemophilia A patients with FVIII inhibitors.  Extrapolation of efficacy from the adult 
population to the pediatric population has helped to maximize the use of existing 
information to increase the efficiency of pediatric drug development programs while 
maintaining the goal of increasing the number of safe effective medicines approved for 
pediatric use on the basis of scientifically robust data (Dunne et al. 2011).  As such, no 
formal hypothesis is planned.  There are no anticipated differences in the effect of 
emicizumab in pediatric patients compared with adults, and similar exposure in 
adult/adolescent and pediatric patients 12 years of age is assumed to produce similar 
efficacy.  This strategy is consistent with recent recommendations published by the 
International Society on Thrombosis and Haemostasis (ISTH).  The Project Group on 
Clinical Trials for New Products in Hemophilia recommends, in the framework of the U.S. 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) pediatric 
regulation mandating the generation of pediatric data to support Marketing Authorization 
Application (MAA), to adopt an appropriate clinical development approach to limit the 
risks in delaying access to products for all patients with hemophilia for an extended time, 
given the relative rarity of this condition and logistics of conducting clinical studies 


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(DiMichele et al 2015).  The proposed study, BH29992, will therefore evaluate the use of 
prophylactic emicizumab, in children with inhibitors to FVIII previously treated with 
bypassing agents in a non-randomized, multicenter, open-label study.
3.3.1
Rationale for Emicizumab Dose and Schedule
Loading doses of 3 mg/kg QW emicizumab for 4 weeks will be followed by a 
maintenance dose of 1.5 mg/kg QW for patients enrolled in Cohort A.  Subsequent
dose adaptation will be made as required based on efficacy and exposure, as detailed 
below.
Emicizumab prophylaxis has been administered subcutaneously in 18 Japanese patients 
with hemophilia A (with and without FVIII inhibitors) in Study ACE001JP and in its 
ongoing extension Phase I/II Study ACE002JP. One patient receiving weekly doses of 
1 mg/kg discontinued emicizumab during Study ACE001JP.  Three dose cohorts (of 
6 patients each) received the following treatment (administration period of 12 weeks):

Cohort C-1: a loading dose of 1 mg/kg followed by weekly doses of 0.3 mg/kg

Cohort C-2: a loading dose of 3 mg/kg followed by weekly doses of 1 mg/kg

Cohort C-3: weekly doses of 3 mg/kg
Three dose cohorts included 5 adolescent patients:  1 patient (
-year-old inhibitor) in 
Cohort C-1; 2 patients (
-year-old inhibitor, 
-year-old non-inhibitor) in Cohort C-2; 
and 2 patients (
-year-old inhibitor, 
-years-old inhibitor) in Cohort C-3.
Emicizumab was safe and well-tolerated in these patients (see Section 1.2 and the 
Emicizumab Investigator's Brochure).  The maximum clinical dose of 3 mg/kg weekly is 
associated with a 10.3-fold and 11.2-fold safety margin relative to the preclinical NOAEL 
based on Cmax and AUC, respectively.  No clear difference in the plasma concentrations 
of emicizumab was observed between adolescent and adult (aged 1958 years) patients.
A substantial reduction in bleeding events has been observed with prophylactic 
emicizumab treatment, especially at doses 1 mg/kg weekly (see Table 1).  ABR 
decreased in all patients, regardless of age or the presence of FVIII inhibitors. See the 
Emicizumab Investigator's Brochure for additional details on clinical studies with 
emicizumab. 
Table 1
Mean Reduction (%) of Annualized Bleeding Rates in Inhibitor 
and Non-Inhibitor Patients Enrolled in ACE001JP/ACE002JP
Emicizumab Dose
0.3 mg/kg weekly
1 mg/kg weekly
3 mg/kg weekly
Mean ABR reduction
74.7%
85.8%
93.0%
ABRannualized bleeding rate.


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A median ABR of 0 was achieved with weekly maintenance doses of 1 and 3 mg/kg.  
The number of bleeding events decreased with increased emicizumab plasma 
concentrations (see Figure 2).
Figure 2
Individual Pharmacokinetic Profile with Corresponding 
Bleeding Event
ACE910emicizumab.
●
Joint bleed
Ο
Non-joint bleed
The exposure-response relationship of emicizumab was quantitatively characterized and 
simulations suggested that a median ABR of 0 is achieved for emicizumab trough 
plasma concentration 45 g/mL.  On the basis of population PK modeling, a median 
trough plasma concentration of 45 g/mL is predicted to be achieved after treatment with 
4 weekly doses of 3 mg/kg and maintained, thereafter, with weekly doses of 1.5 mg/kg.  


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The loading doses of 3 mg/kg weekly for 4 weeks were chosen in order to rapidly 
achieve the effective trough concentration of 45 g/mL without exceeding the maximum 
dose of 3 mg/kg weekly investigated in the Phase I/II studies.  Thereafter, a dose and 
schedule of 1.5 mg/kg weekly was chosen in order to reduce the peak-trough 
fluctuations and to maintain emicizumab plasma concentrations above 45 g/mL over 
the entire dosing interval.  This dosing regimen (i.e., 3 mg/kg weekly for 4 weeks 
followed by 1.5 mg/kg weekly) was, therefore, chosen to be investigated in the adult and 
adolescent study, BH29884.
Due to the similarity of the disease between adults/adolescents and children, as well as 
the availability of a physiologically functioning coagulation system from 6 months 
onwards (including the targets of emicizumab, FIX and FX), there are no anticipated 
differences in the action of emicizumab in pediatric patients compared with adults.  
Indeed, pediatric and adult patients with hemophilia A have shown a similar response to 
treatment with FVIII compounds (Mahlangu et al. 2014; Young et al. 2015) and 
bypassing agents (Young et al. 2012).  Furthermore, in the Japanese Phase I/II clinical 
studies with emicizumab, adolescent patients (aged 1218 years) with hemophilia A 
have demonstrated similar safety and efficacy results to those observed in adults. 
Therefore, the dosing regimen to be investigated in the present study in patients 
12 years of age is to be selected to target a similar plasma emicizumab concentration 
trough level as the one being targeted in adolescents and adults (i.e., 45 µg/mL).
Preliminary investigations of the effect of body weight on emicizumab pharmacokinetics 
suggest that exposure decreases slightly with decreased body weight.  A maintenance 
dose of 1.5 mg/kg/week is predicted to maintain a median trough concentration above 
the cutoff of 45 μg/mL in patients weighing 40 kg.  In order to predict which weekly 
maintenance dose would be needed in pediatric patients to achieve the desired trough 
plasma concentration of emicizumab, simulations of steady-state trough plasma 
concentrations were performed using age as a predictor of body weight.  Simulations 
based on this body weight effect indicated that a weekly maintenance dose of 
2.25 mg/kg/week would be needed in patients aged 112 years, and 3 mg/kg/week in 
patients aged 1 year.  However, body weight changes, alone, do not explain changes 
in drug disposition due to maturation of organ, tissue, enzyme, and transporter systems 
in neonates and infants (Anderson 2008; 2013).  Age was, therefore, also used as a 
predictor of maturation of clearance, in addition to body weight, and simulations 
indicated that a weekly maintenance dose of 1.5 mg/kg would be needed in patients 
aged 112 years, and 2.25 mg/kg in patients aged 1 year.  In light of the opposing 
effect of body weight and clearance maturation on the emicizumab exposure, and the 
uncertainty associated with the effect of clearance maturation, there is a possibility that 
the same dosing regimen in adolescent/adult and pediatric patients (i.e., loading doses 
of 3 mg/kg QW for 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW) provides 
the same efficacy trough of 45 μg/mL.  Thus, Study BH29992 will evaluate the 
appropriate dosing regimen in children by starting with the same dosing regimen as the 
adult and adolescent study, BH29884.


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Individual pediatric patients may have their dose up-titrated if they experience 
suboptimal control of bleeding on emicizumab (see Section 4.5.2).  Prophylactic 
treatment with FEIBA currently provides the most efficacious treatment for hemophilia A 
patients with inhibitors, with a median ABR of 8 (Antunes et al. 2014); thus, suboptimal 
control of bleeding in this study has been defined as an ABR 8.  In Study BH29992, 
up-titration may be required if the patient experiences more than two bleeding events 
during a 12-week treatment period at a given dose (which corresponds to an ABR of 8). 
Dose up-titration will, therefore, be guided by bleeding control on the current dose and 
by discussion with and approval of the Medical Monitor.  Using a safety and efficacy 
guided up-titration scheme allows for more accurate assessment of bleeding events in 
light of safety considerations and each patient’s duration of exposure at a particular dose.
If a majority of the initially enrolled patients require up-titration, or their emicizumab 
trough plasma concentration is on average lower than 45 g/mL, the choice of the initial 
maintenance dose may not be appropriate.  Thus, the Sponsor plans to re-evaluate the 
starting maintenance dose after the first 35 patients (211 years of age) have been 
treated for a minimum of 12 weeks.  All cumulative data (safety, efficacy, and 
pharmacokinetics) will be evaluated by a JMC to provide recommendations of changing 
the starting maintenance dose for the subsequent patients enrolled (see Section 4.5.2).
3.3.1.1
Interim Analysis, JMC Recommendations, and Rationale for 
Enrollment of Q2W/Q4W in Pediatric Patients
The initial maintenance dose of 1.5 mg/kg QW was evaluated by the Study BH29992 
JMC during an interim data review (clinical cutoff date: 28 October 2016). As 
enrollment occurred faster than anticipated, the two planned data review meetings were 
combined into one. All available data (including safety, efficacy, and pharmacokinetics) 
from the first 20 patients enrolled in Cohort A was assessed by the JMC to determine 
the appropriateness of the starting maintenance dose, as well as to decide whether the 
study could begin enrolling patients 2 years of age. On 7 December 2016, the JMC 
recommended continuing enrollment of patients in Cohort A at the maintenance dose of 
1.5 mg/kg QW, as well as to open enrollment to patients 2 years of age at that same 
maintenance dose. Since exposure at 1.5 mg/kg QW was similar between patients 312
years of age and adolescent/adult patients, the up-titration scheme for children has been 
modified to be the same as the one used in adolescent/adult patients, that is, individual 
up-titration to 3 mg/kg QW should they experience suboptimal control of bleeding on 
emicizumab (see Section 4.5.2).
Furthermore, two Phase III studies investigating 3 mg/kg Q2W (BH30071) and 
6 mg/kg Q4W (BO39182) have been initiated in adolescent/adult patients with 
hemophilia A without inhibitors (BH30071) and with and without inhibitors 
(BO39182). All three dosing regimens are predicted to achieve similar exposure (in 
terms of steady-state average concentration, Cavg,ss; see Table 2), and despite higher peak 
concentrations and lower trough concentrations with less frequent dosing regimens, all 
are expected to result in similar treatment response (all three dosing regimens provide 


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similar predicted ABR distribution) and safety profiles.  Of note, the exposures 
achieved with these three dosing regimens remain well below the safe and well-tolerated 
one achieved with the highest dose of 3 mg/kg QW (observed trough concentration of 
120 26.8 g/mL). Ultimately, these three dosing regimens will provide the option for 
patients to receive emicizumab at different scheduled intervals, while still delivering 
the same cumulative dose.
Table 2
Simulated Median Pharmacokinetic Parameters
Parameters
Maintenance Dose
1.5 mg/kg QW
3 mg/kg Q2W
6 mg/kg Q4W
Cmax,ss (g/mL)
54.6
56.8
63.4
Ctrough,ss (g/mL)
51.5
48.0
40.7
Cavg,ss (g/mL)
53.0
53.1
53.0
Cavg,ss average concentration (AUC/) at steady state; Cmax,ss maximum plasma 
concentration at steady state; Ctrough,ss trough concentration at steady state; Q2W every 2 
weeks; Q4W every 4 weeks; QW once weekly.
An independent Data Monitoring Committee (iDMC) conducted a scheduled review of 
the safety data in Study BH30071, which detected no unforeseen safety signals in 
adult/adolescent patients treated with emicizumab at 3 mg/kg Q2W. Meanwhile, an 
interim analysis of 6 mg/kg Q4W in a run-in cohort of 7 adolescent/adult patients in 
Study BO39182 indicated that observed PK parameters at 6 mg/kg Q4W were as 
expected, in line with earlier simulations. This study is ongoing with no safety 
concerns raised by the iDMC to date. Therefore in this current study, following 
completion of accrual to Cohort A (1.5mg/kg QW), enrollment to Cohorts B (3 mg/kg 
Q2W) and C (6 mg/kg Q4W) can commence.
The emicizumab regimens to be evaluated in this study consist of a loading dose of 
3 mg/kg weekly for 4 weeks, followed by a maintenance dose administered either 
1.5 mg/kg QW, 3 mg/kg every Q2W, or 6 mg/kg Q4W. Of note, a maintenance dose of 
3 mg/kg QW may also be evaluated in the setting of patients who have their dose 
up-titrated.
3.3.2
Rationale for Patient Population
As described in Section 1.1, pediatric patients from birth to 11 years of age with 
hemophilia A and inhibitors against FVIII who are treated with bypassing agents prior to 
study entry will comprise the primary population for this Phase IIII study evaluating the 
pharmacokinetics, safety, and efficacy of prophylactic emicizumab.  However, due to the 
current uncertainty of dosing in patients 40 kg (with some patients 12 years of age 
falling into this category), patients 1217 years of age who weigh 40 kg will also be 
allowed to enroll (in Cohort A).


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Although the initial severity of a patient’s hemophilia A is directly related to the
endogenous FVIII activity, the treatment of patients of any severity (mild, moderate, or 
severe) with high-titer inhibitors is similar (i.e., with bypassing agents).  Because the 
initial severity of hemophilia A, which is defined at diagnosis on the basis of FVIII activity,
is no longer prognostic of clinical phenotype and risk of bleeding in patients who have 
developed high titer inhibitors, this will not be used to determine study eligibility.
Instead, eligibility criteria aim to select a cohort of hemophilia A patients with inhibitors 
who have a high, unmet medical need.  Thus, pediatric patients 2 years of age with 
inhibitors treated with bypassing agents on an episodic basis will be required to have an
ABR of 6 (e.g., 3 bleeds in the last 24 weeks). Patients treated with bypassing 
agents on a prophylactic basis will be required to be inadequately controlled (e.g., 
2 bleeds since starting prophylaxis or 1 life-threatening bleed) or with CVAD placement 
medically not feasible or deemed unsafe by investigator.  In such cases, deficiencies 
associated with bypassing agents, including decreased efficacy, increased thrombotic 
risk, and increased burden of care, render these patients on prophylaxis in high unmet 
medical need.  Finally, pediatric patients 2 years of age with inhibitors treated with 
bypassing agents, and determined by investigator to be at high risk of bleed, will also be 
allowed to enroll (in Cohort A).
Based on its mechanism of action (mimetic of FVIII co-factor activity) and clinical study 
results to-date, prophylactic emicizumab is expected to provide significant and clinically 
meaningful benefit for pediatric patients with inhibitors who are in need of a reliably 
efficacious therapy to prevent bleeds.
Based on current treatment algorithms for patients with hemophilia A with inhibitors 
(Kempton and White 2009; Srivastava et al. 2013), it is anticipated that the majority of 
adults and adolescents treated with emicizumab will have previously undergone ITI 
without success or are not candidates for ITI, although prior ITI will not be required for 
study entry.
Because clinical safety data related to the concomitant use of prophylactic emicizumab 
in the presence of high doses of FVIII, such as are administered during ITI, are not 
available at this time, patients currently receiving ITI will not be eligible for enrollment in 
this study.  Because the presence or amount of FVIII inhibitors in their plasma does not 
impact the efficacy of emicizumab, and inhibitor titers may drop when patients are not 
exposed to FVIII for a prolonged period of time, patients’ inhibitor titers at the time of 
study entry will not influence their study eligibility.  However, patients will be required to 
have a history of a high-titer inhibitor documented in the medical record in order to be 
eligible for the study.
3.3.3
Rationale for the Efficacy Analyses
The objective of the efficacy analysis is to evaluate the clinical effect of prophylactic 
emicizumab on the number of bleeds over time (i.e., bleed rate). Another efficacy 


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analysis will also characterize the efficacy of up-titration on an intra-patient level.  As 
mentioned in Section 3.1, the primary efficacy analysis will be performed 52 weeks after 
the last patient from the primary population of Cohort A has been enrolled or withdrawn 
prematurely, whichever occurs first. Primary efficacy analyses for Cohorts B and C will 
occur at the time of the primary analysis for Cohort A.  Additional efficacy analyses
will be performed at the end of the study and as needed to support regulatory 
interactions. 
In the multiple-ascending dose Phase I study involving Japanese patients with
hemophilia A (Study ACE001JP), a clinically meaningful reduction in median ABR to 0 
after 12 weeks of treatment in the 1 and 3 mg/kg/week emicizumab dose cohorts was 
demonstrated. In the Japanese Phase I/II extension study (ACE002JP), the median 
ABR of the 1 and 3 mg/kg/week dose cohorts remained 0 in patients who continued to 
receive prophylactic emicizumab after a minimum of 24 weeks, which is consistent with 
evidence suggesting longer duration of prophylactic therapy in inhibitor patients is 
associated with maintenance of ABR reduction (Antunes et al. 2014). At the cutoff date 
of 17 April 2015, the duration of safety follow-up for all patients in the 1 and 
3 mg/kg/week cohorts in Study ACE001JP/Study ACE002JP ranges from 
69.380.3 weeks and 45.154.6 weeks, respectively (see the Emicizumab Investigator's 
Brochure for additional details on clinical studies with emicizumab).
3.3.4
Rationale for Patient-Reported Outcome Assessments
HRQoL is an important outcome in the care of children with hemophilia 
(Brown et al. 2009).  HRQoL in hemophilic patients is multifaceted and impacted by
disease symptoms (pain, bleeding), treatment (prophylactic and on-demand), anxiety 
(around injections), and limitations in daily activities. 
The goal of measuring HRQoL is to quantify the benefit of treatment from the patient 
perspective.  Previous studies that have used the Haemo-QoL, a measure of different 
dimensions of HRQoL affected by hemophilia in children and adolescents, have reported 
improvements in physical health, feelings, view of self, family relations, friend relations, 
perceived support, relation with others, participation in sports, dealing with hemophilia, 
views of treatment, views of the future, and relationships (Santagostino et al. 2014). 
Because children often require assistance in the administration of their hemophilia 
medication, it is equally important to assess the potential burden and impact on HRQoL 
that this may have on caregivers.  In a recent study of caregivers of hemophilic children 
with inhibitors, an increased burden and higher impact of the disease on the family was 
reported (Lindvall et al. 2014).  This burden was reported in a variety of areas including 
financial, emotional, general strain, isolation, and activities.
The inclusion of HRQoL measures in the current study will allow for the assessment of 
the impact of prophylactic treatment with emicizumab in children with hemophilia A and 
their caregivers and an evaluation of the changes in HRQoL in patients prior to and 
following treatment with emicizumab.  These HRQoL measures will be assessed at 


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baseline and every 12 weeks using a tablet device during a patient’s visit in clinic.  
HRQoL questionnaires include the Haemo-QoL-SF (to be completed by patients 
817 years of age) and the Adapted InhibQoL with Aspects of Caregiver Burden (to be 
completed by caregivers of all patients enrolled in this study).  
3.3.5
Rationale for Biomarker Assessments
Some biomarkers to measure the PD effect of emicizumab on hemostasis have not been 
fully validated to date and require further testing to determine which assays and 
technical conditions are most suitable for use with emicizumab treatment.  Refer to 
Section 5.1.3 for more information about effects of emicizumab on existing laboratory 
assays.  Plasma samples will be collected for central PD biomarker assessment in 
parallel with PK samples to demonstrate evidence of biologic activity of emicizumab in 
patients and to monitor the patients’ coagulation status.  These biomarkers include but 
are not limited to coagulation-related assays such as aPTT, PT/INR, D-dimer, and FVIII 
activity assays. The aPTT and thrombin generation assays were previously shown in 
the Phase I/II study to exhibit a dose-response relationship to emicizumab concentration 
(for more information, see the Emicizumab Investigator’s Brochure).  The central aPTT 
assay will be run both in standard form and with a modification to ensure that the assay 
range covers all levels of emicizumab exposure.  
Exploratory plasma biomarkers will include factor IX antigen (FIX:Ag) and factor X 
antigen (FX:Ag) to assess whether drug treatment causes a change in the circulating 
levels of these coagulation factors, which are the binding targets of emicizumab, and 
may include measurement of other coagulation or hemophilia-related factors or assays.  
Finally, residual blood from collected samples may be used for additional 
emicizumab-related research.  These banked plasma samples will not be used for 
general, disease-related research purposes but instead for research directly related to 
emicizumab.
Assessments that require blood draws should be monitored closely to ensure that 
institutional mandates regarding total sample blood volumes are followed. In situations 
where no institutional guidance is available, the following limits should be utilized and 
have been included in the design of the sampling program:  no more than 1% of the total 
blood volume should be taken at one time and no more than 3% of the total blood 
volume should be taken over a 30 day period.  (Total blood volume is defined as 
8090 mL/kg [European Union 2008]). Thus, blood sampling timepoints and volumes 
follow the EC Guideline on Ethical considerations for clinical studies on medicinal 
products conducted with the pediatric population. In situations where the total volume of 
blood drawn might exceed the limits stated above, clinical (safety) laboratory 
assessments should be prioritized. Any remaining permitted blood volume should be 
collected for PK and immunogenicity samples, followed by biomarker and PD samples.  
Refer to the laboratory manual for detailed weight-based blood sampling guidelines.


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3.3.6
Rationale for Pharmacokinetic Sample Schedule
One of the aims of this study is to provide dosing recommendations for pediatric patients 
aged less than 12 years.  A median ABR of 0 has been predicted to be achieved for an 
emicizumab trough plasma concentration of 45 g/mL based on data in adolescent and 
adult patients with hemophilia A (Study ACE001JP/ACE002JP).  As no differences in the 
action of emicizumab are anticipated between pediatric and adult patients (see 
Section 3.3.1), it is the Sponsor’s intention to identify a dose in children 12 years that 
may provide such a trough plasma concentration.
Plasma samples will, therefore, be collected weekly during the loading dose period and 
at subsequently less frequent intervals while at steady state in order to document the 
exposure in pediatric patients.  This will ultimately allow for optimization of the dosing 
regimen of emicizumab in children.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 80 children 12 years of age with hemophilia A and with FVIII inhibitors
previously treated with bypassing agents will be enrolled in the study (approximately 
60 patients in Cohort A, 10 patients in Cohort B, and 10 patients in Cohort C). In
addition to this primary population of children 12 years of age, patients 1217 years of 
age who weigh 40 kg at the time of informed consent will also be eligible to enroll. 
These patients, as well as those 2 years of age at the time of informed consent, will 
only be eligible to enroll in Cohort A. Of note, enrollment in Cohort A may be left open 
exclusively for patients 2 years of age until approximately 510 such patients have 
been enrolled prior to the closure of Cohorts B and C, whichever occurs first.   
4.2
INCLUSION CRITERIA
Children must meet all the following criteria for study entry:

Written informed consent must be obtained from parent/legally acceptable 
representative and an assent from the child when applicable (latest approved 
version by the Independent Ethics Committee [IEC]/Institutional Review Board [IRB]) 
prior to any of the study-specific assessments and procedures being performed.

Children 12 years of age at time of informed consent with allowance for the 
following:
Patients 1217 years of age and who weigh 40 kg at the time of informed 
consent (Cohort A only)
Patients 2 years of age will be allowed to participate only after the 
protocol-defined interim data review criteria are met (Cohort A only)

Body weight 3 kg at time of informed consent


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
Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures including the completion of applicable 
patient-reported outcome (PRO) questionnaires

Caregivers of all children must have the willingness and ability to comply with all 
study procedures including the completion of the bleed/medication questionnaire 
and applicable HRQoL questionnaires 

Diagnosis of congenital hemophilia A of any severity and documented history of 
high-titer inhibitor (i.e., 5 BU)

Requires treatment with bypassing agents

For patients 2 years of age: 
If on an episodic bypassing agent regimen: ABR of 6 (e.g., 3 bleeds in the last 
24 weeks) 
OR 
If on a prophylactic bypassing agent regimen: inadequately controlled (e.g., 
2 bleeds since starting prophylaxis or 1 life-threatening bleed) or CVAD 
placement medically not feasible or deemed unsafe by investigator

For patients 2 years of age (Cohort A only): determined by investigator to be in
high unmet medical need

Adequate hematologic function, defined as platelet count of 100109 cells/L and 
hemoglobin 8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5age adapted upper limit 
of normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT 3age 
adapted ULN at the time of screening

Adequate renal function: serum creatinine must be 1.5ULN for age.  When the 
serum creatinine is 1.5ULN, creatinine clearance by Bedside Schwartz formula 
must be 70 mL/min/1.73m2

At screening, in the rare cases of hemophilia in female patients who are of 
childbearing potential, patients will be required to have a negative serum pregnancy 
test result (with urine pregnancy tests performed at subsequent specified visits) and 
will have to agree to remain abstinent or use single or combined highly effective 
contraceptive methods that result in a failure rate of 1% per year and are approved 
by local health authorities and ethics committees during the treatment period and for 
at least 5 elimination half-lives (24 weeks) after the last dose of study drug.
4.3
EXCLUSION CRITERIA
Children who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment 
with FVIII  
Patients awaiting initiation of ITI will be eligible 


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Patients in whom ITI has failed will be eligible with a 72-hour washout period 
prior to the first emicizumab administration.

Previous (in the past 12 months) or current treatment for thromboembolic disease 
(with the exception of previous catheter-associated thrombosis for which 
anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic 
disease 

Other diseases (i.e., certain autoimmune diseases [e.g., systemic lupus 
erythematosus], cardiovascular disease) that may increase risk of bleeding or 
thrombosis

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Known infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV)

Patients who are at high risk for TMA (e.g., have a previous medical or family history 
of TMA), in the investigator’s judgment

Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrollment 
or planned use during the study period

Planned surgery (excluding minor procedures such as tooth extraction or incision 
and drainage) during the study

Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood 
products (or any standard-of-care treatment for a life-threatening condition)

Receipt of:
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter
An investigational drug concurrently

Concurrent disease, treatment, or abnormality in clinical laboratory tests that could 
interfere with the conduct of the study or that would, in the opinion of the investigator 
or Sponsor, preclude the patient’s safe participation in and completion of the study 
or interpretation of the study results
4.4
METHOD OF TREATMENT ASSIGNMENT
The study is a non-randomized, open-label, Phase III, multicenter study of emicizumab
in pediatric patients 12 years of age and 1217 years of age who weigh 40 kg with 
hemophilia A with inhibitors. 
The study consists of three cohorts.  Patients will receive an initial loading dose of 
3 mg/kg QW for the first 4 weeks followed by a maintenance dose of either 1.5 mg/kg 
QW (Cohort A), 3 mg/kg Q2W (Cohort B), or 6 mg Q4W (Cohort C).  The study will 
begin by recruiting patients in Cohort A.  Once 1) the exposure at 1.5 mg/kg QW has 
been characterized in this pediatric population; 2) Cohort A is fully enrolled; and 3) 


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review of data in adults and adolescents from two ongoing Phase III studies evaluating 
emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg Q4W (BO39182) identifies no 
safety concerns, this study will open two additional non-randomized cohorts to 
investigate Q2W and Q4W regimens in pediatric patients. Recruitment to Cohort B 
(3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W) will occur in parallel with alternate 
cohort allocation via IxRS.    
The time between screening and enrollment of eligible patients should be ≤ 28 days;
otherwise, patients must be re-screened to determine if they continue to meet the 
inclusion and exclusion criteria. 
4.5
STUDY TREATMENT 
4.5.1
Formulation, Packaging, and Handling
4.5.1.1
Emicizumab
Emicizumab IMP will be supplied by the Sponsor as a sterile liquid for SC injection, 
contains no preservatives, and requires storage at 28° Celsius (do not freeze and 
protect from light).  Single-use vials contain 30, 60, or 150 mg (nominal) of emicizumab
at pH 6.0.  The emicizumab IMP is formulated in 150 mmol/L arginine, 0.5 mg/mL 
poloxamer 188, 20 mmol/L histidineaspartic acid buffer (pH 6.0).  Because emicizumab
is administered on a weight-based dosing regimen, three configurations of the IMP are 
intended to be used in this study, differing from each other only in emicizumab
concentration or filling volume:  nominal vial strength 150 mg (150 mg/mL, 1.0 mL); 
nominal vial strength 60 mg (150 mg/mL, 0.4 mL); nominal vial strength 30 mg 
(30 mg/mL, 1.0 mL).  This will enable safe subcutaneous weight-based volume dosing of 
small children with sufficient precision.  The excipient composition and primary 
packaging is identical for all configurations.  For information on the handling of 
emicizumab, see the “Instructions for Use” (IFU) document.
4.5.2
Dosage, Administration, and Compliance
Emicizumab treatment will begin with a loading dose of 3 mg/kg QW for the first 
4 weeks (Day 1 of each week) followed on Week 5 by a maintenance dose of either 
1.5 mg/kg QW (Cohort A), 3 mg/kg Q2W (Cohort B), or 6 mg/kg Q4W (Cohort C).  
Note that the cumulative dose studied in all three cohorts is identical, but the dose 
administration schedule differs between cohorts. Patients will receive prophylactic
emicizumab for a minimum of 52 weeks, or until unacceptable toxicity or discontinuation 
from the study due to any cause.
On 7 December 2016, the JMC recommended continued enrollment to Cohort A at the 
original starting maintenance dose of 1.5 mg/kg QW, and to open enrollment to 
patients 2 years of age at that same maintenance dose.  Moreover, review of data in 
adults and adolescents from two ongoing Phase III studies evaluating emicizumab at 
3 mg/kg Q2W (BH30071) and 6 mg/kg Q4W (BO39182) has identified no safety 
concerns to date. See Section 3.3.1.1 for details.


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During the 52-week treatment period, individual patients may have their dose up-titrated 
if they experience suboptimal bleeding control on emicizumab. Patients in Cohorts A, B, 
or C with 2 qualifying bleeds within a 12-week interval may have the opportunity to 
have their maintenance emicizumab dose increased to 3 mg/kg QW starting on Week 17, 
if they receive approval from the Medical Monitor. Of note, for patients from Cohorts 
B or C who have a dose up-titration, their dosing regimen will change from Q2W or 
Q4W to QW. Qualifying bleeds are defined as spontaneous and clinically significant, 
physician verified (e.g., with diagnostic imaging, clinical examination, photograph), 
and occurring while on prophylactic emicizumab at steady-state on the maintenance 
dose (after Week 5). Should patients meet protocol-defined criteria for up-titration, the 
investigator will contact the Medical Monitor to initiate a discussion about possible 
up-titration. Upon up-titration to the new maintenance dose of 3 mg/kg QW, the 
patient’s schedule of assessments will reset to Week 1, and the next five visits must 
take place at the site.
Based on ongoing evaluation of efficacy, safety, and PK data, including interim analyses, 
the Sponsor and/or the JMC may recommend a dose higher than 3 mg/kg QW for a 
patient or a patient population.  Dosing above 3 mg/kg QW (not higher than 6 mg/kg
QW) may, therefore, occur while ensuring that the exposure will not exceed the
exposure achieved with the safe and well tolerated highest dosing regimen tested in 
clinic.
If a patient has a systemic hypersensitivity reaction or severe adverse reaction that may 
be attributable to emicizumab, subsequent doses should be held until the situation is 
discussed with the Medical Monitor and approval to resume dosing is given.  Should 
unanticipated events occur during the study that require treatment with multiple daily 
administrations of bypassing agents or FVIII concentrates for multiple days, such as 
non-elective surgery or severe/life-threatening bleeds, the investigator should contact 
the Medical Monitor immediately to discuss such cases and the management of future 
emicizumab doses.  Any other emicizumab dose adjustment request will require 
discussion of the clinical case with and approval from the Medical Monitor.
Study site healthcare providers (HCPs) will be trained on how to properly prepare the 
study medication and administer the correct calculated dose subcutaneously as 
described in the IFU document.  Patients/caregivers will in turn be trained by an HCP on 
study medication preparation and self-administration/administration at the recommended 
sites of injection as detailed in the IFU.  The HCP is to inform the patient/caregiver of the 
volumetric dose to be administered and dosing frequency. Note that during the course 
of the study, should the patient’s body weight change to affect the dose (e.g., 10%), 
the new volumetric dose to be administered must be communicated to the 
patient/caregiver.
In order to minimize the number of injections for pediatric patients in certain high weight 
categories, the administration per single injection of up to 2 mL of drug product solution 


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may be permitted, pending approval from the Sponsor, individual countries, and 
participating sites.  This will require combining emicizumab drug product solution from 
more than 1 vial of a given concentration (i.e., vial pooling) into a single syringe using a 
new transfer needle for each vial.  The detailed procedure for vial pooling is described in 
the IFU. Vials of different emicizumab concentrations must not be combined.
Details on the devices to be used for study medication withdrawal from the vial and SC 
injection are provided in the Pharmacy Manual.
Emicizumab will be administered as a SC injection in the home setting after a period of 
in-clinic administration and training.  The first five drug administrations must be 
performed in a monitored setting such as an infusion center, clinic, or hospital, with a 60-
minute observation period following each of the first three doses.  For patients with a 
previous history of a clinically significant hypersensitivity reaction, additional precautions
as described in Section 5.1.1.2 should be considered.  The fourth and fifth scheduled 
study drug administrations must also be performed in the monitored setting, and the 
patient/caregiver will be trained and have the opportunity to ask any questions to the 
HCP before the scheduled start of home administration.  The patient (7 years of 
age)/caregiver will observe at least one SC injection performed by the HCP and 
successfully administer at least one SC injection while being observed by the HCP prior 
to starting home administration.  Each site will have the discretion to provide additional 
training if deemed appropriate.  If, despite additional training, the investigator determines 
that the patient/caregiver is unable to inject emicizumab correctly, then arrangements 
may be made to identify a trained caregiver or HCP to administer the SC injections. 
Patients/caregivers will be provided with the clinic contact information, to use in case 
they have questions related to self-administration between visits.
Medication administration errors during training will be recorded and competence of the 
patient or caregiver to administer at home will be documented in the electronic Case 
Report Form (eCRF).  If necessary, patients/caregivers or their HCP may choose to 
continue administration of study drug in the clinic.  Compliance in the home setting is to 
be monitored by recording emicizumab administration on an electronic, handheld device 
and recording collected used and unused vials during each patient’s clinic visit.
Study medication should be administered on the scheduled dosing day. On days when 
trough plasma PK samples are to be collected, patients will be dosed after those samples 
are drawn. 

For patients in Cohort A (QW dosing), if the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, the study medication 
should be administered as soon as possible within a window of 3 days from the 
scheduled dosing date.  If more than 3 days has passed, the missed dose should be 
skipped, and the patient/caregiver should administer his or her next dose at the next 


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scheduled time (with the study medication dosing resumed in accordance with the 
original dosing schedule).

For patients in Cohort B (Q2W dosing), if the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, study medication should 
be administered as soon as possible within a window of 7 days from the scheduled 
dosing date.  If more than 7 days have passed, the patient/caregiver should take his 
or her next dose at the next scheduled time with the study medication dosing 
resumed in accordance with the original dosing schedule.

For patients in Cohort C (Q4W dosing), if the patient/caregiver forgets or cannot 
administer study medication on the scheduled dosing day, study medication should 
be administered as soon as possible within a window of 14 days from the scheduled 
dosing date.  If more than 14 days have passed, the patient/caregiver should take 
his or her next dose at the next scheduled time with the study medication dosing 
resumed in accordance with the original dosing schedule.
All emicizumab dosing should be clearly documented on the handheld, electronic 
patient-reported outcome (ePRO) device, both during patient’s visits in clinic and when
the patient is out of the clinic.
Any overdose or incorrect administration of study drug will be determined from 
emicizumab data entered into the handheld ePRO device.  Adverse events associated 
with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.
Patients and/or caregivers will be provided with alert cards, which they will be requested 
to carry at all times.  These will include guidance on recognizing signs/symptoms of 
thromboembolic events or allergic/anaphylactic/anaphylactoid reactions and how to 
obtain emergency care. In addition, alert cards are designed to notify non-study 
healthcare providers that emicizumab will interfere with certain coagulation laboratory 
tests (see the Emicizumab Investigator’s Brochure for more information) and the 
investigator should be contacted for assistance in interpreting the test results.
Guidelines for treatment interruption or discontinuation are provided in Section 4.8.2.
If in the investigator’s judgment, the individual patient would be eligible for or benefit 
from ITI therapy, the discontinuation of emicizumab and initiation of this ITI therapy 
should be discussed with the Medical Monitor.  
4.5.3
Investigational Medicinal Product Accountability
Emicizumab, the only investigational medicinal product (IMP) in Study BH29992, is 
required for completion of this study and will be provided by the Sponsor, and 
accountability for each vial is required throughout the study.  The study site will 
acknowledge receipt of IMPs using the interactive voice or Web response system (IxRS) 
to confirm the shipment condition and content.  Any damaged shipments will be replaced.


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Used and unused IMP vials will be returned by patient’s caregiver to the study site and 
appropriately accounted for.  Used vials will then be disposed of at the study site 
according to the study site’s institutional standard operating procedure.  Instructions 
regarding how to handle unused vials should be obtained from the Sponsor.  If the 
investigator prefers to destroy the IMP at his or her site, the site's method of IMP 
destruction must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.5.4
Post-Study Access to Emicizumab
The Sponsor will offer post-study access to the study drug (emicizumab) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for hemophilia A with FVIII inhibitors

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for hemophilia A

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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4.6
CONCOMITANT AND RESCUE THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
4 weeks prior to initiation of study treatment to the study completion/discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF page.
Medications given to treat a bleed (e.g., rFVIIa or aPCC) will be reported only via the 
electronic, handheld device and not in the eCRF.
4.6.1
Permitted Therapy 
Concomitant use of the following drugs and therapies will be permitted:

Drugs intended to control or prevent bleeds, including rFVIIa should be used at the 
lowest dose expected to achieve hemostasis.  Given that circulating emicizumab 
increases patients’ coagulation potential, the doses required to achieve hemostasis 
may be lower than the bypassing agent doses used prior to starting the study.  
Caution should be taken for patients who are using rFVIIa (e.g., consideration of 
using no more than 90 g/kg rFVIIa as an initial dose). 
Use of aPCC in combination with emicizumab should be avoided completely in 
patients who have the option of using other bypassing agents to treat bleeds. In the 
event that aPCC is the only available bypassing agent, the lowest dose expected to 
achieve hemostasis should be prescribed, with no more than 50 units/kg of aPCC to 
be administered as an initial dose.
Other bypassing agents (e.g., Byclot) should be avoided. In cases where such 
agents are the only available bypassing agent, the lowest dose expected to achieve 
hemostasis should be prescribed, with no more than the lowest dose described in 
the prescribing information to be administered as an initial dose (e.g., no more than 
60 g/kg of Byclot).
Exact dose and schedule of bypassing agents should be discussed with caregivers 
at the beginning and throughout the study.  Repeated dosing of rFVIIa, aPCC, or 
other bypassing agents should be performed only under medical supervision and 
consideration should be given to verifying bleeds prior to repeated dosing. For 
rFVIIa, aPCC, and other bypassing agents, laboratory monitoring by additional local 
and central laboratory assessments should be performed as per the schedule of 
assessments (see Appendix 1).

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

Local anesthetic cream for emicizumab SC administration

Vaccinations should be administered following national immunization schedules.  As 
per the WFH recommendations for vaccinations (WFH 2012b), patients with 
hemophilia should be vaccinated.  Thus, vaccinations should be administered
according to the WFH recommendations and local Hemophilia Treating Center 


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practice and ideally during a period when the bleeding status of the child is well 
controlled and stable.  Vaccinations should not be administered on the same day as 
an emicizumab administration but ideally at a timepoint between two emicizumab
administrations (48 hours after emicizumab administration).  Children who receive 
vaccinations must be carefully followed for any adverse reactions in the subsequent 
days following vaccine administration.

Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in 
patients receiving emicizumab
4.6.2
Prohibited Therapy
Use of the following therapies is prohibited during the study and for at least 4 weeks 
prior to initiation of study treatment unless otherwise specified:

Use of aPCC or Byclotas concomitant prophylactic treatment, including for short-
term prophylaxis (note: this criterion does not apply to the 4 weeks prior to 
initiation of study treatment)

Use of anti-fibrinolytics in conjunction with aPCC or Byclot

Use of concomitant prophylactic regimen with FVIII or rFVIIa  (note: this criterion 
does not apply to the 4 weeks prior to initiation of study treatment)
Intermittent doses or short-term prophylaxis (e.g., around the time of surgery),
however, are permitted

Use of drugs that would affect hemostasis (e.g., aspirin, non-steroidal 
anti-inflammatory drugs that are not selective or preferential COX-2 inhibitors, or 
anticoagulants [other than to flush, dwell, or de-clot a 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

Use of systemic immunomodulators (e.g., rituximab, corticosteroids) other than 
anti-retroviral therapy

Elective surgery (excluding minor procedures such as tooth extraction, CVAD 
removal, incision and drainage, as well as emergency surgeries) 

Use of other investigational drugs
If prohibited therapy is administered for any reason, it should be recorded on the eCRF 
(except any hemophilia-related medication, which will be recorded on the 
bleed/medication questionnaire).  If prohibited treatment is prescribed or considered 
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.
4.7
STUDY ASSESSMENTS 
4.7.1
Informed Consent Forms and Screening Log
For participation in the study, written informed Consent must be obtained from 
parent/legally acceptable representative and an Assent from the child when applicable 
(latest approved version by the IEC/IRB) before performing any study-specific screening 


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tests or evaluations.  Informed Consent/Assent Forms for enrolled patients and for 
patients who are not 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.
4.7.2
Medical History and Demographic Data
Medical history includes hemophilia-related history, clinically significant diseases, 
procedures within the past year, and medication allergies.  In particular, sites should 
record whether the patient has any history of prior ITI, anaphylaxis, or known 
thrombophilia.  It should also include all medication taken in the 4 weeks prior to 
screening (including prescription, over-the-counter, and herbal/homeopathic remedies 
and therapies), see Section 4.6 for details.  Bleed information (i.e., number, type) should 
be documented during the last 24 weeks prior to study entry.  Number of daycare/school 
days missed and number of days hospitalized should be documented prior to study 
entry.
Demographic data will include age, sex, and self-reported race and ethnicity (as per 
specific country regulations).
4.7.3
Physical Examinations
A complete physical examination should include but not necessarily be limited to the 
evaluation of head, eye, ear, nose, and throat and include cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  
Additional targeted physical examination of joints (for bleeds, evidence of arthropathy) 
and skin (for bruises, hematomas, injection-site reactions, and lipodystrophies) should 
be conducted as noted in the schedule of assessments (see Appendix 1) or as clinically 
indicated. Any abnormality identified during screening should be recorded on the 
General Medical History and Baseline Conditions eCRF.  New or worsened 
abnormalities from screening should be recorded as adverse events.
4.7.4
Vital Signs
Vital signs will include measurement of pulse and respiratory rate, temperature (oral, 
rectal, axillary, or tympanic), systolic and diastolic blood pressure using age-adapted 
measurements, height/length and weight and should be recorded before study drug 
administration.  Frequency of vital sign assessments should follow the schedule of 
assessments (see Appendix 1) but may also be taken any time as unscheduled 
assessments as judged by the investigator.
4.7.5
Laboratory, Biomarker, and Other Biological Samples
Local laboratory assessments will be performed as indicated on the schedule of 
assessments (see Appendix 1).  On days of study drug administration, laboratory 


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samples should be drawn before the administration of study drug.  Laboratory 
assessments will include the following:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells], mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width)

Serum chemistries (sodium, potassium, chloride, glucose, blood urea nitrogen, 
creatinine, calcium, phosphorus, magnesium, creatine phosphokinase, total protein, 
albumin, creatinine, total and direct bilirubin, alkaline phosphatase, ALT, and AST)

Pregnancy test:  All female patients who are of childbearing potential will be 
required to have a serum pregnancy test at screening.
Urine pregnancy tests will be performed at specified subsequent visits.  If a 
urine pregnancy test result is positive, it must be confirmed by a serum 
pregnancy test.

In patients who receive bypassing agents, the following local laboratory tests will be 
performed within 2448 hours of initial bypassing agent use so the investigator may 
monitor for of potential thromboembolic events and TMA:  
Platelet count
Serum creatinine
LDH
Peripheral blood smear analysis to evaluate for schistocytes
A plasma sample should also be provided for local (first aliquot) and central (second 
aliquot) laboratory monitoring of:
Prothrombin fragment 12
Fibrinogen
D-dimer
If the test for prothrombin fragment 12 is not available at the site, the sample 
should be sent to the local reference laboratory, if available and if the results from 
the local reference laboratory can be obtained within a reasonable timeframe to 
allow for decision-making.
For patients who require multiple doses of bypassing agents, laboratory monitoring 
should be performed every 2448 hours thereafter until 2448 hours following the 
last dose of bypassing agents administered to treat a given bleed.
If applicable, laboratory results should be recorded in the “Local Lab Following 
Treatment with Bypassing Agents” eCRF page.
The following samples will be sent to the Sponsor or a designee for centralized analysis:

Plasma samples for PK analysis

Plasma samples for immunogenicity assessment (anti-FVIII antibodies and 
anti-emicizumab antibodies)


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
Plasma for exploratory PD biomarker assessments (aPTT, FVIII activity, and others 
as listed in Appendix 2)
4.7.6
Electrocardiograms
ICH guidelines note large targeted proteins and monoclonal antibodies have a low 
likelihood of direct ion channel interactions and a thorough QT/QTc study is not 
necessary, unless the potential for pro-arrhythmic risk is suggested by mechanistic 
considerations or data from clinical or nonclinical studies (ICH 2015).  Current data from 
the Phase I/II studies did not reveal clinically significant or dose-dependent changes in 
ECG parameters. Though dedicated QT assessments have not been required from any 
regulatory authority, the Sponsor committed to ensure some collection of baseline and 
periodic on treatment ECGs.  Collection times will be targeted around expected steady 
state concentrations of emicizumab.  Single ECG recordings will be obtained at specified 
timepoints, as outlined in the schedule of assessments (see Appendix 1) and may be 
obtained at unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  The following parameters will be 
obtained (and reported by the instrument): QT, RR, HR, QTcB, QT interval corrected 
using Fridericia’s formula [QTcF], PR, and QRS and T- and U-wave morphology.  ECG 
recordings must be performed after the patient has been resting in a supine position for 
at least 10 minutes.
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
Any ECG changes that are associated with symptoms or lead to a change in study 
treatment or concomitant treatment, or discontinuation from study treatment, must be 
reported as an adverse event on the adverse event eCRF.  The investigator or designee 
must review, sign, and date all ECG tracings.  The ECG may be repeated if investigator 
deems it appropriate.  Paper copies will be kept as part of the patient’s permanent study 
file at the site.
4.7.7
Electronic Patient-Reported Outcomes
To capture bleed data, emicizumab use, and other hemophilia medication use during 
study treatment, caregivers will complete the Bleed/Medication Questionnaire on an 
electronic, handheld device that will be provided to them during the Week 1 visit at the 
site.  This device will remain with the caregiver for the duration of the study to enter 
bleed and medication data on a weekly basis at minimum.  Patients and/or caregivers 
will complete HRQoL, proxy HRQoL, and aspects of caregiver burden questionnaires at 


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designated timepoints during clinic visits on a separate electronic, handheld device 
(tablet) that will remain at sites.  The electronic, handheld device and instructions for 
completing the various questionnaires will be provided by the investigator staff.  After 
bleed, medication, HRQoL, proxy HRQoL, and aspects of caregiver burden entries have 
been saved, the data will be transmitted automatically from the respective devices to a 
centralized vendor database.  Bleed and medication use data entered since the patient’s 
previous clinic visit will be reviewed at subsequent clinic visits, as per the schedule of 
assessments, for completeness and accuracy.  Of note, if the electronic data collection 
system becomes unavailable, the Sponsor may instruct sites to collect PRO data (bleed 
data, emicizumab use, hemophilia medication use, and HRQoL on paper.  Investigators 
will review the bleed and bleed medication data as per the schedule of assessments 
(see Appendix 1) and have the ability to correct or complete entries once verified with 
the patient/caregiver using a Data Change Request (DCR) Form process or via a Web-
based portal, once implemented.
HRQoL:
Only patients 8 years of age and above will be assessed for HRQoL using the 
Haemo-QoL-SF questionnaire (Short Form), which will be completed by the patients
during clinic visits (see Appendix 3).  The Haemo-QoL-SF is derived from the 
Haemo-QoL questionnaire, which has been developed in a series of age-related 
questionnaires to measure HRQoL in children and adolescents with hemophilia 
(Bullinger et al. 2002; von Mackensen and Bullinger 2004; Pollak et al. 2006).  The 
Haemo-QoL-SF version contains 35 items, which cover nine dimensions considered 
relevant for the children’s HRQoL (physical health, feelings, view of yourself, family, 
friends, other people, sports and school, dealing with hemophilia and treatment).  Items 
are rated with five respective response options:  never, seldom, sometimes, often, and 
always.
Adapted InhibQoL Including Aspects of Caregiver Burden:
Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless 
of age, will be collected using the Adapted InhibQoL Including Aspects of Caregiver 
Burden questionnaire (see Appendix 4).  This will be completed by caregivers as per the 
schedule of assessments during clinic visits (see Appendix 1).  
Daycare/School Absences and Hospitalizations:  Caregivers will also be asked to 
report on an electronic, handheld device the number of days of daycare/school that were 
missed (if applicable).  The number of days the child was hospitalized, (if applicable) will 
be derived from data collected on eCRF.
4.7.8
Bleed Definitions
Definition of a Bleed
For the purposes of the efficacy analyses, a standardized definition of bleed, adapted 
from standard criteria defined by the Subcommittee on Standards and Criteria, FVIII/FIX 


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subcommittee of the ISTH and similar to that used in a recent clinical study, will be 
utilized in this study (Blanchette et al. 2014; Mahlangu et al. 2014).

An event is considered a bleed if coagulation factors are administered to treat signs 
or symptoms of bleeding (pain, swelling, etc.). An additional definition of all bleeds 
(i.e., both treated and not treated with coagulation factors) will be applied as well.

Bleeds starting from the first sign of bleed and ending 72 hours after the last 
treatment for the bleed, within which any symptoms of bleeding at the same location 
or injections are 72 hours apart, are considered the same bleed.

Any injection to treat the bleed, taken 72 hours after the preceding injection, is 
considered the first injection to treat a new bleed at the same location.

Any bleed at a different location is considered a separate bleed regardless of time 
from last injection.
Definitions of Bleed Sites

Target joints are defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and 
ankle) into which repeated bleeds occur (frequency of 3 bleeds into the same joint 
over the last 24 weeks prior to study entry)

Joint bleeds (sites as per the Bleed/Medication Questionnaire)

Muscle bleeds (sites as per the Bleed/Medication Questionnaire)

Other bleeds (sites as per the Bleed/Medication Questionnaire)
Definitions of Bleed Types
In addition, the assessment of a bleed will be separated into spontaneous bleeds, 
traumatic bleeds and bleeds related to procedure/surgery.  Both spontaneous bleeds 
(i.e., the occurrence of hemorrhage where neither the patient nor a caregiver can identify 
a reason) and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such 
as trauma, “strenuous” activity, or “overuse”) will be collected.

Spontaneous bleeds:  Bleeds will be classified as spontaneous if a caregiver 
records a bleed when there is no known contributing factor such as definite trauma, 
antecedent “strenuous” activity or “overuse” or “procedure/surgery.“  The 
determination of what constitutes “strenuous” or “overuse” will be at the discretion of 
the caregiver.  For example, light jogging may be considered “non-strenuous” while 
sprinting may be considered “strenuous,” lifting of weights for a short period of time 
may be considered “moderate use” while repetitive weightlifting may be considered 
“overuse.” 

Traumatic bleeds:  Bleeds should be classified as traumatic if a caregiver records a 
bleed when there is a known or believed reason for the bleed.  For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 
obvious injury, the bleed would be recorded as a traumatic bleed because, although 
no injury occurred, there was antecedent “strenuous” activity.  Bleeds with 
preceding injuries would certainly be classified as traumatic.  

Bleeds related to procedure/surgery:  such as hematomas resulting from any 
surgeries or invasive procedures (e.g., tooth extractions, venipuncture, or SC drug 


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administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy, etc.) would not be counted 
as bleeds but will be collected on the bleed/medication questionnaire.  Bleeds 
related to procedure/surgery are not associated with any trauma except 
procedure/surgery-induced trauma.  
Caregivers will complete the bleed/medication questionnaire any time a patient 
experiences a bleed.  At this time, the caregivers will also answer questions detailing the 
location, type and time of the bleed. Caregivers will also complete this medication 
questionnaire weekly as well as any time a hemophilia medication is administered, 
whether for prophylaxis (i.e., weekly emicizumab) or for treatment of bleed (i.e., 
bypassing agent).
4.8
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.8.1
Patient Discontinuation
Patients and parents/legally acceptable representatives 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 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 
appropriate eCRF page.  However, patients will not be followed for any reason after 
consent has been withdrawn.
4.8.2
Study Treatment Discontinuation
Patients must stop study treatment if they experience the following:

Pregnancy
If the patient discontinues study treatment, bleed and bleed medication data should be 
provided by the caregiver via the electronic, handheld device until the safety follow-up 
visit (24 weeks after last study drug administration).
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF page.  Patients who discontinue study treatment prematurely will not 
be replaced.  Patients who become pregnant should immediately stop treatment and be 
managed as per local guidelines.  


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4.8.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

Incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence (e.g., bleed/medication questionnaire data not checked by 
investigator/co-investigator for 8 weeks)

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Emicizumab is not approved and is currently in clinical development.  Thus, the 
complete safety profile is not known at this time.  The safety plan for this study is 
designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below. Refer to the Emicizumab Investigator's 
Brochure for a complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
5.1.1
Risks Associated with Emicizumab
5.1.1.1
Injection-Site Reactions
In the completed and ongoing Japanese studies, injection-site reactions have been 
observed in some patients with hemophilia A.  These local injection-site reactions 
included injection-site erythema, injection-site hematoma, injection-site rash, 
injection-site discomfort, injection-site pain, and injection-site pruritus.  All local 


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injection-site reactions were of mild intensity.  Further details of the observed 
injection-site reactions are available in the Investigator’s Brochure.
Instructions for emicizumab administration should be followed as outlined in 
Section 3.3.1 and Section 4.5.2 and in the IFU. This includes alternating the site of 
injection, from one injection to the next, in the recommended injection-site locations 
listed in the IFU.
5.1.1.2
Hypersensitivity Reaction, Anaphylaxis, Anaphylactoid 
Reaction
Since emicizumab is a biological product, acute, systemic hypersensitivity reactions, 
including anaphylaxis and anaphylactic reactions, may occur.  In completed and ongoing 
clinical studies of emicizumab, no severe hypersensitivity reactions have been reported.  
These events should be reported as Serious Adverse Events or Adverse Events of 
Special Interest as described in Section 5.2.3.
HCPs administering the study medication in the clinic must be trained in the appropriate 
administration procedures, be able to recognize the signs and symptoms associated with 
potential hypersensitivity, anaphylactic, and anaphylactoid reactions, and should be 
familiar with Sampson’s criteria for defining anaphylaxis (Sampson et al. 2006; see 
Appendix 6).  HCPs should also instruct patients how to recognize the signs and 
symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact 
an HCP or seek emergency care in case of any such occurrence.  Patients and/or 
caregivers will also receive two alert cards to remind them of this information and these 
instructions should any of these reactions occur. 
For patients with a previous history of a clinically significant hypersensitivity reaction, for
the first three doses, the site will call the patient 24 hours after each dose to assess the 
status of the patient.  Additional precautions following each of these doses may also be 
considered including having an extended observation period or IV access prior to dosing, 
etc.  The investigator may include these or other precautions, as deemed appropriate.
5.1.1.3
Hypercoagulation and Thromboembolic Events
As of April 2017, there have been 3 serious thromboembolic events reported in 
2 patients who were treated with bypassing agents while receiving emicizumab
prophylaxis in Study BH29884.  
 
 
 
  
 
 
 
 
 


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 For more details please refer to the 
Emicizumab Investigator’s Brochure.
These events should be reported as Serious Adverse Events or Adverse Events of 
Special Interest as described in Section 5.2.3.  HCPs should educate patients/caregivers 
to recognize signs and symptoms of potential thromboembolism or thrombosis (i.e., 
dyspnea, chest pain, leg pain or swelling; or if in the head, headache, numbness in the 
face, eye pain or swelling, or vision impairment; or if in the skin, blackening and
associated pain) and ensure that they understand the importance of seeking appropriate 
medical attention.  Patients and/or caregivers will also receive two alert cards to remind 
them of this information and these instructions should thromboembolism be suspected.
5.1.1.4
Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) is used to describe a group of disorders with clinical 
features of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage 
that can include the kidneys, gastrointestinal system, or central nervous system, and so.  
As of April 2017, 3 cases of TMA were observed in Study BH29884 involving patients 
with hemophilia A with inhibitors who were treated with bypassing agents while receiving 
emicizumab. 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 


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  For more details please refer to the Emicizumab 
Investigator’s Brochure.
Any TMA event should be reported as an adverse event of special interest and also as a 
serious adverse event, if it meets criteria for such (see Sections 5.2.2 and 5.2.3). HCPs 
should educate patients/caregivers to recognize signs and symptoms of potential TMA 
(i.e., confusion, weakness, swelling of arms and legs, yellowing of skin and eyes, vague 
abdominal or back pain, nausea, vomiting, or decreased urination, etc.) and ensure that 
they understand the importance of seeking appropriate medical attention.  Patients 
and/or caregivers will also receive two alert cards to remind them of this information and 
these instructions should TMA be suspected.
5.1.1.5
Life-Threatening Bleeding Due to Unreliable Standard 
Coagulation Tests and Inhibitor Assays in the Setting of 
Emicizumab
Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII 
activity, and FVIII inhibitor measurement by Bethesda assay) are not reliable and do 
not accurately reflect the patient’s underlying hemostatic status while receiving 
emicizumab prophylaxis (see Section 5.1.3 and the Emicizumab Investigator’s 
Brochure).  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 if a patient is treated by a practitioner
other than the emicizumab-prescribing practitioner in settings such as an emergency 
room or in an acute-care setting.
Emicizumab’s mechanism of action and resulting interference were clearly 
demonstrated in a wide variety of coagulation laboratory tests approved for in vitro 
diagnostic use.  Clinical trials also demonstrated the effects of emicizumab on 
laboratory tests.  However, as of 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.


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5.1.2
Management of Specific Adverse Events
Guidelines for management of specific adverse events are outlined in Table 3.  
Additional guidelines are provided in the subsections below.
Table 3
Guidelines for Management of Specific Adverse Events
Event
Actions to Be Taken
Injection-Site Reaction

Injection-site reactions should be treated as clinically indicated.

Emicizumab should not be injected into areas where the skin is red, 
bruised, tender, or hard or into areas where there are moles or scars.  

In the clinic setting, patients will be monitored for signs of injection-site 
reactions in the period immediately following injections.  Patients and 
caregivers will be given guidance on reporting injection-site reactions
when administering drug at home or after they leave the clinic.
Hypersensitivity Reaction, 
Anaphylaxis, 
Anaphylactoid Reaction

Suspected cases should be fully evaluated and treated as clinically 
indicated.

Medicinal products for the treatment of hypersensitivity reactions (e.g., 
epinephrine, antihistamines, and glucocorticoids) and resuscitation 
equipment must be available for immediate use during the initial 
administrations in the infusion center, clinic, or hospital.

If a patient has symptoms of anaphylaxis or severe hypersensitivity, 
administration of study drug must be immediately stopped and 
treatment of the reaction be initiated. 

The investigator should contact the Medical Monitor to assess if the 
clinical benefit clearly outweighs the risk to determine if and when the 
patient should resume taking emicizumab and discuss the patient’s 
continued study participation.  If patient continues in the study, the next 
two scheduled doses must be in a monitored setting with at least a 60-
minute observation period and resuscitation treatment immediately 
available.  After each of these two doses in the clinic, the site will call 
the caregiver 24 hours after each dose to assess status of the patient. 

Investigators may order any pertinent laboratory tests, including an 
unscheduled anti-drug antibody, in the event any of these reactions 
occur.
Hypercoagulation and 
Thromboembolic Events

Please see Section 4.7.5 for guidance on required laboratory monitoring
in the event of use of bypassing agents.

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with thromboembolic events and immediately begin work-up 
and treatment, as per local guidelines.  

If a patient has a thromboembolic event, further administration of study 
drug should be interrupted. Decision to resume emicizumab after a 
thromboembolic event must be discussed with and approved by the 
Medical Monitor. 


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Table 3
Guidelines for Management of Specific Adverse Events (cont.)
Event
Actions to Be Taken
Thrombotic 
microangiopathy

Please see Section 4.7.5 for guidance on required laboratory 
monitoring in the event of use of bypassing agents.

HCPs should be vigilant for patients who exhibit signs/symptoms 
consistent with TMA and immediately begin work-up and treatment, as 
per local guidelines.  

If a patient has a TMA event, further administration of study drug 
should be interrupted.  Decision to resume emicizumab after an event 
of TMA must be discussed with and approved by the Medical Monitor.  
HCPhealthcare provider; TMAthrombotic microangiopathy.
5.1.3
Interpretation of Coagulation Assays for Patients Receiving 
Emicizumab
Emicizumab interacts with standard laboratory assays used in the management of 
patients with hemophilia A.  In one-stage assays, emicizumab is associated with a 
supra-physiologically short time to clot formation and thus normalization of aPTT at 
subtherapeutic levels and an overestimation of true FVIII activity.  Emicizumab is not 
recognized or neutralized by FVIII inhibitors, and therefore cannot be detected by a 
functional test such as Bethesda or Nijmegen-Bethesda assays, which use a one-stage 
clotting based readout.  Emicizumab activity cannot be detected by chromogenic assays 
using purified bovine coagulation proteins and can only be detected using an assay 
composed of human proteins.  Table 4 summarizes the coagulation tests affected and 
unaffected by emicizumab. See the Emicizumab Investigator's Brochure for additional
details on which tests can be used and how the test results can be interpreted.


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Table 4
Coagulation Test Results Affected and Unaffected by 
Emicizumab
Results Affected by Emicizumab
Results Unaffected by Emicizumab
Activated partial thromboplastin time (aPTT)
Activated clotting time (ACT)
One-stage, aPTT-based, single-factor assays
aPTT-based Activated Protein C Resistance 
(APC-R)
Bethesda assays (clotting-based) for FVIII 
inhibitor titers 
Thrombin time (TT)
One-stage, PT-based, single-factor assays
Chromogenic-based single-factor assays other 
than FVIII a
Immuno-based assays (e.g., ELISA, 
turbidometric methods)
Bethesda assays (bovine chromogenic) for 
FVIII inhibitor titers
Genetic tests of coagulation factor mutations 
(e.g., Factor V Leiden, Prothrombin 20210) 
ACT = activated clotting time; APC-R =Activated Protein C Resistance; aPTT = activated 
partial thromboplastin time; ELISA = enzyme linked immunosorbent assay; FVIII = factor 
VIII; PT = prothrombin time; TT = thrombin time.
a For important considerations regarding FVIII chromogenic activity assays, please see
information provided above in Section 5.1.3.
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 
Section 5.3.5.10.

Recurrence of an intermittent medical condition (e.g., headache) not present at 
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
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
Bleeds considered as serious adverse events should be reported on the appropriate 
adverse event eCRF page regardless of whether the bleeds are consistent with patients’ 
pre-study disease state (the bleed will remain recorded as well on the bleed/medication 
questionnaire).  New, non-serious bleeds consistent with patients’ pre-study disease 
state will not be considered adverse events and will not be recorded on the eCRF but 
will be captured on the bleed/medication questionnaire).
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as Grade 14, according to the World Health Organization 
[WHO] Toxicity Grading Scale for Determining The Severity of Adverse Events criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.


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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 may include suspected or confirmed 
cases.  Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
(see Sampson’s Criteria in Appendix 6)

Thromboembolic events

Microangiopathic hemolytic anemia or TMA (e.g., thrombotic thrombocytopenic 
purpura, hemolytic uremic syndrome)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient/caregiver or noted by study personnel,
will be recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 


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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until the patient 
completes his or her last study visit, which includes the post-treatment visit 24 weeks 
following discontinuation of the drug. After this period, the investigator should report any 
serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The World Health Organization (WHO) toxicity grading scale (see Appendix 5) will be 
used for assessing adverse event severity.  Table 5 will be used for assessing severity 
for adverse events that are not specifically listed in the WHO toxicity grading scale.
Table 5
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).


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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection-Site Reactions
Local adverse events that occur within 24 hours after study drug administration and are 
judged to be related to study drug injection should be captured as an “injection-site 
reaction” on the Adverse Event eCRF.  Associated signs and symptoms (e.g., 
injection-site erythema or injection-site rash) should be recorded on the dedicated 
Injection-Site Reaction eCRF. If a patient experiences both a local and systemic 
reaction to the same administration of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF.  Only for local injection-site reactions should the 
dedicated Injection-Site Reaction eCRF be used to capture the individual 
signs/symptoms.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, other than injection-site reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 


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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 patient, only 
vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
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 5.1.3 or contact the Medical Monitor.
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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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 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of hemophilia.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").


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If the death is attributed to progression of hemophilia, "hemophilia progression" should 
be recorded on the Adverse Event eCRF.  
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Hemophilic Bleeds
Medical occurrences or symptoms of deterioration that are anticipated as part of 
hemophilia should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in terms of severity (e.g., increased number of doses of 
bypassing agents to stop bleeds with emicizumab, in the absence of neutralizing 
anti-emicizumab antibodies, compared with before study entry), frequency of bleeds, or 
nature of hemophilia at any time during the study.  Should any of these occur (according 
to the investigator’s clinical assessment), they should be documented as an adverse 
event on the Adverse Event eCRF, conveying that the underlying condition has 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., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol (e.g., for study drug administration)

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


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing or drug administration error of emicizumab are 
available, as no such instances have been observed to-date.  To minimize the risk of 
errors associated with future home administration of emicizumab, data related to 
medication errors with observed patient/caregiver administration of emicizumab during 
the first 5 weeks at the site by the investigator and/or clinical staff will be recorded and 
corrected at the time of occurrence.  In addition, the recording of medication and 
handling errors associated with home administration, as well as drug compliance, will be 
collected at each clinic visit.  
5.3.5.13
Patient-Reported Outcome Data
The PRO measurements are described in Section 4.7.7.  The methods for collecting and 
analyzing PRO data are different from those for the ascertainment of observed or 
volunteered adverse events.  Adverse event reports will not be derived from PRO data 
by the Sponsor, and safety analyses will not be performed using PRO data.  Although 
sites are not expected to review the PRO data pertaining to the HRQoL, they are 
expected to review the Bleed/Medication Questionnaire.  Given that, it is possible that an 
investigator could become aware of PRO data that may be indicative of an adverse 
event.  Under these circumstances, the investigator will determine whether the criteria 
for an adverse event have been met and, if so, will report the event on the Adverse 
Event eCRF.  The patient-reported data will be presented in separate tables, figures, 
and data listings from the adverse event data and will be included in the appropriate 
section of the final study report.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 


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place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D., M.A.S. (primary)
Telephone No.:
Medical Monitor:
, M.D. (secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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 


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by scanning and emailing the form with use of the fax number or email address provided 
to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the last scheduled study visit (see Section 5.6).  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form with 
use of 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 post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Caregivers of female patients of childbearing potential will be instructed to immediately
inform the investigator if the patient becomes 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 with use of the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the caregivers and the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2
Pregnancies in Female Partners of Male Patients
Although embryo-fetal development studies are not available, condom use will not be 
required in male patients enrolled in the study, as the margin between the minimal 
anticipated biological effect level (MABEL) plasma concentration (7 ng/mL) and the 
estimated maternal Cmax (at both 1.5 and 3 mg/kg QW dosing regimens) is greater than 
10-fold (Banholzer et al. 2012).  At this time, very little emicizumab is thought to transfer 


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into semen, and there are no known reproductive risks to female partners of male 
patients treated with emicizumab.  Therefore, contraception use by male patients is not 
required for participation in the study, and to be consistent with this, no proactive
collection of pregnancy information for female partners of male patients treated with 
emicizumab will be required.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
At the time of pregnancy outcome, reporting instructions provided in Section 5.4.3
should be followed.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 


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24 weeks after the last dose of study drug or rollover to a future separate extension 
study), if the event is believed to be related to prior study drug treatment.  These events 
should be reported through use of the Adverse Event eCRF.  However, if the EDC 
system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form with use of the fax 
number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest (see Section 5.2.3) against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, Ethics 
Committees (ECs), and applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Emicizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
No formal hypothesis testing is planned in the study.  All the analyses will be descriptive
and be performed for each cohort separately.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited 
number of pediatric patients with hemophilia A with inhibitors available for participation in 
this study.  Hence, at least 40 children younger than 12 years of age and up to 
80 patients with hemophilia A and FVIII inhibitors who are currently receiving treatment 
with bypassing agents will be enrolled in this study: approximately 60 patients in 
Cohort A with allowance of patients 1217 years of age who weigh 40 kg at the time of 
informed consent and approximately 10 patients each in Cohort B and Cohort C.


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During the study, a re-assessment of the initially specified sample size based on 
enrollment consideration may be performed.  This may result in an increase in sample 
size, if necessary, to expand the safety database.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study in each cohort will
be summarized.  Moreover, 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.
Variables from the eCRF used to establish how many subjects reached the various 
stages of the study, how many dropped out and for what reasons will be described in the 
statistical analysis plan (SAP).
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, weight etc.) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented by cohort (i.e., Cohort A:  1.5 mg/kg QW; Cohort B:  3 mg/kg Q2W;
Cohort C:  6 mg/kg Q4W) and overall as appropriate.
6.4
EFFICACY ANALYSES
The efficacy analyses are to evaluate the clinical effect of prophylactic emicizumab on 
the number of bleeds over time (i.e., bleed rate), and to characterize the efficacy of 
up-titration on an intra-patient level.  These analyses will be conducted using different 
bleed definitions such as treated bleeds, all bleeds, treated spontaneous bleeds, treated 
joint bleeds, and treated target joint bleeds.
The primary analysis will be performed 52 weeks after the last patient in the primary 
population of Cohort A has been enrolled or withdrawn prematurely, whichever occurs 
first.  The primary population consists of all patients enrolled in Cohort A prior to the 
close of enrollment for patients 2 years of age (up to approximately 60 patients), and is 
used to define the timing of the primary analysis. The primary analysis will also include 
all available data from patients enrolled in Cohorts B and C, regardless of their follow-
up time.  Enrollment in Cohort A may be left open exclusively for patients 2 years of 
age in order to enroll approximately 510 such patients.  Note that these patients will be 
included in the primary population analysis regardless of their follow-up time.  Further 
analyses may be conducted while the study is ongoing (see Section 6.9).
6.4.1
Efficacy Endpoints
One efficacy objective is to evaluate the clinical effect of prophylactic emicizumab on the 
number of bleeds over time. This analysis will be performed for each cohort separately 


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as well as overall as appropriate. Another objective is to characterize the efficacy up-
titration on an intra-patient level.  The comparison between historical and on-study 
treatment period for bleeds over time will also be evaluated for patients who were 
previously enrolled in Study BH29768. These patients will enroll exclusively in Cohort 
A, therefore this intra-patient analysis will be conducted only in patients receiving the
1.5 mg/kg QW maintenance dose.  The definition of a bleed is described in Section 4.7.8.
All definitions (i.e., treated bleeds, all bleeds, treated spontaneous bleeds, treated joint 
bleeds, treated target joint bleeds) will be evaluated for each of the efficacy objectives.
Characterizing the effect of emicizumab on-study treatment period for bleed over time as 
well as analyses of up-titration and the comparison between historical and on study 
treatment period for bleed over time will be performed for Cohort A and for the overall 
analysis using a negative binomial regression model, which accounts for different follow-
up times, with the patient’s number of bleeds as a function of the time that each patient
stays in the study included as an offset in the model. 
The number of bleeds will be also annualized (Annualized Bleeding RateABR) for 
Cohorts B and C as well as for each patient using the following formula:
Of note, if the convergence of the negative binomial model is not achieved or is 
questionable, the efficacy analysis will be based on the ABR (formula just above).
The number of bleeds, sites of bleeds, and types of bleeds will be summarized for all 
patients and listed for each patient individually. Several exploratory analyses will be 
conducted to characterize the type, location, duration, frequency, and pattern of bleeds. 
For continuous endpoints, descriptive statistics will be calculated and categorical 
endpoints will be characterized through frequency tables. 
Efficacy endpoints will be analyzed separately by cohort (i.e., Cohort A:  1.5 mg/kg 
QW; Cohort B:  3 mg/kg Q2W; Cohort C:  6 mg/kg Q4W) and overall as appropriate. 
Patients who require up-titration will be reported in their original maintenance dose
group, and a listing based on their up-titration period will be provided. A detailed 
description of the statistical methods that will be used for the efficacy analyses will be 
provided in the SAP.
6.4.2
Exploratory Efficacy Endpoints
Summary statistics of the number of daycare/school and days hospitalized will be 
presented for each cohort separately.


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6.5
SAFETY ANALYSES
Safety analyses will be performed for each cohort separately and overall as appropriate.
The safety analyses population will be based on all patients who received at least one 
administration of emicizumab. Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including 
complete blood count with differential and platelet counts), ECGs, vital signs, and 
anti-emicizumab antibodies.
To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate 
thesaurus level, and toxicity grade.  
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading 
scale (WHO 2003).
Data on the impact of immunogenicity (anti-emicizumab antibodies and anti-FVIII 
antibodies) on safety, efficacy, and/or pharmacodynamics and pharmacokinetics will be 
summarized using standard language/terminology (Shankar et al. 2014).
6.6
PHARMACOKINETIC ANALYSES
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be 
presented descriptively by dose groups (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W, 
3 mg/kg QW in case of up-titration), including arithmetic and geometric means, median, 
range, standard deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various 
covariates, such as age, sex, and body weight, on these parameters will be investigated 
graphically.  Secondary PK parameters, such as area under the curve, will be derived 
from individual post-hoc predictions.  Data may be pooled with data from previous 
Phase I/II studies and Phase III Studies.  These analyses will be reported in a dedicated 
report.
6.7
PATIENT-REPORTED OUTCOME ANALYSES
Scale scores for the Haemo-QoL-SF and the Adapted InhibQoL Including Aspects of 
Caregiver Burden will be calculated for each assessment, with change scores being 
examined for the assessments over the course of the study.  These will be summarized 
descriptively by cohort.  A descriptive summary of the number of daycare/school days 
missed and days hospitalized will also be presented by cohort.


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6.8
PHARMACODYNAMIC BIOMARKER ANALYSES
PD parameters (e.g., aPTT, FVIII activity) will be presented using summary statistics by 
dose groups, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation. These analyses will be presented by cohort.
6.9
INTERIM DATA REVIEW
6.9.1
Planned Interim Data Review
In a first interim data review, the appropriateness of the initial dosing regimen will be 
evaluated (maintenance dose of 1.5 mg/kg/week).  This dosing regimen may be adapted 
following analysis of all available data (e.g., safety, efficacy, pharmacokinetics) by the 
JMC (see Section 9.5) if a majority of the first 35 patients (aged 2 to 12 years of age) 
fail to achieve optimal control of bleeds after the first 12 weeks of treatment; or if their 
plasma emicizumab concentration trough level is lower than the one being targeted in 
adolescents and adults (i.e., 45 µg/mL). Should patients 12 years of age and 40 kg 
be enrolled at the time of this first interim data review, available data from these patients 
will also be included.  
A second interim data review will occur once at least 10 patients between 2 and 
12 years of age have been dosed for a minimum of 12 weeks.  All available cumulative 
data (e.g., safety, efficacy, pharmacokinetics) will be evaluated by the JMC to provide
recommendations for the enrollment of children 2 years of age, as well as on any 
further adaptations of the maintenance dose if necessary.  Again, should patients 
12 years of age and 40 kg be enrolled at the time of this second interim data review, 
available data from these patients will also be included.
The evaluation of the interim data review will be performed on the efficacy 
endpointnumber of bleeds over timeas well as on the safety and PK results.
Should patient recruitment be faster than anticipated, enrollment will be placed on a 
temporary hold following the first 20 patients until the JMC releases its recommendations 
on the appropriateness of the maintenance dose.  
6.9.1.1
JMC Recommendations and Enrollment of Q2W/Q4W in 
Pediatric Patients
On 7 December 2016, based on a combined interim analysis of the first 20 patients 
enrolled, the JMC recommended to continue enrolling patients to Cohort A at the 
maintenance dose of 1.5 mg/kg QW, and to begin enrollment of patients 2 years of 
age. See Section 3.3.1.1 for details.
After the JMC recommendations were released following this interim analysis, the study 
continued to enroll up to approximately 60 patients in Cohort A. Upon completion of 
recruitment to Cohort A, and following review of data in adults and adolescents from 
two ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) and 
6 mg/kg Q4W (BO39182) identifying no safety concerns, recruitment with alternating 


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allocation of patients to Cohorts B and C via IxRS could begin up to a maximum of
approximately 10 patients in each cohort. See Section 3.3.1.1 for details.
Additional interim data reviews will be pre-specified in the Statistical Analysis Plan; other 
analyses may be conducted at various timepoints to support regulatory submissions.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
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
PATIENT-REPORTED OUTCOME DATA
Patient-reported outcome data will be collected with use of electronic, handheld devices 
provided by a vendor.  The electronic, device is designed for entry of data in a way that 
is attributable, secure, and accurate, in compliance with FDA regulations for electronic 
records (21 Code of Federal Regulations, Part 11).  The data will be transmitted 
electronically in real-time to a centralized, secure database.  The data from the 
bleed/medication, HRQoL, proxy HRQoL, and Aspects of Caregiver Burden 
questionnaires are available for view only via secure access to a Web portal provided by 


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the vendor.  The Sponsor will have view access only.  Regular data transfers will occur 
from the centralized database at the vendor to the database at the Sponsor.  The 
Sponsor will receive all data entered by patients on the electronic devices and all 
relevant study documentation.
Once the study is complete, the PRO data, audit trail, and study and system 
documentation will be archived.  The investigator will receive data for the site in both 
human- and machine-readable formats on an archival-quality compact disc that must be 
kept with the study records as source data.  Acknowledgement of receipt of the compact 
disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, 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 study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 


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acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for 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 FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and additional local regulatory requirements.  Assessments that require 
blood draws will be monitored closely to ensure that institutional mandates or EU 
guidelines (European Union 2008) regarding total sample blood volumes are followed.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form for parent/legally acceptable 
representative and Assent Form for the child (when applicable, in age-adapted format)
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 and Assent 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.


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If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient and 
parent/legally acceptable representative the objectives, methods, and potential risks 
associated with each optional procedure.  Patient and parent/legally acceptable 
representative 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 
from the parent/legally acceptable representative and the child (when applicable) 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’s legally authorized 
representative and the patient (when applicable) before his or her participation in the 
study.  The case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained prior to participation in 
the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient’s legally authorized 
representative and the patient.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
Pediatric patients who could potentially participate in this study are declared legally 
incompetent. When a child meets the qualifications for participation in the study and 
because emicizumab prophylaxis may directly benefit this population with high unmet 


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medical need, investigator or authorized designee will obtain informed consent from 
parent/legally acceptable representative in accordance with applicable law.  In addition, 
the investigator must also obtain the assent of the patient when they are able to give 
assent to decisions made on his or her behalf.  Any indication on the part of the patient 
that he or she is not willing to participate in the study will be honored.
In cases where there is reason to question the competence of a parent/legally 
acceptable representative who has not been declared incompetent (e.g., a patient in the 
early stages of Alzheimer’s disease), a patient advocate will be involved in the consent 
process and throughout the duration of the patient’s participation in the study.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent and Assent Forms, any information to be given to 
the parent/legally acceptable representative and 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 9.7).
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 
authorization for use and disclosure of personal health information) signed by the 
parent/legally acceptable representative, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
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Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures,
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
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
Enrollment and drug assignment will be performed by an IxRS, which will also manage 
emicizumab inventory for all sites globally.


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Patient-reported outcomes will be captured on electronic, handheld devices provided by 
a third-party vendor for all patients globally.
Central laboratories will be used for a subset of laboratory assessments specified in 
Section 4.7.5.
9.5
JOINT MONITORING COMMITTEE 
A JMC composed of selected internal Sponsor members (Pediatric Medical Specialist, 
Safety Scientist, Clinical Pharmacologist, and Statistician) constituting the Internal 
Monitoring Committee and external pediatric hemostasis/thrombosis Experts (including 
an external Clinical Pharmacology Expert) will be in place throughout the duration of the 
study. Internal Monitoring Committee members will be selected on the basis that they 
have no contact with the sites as part of their responsibilities. The external pediatric 
hemostasis/thrombosis experts will have as a role to enhance safety monitoring and 
leverage external experts’ scientific expertise by providing advice on data interpretation 
and will function as a consultative body to the Sponsor.
If a majority of the initial 35 patients 211 years of age treated for a minimum of 
12 weeks require up-titration, or if their plasma emicizumab concentration trough does 
not meet a target of 45 µg/mL, the Sponsor may suggest adaptation of the starting 
maintenance dose.  Thus, in a first interim data review, all cumulative data (e.g., safety, 
efficacy, and pharmacokinetics) will be evaluated by the JMC to provide 
recommendations of changing the starting maintenance dose for the subsequent 
patients to be enrolled (see Section 4.5.2).
Once at least 10 patients, aged 211 years have been dosed for a minimum of 12 weeks, 
a second interim data review of all available data (e.g., safety, efficacy, and 
pharmacokinetics) will be conducted to draw study and/or dosing recommendations 
produced by the JMC to allow children from 2 years of age to participate.  As a result of 
this interim data review, further adjustments to the maintenance dose can also be made 
if necessary.  The JMC will also monitor patient safety at pre-specified intervals and ad 
hoc as needed throughout the study.  Specific operational details, such as committee 
composition, member roles and responsibilities, frequency, and timing of meetings and 
interim data review will be detailed in a separate JMC Agreement.
9.6
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on both the interim data review and final analysis of the study 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: 


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The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
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.
9.7
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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Emicizumab—F. Hoffmann-La Roche Ltd
121/Protocol BH29992, Version 4
Appendix 1
Schedule of Assessments
Schedule of Assessments—Cohorts A, B, C
Screening
Wk 
1
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Wk 
29
Wk 
33
Wk 
37
Wk
41
Wk 
49
Study Drug
Discontinuation
Visit a
Safety 
F/U 
Visit a
Informed consent/assent b
x
Inclusion/exclusion 
criteria
x
Medical history and 
demographics c
x
Physical examination d
x
x
x
x d
x
x
x d
x
Vital signs e
x
x e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG g, h
x
x
x
x
Safety laboratory 
assessments h, i, j
x i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-FVIII antibodies j, k
x k
x
x
x
x
x
x
Anti-emicizumab 
antibodies h, j, l
x
x
x
x
x
x
x
Bleed/medication 
questionnaire m, n
----------------------------------------weekly o ----------------------------------------
x
x
x
Bleed/medication data 
review o
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
122/Protocol BH29992, Version 4
Schedule of Assessments—Cohorts A, B, C
Screening
Wk 
1
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Wk 
29
Wk 
33
Wk 
37
Wk
41
Wk 
49
Study Drug
Discontinuation
Visit a
Safety 
F/U 
Visit a
Following treatment with 
bypassing agents
Monitoring for thromboembolic events and thrombotic microangiopathy p
Adverse events q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IMP management r
x
x
x
x
x
x r
x
x
x
x
x
x
x
x
x
x
x
Haemo-QoL-Short Form s
x
x
x
x
x
x
Adapted InhibQoL t
x
x
x
x
x
x
PK assessment h, j, u
x
x
x
x
x
x r
x
x
x
x
x
x
x
x
x
x
x
x
PD biomarkers 
assessment h, j, v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
123/Protocol BH29992, Version 4
Schedule of Assessments—Cohorts A, B, and C
Every 12 Weeks 
from Wk 57
Every 
24 Weeks from 
Wk 57
Study 
Completion/ET a Safety F/U Visit a
Physical examination d
x
x
x
Vital signs e
x
x
x
Concomitant medications f
x
x
x
ECG g, h
x
Safety laboratory assessments h, i, j
x
x
x
Anti-FVIII antibodies j, k
x
x
Anti-emicizumab antibodies h, j , l 
x
x
x
Bleed/medication questionnaire m, n
x
x
x
Bleed/medication data review o
x
x
x
Adverse events q
x
x
x
IMP management r
x
x
Haemo-QoL-Short Form s
x
x
Adapted InhibQoL t
x
x
PK assessment h, j, u
x
x
x
PD biomarkers assessment h, j, v
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
124/Protocol BH29992, Version 4
eCRFelectronic Case Report Form; ePRO electronic patient-reported outcome; ET early termination; F/U follow-up; FVIIIfactor VIII; 
HRQoLHealth-Related Quality of Life; IMPinvestigational medicinal product, PDpharmacodynamic; PK pharmacokinetic; Wk Week.
Notes:  The maximum allowable time between screening and enrollment is 28 days; if the elapsed time between screening and enrollment is more 
than 28 days, screening must be repeated.  All assessments should be performed within 2 days of the scheduled visit for the first 12 weeks 
(including the Week 13 visit), then 7 days thereafter. Study assessments may be delayed or moved ahead of the window to accommodate 
holidays, vacations, and unforeseen delays.  Except for the bleed/medication questionnaire, all other patient data will be collected during office 
visits.  On treatment days, pre-injection blood collection should be made 0120 minutes before the injection.  Emicizumab will be administered 
subcutaneously at a loading dose of 3 mg/kg QW for the first 4 weeks (Day 1 of each week) followed by a starting maintenance dose of 1.5 mg/kg
QW (Cohort A), 3 mg/kg Q2W (Cohort B), and 6 mg/kg Q4W (Cohort C).  During the 52-week treatment period, individual patients may have 
their dose up-titrated if they experience suboptimal bleeding control on emicizumab (see Section 4.5.2).  In case of up-titration to a new 
maintenance dose, the next five weekly visits must occur at the site.
a The study treatment discontinuation visit refers to the visit that occurs when a patient discontinues study drug. A safety follow-up visit will
occur 24 weeks after discontinuing emicizumab for any reason.
b Written informed consent must be obtained from parents/legally acceptable representative and an assent from the child (when applicable) before 
distribution of the electronic, handheld device and collection of any data.  Enrollment form will be completed after informed consent form and 
assent form (when applicable) are obtained. If patient fulfills the inclusion/exclusion criteria, the patient should be enrolled in the study on the 
same day when the first dose of emicizumab is administered (Day 1).
c Collected from patient medical records and documented in the eCRF. 
d A complete physical examination will be performed at screening and targeted physical examination will be performed at subsequent visits.  
Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for bruises, hematomas, and injection-site reactions), in 
addition to other organ systems as clinically indicated and/or report of new or worsening adverse event.
e Body temperature (oral, rectal, axillary, or tympanic), blood pressure, pulse rate, respiratory rate, height/length, and weight to be entered into 
eCRF.  If Screening and Week 1 occur on the same date, the vital signs should be measured only once.  If Screening and Week 1 occur on 
different dates, vital signs should be repeated for both assessments.
f
Concomitant medications (e.g., extra pain medication with bleed) will be asked about at each clinic visit and documented in the eCRF, excluding 
treatments for bleeds (i.e., bypassing agents and other medications to treat bleeds), which will be collected on the bleed/medication 
questionnaire.  Hemostatic medications to treat or prevent bleeds in the 4 weeks prior to starting emicizumab will be collected on eCRF.
g If screening ECG abnormal, repeat at Week 1 (or Week 2 if Screening and Week 1 occur on the same date).  ECGs will also be performed 
4 weeks after starting emicizumab or after each dose up-titration, as well as at study completion/early termination.
h In case of up-titration, additional assessments including PK, PD biomarkers, anti-emicizumab antibodies, safety laboratory samples, and ECG 
will be required, with the schedule of assessments resetting back to Week 1, including an ECG.


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
125/Protocol BH29992, Version 4
i
Laboratory data (performed locally) includes complete blood count with differential and serum chemistries (i.e., sodium, potassium, chloride,  
glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, creatine phosphokinase, total protein, albumin, creatinine, total and 
direct bilirubin, alkaline phosphatase, ALT, and AST).  Female patients of childbearing potential will be required to have a negative serum 
pregnancy test result at screening and urine pregnancy tests performed at Weeks 13, 25, 37, and 49; every 12 weeks starting from Week 57; 
and study completion/early termination.
j
When blood is drawn via catheter or CVAD, a discard tube must be used prior to collection of samples for any laboratory assessment, due to the 
possibility of contamination by saline or anticoagulants used to flush the device.  Please consult the study Laboratory Manual for details on 
sample collection and processing. 
k Anti-FVIII antibodies will be measured at a central laboratory using citrate plasma.  Anti-FVIII antibodies is the only biomarker sample taken at 
screening.  In case a patient screen fails or does not enroll in the study for any reason, the sample should be destroyed and not sent to the 
central laboratory.  Throughout the study, additional blood samples may also be drawn on an unscheduled basis (at the clinical judgment of the
investigator) for analysis at a central laboratory.  
l
Samples to detect anti-emicizumab antibodies will be collected prior to emicizumab injection at Weeks 1, 5, 17, 33, 49, every 12 weeks starting 
from week 57, study completion/early termination and at the 24-week safety follow-up visit.  If patients continue on emicizumab past 52 weeks of 
treatment, anti-emicizumab antibodies will be collected every 12 weeks.  If any of these samples are positive and/or if there is suboptimal clinical 
response or low pharmacokinetic exposure, additional samples may be collected and analyzed for anti-emicizumab antibodies.  Anti-emicizumab 
antibodies should also be drawn at the time of systemic hypersensitivity events.  For each additional anti-emicizumab sample, a PK sample 
should be concomitantly drawn.
m At the Week 1 visit, caregivers will be trained on how to use their handheld device to record the bleeds and the hemophilia medication use.  The 
bleeding/medication questionnaire will be completed by the caregiver and includes start date and time, reason, type, location of each bleed, as 
well as start date and time, reason, type, and dose of each injection.
n Caregivers will be instructed to complete on weekly basis to complete the bleed/medication questionnaire when the patient has a bleed or 
hemophilia medication use.
o At subsequent visits as marked, investigator review of patient-reported bleed/medication questionnaire information will be conducted for 
completeness and accuracy.
p Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic 
microangiopathy for platelet count, serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent use. A plasma sample 
should also be provided for local (one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 12, and 
D-dimer.  If prothrombin fragment 12 test cannot be done at the site, the sample should be send to the local reference laboratory, if available, 
and if the results from the local reference laboratory can be obtained within a reasonable timeframe to allow for decision making.  For patients 
who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 2448 hours 
following the last dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory results should be recorded in the eCRF
page titled “Local Lab Following Treatment with Bypassing Agents.”


Appendix 1
Schedule of Assessments (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
126/Protocol BH29992, Version 4
q Patients are advised to inform the investigator about adverse events at every visit.  Adverse events will be reported on the eCRF by the 
investigator.  Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected 
worsening of the patient’s hemophilia in terms of severity (e.g., increased number of doses of bypassing agents to stop bleeds compared with 
before study entry), frequency of bleeds, or nature at any time during the study, this should be documented as an adverse event on the Adverse 
Event eCRF, conveying that the underlying condition has changed by including applicable descriptors (e.g., "increased clinical severity of 
hemophilia"). 
r
Drug accountability will not be performed at the first visit of emicizumab receipt.  Drug dispensation will not occur at the study completion/early 
termination visit. Note:  for Cohort C, there are visits where emicizumab is not administered per schedule.
s Haemo-QoL-Short Form (children 8 years of age and older) assessed on an electronic, handheld device by patients during patient’s visit in clinic 
prior to emicizumab injection at Weeks 1, 13, 25, 37, 49, every 24 weeks from Week 57, and study completion/early termination.
t
Proxy assessment of HRQoL and aspects of caregiver burden using the Adapted InhibQoL Including Aspects of Caregiver Burden questionnaire 
for all children assessed on electronic, handheld device by caregivers during patient’s visit in clinic prior to emicizumab injection at Weeks 1, 13, 
25, 37, 49, every 24 weeks from Week 57 and study completion/early termination. 
u Emicizumab concentration. Plasma samples for this assessment should be taken prior to emicizumab injection. 
v PD biomarkers will be measured at a central laboratory.  See Appendix 2, for detailed explanation of PD biomarker assessments.  Blood 
samples may also be drawn to conduct biomarker assays at the central laboratory on an unscheduled basis (at the clinical judgment of the 
investigator) at any time.  


Emicizumab—F. Hoffmann-La Roche Ltd
127/Protocol BH29992, Version 4
Appendix 2
Schedule of PD Assessments
Sample
Visit a
Biomarker assays b
PD Set 1
Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, every 
8 weeks from Week 41, every 12 weeks from Week 57
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the investigator) 
while on emicizumab c
PT/INR
D-dimer
aPTT
PD Set 2 d
Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, every 
8 weeks from Week 41, every 12 weeks from Week 57
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the investigator) 
while on emicizumab c
FVIII activity
FIX antigen
FX antigen
FIX factor IX; FVIIIfactor VIII; FX factor X; PDpharmacodynamic.
a All samples are to be collected on Day 1 of the indicated week, prior to emicizumab
injection (if applicable).  All PD samples will be citrate plasma.  
b Biomarker assays will include but are not limited to those listed.  Where blood volumes 
allow, additional plasma may be frozen and banked for future exploratory research related 
to emicizumab.  Blood volumes and processing procedures will be specified in the 
Laboratory Manual.
c Reasons for unscheduled visits may include evaluation or treatment for bleeds or 
hypersensitivity reactions.
d These plasma samples will only be collected if the permitted blood volumes allow (based on 
patient body weight as described in Section 3.3.5).  Please refer to the Laboratory Manual 
for details.


Emicizumab—F. Hoffmann-La Roche Ltd
128/Protocol BH29992, Version 4
Appendix 3
Haemo-QoL-SF (United States/English)


Emicizumab—F. Hoffmann-La Roche Ltd
129/Protocol BH29992, Version 4
Appendix 3
Haemo-QoL-SF (United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
130/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English)


Emicizumab—F. Hoffmann-La Roche Ltd
131/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
132/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
133/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
134/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
135/Protocol BH29992, Version 4
Appendix 4
Adapted InhibQoL Including Aspects of Caregiver Burden
(United States/English) (cont.)


Emicizumab—F. Hoffmann-La Roche Ltd
136/Protocol BH29992, Version 4
Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
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


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
137/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
116 or mental status 
changes or seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
165 mEq/L or mental 
status changes or seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or 
intensive replacement 
Rx required or
hospitalization required.
2.0 mEq/L
or paresis or ileus or life-
threatening arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L
or life-threatening
arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental 
status changes or coma
Hyperglycemia (note if 
fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or 
ketoacidosis or seizures
Hypocalcemia (corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or 
life-threatening arrhythmia 
or tetany
Hypercalcemia (correct for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL
life-threatening arrhythmia


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
138/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CHEMISTRIES continued
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or 
life-threatening arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or
replacement Rx required
1.01.4 mg/dL intensive 
Rx or hospitalization
required
1.0 mg/dL or 
life-threatening arrhythmia
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
6ULN or required 
dialysis
URINALYSIS
Proteinuria
1or 0.3% or 3g/L
or 200 mg1 g loss/day
23or 0.31.0% or
310 g/L
12 g loss/day
4or 1.0% or 10 g/L
23.5 g loss/day
nephrotic syndrome or 
3.5 g loss/day
Hematuria
microscopic only
gross, no clots
gross clots
obstructive or required 
transfusion
CARDIAC DYSFUNCTION
Cardiac Rhythm
asymptomatic, transient
signs, no Rx required
recurrent/persistent; no 
Rx required
requires treatment
Hypertension
transient inc. 20 mm;
no Rx
recurrent, chronic, 
20 mm, Rx required
requires acute Rx; no
hospitalization
requires hospitalization


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
139/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
CARDIAC DYSFUNCTION continued
Hypotension
transient orthostatic
hypotension, no Rx
symptoms correctable
with oral fluids Rx
requires IV fluids; no
hospitalization required
requires hospitalization
Pericarditis
minimal effusion
mild/moderate
asymptomatic effusion, 
no Rx
symptomatic effusion;
pain; EKG changes
tamponade;
pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
12 units transfused
massive blood loss;
3 units transfused
RESPIRATORY
Cough
transient; no Rx
treatment-associated
cough
local Rx
uncontrolled
Bronchospasm, Acute
transient; no Rx
70%79% FEV1
(or peak flow)
requires Rx normalizes 
with bronchodilator; FEV1
50%69%
(or peak Flow)
no normalization with
bronchodilator;
FEV1 25%49%
(or peak flow retractions)
cyanosis: FEV1
25%
(or peak flow) or intubated
GASTROINTESTINAL
Stomatitis
mild discomfort; no limits 
on activity
some limits on
eating/drinking
eating/talking very
limited
requires IV fluids


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
140/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
GASTROINTESTINAL continued
Nausea
mild discomfort;
maintains reasonable
intake
moderate discomfort;
intake decreased
significantly; some
activity limited
severe discomfort; no
significant intake;
activities limited
minimal fluid intake
Vomiting
transient emesis
occasional/moderate
vomiting
orthostatic hypotension 
or IV fluids required
hypotensive shock or 
hospitalization required for 
IV fluid therapy
Constipation
mild
moderate
severe
distensions w/vomiting
Diarrhea
transient 34 loose
stools/day
5-7 loose stools/day
orthostatic hypotension 
or
7 loose stools/day or
required IV fluids
hypotensive shock or 
hospitalization for IV fluid 
therapy required
NEURO AND NEUROMUSCULAR
Neuro-cerebellar
slight incoordination
dysdiadochokinesis
intention tremor,
dysmetria, slurred
speech; nystagmus
locomotor ataxia
incapacitated
Mood
mild anxiety or
depression
moderate anxiety or
depression and therapy 
required
severe anxiety or
depression or mania;
needs assistance
acute psychosis;
incapacitated, requires
hospitalization


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
141/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
NEURO AND NEUROMUSCULAR continued
Neuro control
(ADLactivities of daily 
living)
mild difficulty
concentrating; no Rx;
mild confusion/agitation;
ADL unaffected
moderate
confusion/agitation some 
limitation of ADL; minimal 
Rx
severe 
confusion/agitation
needs assistance for
ADL; therapy required
toxic psychosis;
hospitalization
Muscle strength
subjective weakness
no objective 
symptoms/signs
mild objective
signs/symptoms no 
decrease in function
objective weakness
function limited
paralysis
OTHER PARAMETERS
Fever: oral, 12 hours
37.738.5 C or
99.9101.3 F
38.639.5 C or
101.4103.1 F
39.640.5 C or
103.2104.9 F
40.5 C or
104.9 F
Headache
mild, no Rx therapy
transient, moderate; Rx
required
severe; responds to
initial narcotic therapy
intractable; required
repeated narcotic therapy
Fatigue
no decrease in ADL
normal activity decreased 
2550%
normal activity
decreased 50% can’t
work
unable to care for self
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria;
angioedema
anaphylaxis
Local Reaction
tenderness or erythema
induration 10 cm or
phlebitis or inflammation
Induration 10 cm or
ulceration
necrosis


Appendix 5
WHO Toxicity Grading Scale for Determining the Severity of Laboratory Abnormalities and Adverse
Events (cont.)
Emicizumab—F. Hoffmann-La Roche Ltd
142/Protocol BH29992, Version 4
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
OTHER PARAMETERS continued
Mucocutaneous
erythema; pruritus
diffuse, maculo-papular 
rash, dry desquamation
vesiculation, moist
desquamation, or
ulceration
exfoliative dermatitis, 
mucous membrane
involvement or erythema,
multiforme or suspected 
Stevens-Johnson or 
necrosis requiring surgery
NOTE:  For coding purposes, the following toxicity grades may be used interchangeably: 1mild; 2moderate; 3severe; 4life 
threatening.


Emicizumab—F. Hoffmann-La Roche Ltd
143/Protocol BH29992, Version 4
Appendix 6
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 pressure2

Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline
_____________________________________
1
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006;117:391–7.
2
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg [2 x age]) from 1 to 10 years, and less than 90 mmHg from 
11 to 17 years.

SAP_001.pdf: 
 
 
Official Title:  
 
A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO 
EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN 
HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS 
NCT Number: 
NCT02795767 
Document: 
Version & Date:  
STATISTICAL ANALYSIS PLAN 
Version 3: 14 March 2018 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Emicizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BH29992 
STATISTICAL ANALYSIS PLAN
TITLE: 
A MULTICENTER, OPEN-LABEL, PHASE 
III CLINICAL TRIAL TO EVALUATE THE 
EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF ONCE WEEKLY 
SUBCUTANEOUS ADMINISTRATION OF 
EMICIZUMAB IN HEMOPHILIA A 
PEDIATRIC PATIENTS WITH INHIBITORS
PROTOCOL NUMBER: 
BH29992 
STUDY DRUG: 
RO5534262 
VERSION NUMBER: 
3 
IND NUMBER: 
122954 
EUDRACT NUMBER: 
2016-000073-21 
SPONSOR: 
F. Hoffmann-La Roche Ltd and Chugai 
Pharmaceutical Co., Ltd. 
PLAN PREPARED BY: 
 
DATE FINAL: 
Version 1: 15 July 2016
DATE AMENDED: 
Version 2: 29 November 2016 
Version 3: See electronic date stamp below. 
Name                                                             Reason for Signing                              Date and Time
(UTC)
14-Mar-2018 10:33:43
Company Signatory


Emicizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan BH29992 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
The Statistical Analysis Plan was amended because the study protocol was amended to 
add two additional cohorts to investigate less frequent emicizumab dosing schedules 
(every 2 weeks [Q2W] and every 4 weeks [Q4W]). The addition of these cohorts is 
reflected throughout the Statistical Analysis Plan.
Additional minor changes have been made to improve consistency and clarity. 


Emicizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan BH29992 
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 9
2.2
Collection of Bleed and Medication Data............................... 10
2.3
Objectives and Endpoints...................................................... 11
2.3.1
Efficacy Period for All the Endpoints...................................... 11
2.3.2
Bleed-Related Objectives and Endpoints .............................. 11
2.3.2.1
Treated Bleeds ...................................................................... 11
2.3.2.2
All Bleeds............................................................................... 12
2.3.2.3
Treated Spontaneous Bleeds ................................................ 12
2.3.2.4
Treated Joint Bleeds.............................................................. 12
2.3.2.5
Treated Target Joint Bleeds .................................................. 13
2.3.2.6
Intra-Patient Comparison....................................................... 13
2.3.2.7
Up-Titration............................................................................ 13
2.3.3
Health-Related Quality of Life (HRQoL) 
Objectives and Endpoints...................................................... 13
2.3.4
Pharmacokinetic Endpoint..................................................... 15
2.3.5
Safety Objectives and Endpoints........................................... 15
2.3.6
Biomarker Objectives and Endpoints..................................... 15
2.4
Determination of Sample Size ............................................... 15
2.5
Analysis Timing ..................................................................... 15
3.
STUDY CONDUCT..................................................................................... 16
3.1
Data Monitoring ..................................................................... 16
4.
STATISTICAL METHODS .......................................................................... 17
4.1
Output Layouts ...................................................................... 17
4.2
Analysis Populations ............................................................. 18
4.2.1
All Patients............................................................................. 18
4.2.2
Treated Population ................................................................ 18
4.2.3
Non-Interventional Population ............................................... 18


Emicizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan BH29992 
4.2.4
Pharmacokinetic-Evaluable Population ................................. 18
4.2.5
Patients 12-17 Years of Age Who Weigh 40 kg................. 18
4.2.6
Patients 2 Years of Age...................................................... 18
4.2.7
Up-titrated Patients................................................................ 18
4.3
Analysis of Study Conduct..................................................... 18
4.4
Efficacy Analysis.................................................................... 19
4.4.1
Efficacy Endpoint................................................................... 19
4.4.1.1
Bleed Rate............................................................................. 19
4.4.1.2
Intra-Patient Comparison....................................................... 19
4.4.1.3
Health-Related Quality of Life (HRQoL)................................. 20
4.4.2
Subgroup Analyses ............................................................... 21
4.5
Pharmacokinetic Analyses..................................................... 21
4.6
Safety Analyses..................................................................... 22
4.6.1
Exposure to Study Medication............................................... 22
4.6.2
Adverse Events ..................................................................... 22
4.6.3
Laboratory Data..................................................................... 22
4.6.4
Vital Signs.............................................................................. 23
4.6.5
ECG....................................................................................... 23
4.7
Biomarker Analysis................................................................ 23
4.8
Missing Data.......................................................................... 23
4.9
Interim Analyses .................................................................... 23
5.
REFERENCES ........................................................................................... 24
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 25
Appendix 2
Schedule of Assessments........................................................... 35
Appendix 3
Schedule of PD Assessments..................................................... 41


Emicizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan BH29992 
1.
BACKGROUND
Hemophilia A is an X-linked recessive bleeding disorder that occurs in approximately 1 
in 5,000 live male births.  Patients with hemophilia A have a deficiency or absence of 
blood coagulation factor VIII (FVIII), an essential component of the intrinsic pathway in 
the coagulation cascade (Franchini and Mannucci 2013).
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 of FVIII administered as replacement therapy.  For patients
with a history of 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”). 
Current standard prophylactic regimens commonly use infusion therapy administered 
three times a week; other regimens require daily or every other day administration, 
depending on the patient’s needs (Shapiro 2013).  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.  Thus, both 
the disease and its treatment have the potential to affect health-related quality of life 
(HRQoL), the latter through limitations on daily activities that treatment may impose. 
The development of effective prophylactic treatment options with decreased 
immunogenicity and less frequent dosing requirements is a high unmet medical need in 
the population of hemophilia A patients with FVIII inhibitors.  Given the significant unmet 
medical need among pediatric patients with hemophilia A with FVIII inhibitors and 
positive benefit-risk assessment for emicizumab, initiation of a pediatric Phase III study 
is appropriate.
Emicizumab is a recombinant, humanized, bispecific, immunoglobulin G4 (IgG4) 
monoclonal antibody that binds with moderate affinity to activated factor IX (FIXa) and 
factor X (FX), mimicking the co-factor function of FVIII.  In patients with hemophilia A, 
hemostasis can be restored irrespective of the presence of FVIII inhibitors, as 
emicizumab shares no sequence homology with FVIII.  In addition, emicizumab offers 
the possibility of subcutaneous (SC) administration, removing the need for venous 
access.  Finally, because of the expected pharmacokinetic properties of this antibody, 
markedly extending the dosing interval to once weekly or even less frequently, this novel 
compound has the potential to dramatically change the treatment of patients with 
hemophilia A with and without FVIII inhibitors who are in need of effective, safe, and 
convenient prophylactic therapy. 


Emicizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan BH29992 
Currently available experience with emicizumab in humans includes data from one 
Phase I study (Study ACE001JP), its ongoing extension, a Phase I/II study 
(Study ACE002JP), and a site of injection and relative and absolute bioavailability study 
in healthy Japanese subjects (Study JP29574).  See Protocol Section 1.2 for detailed 
description of the study results (Shima et al. 2016).  On the basis of these compelling 
Phase I/II data, a clinical development program in adult and pediatric patients with 
hemophilia A (both with and without FVIII inhibitors) has been initiated. Four Phase III 
studies are currently ongoing and are aimed at evaluating the efficacy and safety of 
emicizumab at various dosing regimenses and in different populations.  The studies are 
Study BH29884, which evaluates 1.5 mg/kg weekly (QW) in an adult and adolescent 
population with FVIII inhibitors; Study BH29992, which evaluates 1.5 mg/kg QW, 
3mg/kg every 2 weeks (Q2W) and 6mg/kg every 4 weeks (Q4W) in pediatric patients 
with inhibitors; Study BH30071, which evaluates 1.5mg/kg QW and 3mg/kg Q2W in a 
population without inhibitors; and Study BO39182, which evaluates 6mg/kg Q4W in a 
population with or without inhibitors.
 meetings have been held with United States Food and Drug 
Administration (FDA) to discuss the development program of emicizumab.  
 
  The Paediatric 
Investigational Plan (PIP) was submitted to EMA/Paediatric Committee (PDCO) on 10 
August 2015.  On 
, the protocol for this study (plus the Informed 
Consent Form [ICF] and assent forms) was sent to the FDA, and the core Clinical Trial 
Application (CTA) was dispatched to the affiliates on 
.
On 16 November, 2017, the FDA approved the Biologics License Application (BLA) for 
HEMLIBRA (emicizumab-kxwh) for routine prophylaxis to prevent or reduce the 
frequency of bleeding episodes in people with haemophilia A with factor VIII inhibitors 
(PwHAi).  In addition, on 27 February, 2018, the European commissionapproved  
Hemlibra(emicizumab) for routine prophylaxis of bleeding episodes in people with 
haemophilia A with factor VIII inhibitors. 
2.
STUDY DESIGN
This non-randomized, multicenter, open-label, Phase III clinical study will enroll children 
with hemophilia A who have inhibitors against FVIII.  Children with hemophilia A and 
documented historical FVIII inhibitor titer ( 5 BU) must currently be receiving treatment 
with bypassing agents.  At least 40 patients younger than 12 years of age and up to 
approximately 80 patients are planned for enrolment, with allowance for patients 12-17 
years of age who weigh 40 kg at the time of informed consent.  Patients will receive 
weekly SC doses of emicizumab at 1.5 mg/kg QW (Cohort A) for a minimum of 52
weeks or until unacceptable toxicity, discontinuation from the study due to any cause, or 
other criteria set forth in the protocol, whichever occurs first (see Figure 1).  After 52 


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weeks of treatment, an individual patient who continues to derive clinical benefit may 
continue receiving prophylactic emicizumab as part of this study or a future separate 
emicizumab extension study. 
Because of the uncertainty of the dosing regimen needed in patients 12 years of age 
or 40 kg to achieve similar exposure as in adults and adolescents, this study will first 
evaluate the appropriate dosing regimen in children by starting with the same weekly
dosing regimen (1.5mg/kg QW) being evaluated in the Phase III study (Study BH29884) 
in adult and adolescent patients with hemophilia A with inhibitors.  Emicizumab will be 
administered with a weekly loading dose of 3.0 mg/kg QW for the first 4 weeks (Day 1 of 
each week) followed by a maintenance dose of 1.5 mg/kg QW (Cohort A) for the 
remainder of the treatment period (Day 1 of each week).  Individual patients may have 
their dose up-titrated if they experience suboptimal bleeding control on emicizumab.  
Investigators will monitor patients regularly with the guidance of an up-titration algorithm.  
If patients meet protocol-defined criteria for efficacy-guided up-titration, the investigator 
will contact the Medical Monitor to initiate a discussion about possible up-titration.  
In a first interim data review, the appropriateness of the initial dosing regimen will be 
evaluated (maintenance dose of 1.5 mg/kg QW) after the first 3-5 patients ( 2 to 12 
years of age) have been dosed for a minimum of 12 weeks.  A Joint Monitoring 
Committee (JMC) will review all cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) at the first interim data review and provide recommendations on 
increasing the starting maintenance dose if a majority of the first 3-5 patients fail to 
achieve optimal control of bleeds after the first 12 weeks of treatment or their plasma 
emicizumab trough concentration is lower than the one being targeted in adolescents 
and adults (i.e., 45 µg/mL).  All patients enrolled following the first interim data review will 
receive the starting maintenance dose selected/confirmed by the JMC.  Patients enrolled 
prior to the first interim data review will remain on their current maintenance dose unless 
they meet eligibility for up-titration based on protocol-defined criteria. 
In order to include and safely treat the youngest patients (birth to 2 years of age), this 
study will include a staggered approach to enrolment by age.  Patients 2 to 12 years 
of age and patients 12-17 years of age who weigh < 40 kg will enroll first.  A second 
interim data review will occur once at least 10 patients between 2 and 12 years of
age have been dosed for a minimum of 12 weeks, at which time all cumulative data (e.g., 
safety, efficacy, and pharmacokinetics) will be evaluated by the JMC to provide 
recommendations for enrolment of children 2 years of age, as well as 
recommendations on any additional adaptations of the maintenance dose, if necessary.
If patient recruitment is faster than anticipated, enrolment will be placed on a temporary 
hold following the first 20 patients until the JMC releases its recommendations on the 
appropriateness of the maintenance dose (Cohort A).  After the JMC recommendations 


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are released following both interim data reviews, the study will continue to enrol in 
Cohort A up to a maximum of approximately 60 patients. 
Once 1) the exposure at 1.5 mg/kg QW has been characterized in this pediatric
population; 2) Cohort A is fully enrolled; and 3) review of data in adults and adolescents 
from two ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) 
and 6 mg/kg Q4W (BO39182) identifies no safety concerns, this study will open two 
additional non-randomized cohorts to investigate Q2W and Q4W regimens in pediatric 
patients. Parallel enrolment with alternate cohort allocation to Cohort B (3 mg/kg Q2W) 
and Cohort C (6 mg/kg Q4W) will occur, for a total of approximately 10 patients per 
cohort. Of note, enrolment to Cohorts B and C will be limited to patients 2-11 years of 
age. Emicizumab will be administered with a loading dose of 3 mg/kg QW for the first 4 
weeks followed by a maintenance dose of 3 mg/kg Q2W (Cohort B) and 6mg/kg Q4W 
(Cohort C) for a minimum of 52 weeks, or until unacceptable toxicity, discontinuation 
from the study due to any cause, or other criteria set forth in the protocol, whichever 
occurs first (see Figure 1). Individual patients may have their dose up-titrated if they 
experience suboptimal bleeding control on emicizumab.  The entire study will enrol up to 
approximately 80 patients  . 
All patients will continue to receive prior therapy as prescribed by their treating physician 
with episodic bypassing agents to treat breakthrough bleeds as needed.  However, 
prophylactic use of bypassing agents should be discontinued by the time the first dose of 
emicizumab is given.
Figure 1
Study Schema
JMC Joint Monitoring Committee; Q2W every 2 weeks; Q4W every 4 weeks; QW once 
weekly; Scr screening.


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* In a first interim data review, the starting maintenance dose will be re-evaluated after the first 
3−5 patients (2 to 12 years of age) have been dosed for a minimum of 12 weeks.  A JMC will 
review all cumulative data (e.g., safety, efficacy, and pharmacokinetics) to provide 
recommendations on increasing the starting maintenance dose.  A second interim data review by 
the JMC will occur once at least 10 patients (2 to 12 years of age) have been dosed for a 
minimum of 12 weeks, at which time all available cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) will be evaluated to provide recommendations for the enrolment of 
children 2 years of age, as well as on the maintenance dose.  If patient recruitment is faster 
than anticipated, enrolment will be placed on a temporary hold after the first 20 patients until the 
JMC releases its recommendations on the appropriateness of the maintenance dose.  After the 
JMC recommendations are released following both interim data reviews, the study will continue 
to enroll up to a maximum of approximately 60 patients in Cohort A. Subsequently, should no 
safety concerns arise from review of adult/adolescent data at Q2W (BH30071) and Q4W 
(BO39182) dosing, parallel enrolment with alternate cohort allocation to Cohorts B and C (up to 
approximately 10 patients per cohort) will commence.
The primary analysis for all cohorts will be performed 52 weeks after all patients in the 
primary population of Cohort A have been enrolled or withdrawn prematurely, whichever 
occurs first (see Section 2.5).  The primary population of Cohort A consists of all 
patients enrolled prior to the close of enrolment for patients ≥ 2 years of age (up to 
approximately 60 patients) and is used to define the timing of the primary analysis of the 
study.  The efficacy analysis will evaluate the clinical effect of prophylactic emicizumab 
on the number of bleeds over time (i.e., bleed rate) and will characterize the efficacy of 
up-titration on an intra-patient and population level.  If no patients < 2 years of age are 
included in the primary population of Cohort A, the primary analysis will still occur at the 
specified time; however, enrolment to Cohort A may be left open exclusively for 
patients 2 years of age in order to enrol approximately 5 such patients.  Note that 
these patients will be included in the primary analysis of Cohort A regardless of their 
follow-up time.  Additionally, all available data from patients enrolled in Cohorts B and C 
(regardless of their follow-up time) will be included at the time of the primary analysis.  
In order to complement the analysis of Study BH29884 in adult and adolescents with 
inhibitors an interim analysis will be performed for Study BH29992 at the same time as 
the primary analysis of Study BH29884.  An interim clinical study report (CSR) will be 
written for Study BH29992, in which some analyses may differ from the final study 
analyses.  These differences are outlined in this SAP. 
Other interim analyses might occur at any time in order to support health authorityies’ 
requests or submissions.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  


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2.2
COLLECTION OF BLEED AND MEDICATION DATA
Bleed and medication data are collected through a bleed and medication questionnaire 
(BMQ), which was developed by the Sponsor given that no standard questionnaire for 
collection of these data was available.
The BMQ was developed as a patient-reported outcome measure of bleeding episodes 
(including cause, type, and location of bleeds) and hemophilia-related medication use.  
The draft questions were developed following a review of the hemophilia A literature and 
discussions with medical professionals regarding what information related to bleeds was 
most important to capture.
The BMQ is completed by the caregiver, with use of an electronic handheld device.  All 
bleeds, hemophilia related medications, and emicizumab administrations are entered at 
minimum weekly and as they occur.  If a patient does not experience a bleed or does not 
receive any hemophilia related medications for a week, the caregiver will be prompted to 
log in to the device and confirm this.  Of note, the caregiver is able to enter bleeds and 
medications for the past 8 days, including the day entries are made.  This retrospective 
data entry window was considered acceptable in terms of recall bias and was added in 
order to optimize the completeness of data collection.
The caregiver is able to edit and delete bleeds and medications immediately after they 
are entered.  However, if the data have been submitted to the vendor’s database (i.e., 
after responses have been confirmed by the caregiver), the caregiver is no longer able 
to edit or delete the data.  Furthermore, the investigator, the caregiver, and the patient 
are instructed to review the data together at every clinic visit.  If the caregiver was 
unable to enter bleed, medication, or emicizumab data within the 8 days’ timeframe, if 
the caregiver mistakenly entered data that require deletion, or if the caregiver mistakenly 
entered data that require modification (e.g., incorrect emicizumab dose), the investigator 
is able to submit a data clarification request (DCR) to the vendor on the caregiver’s 
behalf at any time.
Furthermore, the Sponsor’s data manager and Medical Monitor will review the data 
entered by the caregiver on the BMQ for inconsistencies against data collected on the 
electronic case report form (eCRF) or to identify obvious data points to be clarified (e.g., 
missing entry of the weekly emicizumab injection).  These clarification requests are sent 
to the investigator, who reviews them together with the caregiver and the patient (if the 
patient is old enough) and may enter or change the data via a DCR, if necessary.  In 
addition, HRQoL using the Haemo-QoL-Short Form (SF) (completed by patients aged 8 
years and above), proxy-reported HRQoL and the Adapted InhibQoL including Aspects 
of Caregiver Burden questionnaire (completed by caregivers for all children), and the 
number of days of missed daycare/school (completed by caregivers for all children) will 
be assessed every 3 months as outlined in the schedule of assessments.  The number 


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of days the child was hospitalized (if applicable) will be derived from data collected on 
eCRF. 
The Haemo-QoL-SF, Adapted InhibQoL including Aspects of Caregiver Burden 
questionnaires, and number of days of missed daycare/school are completed with use of 
a tablet at the site during clinic visit. However, for this type of data, there is no possibility 
for retrospective data entry or data modification and these data will not be queried. 
2.3
OBJECTIVES AND ENDPOINTS
2.3.1
Efficacy Period for All the Endpoints
The start of the efficacy period for each individual patient is defined as the day of the first 
emicizumab dose.
The end of the efficacy period is defined as the date of the clinical cutoff or the date of 
withdrawal from the initial study period (i.e., treatment period according to eCRF), 
whichever is earlier.  For patients who withdraw from the study before reaching the 
Week 1 visit, the duration of efficacy period is set to 1 day and it starts and ends on the 
day of enrolment.
For patients whose dose is up-titrated, the bleeds on the up-titrated dose are analyzed 
separately.  The efficacy period on a given up-titrated dose starts with the first day on 
this dose and ends on the day of the clinical cut-off, the date of withdrawal, or on the last 
day on this specific dose, whichever is earlier.
2.3.2
Bleed-Related Objectives and Endpoints
The bleed efficacy objectives for this study are as follows:  

To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds 
over time  

To evaluate the reduction in bleeding rate on-treatment with emicizumab compared 
with the patient’s historical bleeding rate (intra-patient comparison, only patients in 
Cohort A who previously participated in the non-interventional study (NIS), as 
patients enrolled in Cohorts B and C will not have previously participated in the NIS)

To characterize the efficacy of up-titration on an intra-patient level, based on the 
number of bleeds over time.
The endpoint is the bleed rate and is defined as the number of bleeds over the efficacy 
period.  Different analyses will be conducted as outlined in the sections below. 
2.3.2.1
Treated Bleeds
A bleed is considered to be a “treated bleed” if it is directly followed (i.e., there is not an 
intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, 
irrespective of the time between the treatment and the preceding bleed.  A bleed and the 
first treatment thereafter are considered to be pairs (i.e., one treatment belongs to one 


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bleed only), with the following exception:  If multiple bleeds occur on the same calendar 
day, the subsequent treatment is considered to apply for each of these multiple bleeds. 
Bleeds due to surgery/procedure are not included in the analysis.  Only treatments that 
were recorded as “treatment for bleed” are included in the determination of a treated 
bleed. Note that a bleed can be treated with more than one treatment.
72-Hour Rule: 
Two bleeds of the same type (e.g., “joint”, “muscle”, or “other”) and at the same 
anatomical location are considered to be one bleed if the second bleed occurs within 
72 hours from the last treatment for the first bleed.  The last treatment is defined as the 
last treatment before a new bleed occurs, either in the same or in a different location.  
This is consistent with the above definition that bleeds and treatments are considered to 
be pairs. 
2.3.2.2
All Bleeds
Given that some patients may report bleeds that they did not treat, ‘all bleeds’ will be 
analyzed as an additional endpoint definition to treated bleeds and comprise both 
treated and non-treated bleeds.  In this definition, all bleeds are included, irrespective of 
treatment with coagulation factors, with the following exception:  Bleeds due to 
surgery/procedure are excluded as for the ‘treated bleed’ analysis. 
The endpoint of all bleeds fulfills the adapted ISTH criteria, as described in the protocol 
and the 72-hour rule, in particular.  For treated bleeds, it is implemented exactly as 
defined for the ‘treated bleed’ definition (see Section 2.3.2.1).  For non-treated bleeds 
(not followed by any treatments with coagulation factors before the recording of a 
subsequent bleed), it is implemented by calculating a treatment-free period of 72 hours 
from the bleed itself.  
2.3.2.3
Treated Spontaneous Bleeds 
In the analysis of spontaneous bleeds, only treated bleeds that fulfill the 72 hour rule are 
included.
Bleeds are classified as “spontaneous” if there is no other known contributing factor such 
as trauma or procedure/surgery.
2.3.2.4
Treated Joint Bleeds 
In the analysis of treated joint bleeds, only treated bleeds that fulfill the 72 hour rule are 
included.  Bleeds due to procedure/surgery are, again, excluded. Joint bleeds are 
defined as bleeds where the bleed type is “joint”.


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2.3.2.5
Treated Target Joint Bleeds 
Target joints are major joints into which repeated bleeds occur (i.e., 3 bleeds into the 
same joint over the last 24 weeks prior to study entry). 
The target joints prior to study entry are identified through the eCRF.  The bleeds in 
target joints during the efficacy period are defined by first selecting the bleeds that fulfill 
the definition of a treated joint bleed (see Section 2.3.2.4) and then counting how many 
of these occurred in a target joint prior to study entry.  The locations to be taken into 
account are:  shoulder, elbow, wrist, fingers/thumb, hip, knee, ankle, sole/heel, and toes.  
Left and right side of the same joint type are considered to be separate joints. 
2.3.2.6
Intra-Patient Comparison 
In the intra-patient comparison (on All Bleeds and on Treated Bleeds), only patients who 
participated in the NIS BH29768 are included.  This is because it is possible to apply the 
detailed definition only if the data are collected with the same granularity for both time 
periods.  Of note, for some patients who participated in NIS BH29768, the total time in 
that study prior to enrolment in Study BH29992 may be short. 
The efficacy period in NIS BH29768 is defined as the time from the first entry on the 
electronic, handheld device or site data entry system to the day before the patient is 
enrolled in Study BH29992.  Usually, the date of the first entry is the date the Training 
Module on the electronic, handheld device is completed. 
2.3.2.7
Up-Titration
In the analysis of efficacy of the up-titration, only patients whose dose was up-titrated will 
be included.  The analyses will be done with both treated bleeds and all bleeds 
definitions. Of note, for the interim CSR these analyses will not be performed. 
2.3.3
Health-Related Quality of Life (HRQoL) Objectives and
Endpoints
The patient-reported outcome (PRO) objectives and endpoints for this study are as 
follows:

Evaluate the HRQoL of children 8-17 years of age according to Haemo-QoL-SF 
(completed by patients) 
The Haemo-QoL-SF is a self-report questionnaire for children.  Only patients 8 
years of age and above will be assessed for HRQoL with use of this questionnaire, 
which will be completed by the patients as per the schedule of assessments.  The 
Haemo-QoL-SF is derived from the Haemo-QoL questionnaire, which has been 
developed in a series of age-related questionnaires to measure HRQoL in children 
and adolescents with hemophilia.
The Haemo-QoL-SF version contains 35 items, which cover nine dimensions 
considered relevant for the children’s HRQoL (Physical Health, Feelings, View of 


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self, Family, Friends, Other people, Sports and school, Dealing with hemophilia, and 
Treatment).  The Physical Health scale assesses hemophilia-related symptoms 
(painful swellings and presence of joint pain) and physical functioning (pain with 
movement) and is of particular interest given that it has been responsive to change 
with modifications in treatment regimen (Santagostino et al. 2014).  Items are rated 
with five respective response options:  never, seldom, sometimes, often, and always. 

Evaluate proxy-reported HRQoL and aspects of caregiver burden using the Adapted 
InhibQoL including Aspects of Caregiver Burden questionnaire for all children 
(completed by caregivers) 
This will be completed by caregivers as per the schedule of assessments for all 
children regardless of age.  The Adapted InhibQol Including Aspects of Caregiver 
Burden is composed of 32 items that make up 7 domains (Physical Health, 
Treatment, Perceive condition, Dealing with Inhibitor, Perceive treatment, Family life, 
Others). In addition, if the child has siblings, there is an additional question that 
creates 1 domain (Siblings) for a total of 8 domains. All questions on the Ada[ted 
InhibQoL are responded to on 5-point scale from ‘Never’ (1) to ‘All the time’ (5).
The Physical Health domain consists of five questions focused on the child’s 
hemophilia-related symptoms (bruises, bleeds, painful swellings, presence of joint 
pain and joint stiffness) and two questions on physical functioning limitations (pain 
with movement, sleep through the night because of pain) because of hemophilia. 
Two other domains cover issues related to the burden on caregivers of dealing with 
a child with inhibitors. The Dealing with Inhibitor domain includes questions on the 
psychological impact (anxiety, fear and worry) associated with their son’s 
hemophilia A. Additionally, the Perceive treatment domain includes questions 
focused on the impact that treatment has on the caregiver in terms of the 
interference with daily life, difficulty in preparing the injections, and satisfaction with 
the amount of time to administer treatment. These three domains are of particular 
interest given the consistency with the Haemo-QoL-SF (for Physical Health) and the 
potential reduction in burden as a result of emicizumab treatment. 

Assess the number of days missed from daycare/school (completed by caregivers) 
and days hospitalized  
Caregivers will be asked to report as per the schedule of assessments the number 
of days of daycare/school that were missed and this will be completed following the 
Adapted InhibQoL including Aspects of Caregiver Burden questionnaire.  The 
number of days the child was hospitalized (if applicable) will be derived from data 
collected on eCRF. 
Of note, the Haemo-QoL-SF, caregiver-reported HRQoL, and aspects of caregiver 
burden questionnaires are completed every 3 months from the Week 1 assessment and 
request inputs from the past 4 weeks. 


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2.3.4
Pharmacokinetic Endpoint
The pharmacokinetic (PK) endpoint for this study is the exposure (Ctrough) of 
emicizumab in patients receiving 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W, 
assessed prior to drug administration on Day 1 and at the following timepoints: 

Every week during Weeks 1-4 on emicizumab

Every 2 weeks during Weeks 5-9 on emicizumab

Every 4 weeks during Weeks 13-37 on emicizumab

Every 8 weeks during Weeks 41-49 on emicizumab

Every 12 weeks from Week 57 thereafter while continuing on emicizumab until the 
end of the study.
Additional PK samples will be taken in patients who require up-titration. 
2.3.5
Safety Objectives and Endpoints
Safety parameters to be measured include exposure, adverse events (AEs; including 
serious AEs [SAEs]; AEs of special interest [AESI], AEs leading to drug discontinuation, 
and deaths), clinical laboratory values and abnormalities (including hematology, 
coagulation, chemistry, and anti-emicizumab antibodies), vital signs, ECG, and 
concomitant medication use.
2.3.6
Biomarker Objectives and Endpoints
Biomarker parameters to be measured include but are not limited to coagulation-related 
assays such as aPTT, PT/INR, D-dimer, and FVIII activity assays. 
2.4
DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on feasibility and clinical considerations rather 
than statistical considerations, taking into account the number of pediatric patients with 
hemophilia A with inhibitors available for participation in this trial.  Hence, at least 
40 children younger than 12 years of age and up to approximately 80 patients with 
hemophilia A and FVIII inhibitors who are currently receiving treatment with bypassing 
agents will be enrolled in this study: approximately 60 patients in Cohort A  with 
allowance of patients 12-17 years of age who weigh < 40 kg at the time of informed 
consent and with allowance for approximately 5 additional patients < 2 years of age in 
Cohort A - and approximately 10 patients each in Cohort B and Cohort C.
During the study, a re-assessment of the initially specified sample size based on 
enrolment consideration may be performed.  This may result in an increase in sample 
size, if necessary, to expand the safety database.
2.5
ANALYSIS TIMING
The primary analysis will be performed 52 weeks after the last patient in the primary 
population of Cohort A has been enrolled or withdrawn prematurely, whichever occurs 


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first.  The primary population of Cohort A consists of all patients who will receive 
emicizumab at 1.5 mg/kg QW enrolled prior to the close of enrollment for patients ≥ 2 
years of age (up to approximately 60 patients) and is used to define the timing of the 
primary analysis.  If no patients < 2 years of age are included in the primary population 
of Cohort A, the final analysis will still occur at the specified time; however, enrolment in
the study may be left open exclusively for patients < 2 years of age in order to enroll up 
to 5 such patients. 
The final analysis will occur at the end of the study as defined in the protocol.  Additional 
updates may be performed between the primary and final analysis as requested by 
Health Authorities or deemed necessary by the Sponsor. 
Timing of interim analyses is detailed in Sections 3.1and 4.9. 
3.
STUDY CONDUCT
3.1
DATA MONITORING
A Joint Monitoring Committee (JMC) composed of selected internal Sponsor members 
(Pediatric Medical Specialist, Safety Scientist, Clinical Pharmacologist, and Statistician) 
constituting the Internal Monitoring Committee and external pediatric 
hemostasis/thrombosis experts (including an external Clinical Pharmacology expert) will
be in place throughout the duration of the study.  Internal Monitoring Committee 
members have been selected on the basis that they have no contact with the sites as 
part of their responsibilities.  The external pediatric hemostasis/thrombosis experts 
function to enhance safety monitoring, leverage external experts’ scientific expertise by 
providing advice on data interpretation, and serve as a consultative body to the Sponsor. 
If a majority of the initial 3-5 patients, aged 2 to 12 years, treated for a minimum of 
12 weeks require up-titration or if their plasma emicizumab trough concentrations do not 
meet a target of 45 µg/mL, the JMC may suggest adaptation of the starting maintenance 
dose.  Thus, in a first interim data review, all cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) will be evaluated by the JMC to provide recommendations of 
changing the starting maintenance dose for the subsequent patients to be enrolled. 
Once at least 10 patients, aged 2 to 12 years, have been dosed for a minimum of 
12 weeks, a second interim data review of all available data (e.g., safety, efficacy, and 
pharmacokinetics) will be conducted to draw study and/or dosing recommendations 
produced by the JMC and to allow children from 2 years of age to participate.  As a 
result of this interim data review, further adjustments to the maintenance dose may also 
be made, if necessary.  The JMC may, if needed, monitor patient safety at pre-specified 
intervals and ad hoc as needed throughout the study.


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If rapid study enrolment occurs and the fifth and tenth patient are enrolled within 2 weeks 
of each other, the two data review meetings may be combined and take place at the 
same time. 
The evaluation of the interim data reviews will be performed on the efficacy endpoints⎯
number of bleeds over time⎯as well as on the safety and PK results.
Specific operational details, such as committee composition, member roles and 
responsibilities, frequency, and timing of meetings and interim data review are detailed 
in a separate JMC Agreement.  
Of note, because patient recruitment occurred faster than anticipated, the first and 
second interim data reviews were combined into one interim data review. Following the 
interim review on 7 December 2016, the JMC recommended that enrolment to Cohort A 
could continue with the selected maintenance dose of 1.5 mg/kg QW and that the 
Cohort A of the study should be opened for recruitment of children 2 years of age.
4.
STATISTICAL METHODS
For continuous variables, means, medians, ranges, and standard deviations will be 
presented.  For categorical variables, the number and percentage of patients within each 
category will be presented.  For each variable (continuous or categorical), the number of 
available observations will be reported.  No formal hypothesis testing will be performed 
as the study is entirely descriptive. 
4.1
OUTPUT LAYOUTS
The key output layout is designed to address the study objectives in a flexible manner 
and provide an overall view of the efficacy and safety of emicizumab for all dosing 
regimens.  The key output layout is as follows: 
All patients: these outputs will provide an overall view of all the data collected under 
emicizumab prophylaxis. Patients will be grouped according to their original 
maintenance regimen at study entry (QW, Q2W and Q4W) with a total column provided 
as well. 
Listings will include all the data for all the patients with a flag indicating the dose related 
to each event and the dosing regimen of the patients.  As appropriate, outputs will be 
produced for each dosing regimen separately. 
Patients may be allowed to up-titrate their emicizumab dose if they meet the 
pre-specified criteria as described in the protocol. Patients will be grouped according to 
their original maintenance dose at study entry. 


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The data under the new, higher dose will be analysed and reported separately. 
Additional summaries will be produced for key safety and exposure on all data (i.e., data 
before and after up-titration).
For Cohort A, the primary set of outputs will include patients from 0 to 12 years of age.  
Three additional limited sets of outputs will be produced: one for patients 12 years of 
age, one for the combined sets (0 to 12 years of age and 12 years of age) and one
for patients ≤2 years old at time of enrolment.
For Cohorts B and C, only one set of outputs will be produced for each cohort and will 
include all the patients enrolled in these cohorts.
4.2
ANALYSIS POPULATIONS
4.2.1
All Patients
All patients’ population includes all patients enrolled in the study.  
4.2.2
Treated Population 
Treated population corresponds to all patients who received at least one dose of 
emicizumab.  This population will be the primary population for efficacy and safety
analyses. 
4.2.3
Non-Interventional Population 
This population includes patients who participated in Cohort B of the NIS BH29768 prior 
to enrolment to this study. All the NIS patients enrolled in BH29992 are enrolled to 
Cohort A.
4.2.4
Pharmacokinetic-Evaluable Population 
The PK population includes all patients who have received at least one dose of 
emicizumab and have at least one post-dose emicizumab concentration result. 
4.2.5
Patients 12-17 Years of Age Who Weigh 40 kg
This population includes patients 12-17 years of age who weigh 40 kg at the time of 
informed consent. 
4.2.6
Patients 2 Years of Age
This population includes patients 2 years of age at the time of informed consent.
4.2.7
Up-titrated Patients
This population includes patients who had at least one dose up-titration. 
4.3
ANALYSIS OF STUDY CONDUCT
The flow of patients through the study will be displayed in a ‘CONSORT’ diagram.  A 
clear account of all patients who entered the study, who were enrolled, who dose up-


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titrated, and who completed each period of the study will be displayed.  In addition, 
reasons for premature discontinuation from study treatment and reasons for withdrawing 
from the study (e.g., during follow-up) will be described.
Major protocol deviations will be summarized.
Observation time and duration of follow up, as well as adherence to planned assessment 
schedule and compliance with data entry into the electronic handheld device, will also be 
evaluated. 
4.4
EFFICACY ANALYSIS
The efficacy objectives of this study will be investigated without any formal hypothesis 
testing.  All analyses will be of descriptive nature only.  
4.4.1
Efficacy Endpoint 
4.4.1.1
Bleed Rate 
A bleed is defined in two ways.  The first definition uses adapted ISTH definition of a 
bleed (Blanchette 2014; see Section 2.3.2.1; see Protocol Section 4.7.8).  The second 
definition is counting all the bleeds regardless of the treatment (see Section 2.3.2.2). 
The number of bleeds over time (bleed rate) will be calculated using a negative binomial 
(NB) regression model, which accounts for different follow-up times, with time that each 
patient stays in the study (efficacy period) included as an offset in the model.  In addition, 
the number of bleeds will also be annualized for each patient using the following formula: 
ABR (Number of bleeds/number of days during the efficacy period)×365.25.  
For the interim CSRs, the population ABR may not be robust as it might be driven by 
only a few extreme observations because of the short follow up time.  Therefore, the 
bleed rate will be characterized through individual patient data collected on the BMQ.  In 
addition, with such short follow up, the NB model might not converge or the results might 
be unreliable.  For all the patients, the number of bleeds will be described with use of 
descriptive statistics.  The individual ABR will be calculated for patients who have been 
on the study for at least 12 weeks on the same dose (including the loading doses) with 
use of the given formula above.  
The number of bleeds, types, and locations of bleed will be summarized for all patients 
and listed for each patient individually.  Several exploratory analyses will be conducted 
to characterize the type, location, frequency, and pattern of bleeds.  
4.4.1.2
Intra-Patient Comparison 
The definition of treated bleeds and all bleeds is described in Section 2.3.2.  The 
analysis methodology is the NB regression model.  


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This analytic model estimates the rate ratio, t/c., which quantifies the risk of bleeding 
associated with prophylactic emicizumab (t) in comparison to the historical bleeding 
events (c).  The analysis will be performed overall and for each dose titration. 
The treatment effect therein is based on a repeated statement in the model with use of 
the SAS GENMOD procedure.  Bleed rates for prophylactic emicizumab and no 
prophylaxis and the rate ratio will be presented and include 95% confidence intervals.  
The intra-patient comparison will be performed on patients who have been enrolled at 
least 12 weeks before the cut-off. 
For the Interim CSR, individual patient’s ABR will be provided in a descriptive manner 
including the reduction in ABR comparing before and after entering into Study BH29992.  
At this stage, the patients included in the analysis will have been on the study for at least 
12 weeks.  
4.4.1.3
Health-Related Quality of Life (HRQoL) 
For Haemo-QoL-SF, descriptive analyses including summaries and 95% confidence 
intervals of change from baseline for each individual subscale and the overall score will 
be performed.  Individual patient plots of the overall score at each timepoint will be 
generated.  For the interim CSRs, individual patient plots will be performed, and if at 
least 8 patients have been on the study for at least 12 weeks, the descriptive analysis 
including summaries and 95% confidence intervals will be performed.  Note that the 
number of patients contributing to the analysis is very limited because the questionnaire 
is completed only by a subset of patients (those 8 years of age and above). 
For aspects of caregiver burden using Adapted InhibQoL including Aspects of Caregiver 
Burden questionnaire for all children (completed by caregivers), descriptive analyses 
and 95% confidence intervals of change from baseline for each individual subscale will 
be performed.  Individual patient plots of the overall score at each timepoint will be 
generated.  For the interim CSRs, individual patient plots will be performed, and if at 
least 8 patients have been on the study for at least 12 weeks, the descriptive analysis 
including summaries and 95% confidence intervals will be performed. 
Number of days of missed day care/school and days hospitalized will be analyzed using 
descriptive statistics and 95% confidence intervals.  For the interim CSR, if at least 
8 patients have been on the study for at least 12 weeks, the descriptive analysis 
including summaries and 95% confidence intervals will be performed. 
The Week 12 timepoint has been chosen because the patients/caregivers are 
completing the QoL questionnaires every 12 weeks.  Therefore at least 1 questionnaire 
in addition to baseline should have been completed for these patients. 


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4.4.2
Subgroup Analyses 
Comparative subgroup analyses describing the bleed rate (treated and all) will be 
conducted.  In addition, estimated ABR including 95% confidence interval will be 
calculated in each subgroup.  Note that due to the small sample size, all subgroup 
analyses will be highly sensitive to variability caused by individual patients and need to 
be interpreted with caution.  
The pre-specified subgroups are: 

Age: 0 to2, 2 to 6, 6 to 12,12 years  

Race: Asian, Black or African American, White, Other 

Pre-study hemophilia treatment type: Episodic versus Prophylactic 

Number of target joints at baseline: no target joint, any target joint 
In addition, region- and/or country-specific analyses will be performed to support 
regulatory submissions as needed. 
These subgroup analyses will not be performed at the time of the interim analyses. For 
the Primary CSR, these analyses will be performed for the all patients population 
regardless of the dosing regimen as sample size will be too small per regimen.
4.5
PHARMACOKINETIC ANALYSES
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be 
presented descriptively at each timepoint by dose group, including arithmetic and 
geometric means, median, range, standard deviations, and coefficients of variation. 
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of emicizumab following SC administration.  Population PK parameters, such as 
clearance and volume of distribution, will be estimated, and the influence of various 
covariates, such as age and body weight, on these parameters will be investigated 
graphically.  Secondary PK parameters, such as area under the curve, will be derived 
from individual post-hoc predictions.  Data may be pooled with data from previous Phase 
I/II studies and Study BH29884.  These analyses will be reported in a dedicated report.
In addition, region- and/or country-specific analyses will be performed to support 
regulatory submissions as needed (e.g., PK analysis in Japanese vs. non-Japanese 
patients or analyses based on ethnicity). 
The PK will be analyzed separately for the three cohorts: Cohort A (1.5 mg/kg/QW), 
Cohort B (3 mg/kg/ Q2W), and Cohort C (6 mg/kg Q4W).


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4.6
SAFETY ANALYSES
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (including serum chemistry, hematology, coagulation, and antibodies to 
emicizumab), ECGs, and vital signs. 
4.6.1
Exposure to Study Medication 
Information on study drug administration will be summarized by duration and cumulative 
dose.  In addition, treatment exposure will be summarized including delays and 
interruptions.  The number of patients whose dose was up-titrated will be summarized. 
Patient withdrawals from study treatment will be reported in listings and summary tables. 
4.6.2
Adverse Events 
To evaluate the overall safety of prophylactic emicizumab, adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate 
thesaurus level, and toxicity grade (WHO Criteria).  All AEs will be coded using the 
current version of MedDRA at the time of each database closure (interim and primary 
analysis).  For the purpose of summarization, a patient is counted once in a system 
organ class or preferred term if the patient reported one or more events in that system 
organ class or preferred term.  Percentages will be based on the number of patients 
overall.  
The total number and percentage of patients with at least one AE and total number of 
AEs will be summarized.  Separate AE summaries for SAEs, AESIs, severity, 
relatedness, and discontinuation/modification will be provided.   
An overall summary of adverse events (including SAEs, AESIs, AEs leading to drug 
discontinuation, and deaths), which tabulates the number and percentage of patients 
who experienced any or serious adverse events and the number and percentage of 
patients who died, will be provided. 
For adverse events with a missing intensity, seriousness, or relationship, the worst case 
will be assumed and the adverse events will be considered life-threatening (Grade 4) or 
serious. 
4.6.3
Laboratory Data 
For clinical laboratory data, which were collected from local laboratories, summary 
statistics in SI units will be presented.  Laboratory data not collected in SI units will be 
converted to SI units as applicable.  In addition, shift tables describing changes from 
baseline will be presented using the WHO toxicity grading scale. 


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Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or clinical pharmacology and pharmacokinetics will be summarized using standard 
language/terminology (Shankar et al. 2014). 
4.6.4
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 pressure.
4.6.5
ECG 
ECG results and corresponding changes from baseline will be summarized by visit for 
QT, RR, HR, QTcB, QTcF, PR and QRS and T- and U-wave morphology. 
4.7
BIOMARKER ANALYSIS
Pharmacodynamic (PD) parameters (e.g., aPTT, FVIII activity) and other exploratory 
markers (FIX and FX antigens, PT/INR, D dimer) will be presented using summary 
statistics, including means, median, range, standard deviations, and coefficients of 
variation.  In addition, individual patient plots will be provided. At the time of the interim 
analysis, only listings and patient plots will be performed. 
4.8
MISSING DATA
On the electronic handheld device, it is not possible to leave questions unanswered or to 
enter partial data in one BMQ.
In the site data entry system, it is possible to leave the time (but not the date) of a 
treatment or a bleed blank because the caregiver might not be able to remember these 
in a reliable way. 
In order to implement the 72 hour rule, it is assumed that the bleeds and treatments with 
missing time occurred at 12:00 a.m. If at a given day only the treatment time or the 
bleed time is partial and the other one complete, the partial time is assumed to be the 
same as the complete time.  In case of multiple events per day, the last complete time is 
used.
4.9
INTERIM ANALYSES
Interim data reviews by the JMC are described in Section 3.1.  An additional interim 
analysis for Study BH29992 will occur at the same time as the primary analysis of Study 
BH29884.  This interim analysis will be based on all available data from these pediatric 
patients and will be reported in an interim CSR.  Other interim analyses might occur at 
any time in order to support health authority requests or submissions.


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5.
REFERENCES
Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from 
the SSC of the ISTH. J Thromb Haemost 2014;12:1935−9. 
Franchini M and Mannucci PM. Hemophilia A in the third millennium. Blood Rev 
2013;27:179−84. 
Mannucci PM and Tuddenham EG. The hemophilias⎯from royal genes to gene therapy. 
N Engl J Med 2001;344:1773−9. 
Santagostino E, Lentz SR, Busk AK, Regnault A, Iorio A.  Assessment of the impact of 
treatment on quality of life of patients with haemophilia A at different ages: insights 
from two clinical trials on turoctocog alfa. Haemophilia (2014), 20, 527–534. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and 
tactical recommendations. AAPS J 2014;16:658−73.  
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Am Soc 
Hematol Educ Program 2013;2013:37−43.  
Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized 
bispecific antibody in hemophilia a. N. Engl J Med 2016;374:2044−53.  


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Appendix 1
Protocol Synopsis
TITLE:
A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO 
EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF SUBCUTANEOUS ADMINISTRATION 
OF EMICIZUMAB IN HEMOPHILIA A PEDIATRIC PATIENTS WITH 
INHIBITORS
PROTOCOL NUMBER:
BH29992
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-000073-21
IND NUMBER:
122954
TEST PRODUCT:
Emicizumab (RO5534262)
PHASE:
Phase III
INDICATION:
Hemophilia A
SPONSOR:
F. Hoffmann-La Roche Ltd and
Chugai Pharmaceutical Co. Ltd.
Objectives and Endpoints
The objectives of the study are to investigate (with no formal hypothesis testing) the efficacy, 
safety, and pharmacokinetics of SC emicizumab administered at 1.5 mg/kg QW, 3 mg/kg Q2W, 
and 6 mg/kg Q4W in pediatric patients with hemophilia A and factor VIII (FVIII) inhibitors who 
are currently receiving treatment with bypassing agents.  A total of approximately 80 patients 
are planned:  approximately 60 patients in Cohort A (1.5 mg/kg QW) and approximately 
10 patients each in Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W).  Patients younger 
than 12 years of age are planned for enrollment, with allowance of patients 1217 years of age 
who weigh 40 kg at the time of informed consent to further evaluate dosing of emicizumab in 
patients 40 kg. Of note, enrollment in Cohort A may be left open exclusively for patients 
2 years of age until approximately 5 such patients have been enrolled.
Efficacy Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as appropriate.
The efficacy objectives for this study are as follows:

To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds over 
time (i.e., bleed rate) *

To evaluate the efficacy in reducing the number of bleeds  over time compared with the 
patient's historical bleed rate (intra-patient comparison, Cohort A only, as patients enrolled 
in Cohorts B and C will not have previously participated in the non-interventional 
study) *

To characterize the efficacy of up-titration on an intra-patient level, based on the basis of the
number of bleeds over time *

To evaluate the health-related quality of life (HRQoL) of children 817 years of age 
according to Haemo-QoL-Short Form (SF) (completed by patients)


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Appendix 1 Protocol Synopsis (Cont)

To evaluate proxy-reported HRQoL and aspects of caregiver burden using the Adapted 
InhibQoL Including Aspects of Caregiver Burden questionnaire for all children (completed 
by caregivers)

To assess the number of days missed from daycare/school and days hospitalized
* Analyses will be performed for:  treated bleeds, all bleeds, treated spontaneous bleeds, 
treated joint bleeds, and treated target joint bleeds.
Safety Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as appropriate.
The safety objective for this study is to evaluate the overall safety of emicizumab in pediatric 
patients with hemophilia A and inhibitors on the basis of the following endpoints:

Incidence and severity of adverse events

Incidence and severity of thromboembolic events

Changes in physical examination findings and vital signs 

Incidence of laboratory abnormalities 

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to drug discontinuation 

Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 

Incidence and severity of thrombotic microangiopathy

Incidence and clinical significance of anti-emicizumab antibodies
Pharmacokinetic Objective
The endpoints will be analyzed separately for the three cohorts:  Cohort A (1.5 mg/kg QW), 
Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W).
The pharmacokinetic (PK) objective for this study is to characterize the exposure (Ctrough) of 
emicizumab in patients receiving 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W prior to 
drug administration on Day 1 and at the following timepoints:

Every week during Weeks 14 on emicizumab

Every 2 weeks during Weeks 59 on emicizumab

Every 4 weeks during Weeks 1337 on emicizumab

Every 8 weeks during Weeks 4149 on emicizumab

Every 12 weeks from Week 57 thereafter while continuing on emicizumab, until the end of 
the study

Additional PK samples will be taken in patients who require up-titration (see schedule of 
assessments in the protocol)
Pharmacodynamic Biomarker Objective
The pharmacodynamic (PD) biomarker objective for this study is as follows:

To assess potential PD biomarkers of emicizumab, including but not limited to aPTT and 
FVIII activity, at designated timepoints throughout the study.


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Appendix 1 Protocol Synopsis (Cont)
Study Design
Description of Study
This non-randomized, multicenter, open-label, Phase III clinical study will enroll children with 
hemophilia A who have inhibitors against FVIII.  Children with hemophilia A and documented 
historical FVIII inhibitor titer (5 BU) must currently be receiving treatment with bypassing 
agents.  At least 40 patients younger than 12 years age and up to approximately 80 patients 
are planned for enrollment, with allowance of patients 1217 years of age who weigh 40 kg at 
the time of informed consent.  Patients will receive SC doses of emicizumab at 1.5 mg/kg QW 
(Cohort A)for a minimum of 52 weeks or until unacceptable toxicity, discontinuation from the 
study due to any cause, or other criteria set forth in the protocol, whichever occurs first.  After 
52 weeks of treatment, an individual patient who continues to derive clinical benefit may
continue receiving prophylactic emicizumab as part of this study or a future separate 
emicizumab extension study.
Because of the uncertainty of the dosing regimen needed in patients 12 years of age or 
40 kg to achieve similar exposure as in adults and adolescents, this study will first evaluate 
the appropriate dosing regimen in children by starting with the same weekly dosing regimen 
(1.5 mg/kg QW) being evaluated in the Phase III study (BH29884) in adult/adolescent patients 
with hemophilia A with inhibitors (see protocol for details).  Emicizumab will be administered 
with a weekly dose of 3 mg/kg QW for the first 4 weeks followed by a maintenance dose of 
1.5 mg/kg QW (Cohort A) for the remainder of the treatment period.  During the 52-week 
treatment period, individual patients may have their dose up-titrated if they experience 
suboptimal bleeding control on emicizumab (see protocol).
In a first interim data review, the appropriateness of the initial dosing regimen will be evaluated 
(maintenance dose of 1.5 mg/kg QW) after the first 35 patients (2 to 12 years of age) have
been dosed for a minimum of 12 weeks.  A Joint Monitoring Committee (JMC; see protocol) will 
review all cumulative data (e.g., safety, efficacy, and pharmacokinetics) to provide 
recommendations on increasing the starting maintenance dose (if necessary) to target a similar 
plasma emicizumab trough concentration as the one being targeted in adolescents and adults 
(i.e., 45 µg/mL).  All patients enrolled following the first interim data review will receive the 
starting maintenance dose selected by the JMC.  Those patients enrolled prior to the first 
interim data review who had not had their dose up-titrated will remain on their current 
maintenance dose, unless they meet eligibility for up-titration based on protocol-defined criteria 
(see protocol).
In order to include and safely treat the youngest patients (birth to 2 years of age), this study 
will include a staggered approach to enrollment by age.  Patients 2 to 12 years of age and 
patients 1217 years of age who weigh 40 kg will enroll first.  A second interim data review will 
occur once at least 10 patients between 2 and 12 years of age have been dosed for a 
minimum of 12 weeks, at which time all cumulative data (e.g., safety, efficacy, and 
pharmacokinetics) will be evaluated to provide recommendations for enrollment of children 
2 years of age, as well as on any additional adaptations of the maintenance dose if necessary.
Furthermore, should patient recruitment be faster than anticipated, enrollment will be placed on
a temporary hold following the first 20 patients until the JMC releases its recommendations on 
the appropriateness of the maintenance dose (Cohort A).  After the JMC recommendations are 
released following both interim data reviews, the study will continue to enroll in Cohort A up to 
approximately 60 patients.
Once 1) the exposure at 1.5 mg/kg QW has been characterized in this pediatric population; 
2) Cohort A is fully enrolled; and 3) review of data in adults and adolescents from two 
ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg 
Q4W (BO39182) identifies no safety concerns, this study will open two additional 
non-randomized cohorts to investigate Q2W and Q4W regimens in pediatric patients.  
Recruitment to Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W) will occur in parallel 
with alternate cohort allocation via IxRS, for a total of approximately 10 patients per cohort.


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Appendix 1 Protocol Synopsis (Cont)
  Of note, enrollment to Cohorts B and C will be limited to patients 211 years of age.  
Emicizumab will be administered with a loading dose of 3 mg/kg QW for the first 4 weeks 
followed by a maintenance dose of 3 mg/kg Q2W (Cohort B) and 6mg/kg Q4W (Cohort C) for 
a minimum of 52 weeks, or until unacceptable toxicity, discontinuation from the study due to 
any cause, or other criteria set forth in the protocol, whichever occurs first (see protocol).  
During the 52-week treatment period, individual patients may have their dose up-titrated if 
they experience suboptimal bleeding control on emicizumab.
The entire study will enroll up to approximately 80 patients with allowance for additional 
patients 2 years of age in Cohort A.
A patient who fulfills the inclusion and exclusion criteria should be enrolled at the Week 1 visit.  
Prophylactic use of bypassing agents should be discontinued the day before the first dose of 
emicizumab is given. 
The primary analysis for all cohorts will be performed 52 weeks after all patients in the primary 
population of Cohort A have been enrolled or withdrawn prematurely, whichever occurs first.  
The primary population of Cohort A consists of all patients enrolled prior to the close of 
enrollment for patients 2 years of age (up to approximately 60 patients) and is used to define
the timing of the primary analysis of Cohorts A, B, and C.  If no patients 2 years of age are 
included in the primary population of Cohort A, the primary analysis will still occur at the 
specified time; however, enrollment to Cohort A may be left open exclusively for patients 
2 years of age in order to enroll approximately 5 such patients.  Note that these patients will 
be included in the primary analysis of Cohort A regardless of their follow-up time.  Additionally, 
all available data from patients enrolled in Cohorts B and C (efficacy period approximately 6 
months) will be included in the primary analysis of Cohort A.
During the study, caregivers will be asked to enter any individual bleeds, hemophilia-related 
medications, and emicizumab treatments that occur on an electronic, handheld device.  Entries 
should be made at least weekly, and also at any time a bleed occurs or a hemophilia medication, 
including emicizumab, is administered.  Detailed information about bleeds (type, location, 
date/time) will be captured.  Detailed information about hemophilia medications (agent, dose,
reason for administration, date/time) and emicizumab dosing (total volume, date/time) will also 
be captured.  In addition, HRQoL using the Haemo-QoL-SF (completed by children 8 years of 
age and older), proxy-reported HRQoL and aspects of caregiver burden using Adapted 
InhibQoL (completed by caregivers of all children) and missed daycare/school will be collected 
on a separate electronic, handheld device during a patient’s visit prior to emicizumab injection at 
Week 1 and every 12 weeks thereafter, as outlined in the schedule of assessments (see
protocol).  The number of days the child was hospitalized, if applicable, will be derived from data 
collected on eCRF.
Emicizumab is intended in this study for prophylactic use only (i.e., not to treat bleeds that have 
already occurred).  Therefore, in this study all patients will continue to receive episodic 
treatment for breakthrough bleeds as needed.  Breakthrough bleeds should preferably be 
treated with rFVIIa at the lowest expected dose to achieve hemostasis and captured as they 
occur on the electronic, handheld device.  There is clinical experience in the ongoing Phase I/II 
clinical studies with the treatment of over 80 breakthrough bleeds in patients receiving 
emicizumab with either FVIII or bypassing agents.  FVIII, aPCC, and rFVIIa do not interfere with 
emicizumab PK assessments, and no safety signals have been observed when breakthrough 
bleeds were treated with standard-of-care regimens during Phase I/II studies.  However, in the 
ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with FVIII 
inhibitors), 3 events of TMA and 3 serious thromboembolic events were observed in patients 
who concomitantly used 100 U/kg/day of aPCC on average for 24 hours for the treatment of 
breakthrough bleeds (see protocol).  Therefore, it is recommended that breakthrough bleeds are
treated with rFVIIa only, if possible, and that the use of aPCC or other bypassing agents should 
be avoided or limited (see protocol).  Also, local and central laboratory assessments are 
required to monitor the risk for thromboembolic events or TMA as per the schedule of 
assessments (see protocol).  Investigators will be asked to contact the Medical Monitor in the 
event of suspected lack or loss of efficacy of emicizumab in order to discuss potential laboratory 


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Appendix 1 Protocol Synopsis (Cont)
evaluations (e.g., anti-emicizumab antibodies, coagulation tests) to be performed as well as to 
re-evaluate the patient’s benefit-risk of continued treatment.
Physical examinations, vital sign assessments, ECG, and safety laboratory assessments will be 
collected as per the schedule of assessments (see protocol).  Adverse events will be captured 
on an ongoing basis as they occur during the study.  All patients in this study will undergo PK 
assessments.  Blood samples will also be collected to assess the PD properties of emicizumab
(i.e., aPTT, FVIII activity), as well as to assess immunogenicity (i.e., anti-emicizumab antibodies 
and anti-FVIII antibodies).  A detailed list is provided in the schedule of assessments (see 
protocol).
Of note, a non-interventional study (Study BH29768) has been initiated to document the number 
and types of bleeds and current treatment with episodic or prophylactic bypassing agents, as 
well as collect information on HRQoL, health status, and safety in patients with hemophilia A 
(including children 12 years of age).  The assessments in the non-interventional study will 
mitigate the risk of inaccurate reporting of bleeds that may occur with historical data collection 
and may provide data collected prospectively for over 24 weeks.  Pediatric patients who are 
enrolled in the non-interventional Study BH29768 are eligible to enroll in this study, as long as 
they meet the inclusion and exclusion criteria and are able to enroll at a participating site while 
the study is open for enrollment.  All patients who participated in the non-interventional 
study will be enrolled in Cohort A.
Number of Patients
At least 40 children younger than 12 years of age and up to 80 patients with hemophilia A and 
FVIII inhibitors who are currently receiving treatment with bypassing agents will be enrolled in 
this study: approximately 60 patients in Cohort A with allowance of patients 1217 years of 
age who weigh 40 kg at the time of informed consent and approximately 10 patients each in 
Cohort B and Cohort C.
Target Population
Approximately 80 children 12 years of age with hemophilia A and with FVIII inhibitors 
previously treated with bypassing agents will be enrolled in the study (approximately 60 
patients in Cohort A, 10 patients in Cohort B, and 10 patients in Cohort C).  In addition to this 
primary population of children 12 years of age, patients 1217 years of age who weigh 40 kg 
at the time of informed consent will also be eligible to enroll.  These patients, as well as those 
2 years of age at the time of informed consent, will only be eligible to enroll in Cohort A.  
Of note, enrollment in Cohort A may be left open exclusively for patients 2 years of age 
until approximately 510 such patients have been enrolled prior to the closure of Cohorts B 
and C, whichever occurs first.
Inclusion Criteria
Children must meet the following criteria for study entry:

Written informed consent must be obtained from parent/legally acceptable representative 
and an assent from the child when applicable (latest approved version by the Independent 
Ethics Committee [IEC]/Institutional Review Board [IRB]) prior to any of the study-specific 
assessments and procedures being performed.

Children 12 years of age at time of informed consent with allowance for the following:
Patients 1217 years of age and who weigh 40 kg at the time of informed consent 
(Cohort A only)
Patients 2 years of age will be allowed to participate only after the protocol-defined 
interim data review criteria are met (Cohort A only)

Body weight 3 kg at time of informed consent

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures including the completion of applicable patient-reported outcome 
(PRO) questionnaires 


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Appendix 1 Protocol Synopsis (Cont)

Caregivers of all children must have the willingness and ability to comply with all study 
procedures including the completion of the bleed/medication questionnaire and applicable 
HRQoL questionnaires 

Diagnosis of congenital hemophilia A of any severity and documented history of high-titer 
inhibitor (i.e., 5 BU)

Requires treatment with bypassing agents

For patients 2 years of age: 
If on an episodic bypassing agent regimen: ABR of 6 (3 bleeds in the last 24 weeks) 
OR 
If on a prophylactic bypassing agent regimen: inadequately controlled (e.g., 2 bleeds 
since starting prophylaxis or 1 life-threatening bleed) or central venous access device 
(CVAD) placement medically not feasible or deemed unsafe by investigator

For patients 2 years of age (Cohort A only): determined by investigator to be in high
unmet medical need

Adequate hematologic function, defined as platelet count of 100 109 cells/L and 
hemoglobin 8 g/dL (4.97 mmol/L) at the time of screening

Adequate hepatic function, defined as total bilirubin 1.5 age adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT 3 age adapted ULN 
at the time of screening

Adequate renal function: serum creatinine must be 1.5 ULN for age.  When the serum 
creatinine is 1.5 ULN, creatinine clearance by Bedside Schwartz formula must be 
70 mL/min/1.73m2

At screening, in the rare cases of hemophilia in female patients who are of childbearing 
potential, patients will be required to have a negative serum pregnancy test result (with 
urine pregnancy tests performed at subsequent specified visits) and will have to agree to 
remain abstinent or use single or combined highly effective contraceptive methods that 
result in a failure rate of 1% per year and are approved by local health authorities and 
ethics committees during the treatment period and for at least 5 elimination half-lives 
(24 weeks) after the last dose of study drug.
Exclusion Criteria
Children who meet any of the following criteria will be excluded from study entry:

Inherited or acquired bleeding disorder other than hemophilia A

Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy or 
prophylaxis treatment with FVIII  
Patients awaiting initiation of ITI will be eligible 
Patients in whom ITI has failed will be eligible with a 72-hour washout period prior to the 
first emicizumab administration.

Previous (in the past 12 months) or current treatment for thromboembolic disease (with the
exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is 
not currently ongoing) or signs of thromboembolic disease 

Other diseases (i.e., certain autoimmune disease [e.g., systemic lupus erythematosus], 
cardiovascular disease) that may increase risk of bleeding or thrombosis

History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the emicizumab injection

Known infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) 

Patients who are at high risk for TMA (e.g., have a previous medical or family history of 
TMA), in the investigator’s judgment


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Appendix 1 Protocol Synopsis (Cont)

Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrollment or 
planned use during the study period

Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study

Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood 
products (or any standard-of-care treatment for a life-threatening condition) 

Receipt of:
An investigational drug to treat or reduce the risk of hemophilic bleeds within 
5 half-lives of last drug administration
A nonhemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter
An investigational drug concurrently

Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere 
with the conduct of the study or that would, in the opinion of the investigator or Sponsor, 
preclude the patient’s safe participation in and completion of the study or interpretation of 
the study results
End of Study
The primary analysis will take place at the same time for Cohorts A, B, and C.  It will occur 
after all patients in the primary population of Cohort A have completed 52 weeks of treatment, 
or have withdrawn prematurely, whichever occurs first.  All data from patients enrolled in 
Cohorts B and C will be included regardless of follow-up time.
After 52 weeks of treatment, an individual patient who continues to derive clinical benefit may 
continue receiving prophylactic emicizumab as part of this study or a future separate 
emicizumab extension study.  Patients who discontinue emicizumab will have a safety follow-up 
visit at 24 weeks after the last emicizumab dose.
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., LPLV), as defined below:

Completed 52 weeks of emicizumab and either transferred to a separate extension study to 
receive further emicizumab as per Roche Global Policy on Continued Access to 
Investigational Medicinal Products or to commercial product
OR

Completed the end of study safety follow-up visit 24 weeks after discontinuing emicizumab
OR

Consent has been withdrawn
OR

Lost to follow-up
Length of Study
The length of the entire study from screening of the first patient to the last patient completing 
52 weeks in the study and/or the end-of-study follow-up visit (24 weeks after discontinuing 
emicizumab) will be approximately 152 weeks.
Investigational Medicinal Product
Test Product (Investigational Drug)
Emicizumab treatment will begin with a loading dose of 3 mg/kg QW for the first 4 weeks 
(Day 1 of each week) followed on Week 5 by a maintenance dose of either 1.5 mg/kg QW 
(Cohort A), 3 mg/kg Q2W (Cohort B), or 6 mg/kg Q4W (Cohort C).  Note that the cumulative 
dose studied in all three cohorts is identical, but the dose administration schedule differs 
between cohorts.  Patients will receive prophylactic emicizumab for a minimum of 52 weeks or 


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32/Statistical Analysis Plan BH29992
Appendix 1 Protocol Synopsis (Cont)
until unacceptable toxicity or discontinuation from the study due to any cause.  See protocol for 
treatment details.
Emicizumab will be administered as a SC injection in the home setting after a period of in-clinic 
administration and training.  The first five drug administrations must be performed in a 
monitored setting such as an infusion center, clinic, or hospital, with a 60-minute observation 
period following each of the first three doses.  For patients with a previous history of a clinically 
significant hypersensitivity reaction, additional precautions should be considered (see protocol).  
The fourth and fifth scheduled study drug administrations must also be performed in the 
monitored setting, and the patient/caregiver will be trained and have the opportunity to ask any 
questions to the HCP before the scheduled start of home administration.  The patient (7 years 
of age)/caregiver will observe at least one SC injection performed by the HCP and successfully 
administer at least one SC injection while being observed by the HCP prior to starting home 
administration.  Each site will have the discretion to provide additional training if deemed 
appropriate.  If, despite additional training, the investigator determines that the patient/caregiver 
is unable to inject emicizumab correctly, then arrangements may be made to identify a trained 
caregiver or HCP to administer the SC injections.
Non-Investigational Medicinal Products
None.
Statistical Methods
Efficacy Analyses
The efficacy analyses are to evaluate the clinical effect of prophylactic emicizumab on the 
number of bleeds over time (i.e., bleed rate), and to characterize the efficacy of up-titration on 
an intra-patient level.  These analyses will be conducted using different bleed definitions such 
as treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated 
target joint bleeds.
The primary analysis will be performed 52 weeks after the last patient in the primary population 
of Cohort A has been enrolled or withdrawn prematurely, whichever occurs first.  The 
primary population consists of all patients enrolled in Cohort A prior to the close of enrollment
for patients 2 years of age (up to approximately 60 patients) and is used to define the timing 
of the primary analysis.  The primary analysis will also include all available data from patients 
enrolled in Cohorts B and C, regardless of their follow-up time.  Enrollment in Cohort A may 
be left open exclusively for patients 2 years of age in order to enroll approximately 510 such 
patients.  Note that these patients will be included in the primary population analysis regardless 
of their follow-up time.  Further analyses may be conducted while the study is ongoing (see 
protocol).
Safety Analyses
Safety analyses will be performed for each cohort separately and overall as appropriate.
The safety analyses population will be based on all patients who received at least one
administration of emicizumab.  Safety will be assessed through descriptive summaries of 
adverse events, laboratory test results (serum chemistry and hematology including complete 
blood count with differential and platelet counts), ECGs, vital signs, and anti-emicizumab 
antibodies.
To evaluate the overall safety of emicizumab, the incidence of adverse events will be 
summarized and presented by System Organ Class mapped term, appropriate thesaurus level, 
and toxicity grade.   
For clinical laboratory data, summary statistics will be presented.  In addition, shift tables 
describing changes from baseline will be presented using the WHO toxicity grading scale.
Data on the impact of immunogenicity (anti-emicizumab antibodies and anti-FVIII antibodies) on 
safety, efficacy, and/or pharmacodynamics and pharmacokinetics will be summarized using 
standard language/terminology.


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Appendix 1 Protocol Synopsis (Cont)
Pharmacokinetic Analyses
For all patients, pre-dose (trough) plasma concentrations of emicizumab will be presented 
descriptively by dose groups (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W, 3 mg/kg QW in 
case of up-titration), including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time data of 
emicizumab following SC administration.  Population PK parameters, such as clearance and 
volume of distribution, will be estimated, and the influence of various covariates, such as age, 
sex, and body weight, on these parameters will be investigated graphically.  Secondary PK 
parameters, such as area under the curve, will be derived from individual post-hoc predictions.  
Data may be pooled with data from previous Phase I/II studies and Phase III Studies.  These 
analyses will be reported in a dedicated report.
Patient-Reported Outcome Analyses
Scale scores for the Haemo-QoL-SF and the Adapted InhibQoL Including Aspects of Caregiver 
Burden will be calculated for each assessment, with change scores being examined for the 
assessments over the course of the study.  These will be summarized descriptively by cohort.  
A descriptive summary of the number of daycare/school days missed and days hospitalized will 
also be presented by cohort.
Pharmacodynamic Biomarker Analyses
PD parameters (e.g., aPTT, FVIII activity) will be presented using summary statistics by dose 
groups, including arithmetic and geometric means, median, range, standard deviations, and 
coefficients of variation. These analyses will be presented by cohort.
Interim Data Review
In a first interim data review, the appropriateness of the initial dosing regimen will be evaluated 
(maintenance dose of 1.5 mg/kg/week).  This dosing regimen may be adapted following 
analysis of all available data (e.g., safety, efficacy, pharmacokinetics) by the JMC (see protocol) 
if a majority of the first 35 patients (aged 2 to 12 years of age) fail to achieve optimal control 
of bleeds after the first 12 weeks of treatment; or if their plasma emicizumab concentration 
trough level is lower than the one being targeted in adolescents and adults (i.e., 45 µg/mL).  
Should patients 12 years of age and 40 kg be enrolled at the time of this first interim data 
review, available data from these patients will also be included.
A second interim data review will occur once at least 10 patients between 2 and 12 years of age 
have been dosed for a minimum of 12 weeks.  All available cumulative data (e.g., safety, 
efficacy, pharmacokinetics) will be evaluated by the JMC to provide recommendations for the 
enrollment of children 2 years of age, as well as on any further adaptations of the 
maintenance dose if necessary.  Again, should patients 12 years of age and 40 kg be 
enrolled at the time of this second interim data review, available data from these patients will 
also be included.
Should patient recruitment be faster than anticipated, enrollment will be placed on a temporary 
hold following the first 20 patients until the JMC releases its recommendations on the 
appropriateness of the maintenance dose.  
JMC Recommendations and Enrollment of Q2W/Q4W in Pediatric Patients
On 7 December 2016, based on a combined interim analysis of the first 20 patients enrolled, 
the JMC recommended to continue enrolling patients to Cohort A at the maintenance dose of 
1.5 mg/kg QW, and to begin enrollment of patients 2 years of age.  See protocol for details. 
After the JMC recommendations were released following this interim analysis, the study 
continued to enroll up to approximately 60 patients in Cohort A. Upon completion of 
recruitment to Cohort A, and following review of data in adults and adolescents from two 
ongoing Phase III studies evaluating emicizumab at 3 mg/kg Q2W (BH30071) and 6 mg/kg 
Q4W (BO39182) identifying no safety concerns, recruitment with alternating allocation of 
patients to Cohorts B and C via IxRS could begin up to a maximum of approximately 10 
patients in each cohort.  See protocol for details.


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34/Statistical Analysis Plan BH29992
Appendix 1 Protocol Synopsis (Cont)
Additional interim data reviews will be prespecified in the Statistical Analysis Plan; other 
analyses may be conducted at various timepoints to support regulatory submissions.
Determination of Sample Size  
The sample size for this study is based on favorable recruitment feasibility and clinical 
considerations rather than statistical considerations, taking into account the limited number of 
pediatric patients with hemophilia A with inhibitors available for participation in this study.  
Hence, at least 40 children younger than 12 years of age and up to 80 patients with hemophilia 
A and FVIII inhibitors who are currently receiving treatment with bypassing agents will be 
enrolled in this study: approximately 60 patients in Cohort A with allowance of patients 
1217 years of age who weigh 40 kg at the time of informed consent and approximately 
10 patients each in Cohort B and Cohort C.  
During the study, a re-assessment of the initially specified sample size based on enrollment
consideration 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 Assessments
Schedule of Assessments—Cohorts A, B, C
Screening
Wk 
1
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Wk 
29
Wk 
33
Wk 
37
Wk
41
Wk 
49
Study Drug 
Discontinuation 
Visit a
Safety 
F/U 
Visit a
Informed consent/assent b
x
Inclusion/exclusion 
criteria
x
Medical history and 
demographics c
x
Physical examination d
x
x
x
x d
x
x
x d
x
Vital signs e
x
x e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medications f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG g, h
x
x
x
x
Safety laboratory 
assessments h, i, j
x i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-FVIII antibodies j, k
x k
x
x
x
x
x
x
Anti-emicizumab 
antibodies h, j, l
x
x
x
x
x
x
x
Bleed/medication 
questionnaire m, n
----------------------------------------weekly o ----------------------------------------
x
x
x


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Appendix 2
Schedule of Assessments (cont.)
Screening
Wk 
1
Wk 
2
Wk 
3
Wk 
4
Wk 
5
Wk 
7
Wk
9
Wk 
13
Wk 
17
Wk 
21
Wk 
25
Wk 
29
Wk 
33
Wk 
37
Wk
41
Wk 
49
Study Drug 
Discontinuation 
Visit a
Safety 
F/U 
Visit a
Bleed/medication data 
review o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Following treatment with 
bypassing agents
Monitoring for thromboembolic events and thrombotic microangiopathy p
Adverse events q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IMP management r
x
x
x
x
x
x r
x
x
x
x
x
x
x
x
x
x
x
Haemo-QoL-Short Form s
x
x
x
x
x
x
Adapted InhibQoL t
x
x
x
x
x
x
PK assessment h, j, u
x
x
x
x
x
x r
x
x
x
x
x
x
x
x
x
x
x
x
PD biomarkers 
assessment h, j, v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Appendix 2
Schedule of Assessments (cont.)
Schedule of Assessments—Cohorts A, B, and C
Every 12 Weeks 
from Wk 57
Every 
24 Weeks from 
Wk 57
Study 
Completion/ET a Safety F/U Visit a
Physical examination d
x
x
x
Vital signs e
x
x
x
Concomitant medications f
x
x
x
ECG g, h
x
Safety laboratory assessments h, i, j
x
x
x
Anti-FVIII antibodies j, k
x
x
Anti-emicizumab antibodies h, j , l 
x
x
x
Bleed/medication questionnaire m, n
x
x
x
Bleed/medication data review o
x
x
x
Adverse events q
x
x
x
IMP management r
x
x
Haemo-QoL-Short Form s
x
x
Adapted InhibQoL t
x
x
PK assessment h, j, u
x
x
x
PD biomarkers assessment h, j, v
x
x
x


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Appendix 2
Schedule of Assessments (cont.)
eCRFelectronic Case Report Form; ePRO electronic patient-reported outcome; ET early termination; F/U follow-up; FVIIIfactor VIII; 
HRQoLHealth-Related Quality of Life; IMPinvestigational medicinal product, PDpharmacodynamic; PK pharmacokinetic; Wk Week.
Notes:  The maximum allowable time between screening and enrollment is 28 days; if the elapsed time between screening and enrollment is more 
than 28 days, screening must be repeated.  All assessments should be performed within 2 days of the scheduled visit for the first 12 weeks 
(including the Week 13 visit), then 7 days thereafter. Study assessments may be delayed or moved ahead of the window to accommodate 
holidays, vacations, and unforeseen delays.  Except for the bleed/medication questionnaire, all other patient data will be collected during office 
visits.  On treatment days, pre-injection blood collection should be made 0120 minutes before the injection.  Emicizumab will be administered 
subcutaneously at a loading dose of 3 mg/kg QW for the first 4 weeks (Day 1 of each week) followed by a starting maintenance dose of 1.5 mg/kg
QW (Cohort A), 3 mg/kg Q2W (Cohort B), and 6 mg/kg Q4W (Cohort C).  During the 52-week treatment period, individual patients may have 
their dose up-titrated if they experience suboptimal bleeding control on emicizumab (see Protocol Section 3.3.5).  In case of up-titration to a new 
maintenance dose, the next five weekly visits must occur at the site.
a The study treatment discontinuation visit refers to the visit that occurs when a patient discontinues study drug. A safety follow-up visit will
occur 24 weeks after discontinuing emicizumab for any reason.
b Written informed consent must be obtained from parents/legally acceptable representative and an assent from the child (when applicable) before 
distribution of the electronic, handheld device and collection of any data.  Enrollment form will be completed after informed consent form and 
assent form (when applicable) are obtained. If patient fulfills the inclusion/exclusion criteria, the patient should be enrolled in the study on the 
same day when the first dose of emicizumab is administered (Day 1).
c Collected from patient medical records and documented in the eCRF. 
d A complete physical examination will be performed at screening and targeted physical examination will be performed at subsequent visits.  
Targeted physical examination of joints (for bleeds, evidence of arthropathy) and skin (for bruises, hematomas, and injection-site reactions), in 
addition to other organ systems as clinically indicated and/or report of new or worsening adverse event.
e Body temperature (oral, rectal, axillary, or tympanic), blood pressure, pulse rate, respiratory rate, height/length, and weight to be entered into 
eCRF.  If Screening and Week 1 occur on the same date, the vital signs should be measured only once.  If Screening and Week 1 occur on 
different dates, vital signs should be repeated for both assessments.
f
Concomitant medications (e.g., extra pain medication with bleed) will be asked about at each clinic visit and documented in the eCRF, excluding 
treatments for bleeds (i.e., bypassing agents and other medications to treat bleeds), which will be collected on the bleed/medication 
questionnaire.  Hemostatic medications to treat or prevent bleeds in the 4 weeks prior to starting emicizumab will be collected on eCRF.
g If screening ECG abnormal, repeat at Week 1 (or Week 2 if Screening and Week 1 occur on the same date).  ECGs will also be performed 
4 weeks after starting emicizumab or after each dose up-titration, as well as at study completion/early termination.
h In case of up-titration, additional assessments including PK, PD biomarkers, anti-emicizumab antibodies, safety laboratory samples, and ECG 
will be required, with the schedule of assessments resetting back to Week 1, including an ECG.


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Appendix 2
Schedule of Assessments (cont.)
i
Laboratory data (performed locally) includes complete blood count with differential and serum chemistries (i.e., sodium, potassium, chloride,  
glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, creatine phosphokinase, total protein, albumin, creatinine, total and 
direct bilirubin, alkaline phosphatase, ALT, and AST).  Female patients of childbearing potential will be required to have a negative serum 
pregnancy test result at screening and urine pregnancy tests performed at Weeks 13, 25, 37, and 49; every 12 weeks starting from Week 57; 
and study completion/early termination.
j
When blood is drawn via catheter or CVAD, a discard tube must be used prior to collection of samples for any laboratory assessment, due to the 
possibility of contamination by saline or anticoagulants used to flush the device.  Please consult the study Laboratory Manual for details on 
sample collection and processing. 
k Anti-FVIII antibodies will be measured at a central laboratory using citrate plasma.  Anti-FVIII antibodies is the only biomarker sample taken at 
screening.  In case a patient screen fails or does not enroll in the study for any reason, the sample should be destroyed and not sent to the 
central laboratory.  Throughout the study, additional blood samples may also be drawn on an unscheduled basis (at the clinical judgment of the 
investigator) for analysis at a central laboratory.  
l
Samples to detect anti-emicizumab antibodies will be collected prior to emicizumab injection at Weeks 1, 5, 17, 33, 49, every 12 weeks starting 
from week 57, study completion/early termination and at the 24-week safety follow-up visit.  If patients continue on emicizumab past 52 weeks of 
treatment, anti-emicizumab antibodies will be collected every 12 weeks.  If any of these samples are positive and/or if there is suboptimal clinical 
response or low pharmacokinetic exposure, additional samples may be collected and analyzed for anti-emicizumab antibodies.  Anti-emicizumab 
antibodies should also be drawn at the time of systemic hypersensitivity events.  For each additional anti-emicizumab sample, a PK sample 
should be concomitantly drawn.
m At the Week 1 visit, caregivers will be trained on how to use their handheld device to record the bleeds and the hemophilia medication use.  The 
bleeding/medication questionnaire will be completed by the caregiver and includes start date and time, reason, type, location of each bleed, as 
well as start date and time, reason, type, and dose of each injection.
n Caregivers will be instructed to complete on weekly basis to complete the bleed/medication questionnaire when the patient has a bleed or 
hemophilia medication use.
o At subsequent visits as marked, investigator review of patient-reported bleed/medication questionnaire information will be conducted for 
completeness and accuracy.
p Following bypassing agent treatment, patients should provide a sample for local laboratory monitoring of thromboembolic events and thrombotic 
microangiopathy for platelet count, serum creatinine, LDH, and schistocytes within 2448 hours of initial bypassing agent use. A plasma sample 
should also be provided for local (one aliquot) and central (a second aliquot) laboratory monitoring of fibrinogen, prothrombin fragment 12, and 
D-dimer.  If prothrombin fragment 12 test cannot be done at the site, the sample should be send to the local reference laboratory, if available, 
and if the results from the local reference laboratory can be obtained within a reasonable timeframe to allow for decision making.  For patients 
who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours thereafter until 2448 hours 
following the last dose of bypassing agents administered to treat a given bleed.  If applicable, laboratory results should be recorded in the eCRF 
page titled “Local Lab Following Treatment with Bypassing Agents.”


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Appendix 2
Schedule of Assessments (cont.)
q Patients are advised to inform the investigator about adverse events at every visit.  Adverse events will be reported on the eCRF by the 
investigator.  Injection-site reaction adverse events will be collected on a separate form from the adverse event form.  If there is unexpected 
worsening of the patient’s hemophilia in terms of severity (e.g., increased number of doses of bypassing agents to stop bleeds compared with 
before study entry), frequency of bleeds, or nature at any time during the study, this should be documented as an adverse event on the Adverse 
Event eCRF, conveying that the underlying condition has changed by including applicable descriptors (e.g., "increased clinical severity of 
hemophilia"). 
r
Drug accountability will not be performed at the first visit of emicizumab receipt.  Drug dispensation will not occur at the study completion/early 
termination visit. Note:  for Cohort C, there are visits where emicizumab is not administered per schedule.
s Haemo-QoL-Short Form (children 8 years of age and older) assessed on an electronic, handheld device by patients during patient’s visit in clinic 
prior to emicizumab injection at Weeks 1, 13, 25, 37, 49, every 24 weeks from Week 57, and study completion/early termination.
t
Proxy assessment of HRQoL and aspects of caregiver burden using the Adapted InhibQoL Including Aspects of Caregiver Burden questionnaire 
for all children assessed on electronic, handheld device by caregivers during patient’s visit in clinic prior to emicizumab injection at Weeks 1, 13, 
25, 37, 49, every 24 weeks from Week 57 and study completion/early termination. 
u Emicizumab concentration.  Plasma samples for this assessment should be taken prior to emicizumab injection. 
v PD biomarkers will be measured at a central laboratory. See Appendix 3, for detailed explanation of PD biomarker assessments.  Blood 
samples may also be drawn to conduct biomarker assays at the central laboratory on an unscheduled basis (at the clinical judgment of the 
investigator) at any time.  


Emicizumab—F. Hoffmann-La Roche Ltd 
41/Statistical Analysis Plan BH29992
Appendix 3
Schedule of PD Assessments
Sample
Visit a
Biomarker assays b
PD Set 1
Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, every 
8 weeks from Week 41, every 12 weeks from Week 57
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the investigator) 
while on emicizumab c
PT/INR
D-dimer
aPTT
PD Set 2
d
Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, every 
8 weeks from Week 41, every 12 weeks from Week 57
Study Completion/Early Termination
Safety Follow-up Visit
Unscheduled visit (at the discretion of the investigator) 
while on emicizumab c
FVIII activity
FIX antigen
FX antigen
FIX factor IX; FVIIIfactor VIII; FX factor X; PDpharmacodynamic.
a All samples are to be collected on Day 1 of the indicated week, prior to emicizumab
injection (if applicable).  All PD samples will be citrate plasma.  
b Biomarker assays will include but are not limited to those listed.  Where blood volumes 
allow, additional plasma may be frozen and banked for future exploratory research
related to emicizumab.  Blood volumes and processing procedures will be specified in the 
Laboratory Manual.
c Reasons for unscheduled visits may include evaluation or treatment for bleeds or 
hypersensitivity reactions.
d These plasma samples will only be collected if the permitted blood volumes allow (based 
on patient body weight as described in Protocol Section 3.3.5).  Please refer to the 
Laboratory Manual for details.