Clinical trial NCT03191799
Conditions: Hemophilia A
Sponsor: Hoffmann-La Roche
Start date: 2017-09-05; Completion date: 2020-11-19
Enrollment: 195 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase IIIb, single arm, open-label, multi-center study to evaluate the safety and tolerability of emicizumab in participants with congenital hemophilia A who have documented inhibitors against Factor VIII (FVIII) at enrollment. Approximately 200 participants, aged 12 or older, will be enrolled in this study and are expected to be enrolled at approximately 85 sites globally. Participants will receive an initial weekly dose of prophylactic emicizumab subcutaneously for 4 weeks, followed by a weekly maintenance dose subcutaneously for the remainder of the 2-year treatment period.

Detailed description:

Arms: arm 1: Participants will receive initial weekly doses of prophylactic emicizumab subcutaneously for 4 weeks, followed by maintenance doses consisting of half the initial dose, administered subcutaneously for the remainder of the 2-year treatment period
Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: Initial dosing will be 3 mg/kg/week subcutaneously for 4 weeks; Maintenance dosing will follow at 1.5 mg/kg/week subcutaneously for the remainder of the 2-year treatment period

Protocol documents:
Prot_000.pdf: 
Official Title: A Single-Arm, Multicenter Phase IIIB Clinical Trial to Evaluate the 
Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A 
Patients With Inhibitors 
NCT Number: NCT03191799 
Document Date: Protocol Version 3: 09-March-2018 


 
PROTOCOL AMENDMENT APPROVAL 
  
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, including 
Genentech, Inc. in the United States.  The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is 
provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your 
staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Emicizumab — F. Hoffmann-La Roche Ltd 
Protocol MO39129, Version 3 
PROTOCOL 
TITLE: 
A SINGLE-ARM, MULTICENTER PHASE IIIB 
CLINICAL TRIAL TO EVALUATE THE SAFETY AND 
TOLERABILITY OF PROPHYLACTIC EMICIZUMAB 
IN HEMOPHILIA A PATIENTS WITH INHIBITORS 
PROTOCOL NUMBER: MO39129 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2016-004366-25 
TEST PRODUCT: 
Emicizumab (RO5534262) 
MEDICAL MONITOR: 
Dr. 
 MD, MBA 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 3: See electronic date stamp below 
DATES AMENDED: 
Version 1: 31 January 2017 
Version 2: 2 June 2017 
 
09-Mar-2018 10:00:09
Title
Approver's Name
Company Signatory
Date and Time (UTC)














 
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PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
 
TITLE PAGE: 
VERSION NUMBER: 
23 
… 
DATE FINAL: 
 
DATES AMENDED: 
         Version 3: See electronic date stamp below 
          
         Version 1: 31 January 2017 
Version 2: See electronic date stamp below2 June 
2017 
 
 
 
FOOTER: 
Emicizumab—F. Hoffmann-La Roche Ltd 
Protocol MO39129, Version 23 
 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
VERSION NUMBER: 
23 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
CTX 
C-terminal telopeptide of collagen 1 
ECL 
electrochemiluminescence 
EDTA 
ethylenediaminetetraacetic acid 
NIS 
non-interventional study 
OPG 
osteoprotegerin 
P1NP 
procollagen type 1 amino-terminal propeptide 
RANK-L 
receptor activator of nuclear factor kappa-B ligand 
SMT 
Study Management Team 
 


 
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1.2.2 
Clinical Experience 
Available experience with emicizumab in humans includes data from one completed Phase I 
study (ACE001JP – Last Patient Last Visit on 17 April 2015) and its ongoing Phase I/II 
extension study (ACE002JP). Currently available experience with emicizumab in humans includes 
data from two completed Phase I studies (ACE001JP and JP29574), one ongoing Phase I/II study 
(ACE002JP) extension in hemophilia A patients, and two ongoing Phase III studies in hemophilia A 
patients with inhibitors (adult patients - BH29884; pediatric patients – BH29992). 
The clinical development program in adult and pediatric patients with hemophilia A (both with and 
without FVIII inhibitors) is ongoing for emicizumab. Refer to the emicizumab Investigator's Brochure 
for details on the preclinical and clinical studies. 
 
1.2.2.1 
Studies ACE001JP and ACE002JP 
ACE001JP was a single study conducted in three parts, which included 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 PD response 
of SC-administered emicizumab in adult Japanese and Caucasian men and to evaluate for 
racial differences, if any, in their PK and PD response. Healthy male volunteers aged 2044 
were eligible for enrollment. A total of 64 healthy male 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 
1259 years of age with congenital hemophilia A who . Patients were eligible for enrollment if 
they were 1259 years of age, ≥ 40 kg in weight, had a diagnosis of congenital hemophilia A, 
and had previous documentation of bleeds and/or coagulation factor treatment in the last 6 
months. For those with inhibitors, patients must have had 6 bleeds in the 6 months prior to 
enrollment, and for those without inhibitors, patients were required to have received 150 
lifetime doses of FVIII replacement, including in the last 6 months. A total of 18 patients with 
hemophilia A were enrolled in Part C from May 2013 to June 2014. 
Parts A 
and 
B 
of 
Study ACE001JP 
(completed) 
consisted 
of 
a 
randomized, 
placebo-controlled, single ascending dose (SAD) study, which was conducted in Japanese 
(n40; Part A) and Caucasian (n24; Part B) healthy men. In total, 48 subjects received a 
single SC injection of 0.001 mg/kg to 1 mg/kg emicizumab and 16 subjects received a single 
SC injection of placebo. Part C of Study ACE001JP was an open-label, multiple ascending 
dose (MAD) study in 18 Japanese patients with hemophilia A, both with and without 
inhibitors. Of note, patients received concurrent coagulation factor products to control 
breakthrough bleeds. Of the 18 patients in Part C of Study ACE001JP, six patients were 
dosed with 0.3 mg/kg/week SC following a single loading dose of 1 mg/kg SC, six patients 
were dosed with 1 mg/kg/week SC following a single loading dose of 3 mg/kg SC, and six 
patients received 3 mg/kg/week emicizumab SC without a loading dose. 
Patients who participated in Part C of Study ACE001JP were offered the opportunity to 
continue in the extension study (ACE002JP). 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. Seventeen of 18 patients in Part C of Study ACE001JP 


 
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completed the 12 week treatment period. One patient discontinued the treatment and moved 
to the post discontinuation 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 
one patient moved to the post treatment observation period of Study ACE001JP. Thus, , 
which includes six patients from the 0.3 mg/kg/week group, five patients from the 
1 mg/kg/week group, and five patients from the 3 mg/kg/week group of Study ACE001JP  
The duration of follow-up for the patients in the 0.3, 1, and 3 mg/kg/week cohorts who 
enrolled in Study ACE002JP ranges from 140 to 145, 116 to 124, and 89 to 98 weeks, 
respectively (cut-off date 15th February 2016).For Studies ACE001JP and ACE002JP, the 
efficacy parameter of annualized bleeding rate (ABR) has been calculated by annualizing the 
number of bleeds that required treatment with coagulation factor products during the 
6 months prior to study enrollment and during the treatment period after the first emicizumab 
administration. During the 6 months before study enrollment, the patients without inhibitors 
received FVIII prophylactic replacement therapy, while the patients with inhibitors received 
episodic therapy and/or prophylactic therapy with bypassing agents. 
After administration of emicizumab to patients with hemophilia A, annualized bleeding rates 
(ABRs) decreased in all patients in Studies ACE001JP and ACE002JP compared with the 
pre-treatment period, regardless of whether or not they had FVIII inhibitors, with the 
exception of one patient in the 3 mg/kg/week group who was previously treated with FVIII 
prophylaxis and had a baseline ABR of 0 (in this patient, the ABR was maintained at 0 while 
receiving emicizumab). Among all patients, percentage reduction in ABR ranged from 22.8% 
to 100% in the 0.3 mg/kg/week group, from 57.5% to 100% in the 1 mg/kg/week group, and 
from 90.1% to 100% in the 3 mg/kg/week group. 
The safety data from completed studies of healthy male volunteers (Japanese and Caucasian) in 
ACE001JP Parts A and B (n=48) showed that emicizumab was well tolerated and the incidence of 
adverse events was similar in the emicizumab dosing groups and the placebo group. Moreover, no 
racial differences or dose-dependent increases in the incidence of adverse events were observed. There 
were no serious adverse events, adverse events leading to discontinuation, or deaths in either study.  
From ACE001JP Part C and its ongoing extension ACE002JP (as of the cut-off date 15 February 
2016), most adverse events were of mild or moderate intensity, except for 2 severe adverse events 
(appendicitis and mesenteric hematoma). The majority of the adverse events were not considered 
related to emicizumab (see the Emicizumab Investigator’s Brochure). 
 
1.2.2.2 
JP29574 
Completed Study JP29574 included 5 groups of 12 healthy Japanese volunteers. This study 
investigated the relative bioavailability between Phase I/II 80 mg/mL formulation and Phase III 150 
mg/mL formulation materials and among three different sites of injection, as well as the absolute 
bioavailability. Results showed no significant difference in the incidence of adverse events observed by 
formulation, injection site, or administration route.  
Emicizumab has been well tolerated in patients in the Phase I/II studies (cut-off date 15th 
February 2016; see the emicizumab Investigator's Brochure). The majority of adverse events 
have been mild in intensity, except for five moderate adverse events (upper respiratory tract 


 
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infection, bipolar I disorder, hemophilia [left hip joint bleeding due to hemophilia], headache, 
and asthma) and two severe adverse events (appendicitis and mesenteric hematoma). Both 
severe events were considered to be serious adverse events and not related to emicizumab 
administration. A total of seven patients have reported injection-site reactions (including 
erythema, hematoma, rash, pain, discomfort, and pruritus). All injection-site reactions were 
mild in intensity. Besides injection-site reactions, the most frequently reported adverse 
events (at least four patients) have been nasopharyngitis, pharyngitis, dental caries, 
excoriation, and headache. There have not been any dose-dependent increases in adverse 
events, and the majority of the adverse events have not been considered to be related to 
emicizumab. Treatment was discontinued for one patient with injection-site erythema in the 
1 mg/kg weekly group; the event was mild in intensity and resolved. The same patient also 
reported one non-related serious adverse event (hemophilia [left hip joint bleeding due to 
hemophilia]) approximately 24 weeks after the last dose of study drug. In the Phase I/II 
studies, no thromboembolic adverse events have been reported when emicizumab has been 
administered alone or concomitantly with FVIII products or bypassing agents as episodic 
therapy. 
 
1.2.2.3 
Studies BH29884 and BH29992 
The ongoing Phase III study (BH29884) is enrolling patients with hemophilia A aged 
12 years or older who have inhibitors against FVIII and have received episodic or 
prophylactic treatment with bypassing agents prior to study entry. 
  As of October 2016, thrombotic microangiopathy (TMA) has been observed in two patients 
receiving emicizumab and bypassing agents see Section 5.1.1.3) and two cases of 
thromboembolic events have been observed in two patients receiving the same regimen 
(see Section 5.1.1.2). 
The HAVEN 1 study (BH29884; NCT02622321) was a randomized, multicenter, open-label, clinical 
trial in 109 adult and adolescent males (aged 12 to 75 years and > 40 kg) with hemophilia A with 
FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with 
bypassing agents. Patients received weekly emicizumab prophylaxis (Arms A, C, and D), 3 mg/kg 
once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis 
(Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on emicizumab 
prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). 
During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once 
weekly. 
Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized 
in a 2:1 ratio to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B), with 
stratification by prior 24-week bleed rate (< 9 or ≥ 9). Patients randomized to Arm B could switch to 
emicizumab prophylaxis after completing at least 24 weeks without prophylaxis. 
Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C 
to receive emicizumab prophylaxis. Seven patients previously treated with episodic (on-demand) 
bypassing agents who had participated in a non-interventional study (NIS) prior to enrollment, but 












 
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The immunogenicity of emicizumab was evaluated using an enzyme-linked immunosorbent assay 
(ELISA) or an electrochemiluminescence (ECL) assay. No patients tested positive for anti-
emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-
emicizumab antibodies in the dose-finding trial (n = 18). The anti-emicizumab antibody positive rate 
may be under-reported due to the limitation of the assay (US Prescribing Information). 
 
1.2.2.6 
Peri-Operative Management of Patients on Emicizumab 
The safety and efficacy of emicizumab has not been specifically tested in patients undergoing 
procedures or surgeries. Limited data are available from pivotal clinical trials, where hemophilia A 
patients with inhibitors receiving emicizumab prophylaxis underwent procedures and surgeries, 
either with or without the additional use of bypassing agents. The use of bypassing agents was at the 
investigator's discretion. 
Procedures/surgeries that were performed without peri-operative bypassing agent use and 
did not result in a bleed included skin biopsy, tooth extraction or restoration, 
esophagogastroduodenoscopy with biopsy, ultrasound fluid aspiration, and port or central 
line removal. Other procedures/surgeries which were performed with peri-operative 
bypassing agent use (preventive and/or treatment for bleeds) included central line catheter 
placement, tooth extractions and appendectomy. One hip replacement was performed with 
peri-operative bypassing agent (rFVIIa) and FVIII use (preventive and treatment for bleed) 
as well as tranexamic acid.  
No emicizumab dose adjustments are recommended for patients undergoing procedures or 
surgeries. Thorough documentation of surgeries will be requested. 
The available data are insufficient to provide specific dosing guidance for the use of 
bypassing agents or FVIII in peri-operative settings. If bypassing agents or FVIII are required 
in the peri-operative period, please refer to the dosing guidance for those concomitant 
medications in Section 4.4 and in the emicizumab Investigator’s Brochure. 
Based on the Phase I/II data described above, a clinical development program in adult and 
pediatric patients with hemophilia A (both with and without FVIII inhibitors) has been 
developed for emicizumab. Refer to the emicizumab Investigator's Brochure for details on 
the preclinical and clinical studies. 
 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
… 
Emicizumab has been well tolerated in patients in the Phase I/II studies (cut-off date 15th 
February 2016). The majority of adverse events have been mild in intensity, with the most 
common being injection site reactions ISRs. The majority of the adverse events have not 
been considered to be related to emicizumab. In these studies, no thromboembolic or 
systemic hypersensitivity adverse events have been observed. However, as of April 2017 
October 2016, two three cases of TMA, and two three thromboembolic events in two patients, 
have been observed in the ongoing Phase III Study BH29884 in patients who received 




 
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and the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) will be completed 
prior to the first emicizumab administration (Week 1), at the Month 3, 6, 12, and 18 month 
assessments, and at study completion as outlined in the Schedule of Activities (Appendix 1
 
 
Schedule of Activities   
). Additional secondary endpoints include assessing patient preference for the emicizumab 
regimen compared with the previous regimen using a questionnaire (EmiPref). 
… 
For the assessment of anti-FVIII antibodies, functional assays for FVIII inhibitors that utilize a 
clotting readout (classic Bethesda or Nijmegen assay) cannot be used for patients on 
emicizumab therapy as emicizumab drives clotting even in the presence of FVIII inhibitors, 
causing a false-negative test result. After the first dose, local measurement of FVIII inhibitors, 
if indicated, requires use of an enzyme linked immunosorbent assay- (ELISA-) based test or 
a chromogenic Bethesda assay. At the discretion of the local investigator, any additional 
urgent request to assess FVIII inhibitors will need to be sent to a central laboratory (see 
Appendix 2  
Schedule of Biomarker Samples 
 for additional information).  
An independent Data Monitoring Committee (iDMC) composed of, at minimum, 
hemostasis/thrombosis experts and a statistician will be in place throughout the duration of 
the study and will monitor the study data at pre specified intervals and ad hoc as needed 
throughout the study. 
The use of aPCC is to be avoided throughout the study. If bypassing agents are needed to 
treat breakthrough bleeds or additional treatment to prevent or treat bleeding during 
surgeries, recombinant activated human Factor VII (rFVIIa) should be used at the lowest 
dose expected to achieve hemostasis. If rVIIa is not available or not an option for medical 
reasons, activated prothrombin complex concentrate (aPCC, including Factor eight inhibitor 
bypassing activity [FEIBA]) may be used. If aPCC is used, 50 units/kg of aPCC should be 
administered as an initial dose and it is critical that the dose administered does not exceed 
the recommended dose (see the local prescribing information for the marketed bypassing 
agent in question).  
Drugs intended to control breakthrough bleeds (e.g. rFVII, FVIII, aPCC) or bleeds during surgeries 
should be used at the lowest dose expected to achieve hemostasis. Given that circulating emicizumab 
may increase the patient’s coagulation potential, the doses required to achieve hemostasis may be 
lower than doses used prior to starting emicizumab. Investigators shall discuss at the start of the 
study with patients recommended doses of any additional coagulation factors used, following the 
guidance below.  
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided if 
possible, and rFVIIa should be the first option used to treat, starting with no more than 90 µg/kg as 
an initial dose. If aPCC needs to be used, no more than 50 IU/kg should be administered as an initial 
dose and doses of > 100 U/kg/24 hours or more should be avoided, as cases of TMA and thrombotic 
events were reported when on average a cumulative amount of > 100 U/kg/24 hours aPCC was 


 
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administered for 24 hours or more. Investigators should provide or remind patients of the exact dose 
and schedule of bypassing agents or FVIII required to treat any bleed. 
When a bleed has occurred, patients (or their legally authorized representative) will be 
required to report bleed information on an ePRO device where possible, including site of bleed, 
type of bleed, time of each individual bleed (day, start and stop time), and treatment for 
bleed (e.g., other than emicizumab in case of breakthrough bleeds). The reason for the use 
of rFVIIa will be documented (e.g., bleeding, preventative dose before activity). Thorough 
documentation of the treatments for bleeds and/or surgeries will be requested, including agent, 
start time, dose, route of administration, and number of infusions needed to treat the bleed. 
Local and central laboratory assessments are required to monitor the risk for 
thromboembolic events or microangiopathic hemolytic anemia or TMA, as per the Schedule of 
Activities (Appendix 1  
Schedule of Activities   
), if bypassing agents are used to treat a breakthrough bleed. 
… 
An independent Data Monitoring Committee (iDMC) will be responsible for monitoring safety the 
duration of the study. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The approximate length of the entire study from the first patient enrolled to the last patient, 
last visit (LPLV; see below) is approximately 3 years. For each individual patient, the study is 
expected to last approximately 2 years (patients will receive 3 mg/kg/week emicizumab for 
the first 4 weeks followed by 1.5 mg/kg/week emicizumab for the remainder of the 2-year 
treatment period). Patients who discontinue emicizumab prior to the completion of the 2-year 
treatment period will undergo a Safety Follow-up Visit 24 weeks after the patient’s last emicizumab 
dose or at 2 years after emicizumab treatment start, whichever occurs first. 
…  
Completed the 24 week Safety Follow-up Visit 24 weeks after discontinuing emicizumab 
 
3.3 
RATIONALE FOR STUDY DESIGN 
The primary objective endpoint of this study is to evaluate the overall safety and tolerability of 
prophylactic administration of emicizumab in patients with congenital hemophilia A who have 
persistent inhibitors against FVIII. This study is being conducted to build on the safety data 
that have been obtained as part of the clinical program. The results from this study will be 
used to substantiate the safety database and provide long-term additional data in patients 
with hemophilia A who have inhibitors against FVIII. The specific focus will be to characterize 
any thromboembolic events, microangiopathic hemolytic anemia or TMA, and systemic 
hypersensitivity reactions, anaphylaxis and anaphylactoid events that may occur in patients with 
hemophilia A treated with emicizumab. 


 
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3.3.1 
Rationale for Emicizumab Dose and Schedule 
… 
The safety results from studies ACE001JP/ACE002JP and BH29884 have showed shown 
that emicizumab has been well tolerated in patients with hemophilia A. The maximum clinical 
dose of 3 mg/kg weekly is associated with a 10.3-fold and 11.2-fold safety margin based on 
Cmax and area under the curve during the dosage interval (AUCτ) results, respectively. No 
clear differences in the plasma concentrations of emicizumab have been observed between 
adolescent and adult patients. 
… 
In study BH29884, the ABR was 2.9 events (95% CI, 1.7 to 5.0) among participants who 
were randomly assigned to emicizumab prophylaxis (Group A, 35 participants) versus 23.3 
events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (Group B, 18 
participants), representing a significant difference of 87% in favor of emicizumab prophylaxis 
(p<0.001). A total of 22 participants in Group A (63%) had zero bleeding events, as 
compared with 1 participant (6%) in Group B. Among 24 participants in Group C who had 
participated in a NIS, emicizumab prophylaxis resulted in a bleeding rate that was 
significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (p<0.001) 
(Oldenburg et al. 2017). 
 
3.3.2 
Rationale for Patient Population 
Patients with congenital hemophilia A who have persistent and documented inhibitors against 
FVIII at enrollment will comprise the primary population for this Phase IIIb study investigating 
the safety, tolerability, efficacy, immunogenicity, and PK of prophylactic administration of 
emicizumab. 
… 
Based on current treatment algorithms for patients with hemophilia A with inhibitors 
(Kempton and White II 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. As clinical safety data relating to the concomitant use 
of prophylactic emicizumab during ITI are not available at this time, patients currently 
receiving ITI will not be eligible for this study.  Patients receiving ITI therapy will be eligible 
following the completion of a 72-hour washout period prior to the first emicizumab administration.  
Owing to the fact that the presence or amount of FVIII inhibitors in their plasma does not 
impact the efficacy of emicizumab, patients’ inhibitor titers at the time of study entry will not 
influence their study eligibility. 
 
3.3.3 
Rationale for Control Group 
This study involves the use of a single-arm study design and therefore a control group will 
not be used. The primary endpoint of this study is to evaluate the overall safety and 


 
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tolerability of prophylactic administration of emicizumab in patients with congenital hemophilia 
A who have persistent inhibitors against FVIII. As hemophilia A is a rare disease (Acharya 2013) 
and the study is designed to investigate the broad safety profile of emicizumab, 
approximately 200 patients will be enrolled. Given the size of the patient population, a single-
arm study design without a control group is considered an appropriate method to capture the 
safety data that will be observed following the use of emicizumab. This type of study design 
has been used extensively in previous clinical studies involving patients with rare diseases 
(Bell and Tudur Smith 2014). 
 
3.3.4 
Rationale for Biomarker Assessments 
The identity of effective PD, safety, and bone and joint biomarkers has not been fully 
elucidated and further testing is required to determine which assays and technical conditions 
are most suitable for use with emicizumab treatment. Plasma and serum samples will be 
collected for PD, safety, and bone and joint biomarker assessments at specific clinic visits in 
order to obtain evidence of the biologic activity of emicizumab in patients and to support the 
selection of a recommended dose (see Appendix 2  
Schedule of Biomarker Samples 
). 
The PD biomarkers include, but are not limited to, coagulation assays such as aPTT and 
FVIII activity assays. The results of the Phase I/II study have showed shown that a dose-
response relationship was apparent between aPTT and emicizumab concentration (for more 
information, see the Investigator’s Brochure). The aPTT assay will be run in a modified form 
to ensure that the assay range covers all levels of emicizumab exposure. In addition, clot 
waveform analysis (CWA) may be run as an exploratory PD coagulation assay. 
… 
Residual blood and/or, plasma, and serum from collected biomarker samples may be stored 
for up to 5 years after the final Clinical Study Report has been completed development of the final 
CSR and may be used for additional exploratory emicizumab-related research, to guide 
development of potential in vitro diagnostic assay(s) related to emicizumab plasma 
concentration, FVIII inhibitor titre and/or coagulation activity.  , or for the potential evaluation 
of germline genomic variation, including, but not limited to, genetic loci coding for FIX and FX. 
 
3.3.5 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected throughout the 2-year study period in order to further investigate 
the PK of emicizumab over the 2 year study period (see the Schedule of Activities; Appendix 
1 
 
Schedule of Activities   
). 
 


 
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3.3.6 
Rationale for Immunogenicity Sample Collection 
Immunogenicity will be monitored by investigating the incidence and clinical significance of 
antibodies to emicizumab at specified time points (see the Schedule of Activities; Appendix 1
 
 
Schedule of Activities   
). The emergence of anti-drug antibodies (ADAs) has been previously observed in clinical 
studies involving monoclonal antibodies of the IgG4 class (Lundkvist et al. 2012; Vennegoor 
et al. 2013). 
 
3.3.7 
Rationale for Disease Response–based Endpoints 
The secondary objective of this study is to evaluate the efficacy of prophylactic 
administration of emicizumab. This objective will be achieved by investigating the number of 
bleeds over time under emicizumab treatment, and assessing HRQoL, and assessments 
evaluating health status according to EQ-5D-5L and patient preference for the emicizumab regimen 
compared with the previous regimen. As mentioned in Section 3.1, this analysis will occur when 
all patients have completed 2 years of treatment or have withdrawn, whichever occurs 
sooner. In order to obtain comprehensive data on each bleed, patients will be asked to 
report bleed information on an ePRO device where possible, including site of bleed, type of bleed, 
time of each individual bleed (day, start and stop time), and treatment for bleed. 
 
3.3.8 
Rationale for Primary Endpoint Selection 
As stated in Section 3.1, the primary objective of this study is to evaluate the overall safety 
and tolerability of prophylactic administration of emicizumab. In order to achieve this 
objective, the incidence and severity of all adverse events, including adverse events of special 
interest, will be captured on an ongoing basis, as they occur during the study. Physical 
examinations, vital signs, and laboratory values will be assessed as per the Schedule of 
Activities (Appendix 1  
Schedule of Activities   
). 
 
3.3.9 
Rationale for Interim Analyses 
Owing to the long-term nature of this study, interim analyses will be conducted in order to obtain 
accurate information on the safety, efficacy, immunogenicity, and PK of prophylactic emicizumab at 
specific points throughout the study. The first interim analysis will be performed once 
approximately 100 patients have received treatment with emicizumab for at least 24 weeks. A 
second interim analysis will be performed when approximately 100 patients have received 
treatment with emicizumab for at least 52 weeks. Owing to the long term nature of this study, 
the interim analyses will be conducted in order to obtain accurate information on the safety, 
efficacy, immunogenicity, and PK of prophylactic emicizumab at specific points throughout 


 
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the study. The data from these analyses will subsequently be presented to the iDMC in order 
to enable them to effectively monitor the study. 
3.3.10 
Rationale for Patient-reported Outcome (PRO) Assessments 
During the study, electronic capture of HRQoL, health status (EQ-5D-5L), and preference 
data (EmiPref) will be obtained using an electronic patient reported outcome (ePRO) device. 
Patient preference data (EmiPref) will be collected on paper forms. 
… 
The goal of measuring HRQoL is to quantify any treatment benefits from the patient 
perspective. Previous studies that have used the Hemophilia Quality of Life questionnaire 
(Haemo-QoL), a measure of HRQoL parameters affected by hemophilia in children and 
adolescents, have reported improvements in physical health, feelings, view of self, family 
relations, friend relations, perceived support, relation with others, participation in sports, 
dealing with hemophilia, views of treatment, views of the future, and relationships 
(Santagostino et al. 2014). Improvements in physical health, feelings, view of self, and 
participation in work have also been observed on the adult version of the measure, the 
Haem-A-QoL (Stasyshyn et al. 2014). 
… 
The EQ-5D-5L is a standardized, preference-based measure of generic health status that is 
applicable to a wide range of health conditions and treatments. It measures five dimensions 
of health: mobility, ability to self-care, ability to undertake usual activities, pain /and 
discomfort, and anxiety / and depression. The EQ-5D-5L also assesses current overall 
health. The goal of measuring EQ-5D-5L is to assess the impact of treatment with 
emicizumab over time on overall health and the different health dimensions. Data from the 
EQ-5D-5L can also be used to inform pharmacoeconomic evaluations.  
 
4.1 
PATIENTS 
This global study will enroll approximately 200 patients with congenital hemophilia A who 
have and documented persistent inhibitors against FVIII at enrollment. The patients are 
expected to be enrolled at approximately 85 sites globally. 
 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
… 
2. As per the investigator’s judgement, a wWillingness and ability to comply with scheduled 
visits, treatment plans, laboratory tests, and other study procedures, including the PRO 
questionnaires and bleed diaries through the use of an electronic device or paper, as per 
the investigator’s judgment 
… 


 
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4. Body weight ≥ 40 kg at the time of screening 
 
4.1.2 
Exclusion Criteria 
… 
13. Positive serum pregnancy test result within 7 days prior to initiation of emicizumab study 
drug (females only) 
 
4.3.1.1 
Emicizumab 
Emicizumab drug product will be supplied by the Sponsor as a sterile colourless to pale 
yellow liquid for SC injection in a single-dose 3-mL glass vials containing 1 mL of emicizumab. 
The recommended storage condition for emicizumab drug product is between 2°C and 8°C 
(36°F to 46°F), and protected from light. Vials should not be frozen or shaken. 
Each single-use vial contains approximately 150 mg/mL emicizumab in a histidine-aspartic 
acid buffered solution (approximately pH 6.0), which contains arginine and Poloxamer 188. 
For information on the formulation and handling of emicizumab, see the Investigator's 
Brochure. 
 
4.3.2.1 
Emicizumab 
As discussed in Section 3.3.1, Eemicizumab will be administered at a dose of 3 mg/kg/week 
subcutaneously for 4 weeks when initiating treatment, followed by 1.5 mg/kg/week 
subcutaneously for the remainder of the 2-year treatment period. There will be an option to 
increase the dose to 3 mg/kg/week in cases of insufficient control of bleeds on the 1.5 
mg/kg/week emicizumab dose. If the investigator believes that a specific patient warrants 
dose up-titration following the occurrence of, for example, at least two spontaneous bleeds, 
significant bleeds, or a traumatic bleed out of proportion to the degree of injury, they must 
discuss the case with the Medical Monitor for consideration and potential approval. 
Recommended injection sites include the front of middle of the patient’s thighs, or the lower 
part of the patient’s abdomen below the navel.  Avoid injecting within a 2” radius around the 
navel. If a caregiver is giving the injection, the outer area of the upper arms may also be 
used. For additional information re the administration of emicizumab, refer to the Instructions 
for Use (IFU) document. 
… 
Study site HCPs will be initially trained on how to properly prepare emicizumab the study 
medication and administer the correct calculated dose subcutaneously as described in the 
instructions for use (IFU) document. 
… 
In order to minimize the number of injections for patients in certain weight categories, the 
administration of a single injection of up to 2 mL drug product solution may be permitted, 


 
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pending approval from the Sponsor, individual countries, and participating sites. This 
administration will require the combination of emicizumab drug product solution from up to 
two 1-mL vials more than one vial (i.e., vial pooling) aseptically into a single syringe, using a 
new transfer needle for each vial. Upon Sponsor approval, Tthe detailed procedure for vial 
pooling will be described in the IFU document. If the patient’s dose is > 2 mL, a second injection 
will be required.  
Medication administration errors during training will be documented in the electronic Case 
Report Form (eCRF). If necessary, patients or their HCP may choose to continue 
administration of emicizumab the study drug within the clinic. Compliance in the home setting 
is to be monitored at each site by reviewing reported hemophilia medication use and 
recording collected used and unused vials. 
If the patient forgets or cannot administer emicizumab the study medication on the scheduled 
dosing day, emicizumab the study medication should be administered as soon as possible before 
the day of the next scheduled dose, and then the patient should resume the usual weekly dosing 
schedule. Do not double doses to make up for a missed dose.  All four loading doses of 3 mg/kg should 
be taken, even if this is done over a period or more than four weeks. as soon as possible within a 
window of 3 days from the scheduled dosing date. If more than 3 days has passed, the 
missed dose should be skipped, and the patient should take their next dose at the next 
scheduled time. If this scenario occurs, study medication dosing should be resumed in 
accordance with the original dosing schedule. 
Any overdose or incorrect administration of emicizumab the study drug should be noted on 
the Study Drug Administration eCRF. Adverse events associated with an overdose or 
incorrect administration of emicizumab the study drug should be recorded on the Adverse 
Event eCRF. Section 5.3.5.12 summarizes available safety data related to overdosing of 
emicizumab. 
 
4.3.3 
Investigational Medicinal Product Accountability 
… 
Used and unused IMP emicizumab vials will be returned by the patients to the study site and 
appropriately accounted for. Used emicizumab vials will then be disposed of at the study site 
according to institutional standard operating procedures. 
 
4.3.4 
Continued Access to Emicizumab 
The Sponsor will offer continued access to the IMP (emicizumab) to study patients who have 
shown a demonstrable benefit from emicizumab treatment during this study (as measured by 
sustained clinical response and/or improvement in clinical symptoms).  
Continued Access to emicizumab the IMP will be provided free of charge, through either an 
Open Label Extension trial, a Post-Trial Access Program, local Patient Support Programs, or 
other local access mechanisms according to each country regulation, as described per 
Global procedural document: Continued Access to Roche Investigational Medicinal Product 


 
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(SOP-0112895), in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, and the Declaration of Helsinki in its 2013 issue. 
 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
from 4 weeks prior to initiation of emicizumab study drug to the Study Completion/Early 
Termination Visit (or to the Safety Follow-up Visit, if applicable). All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
Any hemostatic medications (e.g. bypassing agents) and other medications used to treat or 
prevent bleeds in the 6-month period prior to starting emicizumab treatment will also be 
collected (see Section 4.5.5).  
 
4.4.1 
Permitted Therapy 
Concomitant use of the following drugs and therapies will be permitted: 
• 
Drugs to treat existing conditions at time of study entry, as long as allowed based on eligibility 
criteria (Section 4.1.1 and Section 4.1.2). 
• 
During the study, aAny medication to treat or prevent any medical condition as deemed 
necessary by the treating physician. If prohibited treatment (see Section 4.4.2) is prescribed or 
considered medically necessary, the Medical Monitor should be consulted to discuss any changes 
in the benefit-risk profile and determine whether the patient should continue on the study.  
• 
Any over-the-counter medication used to treat the symptoms of hemophilia 
• 
Supplementary vitamins and minerals. 
• 
Drugs and therapies to treat adverse events and the use of topical antiseptics, anesthetics, eye 
drops, etc., that are not considered to enter the bloodstream and result in systemic exposure 
Concomitant use of the following hemostatic treatments will be permitted: 
• 
Drugs intended to control breakthrough bleeds (e.g. rFVII, FVIII, aPCC) or bleeds during 
surgeries should be used at the lowest dose expected to achieve hemostasis. Given that circulating 
emicizumab may increase the patient’s coagulation potential, the doses required to achieve 
hemostasis may be lower than doses used prior to starting emicizumab. At the start of the study, 
Investigators shall discuss with patients the recommended doses of any additional coagulation 
factors used, given the guidance below.  
• 
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided 
if possible, and rFVIIa should be the first option used to treat, starting with no more than 90 
µg/kg as an initial dose. If aPCC needs to be used, no more than 50 IU/kg should be administered 
as an initial dose and doses of > 100 U/kg/24 hours or more should be avoided, as cases of TMA 
and thrombotic events were reported when on average a cumulative amount of > 100 U/kg/24 
hours aPCC was administered for 24 hours or more. Investigators should provide or remind 
patients of the exact dose and schedule of bypassing agents or FVIII required to treat any bleed. 


 
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• 
Drugs intended to control breakthrough bleeds (e.g. rFVIIa) should be used at the lowest 
dose expected to achieve hemostasis. Given that circulating emicizumab may increase 
the patients’ coagulation potential, the doses required to achieve hemostasis may be 
lower than the FVIII or bypassing agent doses used prior to starting the study: 
o Caution should be used for patients who are taking rFVIIa (e.g., consideration should 
be given to using no more than 90 μg/kg rFVIIa as an initial dose) 
o Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab 
• 
aPCC should only be administered if it is the only available treatment for breakthrough 
bleeds. If used, 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 andthe 
recommended dose.  
• 
Other bypassing agents: 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 mg/kg of Byclot®). For patients receiving Byclot® prior to study entry, a 
washout period of 72 hours prior to the first emicizumab dose is required 
• 
The exact dose and schedule of FVIII or bypassing agents should be discussed with the 
patient at study entry and throughout the study. Repeated dosing of FVIII, rFVIIa, aPCC, 
or other bypassing agents should be performed only under medical supervision and 
consideration should be given to verifying the 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 Activities (see 
Section 4.5.6.9Appendix 1 
 
Schedule of Activities   
• 
). 
• 
Drugs and therapies to treat adverse events and the use of topical antiseptics, 
anesthetics, eye drops, etc., that are not considered to enter the bloodstream and result 
in systemic exposure 
• 
Drugs to treat an existing medical condition that is ongoing at study entry and do not 
violate the eligibility criteria (e.g., anti retroviral therapy for HIV infections). 
• 
Caution should be taken if anti fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab 
 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
… 
• 
Use of aPCC for short-term prophylaxis 
• 
Use of aPCC for any reason should be avoided if possible during the study but use of 
aPCC to treat breakthrough bleeds is permitted (as described in Section 4.4.1above) if 
rFVIIa is not available or not an option for medical reasons (see Section 3.1). 


 
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• 
Use of ITI therapy (a concomitant prophylactic regimens with FVIII and/or bypassing 
agents): 
• 
However, short-term prophylaxis around the time of surgery is permitted as deemed 
needed by the investigator (see Section 4.4.1).   FEIBA can not be used prophylactically.  
• 
Use of anti-fibrinolytics in conjunction with aPCC or Byclot® 
 
4.5.1 
Informed Consent Forms and Screening Log 
… 
The enrollment form will be completed after informed consent and/or assent is obtained. 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. 
 
4.5.2 
Medical History and Demographic Data 
Medical history includes hemophilia-related history, clinically significant diseases, 
procedures (including prior surgeries), use of alcohol and drugs of abuse within the past year, 
and medication allergies. In particular, sites should record whether the patient has any 
history of prior ITI, anaphylaxis, or known thrombophilia. It should also include all medication 
taken in the 4 weeks prior to screening (including prescription drugs, over-the-counter drugs, 
and herbal/homeopathic remedies and therapies). 
 
4.5.3 
Physical Examinations 
A complete physical examination be performed during at Screening and should include, but 
not necessarily be limited to, an evaluation of the head, eyes, ears, nose, and throat and the 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, 
and 
neurological systems. Any abnormality identified during screening should be recorded on the 
General Medical History and Baseline Conditions eCRF. Subsequently, a targeted (i.e., 
musculoskeletal, dermatological) examination should be conducted as noted in the schedule 
of activities (Appendix 1 
 
Schedule of Activities   
) or as clinically indicated. Targeted physical examinations (i.e., joints for bleeds and evidence of 
arthropathy; skin for bruises, hematomas and ISRs; other organ systems as clinically indicated) 
should be conducted at subsequent visits or as clinically indicated. New or worsened clinically 
significant abnormalities from screening should be recorded as adverse events, if 
appropriate, on the Adverse Event eCRF. 
 






 
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4.5.6.4 
Anti-FVIII Antibodies 
For the assessment of anti-FVIII antibodies (inhibitors), functional assays that utilize a 
clotting readout (classic Bethesda or Nijmegen assay) cannot be used for patients on 
emicizumab therapy as emicizumab drives clotting even in the presence of FVIII inhibitors, 
causing a false-negative test result (see Section 5.1.3). After the first dose, local 
measurement of FVIII inhibitors, if indicated, requires use of an ELISA-based test or a 
chromogenic Bethesda assay. 
At the discretion of the local investigator, any additional urgent requests to assess FVIII 
inhibitors will need to be sent to the central laboratory (see Appendix 2  
Schedule of Biomarker Samples 
 for additional information).  
Plasma samples for anti-FVIII antibodies will be analysed at the central laboratory.  
 
4.5.6.5 
Anti-emicizumab Antibodies 
Plasma samples are required for immunogenicity assessments to detect anti-emicizumab antibodies.  
Additional samples to detect anti-emicizumab antibodies may also be drawn at the time of 
hypersensitivity events or following suspected loss of efficacy. Samples will be analysed at the central 
laboratory. 
 
4.5.6.6 
Pharmacokinetics   
Plasma samples are required for PK assessments. On days where PK samples are to be collected, the 
emicizumab injection will be performed in the clinical unit.  One single pre-dose sample is required on 
the applicable visits.  Samples will be analysed by the central laboratory.   
 
4.5.6.7 
Biomarkers 
4.5.6.7.1 
Safety Biomarkers 
Plasma samples for safety biomarker assessment must be citrate plasma.  Tests may 
include, but are not limited to, D-dimer. Samples will be analysed by the central laboratory.  
See Appendix 2. 
 
4.5.6.7.2 
Safety Coagulation System Biomarkers 
Plasma samples for safety coagulation system biomarker assessment must be citrate 
plasma.  Tests include FVIII:Ag, FIX:Ag and FX:Ag. Samples will be analysed by the central 
laboratory.  See Appendix 2. 
 
4.5.6.7.3 
PD Biomarkers 
Plasma samples for PD biomarker assessment must be citrate plasma.  Tests will include, 
but are not limited to FVIII activity and modified aPTT (one stage). Additional plasma 
samples will be collected for future exploratory research, which may include tests such as 
CWA and others (see Appendix 2). Samples will be analysed by the central laboratory.   


 
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4.5.6.7.4 
Bone and Joint Biomarkers 
Serum and plasma ethylenediaminetetraacetic acid (EDTA) samples for bone and joint 
biomarkers must be collected after fasting (no food or drink other than water for at least 8 
hours prior to the blood draw). Ideally these samples should be collected in the morning 
(before noon), in order to control for diurnal variation. Please consult the Central Laboratory 
Services Manual for details. The selection of exploratory bone and joint biomarkers to be 
tested will build on findings from biomarker analyses in other emicizumab trials and may 
include C-terminal telopeptide of collagen 1 (CTX-1), osteoprotegerin (OPG), procollagen 
type 1 amino-terminal propeptide (P1NP), and soluble receptor activator of nuclear factor 
kappa-B ligand (RANK-L) (see Appendix 2  
Schedule of Biomarker Samples 
). Samples will be analysed by the central laboratory.   
 
The following additional study specific plasma samples will be collected and sent to a central 
laboratory for analysis: 
• 
Plasma samples for PK analysis 
• 
Plasma samples for immunogenicity assessments to detect anti emicizumab antibodies 
• 
Plasma samples for safety biomarker assessments (D dimer) 
• 
Plasma samples for safety coagulation system biomarker assessments (FVIII:Ag, 
FIX:Ag, and FX:Ag) 
The following biomarker samples will be collected and sent to a central laboratory for 
analysis (see Appendix 2  
Schedule of Biomarker Samples 
): 
• 
Plasma samples for PD biomarker assessments (aPTT and FVIII activity) 
• 
Plasma and serum samples for bone and joint biomarker assessments. 
 
4.5.6.8 
Extra Testing with Use of Bypass Agents 
In the event of a breakthrough bleed that is treated with bypassing agents, it is 
recommended that the following laboratory tests will be performed within 2448 hours of 
initial bypassing agent use (these tests will be conducted so that the investigator can monitor 
the patient for potential thromboembolic events and microangiopathic hemolytic anemia or 
TMA). These tests include: These tests should ideally be conducted in the central laboratory: 
… 
• 
Lactate dehydrogenase (LDH) 
… 
Ideally, samples for these tests should be analysed at the central laboratory.  Exceptionally 
in urgent situations where results are required quickly, local laboratory testing can be used, 
with results recorded in the eCRF. 


 
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For patients who require multiple doses of bypassing agents, laboratory monitoring should 
be performed every 2448 hours until 2448 hours after the last dose of bypassing agents is 
administered to treat a specific bleed. If applicable, All laboratory results which are required as 
part of the patient’s safety assessment should be recorded in the unscheduled visit eCRFs. 
 
4.5.6.9 
Sampling Procedures and Sample Storage, Shipment and Destruction 
For sampling procedures, storage conditions, and shipment instructions, see the Central 
Laboratory Services Manual. 
HIV and hepatitis serology testing will be done in the local laboratory at screening. All 
women of childbearing potential (including those who have had a tubal ligation) will have a 
serum pregnancy test at screening done in the local laboratory and again within 7 days prior 
to the first dose of emicizumab, if applicable. Urine pregnancy tests will be performed at 
every clinic visit at the local laboratory, except for Weeks 2 and 3. 
… 
• 
Plasma or serum samples, as applicable, collected for anti emicizumab antibody, anti-
FVIII antibody, PD biomarker, safety biomarker, safety coagulation system biomarker, 
and bone and joint biomarker assessments and other future exploratory research will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed. 
 
4.5.7 
Bleed Assessments 
Patients will be trained on how to record their bleeds and hemophilia medication use using an ePRO 
device where possible. When bleeds occur, patients will need to record the site of bleed, type of 
bleed, time of each individual bleed (day, start and stop time), and treatment for bleed. 
Patients will need to record when they have bleeds or hemophilia medication use, including 
emicizumab, or at least every week. At least once a week, patients will need to record any 
hemophilia medication use (including emicizumab) and information regarding any bleeding events. 
Investigator review of patient-reported bleed/medication records with the patient/caregiver 
will occur for completeness and accuracy throughout the study.  
 
4.5.8 
Surgical Events 
Thorough documentation on surgical events will be requested, including type of surgery or 
procedures, treatments, outcomes, etc.  
4.5.9 
Patient-Reported Outcomes 
… 
The PRO questionnaire data will be collected to document the treatment benefit of 
emicizumab. The questionnaires, translated into the local language as required, will be 
completed in their entirety at specified timepoints during the study. To ensure instrument 
validity and that data standards meet health authority requirements, questionnaires will be 
self-administered before the patient/caregiver receives any information on disease status, 


 
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prior to the performance of non-PRO assessments, and prior to the administration of 
emicizumab study treatment, unless otherwise specified. 
 
4.5.9.1 
HRQoL Assessments 
The Haem-A-QoL (version AU 3.0; UK English) and the Hemophilia Quality of Life Short Form 
(Haemo-QoL-SF) (version AU 2.0; UK English) will be completed electronically and used to 
measure HRQoL in adults and adolescents, respectively (see Appendix 33  
EmiPref Patient Preference Questionnaire 
 and Appendix 44 
Clinical Criteria for Diagnosing Anaphylaxis 
). Paper versions of the questionnaires are also available in case of ePRO outage or if an ePRO device 
is otherwise unavailable.  
 
4.5.9.2 
Health Status Assessments (EQ-5D-5L) 
The EQ-5D-5L (version 2; UK English) (see Appendix 55  
WHO Toxicity Grading Scale for Determining the Severity of Laboratory 
Abnormalities and Adverse Events 
) is a generic, self-report, preference-based health utility measure that consists of six 
questions that are completed electronically and is used to assess health status and inform 
pharmacoeconomic evaluations. Paper versions of the questionnaires are also available in case of 
ePRO outage or if an ePRO device is otherwise unavailable. The EQ-5D-5L consists of two 
components. The first part, health state classification, contains five dimensions of health: 
mobility, self-care, usual activities, pain / discomfort, and anxiety / depression (Herdman et al. 
2011; Janssen et al. 2013). Published weights are available that permit the creation of a 
single summary score. Overall scores range from 0 to 1, with low scores representing a 
higher level of dysfunction. The second part is a 0 to 100-point visual analog scale (VAS), 
which assesses current health status and higher scores are reflective of better health. 
 
4.5.9.3 
Treatment Preference Questionnaire 
Patient preference will be assessed through a paper version of the EmiPref questionnaire 
(Appendix 3), which asks patients to specify the treatment they would prefer to continue to 
receive after receiving treatment with their previous episodic or prophylactic regimen and SC 
emicizumab. Patients who express a preference are then asked to identify the reasons 
which may have influenced their decision and indicate the top three reasons for their choice. 
Patients will complete this questionnaire after 3 months of treatment with emicizumab. 
 
4.6 
PATIENT, TREATMENT, STUDY AND SITE DISCONTINUATION 
A Safety Follow up Visit will be conducted 24 weeks after last dose of emicizumab in 
patients who discontinue emicizumab Patients who discontinue emicizumab prior to the 


 
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completion of the 2-year treatment period will undergo a Safety Follow-up Visit 24 weeks 
after the patient’s last emicizumab dose or at 2 years after emicizumab treatment start, 
whichever occurs first (see Appendix 1  
Schedule of Activities   
). 
 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue emicizumab study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize the patient’s 
safety if he or she continues to receive emicizumab 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Requirement of another medication not permitted per protocol 
The primary reason for emicizumab study treatment discontinuation should be documented 
on the appropriate eCRF. Patients who discontinue emicizumab study treatment prematurely 
will not be replaced. Patients who become pregnant should immediately discontinue 
treatment and be managed according to local guidelines. 
 
5.1 
SAFETY PLAN 
Emicizumab is not approved in all countries, and clinical development is still ongoing. Thus, 
the complete safety profile is not known at this time. The safety plan for patients in this study 
is based on clinical experience with emicizumab in completed and ongoing studies. The 
anticipated important safety risks for emicizumab are outlined below. Please refer to the 
emicizumab Investigator's Brochure for a complete summary of safety information. 
 
5.1.1.1 
Injection-Site Reactions 
In the completed and ongoing Japanese studies, injection site reactions ISRs have been 
observed in some patients with hemophilia A. These local injection site reactions ISRs 
included injection-site erythema, injection-site hematoma, injection-site rash, injection-site 
discomfort, injection-site pain, and injection-site pruritus. All local injection site reactions ISRs 
were of mild intensity. Further details on the observed injection site reactions ISRs are 
available in the Investigator’s Brochure. To minimize the risk for injection site reactions ISRs, 
emicizumab should be injected subcutaneously using separate injection sites as described in 
Sections 3.3.1 and 4.3.2.1 and the IFU document. 
 


 
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5.1.1.2 
Hypercoagulation and Risk of ThrombosisThromboembolic Events 
As of April 2017 October 2016, there have been two serious thrombotic embolic events 
reported in two patients with hemophilia A with inhibitors who were treated with bypassing 
agents while receiving who received emicizumab prophylaxis in Study BH29884.  
• 
One patient self-administered greater than 200 units/kg/day of aPCC for two consecutive 
days and developed a cavernous sinus thrombosis. Treatment with emicizumab was 
interrupted, no further aPCC was administered, and the clot resolved without 
anticoagulation in after approximately 2.5 weeks. Emicizumab was restarted after 
approximately 10 days after the resolution of the serious adverse event without recurrence.  
• 
The second patient developed severe skin necrosis (both legs) and contemporaneous 
superficial vein thrombosis in the right leg after self-administering two consecutive doses 
of 100 units/kg/day of aPCC. The patient is recovering recovered on supportive therapy 
(no anticoagulation). For more details please refer to the emicizumab Investigator’s Brochure. 
All thromboembolic events should be reported as adverse events of special interest (see 
Section 5.2.3), and also as serious adverse events if it meets criteria as described in Section 
5.2.2.  should be reported as serious adverse events or adverse events of special interest as 
described 
in 
Sections 
5.2.2 
and 
5.2.3, 
respectively. 
HCPs 
should 
educate 
patients/caregivers on how 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, 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 should thromboembolism be suspected. 
 
5.1.1.3 
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, central nervous system, etc. As of October 2016 April 2017, three 
two cases of TMA were observed in Study BH29884 involving patients with hemophilia A with 
inhibitors who were treated with bypassing agents while receiving emicizumabin two patients with 
hemophilia A with inhibitors who received emicizumab in Study BH29884.  
• 
The first patient self-administered two doses of aPCC 94 units/kg aPCC in 2 days to treat 
his left knee hemarthrosis. The following next day, the patient he started experiencing 
icterus and severe back pain and the patient self-administered two doses of rFVIIa 
85 µg/kg rFVIIa and two doses of aPCC 94 units/kg aPCC. Then the patient presented 
with thrombocytopenia, hyperbilirubinemia, and acute renal failure with schistocytes on 
peripheral blood smears. The patient was diagnosed with TMA and treated with 
plasmapheresis, hemodialysis, and supportive care and his condition improved and 
resolved after 15 16 days. The patient discontinued treatment with emicizumab 
• 
The second patient self-administered five doses of aPCC 74 units/kg aPCC over three 
consecutive days before the serious adverse event occurred onset. The patient had 
abdominal pain and emesis, acute renal failure, thrombocytopenia, elevated LDH, and a 


 
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low haptoglobin with schistocytes on peripheral blood smears. The patient was 
diagnosed with TMA and recovered without plasmapheresis or hemodialysis after 9 18 
days. The patient restarted treatment with emicizumab approximately 10 days after 
resolution of the serious adverse event without recurrence of TMA. 
• 
The third patient presented at the hospital complaining of rectal bleeding, postural dizziness, and 
exertional dyspnea. Of note, 
 
. Multiple doses of rFVIIa were administered and various interventions 
(hemostatic powder application, absorbable hemostat packing, and embolization of rectal arteries) 
were used in an attempt to control bleeding. Despite these measures, the patient continued to have 
rectal hemorrhage. The patient’s bypassing agent treatment was then changed to aPCC and 
temporary cessation of bleeding was achieved. Subsequently, the patient developed a serious 
adverse event of TMA following concomitant bypassing agent treatment. Emicizumab 
prophylaxis and aPCC were discontinued and therapeutic plasma exchange with albumin was 
provided. Three days later, investigators assessed the patient’s TMA to be improving based on 
laboratory assessments (LDH and platelet count). However, the patient experienced recurrent 
rectal hemorrhage. Surgery and arterial embolization were no longer deemed to be feasible and the 
patient was placed on comfort care before passing away the same day. The investigator assessed 
the patient death as related to the serious adverse event of rectal hemorrhage and unrelated to 
emicizumab, and the TMA as related to emicizumab and aPCC. For more details please refer to 
the Emicizumab Investigator’s Brochure. 
These events should be reported as adverse events of special interest (see Section 5.2.3), 
and also as serious adverse events if it meets criteria as described in Section 5.2.2. TMA 
events should be reported as serious adverse events or adverse events of special interest 
as described in Sections 5.2.2 and 5.2.3, respectively. 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. 
 
5.1.1.4 
Hypersensitivity 
Since emicizumab is a biological product, acute systemic hypersensitivity reactions, 
including anaphylactic/anaphylactoid reactions, may occur. In Study ACE001JP, no severe 
hypersensitivity reactions or anaphylactic/anaphylactoid reactions have been observed. 
These events should be reported as serious adverse events or adverse events of special 
interest as described in Sections 5.2.2 and 5.2.3, respectively. 
HCPs administering emicizumab 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 4). HCPs should also instruct patients how to recognize the signs and 
symptoms of hypersensitivity, anaphylactic, and anaphylactoid reactions and to contact an 






 
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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 emicizumab study drug should be recorded on the 
Adverse Event eCRF. If the associated adverse event fulfills seriousness criteria, the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report such 
events to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the investigator learns of the event. The following is a list of events 
that the investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to emicizumab study drug: 
 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for all sites 
Medical Monitor: 
Dr 
 (Primary)  
Telephone No.: 
 
Mobile Telephone No.: 
 
Medical Monitor: 
Dr 
 MD, MBA (Secondary) 
Telephone No.: 
 
Mobile 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 
Responsible individual (listed above and/or on the Roche Medical Emergency List), and 
track all calls. The Emergency Medical Call Center Help Desk will be available 24 hours per 
day, 7 days per week. Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible individual contact information, will be distributed to all investigators. 
 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of emicizumab 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 


 
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(i.e., no more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of emicizumab study drug, serious adverse events and adverse events of 
special interest will be reported until the last scheduled study visit (see Section 5.3.1). 
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. 
 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last dose 
of emicizumab study drug. A Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. Pregnancy should not be recorded on 
the Adverse Event eCRF. The investigator should discontinue emicizumab study drug and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until conclusion of the pregnancy. Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an event 
in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) 
should be reported on the Adverse Event eCRF. In addition, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.  
 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to 
emicizumab 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). 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population is all patients who have received at least one dose of 
emicizumab study medication (safety population). The intent-to-treat (ITT) population includes 
all enrolled patients.  
 


 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Flow of patients through the study will be displayed in a ‘Consolidated Standards of 
Reporting Trials (CONSORT)’ diagram. A clear account of all patients who enrolled in the 
study and who entered, discontinued, and completed the initial and maintenance phases of 
the study will be displayed. The reasons for premature discontinuation from study treatment 
and the reasons for study withdrawal will be described. In addition, the number of patients 
who received dose up-titration will also be described. Enrollment and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of study 
results. The type of Major protocol violations deviations and the number of patients with at 
least one violation major protocol deviation will be summarized in terms of both the safety and 
ITT populations.  
 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, and self-reported race and 
ethnicity) will be summarized using means, standard deviations, medians, and ranges for 
continuous variables and proportions frequencies and percentages for categorical variables, as 
appropriate. For each variable (continuous or categorical), the number of available 
observations will be reported. Medical history will be tabulated and previous concomitant 
medications will be summarized. 
 
6.4 
SAFETY ANALYSES 
The primary objective of this study is to evaluate the overall safety and tolerability of 
prophylactic administration of emicizumab in patients with congenital hemophilia A who have 
persistent inhibitors against FVIII at enrollment. Of primary interest in this study are the 
incidence and severity of all adverse events, including thromboembolic events, 
microangiopathic hemolytic anemia or TMA, systemic hypersensitivity, anaphylaxis, and 
anaphylactoid events. 
All adverse events will be assessed according to the WHO toxicity grading scale. The 
incidence, type, and grade of adverse events will be summarized according to the primary 
system-organ class (SOC) and, within each SOC, by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. For each adverse event, data will be provided on the 
timing (start and stop date, time of onset in comparison with last dose of emicizumab 
received, and doses of emicizumab received), severity, relationship to emicizumab study drug, 
outcome, and effect on therapy. The data may be presented together with two-sided 95% 
Clopper-Pearson CIs if appropriate. 
In addition, as part of the safety evaluation, additional assessments will be summarized 
descriptively as follows: 
… 
• Laboratory parameters (hematology and chemistry): 
o These parameters will be presented in shift tables of WHO toxicity grade at baseline 
versus worst grade during the treatment period. Selected laboratory parameters will 


 
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be summarized in terms of mean, standard deviation, minimum, and maximum. 
Laboratory parameters will also be presented graphically over time, if appropriate. 
All safety variables will be analyzed for the safety population. For each variable, the number 
of available observations will be reported. The safety population includes all patients who 
have received at least one dose of emicizumab study medication. 
… 
The iDMC (see Section 9.4.1) will evaluate the study data, including the emerging safety 
results, at periodic reviews and recommend to the Sponsor whether the protocol should be 
amended or the study should be stopped early. All summaries and analyses will be prepared 
by the Study Management Team (SMT) statistician and presented for review by the iDMC 
review. Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities. 
 
6.5 
EFFICACY ANALYSES 
… 
The definition of a bleed is described in Section 4.5.7.1. Patients will be asked to record 
when they have bleeds or hemophilia medication use, including emicizumab. Patients will be 
asked to record any hemophilia medication use (including emicizumab) and information regarding 
any bleeding events. The patients should record this information at least every week even if 
they do not experience a bleed. The number of bleeds will be compared with patients’ bleed 
rate prior to study entry and will be summarized descriptively. 
… 
As different HRQoL measures (Haem-A-QoL and the Haemo-QoL-SF) will be used for adult 
and adolescent patients, all calculations and analyses will be conducted separately for each 
patient population. Scale scores for the Haem-A-QoL and Haemo-QoL-SF will be calculated 
and summarized descriptively. The HRQoL scale scores for all patients will be evaluated 
after 6 months of treatment, a timepoint which is consistent with other recent registrational 
studies in hemophilia (Lentz et al. 2013; Mahlangu et al. 2014; Powell et al. 2013) and 
analyses of this type of data (Santagostino et al. 2014; Wyrwich et al. 2015). Paired t-tests 
will be used to compare the on-treatment scores with the baseline scale scores for each 
HRQoL measure. Within-patient changes from baseline for the different HRQoL scale scores 
will also be calculated for each of the on-treatment timepoints. The proportion of patients 
who report changes in each group that exceed clinically meaningful thresholds will be 
reported. 
For each of the EQ-5D-5L assessments, the number and percentage of patients in each of 
the five categories for each question for each group will be evaluated. Changes in the EQ-
5D-5L index utility score from baseline will also be reported compared between groups. In 
addition, summary statistics including mean, standard deviation, median, minimum, and 
maximum will be calculated according to the patients’ health state using the EuroQoL visual 
analogue scale (EQ-VAS) both within and between groups. The proportion of patients who 
report changes in each group that exceed the clinically meaningful threshold on the EQ-5D-
5L index and the EQ-VAS scores will be reported. 


 
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6.6 
IMMUNOGENICITY ANALYSES 
… 
The immunogenicity analyses will include patients with at least one pre-dose and one post-
dose anti-emicizumab antibody assessment. The numbers and proportions of antibody-
positive patients and antibody-negative patients during the treatment period will be 
summarized. Patients are considered to be antibody-positive if they are negative at baseline 
but develop an anti-emicizumab antibody response following emicizumab study drug 
administration (treatment-induced antibody response), or if they are positive at baseline and 
the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) 
than the titer of the baseline sample (treatment-enhanced antibody response). … 
 
6.9.1 
Planned Interim Analyses 
The first interim analysis will be performed once approximately 100 patients have received 
treatment with emicizumab for at least 24 weeks. A second interim analysis will be 
performed when approximately 100 patients have received treatment with emicizumab for at 
least 52 weeks. The data from these analyses will subsequently be presented to the iDMC in 
order to enable them to effectively monitor the study (see Section 9.4.1). 
 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
PRO data will be collected electronically through the use of electronic devices provided by 
an ePRO vendor (HRQoL and EQ-5D-5L) or using a paper questionnaire (EmiPref). Paper 
versions of the questionnaires are also available in case of ePRO outage or if an ePRO 
device is otherwise unavailable. The electronic device is designed for entry of data in a 
manner that is attributable, secure, and accurate, in compliance with U.S. FDA regulations 
for electronic records: (21 Code of Federal Regulations, Part 11). The PRO data from the 
device will be transmitted electronically to the eCRF in real time. to a centralized database at 
the ePRO vendor. The data from the ePRO devices will be available for viewing only through 
a secure access to a web portal provided by the ePRO vendor. Only identified and trained 
users may view the data, and their actions (if any) will become part of the audit trail. The 
Sponsor will have view-only access to PRO data. Regular data transfers will occur from the 
centralized database at the vendor to the database provided by the Sponsor. The Sponsor 
will receive all data (including requested meta-data) entered by the patients on the ePRO 
devices and all relevant study documentation. 
 
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 


 
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relevant national or local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, subject to local regulations. 
 
9.4.1 
Independent Data Monitoring Committee 
An iDMC will be assembled to review the safety data collected during the study. The iDMC 
members will consist of, at minimum, independent hemostasis/thrombosis experts and a 
statistician, none of whom will be otherwise involved in the conduct of study. All analyses for 
review by the iDMC will be prepared by the SMT statistician. Monitoring and analysis of all 
significant safety events will be performed on a continuous basis. A first interim aAnalysis of 
the study data will be performed once approximately 100 patients have received treatment 
with emicizumab for at least 24 weeks (see Section 6.9.1), and a. A second interim analysis 
will be performed when approximately 100 patients have received treatment with emicizumab 
for at least 52 weeks. Thereafter, the iDMC will meet at a frequency determined by the iDMC 
and the Sponsor according to the emerging data. 
The SMT statistician will perform analyses and provide tables and listings to support the 
study reviews by the iDMC. The safety data that will be provided will include demographic 
data, adverse events (the incidence and severity of all adverse events, including 
thromboembolic events, microangiopathic hemolytic anemia or TMA, systemic hypersensitivity, 
anaphylaxis, and anaphylactoid events), medication dose information, physical examination 
findings, vital sign data, and laboratory abnormalities (hematology and chemistry). If 
available, the efficacy data that will provided will include the number of bleeds over time, 
ABR data, the HRQoL of patients, the health status of patients according to EQ-5D-5L 
scores, and patient preference for the emicizumab regimen compared with the previous 
regimen used. Further information will be provided on request. 
 
9.7 
STUDY PARTICIPANT SURVEY 
Consenting patients may be asked about their study experience via a short study-specific survey.   
Survey questions will ask the patient to rate their study experience on a scale of 1-5 on topics that 
include the following: information provided prior to the study, the consent and enrolment process, 
study participation, study results and feeling appreciated as a study patient.   
Patients will be asked to complete the survey at the end of the study. The goal of this survey is to 
identify areas where Roche is performing well and areas where improvement may be required.   
Information will be provided to the Sponsor securely and on an anonymous basis and consent to the 
survey is totally voluntary and does not affect patient’s enrolment to the study.  
 
10. 
REFERENCES 
… 
Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of 
therapeutic monoclonal antibodies. Clin Pharmacokinet 2010;49:493 507. 


 
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… 
Mackensen SV, Gringeri A. Quality of life in hemophilia. In: Preedy VR, Watson RR, editors. 
Handbook of disease burdens and quality of life measures. New York: Springer, 2010:1895
920. 
… 
Oldenburg J, Mahlangu JN, Kim B, et al.  Emicizumab prophylaxis in hemophilia A with inhibitors.  
NEJM 2017;277(9):809-18. 
… 
Von Mackensen SV, Gringeri A. Quality of life in hemophilia. In: Preedy VR, Watson RR, editors. 
Handbook of disease burdens and quality of life measures. New York: Springer, 2010:1895–920. 
 








 
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completed instead. Parents or caregivers of adolescents will also complete an Informed Consent Form.  The enrollment form will be completed after informed 
consent and/or assent is obtained. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before enrollment.  
d. Medical history and demographics dData will be collected from patient medical records and documented in the eCRF. Medical history includes hemophilia-
related history, clinically significant diseases, procedures (including prior surgeries), use of alcohol and drugs of abuse within the past year, and medication allergies. In 
particular, sites should record whether the patient has any history of prior ITI, anaphylaxis, or known thrombophilia. It should also include all medication taken in the 
4 weeks prior to screening (including prescription drugs, over-the-counter drugs, and herbal/homeopathic remedies and therapies). Any hemostatic medications (e.g. 
bypassing agents) and other medications used to treat or prevent bleeds in the 6-month period prior to starting emicizumab treatment will also be collected. Demographic 
data will include age, sex, and self-reported race and ethnicity. 
e. A complete physical examination will be performed at during Screening and should include, but not necessarily be limited to, an evaluation of the head, eyes, 
ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological systems. Any abnormality identified during 
screening should be recorded on the General Medical History and Baseline Conditions eCRF.   and targeted physical examinations will be performed at the visits 
indicated. Targeted physical examinations (i.e., of joints (for bleeds, evidence of arthropathy; ) and skin (for bruises, hematomas, and injection site 
reactionsISRs; ), in addition to other organ systems as clinically indicated), should be conducted at subsequent visits or performed as clinically indicated. New 
or worsened clinically significant abnormalities from screening should be recorded as adverse events, if appropriate, on the Adverse Event eCRF. 
f. 
Vital signs include measurement of body temperature (oral, rectal, axillary, or tympanic), heart and respiratory rates, blood pressure, pulse, respiratory rate, 
and weight will be measured.  On treatment days, measurement should occur at each clinic visit prior to any emicizumab administration injection, if applicable. 
Height will be measured and recorded only during at Screening and 6 and 12 months after starting emicizumab. Additional vital signs assessments may also 
be taken anytime as unscheduled assessments as judged by the investigator. In addition, At the investigator's discretion, vital signs may be taken to help monitor 
for hypersensitivity reactions during or after injections at the investigator's discretion,, although these data but they should not be entered into the eCRF.  
g. Patients will be asked about concomitant medications (e.g., extra pain medication following a bleed) at each clinic visit indicated, with the exception of 
treatments for bleeds (i.e., bypassing agents and other medications to treat bleeds), which will be collected in the bleed records. Any hemostatic 
medications used to treat or prevent bleeds in the week prior to starting emicizumab treatment will also be collected. The definition of concomitant 
medications, as well as permitted and prohibited medications is described in Section 4.4.  Concomitant medications used by a patient from 4 weeks prior to initiation of 
emicizumab to the Study Completion/Early Termination Visit (or to the Safety Follow-up Visit, if applicable) should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  Treatments for bleeds (i.e., bypassing agents and other medications to treat bleeds), will be collected in the bleed records. 
h. Hematology and blood chemistry Laboratory assessments will include a complete blood count with differential and serum chemistries (see Section 4.5.6.1). 
Safety Llaboratory assessments completed at during Screening do not have to be repeated at Week 1, if the period between Screening and Week 1 is ≤ 
5 days and there has been no change in the patient’s health status as assessed by the investigator. Laboratory assessments will be analysed at a central 
laboratory. Additional analysis will be performed at a local laboratory, as per the investigator’s discretion.  Samples will be sent to the central laboratory for 
analysis.  
i. 
Pregnancy tests: Female patients of childbearing potential (including those who have had a tubal ligation) will be required to have a negative serum 
pregnancy test result at during Screening (and again within 7 days prior to the first dose of emicizumab).  and Uurine pregnancy tests will be performed 
throughout the study treatment period. at every clinic visit, with the exception of Weeks 2 and 3.  Pregnancy testing will be conductedanalysed at the local 
laboratory. 


 
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j. 
HIV and hepatitis serology will be conducted at Screening at the local laboratory. The specific tests utilized for hepatitis and HIV serology testing are per 
local standard of care. As this patient population is at high risk for HIV, hepatitis A, B and C, sites should consider testing for these. While the specific serological tests 
used is at the discretion of the Investigator, this is with the understanding that the status of that participants’ hepatitis or HIV is confidently known at time at 
enrollment. HIV and hepatitis serology tests will be conducted at the local laboratory. 
k. For the assessment of anti-FVIII antibodies (inhibitors), functional assays that utilize a clotting readout (classic Bethesda or Nijmegen assay) cannot be used for 
patients on emicizumab therapy as emicizumab drives clotting even in the presence of FVIII inhibitors, causing a false-negative test result (see Section 5.1.3). After the 
first dose, local measurement of FVIII inhibitors, if indicated, requires use of an ELISA-based test or a chromogenic Bethesda assay.   anti FVIII antibodies (FVIII 
inhibitor titer) will be analysed at Screening and at the visits indicated. Anti FVIII antibody assessments will be conducted at a central laboratory. 
Additional analysis will be performed at a local laboratory, as per the investigator’s discretion. At the discretion of the local investigator, any additional urgent 
request to assess FVIII inhibitors will need to be sent to the central laboratory (see Appendix 2 for additional information). Plasma samples for anti-FVIII antibodies will 
be analysed at the central laboratory 
l. 
Plasma samples are required for immunogenicity assessments to detect anti-emicizumab antibodies will be.  collected at screening and prior to emicizumab 
administration at the visits indicated.  Additional samples to detect anti-emicizumab antibodies may also be drawn at the time of hypersensitivity events or 
following suspected loss of efficacy. Anti emicizumab antibody assessments will be conducted Samples will be analysed at the a central laboratory. 
Additional analysis will be performed at a local laboratory, as per the investigator’s discretion.  
m. ePRO bleed / medication recording: At the Week 1 visit, patients will be trained on how to record their bleeds and hemophilia medication use on the ePRO 
device where possible. Data that need to be recorded will include the site of bleed, type of bleed, time of each individual bleed (day, start and stop time), and 
treatment for bleed. At least once a week, patients will need to record any hemophilia medication use (including emicizumab) and information regarding any bleeding 
events.Patients will record when they have bleeds or hemophilia medication use, including emicizumab, or at least every week. Investigator review of 
patient-reported bleed/medication records with the patient/caregiver will occur for completeness and accuracy at all of the visits during the treatment 
period, at study completion, at any unscheduled visits (if required), and at the Early Termination Visit (if required). 
n. Thorough documentation on surgical events will be requested, including type of surgery or procedures, treatments, outcomes, etc.  
o. Adverse events:  After informed consent has been obtained but prior to initiation of emicizumab, only serious adverse events caused by a protocol-mandated 
intervention should be reported. Injection-site reaction adverse events will be collected on a the injection site reaction form. separate form from the adverse 
event form. 
p. Management of emicizumab: Drug dispensation will not occur at the Study Completion Visit or the Early Termination Visit (if required). Patients will only 
receive emicizumab IMP during an unscheduled visit if drug dispensation is required at this time. 
q. HRQoL and EQ-5D-5L: Prior to the first emicizumab administration; at the 3, 6, 12, and 18 month assessments; and at study completion (2 years), 
Ppatients will be prompted requested to complete Haem-A-QoL (adults age: ≥ 18 years) or the Haemo-QoL-SF (adolescents ages: 12−17 years) 
questionnaire and the EQ-5D-5L questionnaire. Questionnaires will be self-administered electronically before the patient/caregiver receives any information on 
disease status, prior to the performance of non-PRO assessments, and prior to emicizumab administration (if on a treatment day). Paper versions of the questionnaires 
are also available in case of ePRO outage or if an ePRO device is otherwise unavailable.  
r. 
EmiPref:  At the 3-month assessment, patients will be prompted to complete a paper version of the EmiPref questionnaire (Appendix 3). The questionnaire will 
be self-administered before the patient/caregiver receives any information on disease status, prior to the performance of non-PRO assessments, and prior to emicizumab 
administration (if on a treatment day). 


 
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s. On treatment days, blood collection should occur within 2 hours prior to emicizumab administration unless otherwise specified. Samples for this assessment should 
be taken prior to emicizumab injection. Unless otherwise specified, On days where samples are to be collected, emicizumab injection will be performed in 
the clinical unit.additional analysis will be performed at a local laboratory, as per the investigator’s discretion.  Any additional laboratory results which are required as 
part of the patient’s safety assessment should be recorded in the unscheduled visit eCRFs.  Central labs are part of the non-eCRF data which will be sent to the Sponsor 
directly by the central lab vendor. 
t. 
Plasma samples are required for PK assessments.  On days where samples are to be collected, the emicizumab injection will be performed in the clinical unit.  One 
single pre-dose sample is required on the applicable visits. All biomarker assessments will be conducted at aSamples will be analysed by the central laboratory.. 
Additional analysis will be performed at a local laboratory, as per the investigator’s discretion. 
u. Plasma samples for safety biomarkers must be citrate plasma. Tests may include, but are not limited to, D-dimer.  Samples will be analysed by the central laboratory.  
See Appendix 2. Plasma samples for D dimer testing will be taken at the visits indicated. 
v. Plasma samples for safety coagulation system biomarker assessments must be citrate plasma. Tests include (FVIII:Ag, FIX:Ag and FX:Ag.) will be taken 
at the visits indicated. Samples will be analysed by the central laboratory.  See Appendix 2. 
w. Plasma samples for PD biomarker assessments must be citrate plasma.  Tests will include, but are not limited to, FVIII activity and modified aPTT (one stage).  
will beTime windows for sample collection are specified in Appendix 2  
Schedule of Biomarker Samples 
x. .  assessed at Week 1 (Day 1, Cycle 1); Week 5 (± 2 days); 3 and 6 months (± 7 days); 12 months (± 14 days); and 18 months and study completion (± 
30 days). All samples must be citrate plasma. Additional plasma samples will be collected for future exploratory research, which may include tests such 
as clot waveform analysis (CWA) and others (see Appendix 2 
 
Schedule of Biomarker Samples 
y. ).  Samples will be analysed by the central laboratory. 
z. Bone and joint biomarkers will be assessed at Week 1 (Day 1, Cycle 1); 6 months (± 7 days); and 18 months and study completion (± 30 days). Serum 
and plasma EDTA samples for bone and joint biomarkers must be collected after fasting (no food or drink other than water for at least 8 hours prior to the 
blood draw). Ideally these samples should be collected in the morning (before noon), in order to control for diurnal variation. Please consult the Central 
Laboratory Services Manual for details. The selection of exploratory bone and joint biomarkers to be tested will build on findings from biomarker analyses 
in other emicizumab trials and may include CTX-1, OPG, P1NP, and soluble RANK-L (see Appendix 2  
Schedule of Biomarker Samples 
aa. ). Samples will be analysed by the central laboratory. 
bb. Additional laboratory assessments:  In the event of a breakthrough bleed that is treated with bypassing agents, it is recommended that the following laboratory tests 
will be performed within 2448 hours of initial bypassing agent use (these tests will be conducted so that the investigator can monitor the patient for potential 
thromboembolic events and microangiopathic hemolytic anemia or TMA). These tests include platelet count, serum creatinine, LDH and schistocytes. A plasma sample 
should also be provided for central laboratory monitoring of prothrombin fragment F1+2, fibrinogen and D-dimer. Samples for these tests should ideally be 
analysed at the central laboratory.  Exceptionally in urgent situations where results are required quickly, local laboratory testing can be used, with results recorded in 
the eCRF. For patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours until 2448 hours after the last 
dose of bypassing agents is administered to treat a specific bleed. If applicable, laboratory results should be recorded in the unscheduled visit eCRFs.  
 




 
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d. All samples are required to be citrate plasma. Additional plasma will be collected for future 
exploratory research, which may include tests such as CWA and others. 
 


 
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Appendix 3 
Haem-A-QoL (United States/English) 
Questionnaire deleted 
 


Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 3 
Haem-A-QoL (United States/English) (cont.) 
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Appendix 4 
Haemo-QoL-SF (United States/English) 
Questionnaire deleted 
 


Appendix 4 
Haemo-QoL-SF (United States/English) (cont.) 
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Appendix 5 
EQ-5D-5L (United Kingdom/English) 
Questionnaire deleted 
 


Appendix 5 
EQ-5D-5L (United Kingdom/English) (cont.) 
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Appendix 36  
EmiPref Patient Preference Questionnaire 
(United Kingdom/English) 
(Paper Version, United Kingdom / English) 
… 
 
 
 
 
 


 
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SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Form and Assent Form have been revised to reflect the 
changes to the protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ........................................... 76 
1. BACKGROUND ............................................................................................. 88 
1.1 
Background on Hemophilia A with Inhibitors .................................. 88 
1.2 
Background on Emicizumab .......................................................... 90 
1.2.1 
Preclinical Experience.................................................................... 90 
1.2.2 
Clinical Experience ........................................................................ 92 
1.2.2.1 
Studies ACE001JP and ACE002JP .................................................... 92 
1.2.2.2 
JP29574 .......................................................................................... 93 
1.2.2.3 
Studies BH29884 and BH29992 ........................................................ 93 
1.2.2.4 
Pharmacokinetics ............................................................................. 98 
1.2.2.5 
Anti-drug Antibodies ....................................................................... 98 
1.2.2.6 
Peri-Operative Management of Patients on Emicizumab ...................... 99 
1.3 
Study Rationale and Benefit-Risk Assessment .............................. 99 
2. OBJECTIVES AND ENDPOINTS ................................................................ 100 
3. STUDY DESIGN .......................................................................................... 101 
3.1 
Description of the Study ............................................................... 101 
3.2 
End of Study and Length of Study ............................................... 103 
3.3 
Rationale for Study Design .......................................................... 104 
3.3.1 
Rationale for Emicizumab Dose and Schedule ............................ 104 
3.3.2 
Rationale for Patient Population .................................................. 105 
3.3.3 
Rationale for Control Group ......................................................... 106 
3.3.4 
Rationale for Biomarker Assessments ......................................... 106 
3.3.5 
Rationale for Pharmacokinetic Sample Collection 
Schedule ...................................................................................... 107 
3.3.6 
Rationale for Immunogenicity Sample Collection ......................... 107 
3.3.7 
Rationale for Disease Response–based Endpoints ..................... 107 
3.3.8 
Rationale for Primary Endpoint Selection .................................... 107 
3.3.9 
Rationale for Interim Analyses ..................................................... 108 
3.3.10 
Rationale for Patient-reported Outcome (PRO) 
Assessments ............................................................................... 108 
4. MATERIALS AND METHODS ..................................................................... 109 
4.1 
Patients ........................................................................................ 109 


 
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4.1.1 
Inclusion Criteria .......................................................................... 109 
4.1.2 
Exclusion Criteria ......................................................................... 110 
4.2 
Method of Treatment Assignment and Blinding ........................... 111 
4.3 
Study Treatment .......................................................................... 111 
4.3.1 
Formulation, Packaging, and Handling ........................................ 111 
4.3.1.1 
Emicizumab ................................................................................. 111 
4.3.2 
Dosage, Administration, and Compliance .................................... 111 
4.3.2.1 
Emicizumab ................................................................................. 111 
4.3.3 
Investigational Medicinal Product Accountability ......................... 113 
4.3.4 
Continued Access to Emicizumab ............................................... 114 
4.4 
Concomitant Therapy................................................................... 114 
4.4.1 
Permitted Therapy ....................................................................... 114 
4.4.2 
Prohibited Therapy ...................................................................... 116 
4.5 
Study Assessments ..................................................................... 116 
4.5.1 
Informed Consent Forms and Screening Log .............................. 116 
4.5.2 
Medical History and Demographic Data....................................... 116 
4.5.3 
Physical Examinations ................................................................. 117 
4.5.4 
Vital Signs .................................................................................... 117 
4.5.5 
Concomitant Medications ............................................................... 117 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ................ 117 
4.5.6.1 
Hematology and Blood Chemistry .................................................... 118 
4.5.6.2 
Pregnancy Tests ............................................................................. 118 
4.5.6.3 
HIV and Hepatitis Serology ............................................................ 119 
4.5.6.4 
Anti-FVIII Antibodies .................................................................... 119 
4.5.6.5 
Anti-emicizumab Antibodies ........................................................... 119 
4.5.6.6 
Pharmacokinetics ........................................................................... 119 
4.5.6.7 
Biomarkers .................................................................................... 119 
4.5.6.8 
Extra Testing with Use of Bypass Agents ......................................... 120 
4.5.6.9 
Sampling Procedures and Sample Storage, Shipment and 
Destruction ................................................................................... 120 
4.5.7 
Bleed Assessments ..................................................................... 121 
4.5.7.1 
Definition of a Bleed ..................................................................... 121 
4.5.7.2 
Definition of a Target Joint ........................................................... 122 
4.5.7.3 
Bleed Sites ................................................................................... 122 
4.5.7.4 
Definitions of Bleed Types ........................................................... 122 


 
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4.5.8 
Surgical Events .............................................................................. 123 
4.5.9 
Patient-Reported Outcomes ........................................................ 123 
4.5.9.1 
HRQoL Assessments................................................................... 123 
4.5.9.2 
Health Status Assessments (EQ-5D-5L)...................................... 124 
4.5.9.3 
Treatment Preference Questionnaire ........................................... 124 
4.6 
Patient, Treatment, Study and Site Discontinuation ..................... 124 
4.6.1 
Patient Discontinuation ................................................................ 124 
4.6.2 
Study Treatment Discontinuation ................................................. 125 
4.6.3 
Study and Site Discontinuation .................................................... 125 
5. ASSESSMENT OF SAFETY ....................................................................... 125 
5.1 
Safety Plan .................................................................................. 125 
5.1.1 
Risks Associated with Emicizumab .............................................. 126 
5.1.1.1 
Injection-Site Reactions ............................................................... 126 
5.1.1.2 
Hypercoagulation and Thromboembolic Events .............................. 126 
5.1.1.3 
Thrombotic Microangiopathy ........................................................ 126 
5.1.1.4 
Hypersensitivity ............................................................................ 127 
5.1.2 
Management of Patients Who Experience Specific 
Adverse Events ............................................................................ 128 
5.1.3 
Interpretation of Coagulation Assays for Patients 
Receiving Emicizumab................................................................. 130 
5.2 
Safety Parameters and Definitions .............................................. 130 
5.2.1 
Adverse Events ............................................................................ 131 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ...................................................................................... 131 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .......................................................... 132 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ....................................................................... 132 
5.3.1 
Adverse Event Reporting Period .................................................. 132 
5.3.2 
Eliciting Adverse Event Information ............................................. 133 
5.3.3 
Assessment of Severity of Adverse Events ................................. 133 
5.3.4 
Assessment of Causality of Adverse Events ................................ 133 
5.3.5 
Procedures for Recording Adverse Events .................................. 134 
5.3.5.1 
Injection Reactions ...................................................................... 134 
5.3.5.2 
Diagnosis versus Signs and Symptoms ....................................... 134 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ................. 135 


 
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5.3.5.4 
Persistent or Recurrent Adverse Events ...................................... 135 
5.3.5.5 
Abnormal Laboratory Values ....................................................... 135 
5.3.5.6 
Abnormal Vital Sign Values ......................................................... 136 
5.3.5.7 
Abnormal Liver Function Tests .................................................... 136 
5.3.5.8 
Deaths ......................................................................................... 137 
5.3.5.9 
Pre-existing Medical Conditions ................................................... 137 
5.3.5.10 Lack of Efficacy or Worsening of Hemophilia A ........................... 137 
5.3.5.11 Hospitalization or Prolonged Hospitalization ................................ 138 
5.3.5.12 Adverse Events Associated with an Overdose or Error in 
Drug Administration ..................................................................... 138 
5.3.5.13 Patient-Reported Outcome Data .................................................. 138 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ....................................................................................... 139 
5.4.1 
Emergency Medical Contacts ...................................................... 139 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .............................................. 139 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .......................... 139 
5.4.2.2 
Events That Occur after Study Drug Initiation .............................. 140 
5.4.3 
Reporting Requirements for Pregnancies .................................... 140 
5.4.3.1 
Pregnancies in Female Patients .................................................. 140 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ....................... 140 
5.4.3.3 
Abortions ...................................................................................... 141 
5.4.3.4 
Congenital Anomalies/Birth Defects ............................................ 141 
5.5 
Follow-Up of Patients after Adverse Events ................................. 141 
5.5.1 
Investigator Follow-Up ................................................................. 141 
5.5.2 
Sponsor Follow-Up ...................................................................... 141 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .......................................................................... 141 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ................... 142 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ........................ 142 
6.1 
Determination of Sample Size ..................................................... 142 
6.2 
Summaries of Conduct of Study .................................................. 143 
6.3 
Summaries of Demographic and Baseline Characteristics .......... 143 
6.4 
Safety Analyses ........................................................................... 143 
6.5 
Efficacy Analyses ......................................................................... 144 


 
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6.6 
Immunogenicity Analyses ............................................................ 145 
6.7 
Pharmacokinetic Analyses ........................................................... 146 
6.8 
Biomarker Analyses ..................................................................... 146 
6.9 
Interim Analyses .......................................................................... 146 
6.9.1 
Planned Interim Analyses ............................................................ 146 
6.9.2 
Optional Interim Analysis ............................................................. 146 
7. DATA COLLECTION AND MANAGEMENT ................................................ 146 
7.1 
Data Quality Assurance ............................................................... 146 
7.2 
Electronic Case Report Forms ..................................................... 147 
7.3 
Electronic Patient-Reported Outcome Data ................................. 147 
7.4 
Source Data Documentation ........................................................ 148 
7.5 
Use of Computerized Systems .................................................... 148 
7.6 
Retention of Records ................................................................... 148 
8. ETHICAL CONSIDERATIONS..................................................................... 149 
8.1 
Compliance with Laws and Regulations ...................................... 149 
8.2 
Informed Consent ........................................................................ 149 
8.3 
Institutional Review Board or Ethics Committee .......................... 150 
8.4 
Confidentiality .............................................................................. 150 
8.5 
Financial Disclosure ..................................................................... 151 
9. STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ...................................................................................... 151 
9.1 
Study Documentation................................................................... 151 
9.2 
Protocol Deviations ...................................................................... 151 
9.3 
Site Inspections ........................................................................... 151 
9.4 
Administrative Structure ............................................................... 151 
9.4.1 
Independent Data Monitoring Committee .................................... 151 
9.5 
Publication of Data and Protection of Trade Secrets ................... 152 
9.6 
Protocol Amendments.................................................................. 153 
9.7 
Study Participant Survey ............................................................... 153 
10. REFERENCES ............................................................................................ 154 
 


 
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List of Tables 
Table 1  
Annualized Bleed Rate with Emicizumab Prophylaxis Arm 
versus No Prophylaxis Arm in Patients ≥ 12 Years of Age 
94 
Table 2  
Intra-Patient Comparison of Annualized Bleed Rate with 
Emicizumab Prophylaxis versus Previous Bypassing Agent 
Prophylaxis 
95 
Table 3  
Change in Haem-A-QoL Physical Health Score in Patients (≥ 
18 Years of Age) with No Prophylaxis versus Emicizumab 
Prophylaxis at Week 25 
96 
Table 4 
Annualized Bleed Rate with Emicizumab Prophylaxis in 
Pediatric Patients < 12 Years of Age (Interim Analysis) 
96 
Table 5 
Adverse Reactions Reported in ≥ 5% of Patients from Pooled 
Clinical Trials with Emicizumab 
97 
Table 6 
Characterization of aPCC Treatment in Pooled Clinical Trials 
98 
Table 7 
Objectives and Corresponding Endpoints 
101 
Table 8 
Mean Change (%) in Annualized Bleeding Rates in 
Patients Enrolled in ACE001JP/ACE002JP 
104 
Table 9 
Central vs Local Laboratory Assessments 
117 
Table 10 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events 
128 
Table 11  
Coagulation Test Results Affected and Unaffected by 
Emicizumab 
130 
Table 12 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale 
133 
Table 13 
Clopper-Pearson 95% CIs for the Incidence of AEs 
(Based on N=200) 
143 
 
List of Figures 
Figure 1 
Study Design 
102 
 


 
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List of Appendices 
APPENDIX 1 
SCHEDULE OF ACTIVITIES ................................................. 156 
APPENDIX 2 
SCHEDULE OF BIOMARKER SAMPLES .............................. 162 
APPENDIX 3 
EMIPREF PATIENT PREFERENCE 
QUESTIONNAIRE .................................................................. 164 
APPENDIX 4 
CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS ...................................................................... 166 
APPENDIX 5 
WHO TOXICITY GRADING SCALE FOR 
DETERMINING THE SEVERITY OF LABORATORY 
ABNORMALITIES AND ADVERSE EVENTS ........................ 167 
 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A SINGLE-ARM, MULTICENTER PHASE IIIB 
CLINICAL TRIAL TO EVALUATE THE SAFETY AND 
TOLERABILITY OF PROPHYLACTIC EMICIZUMAB 
IN HEMOPHILIA A PATIENTS WITH INHIBITORS 
PROTOCOL NUMBER: MO39129 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2016-004366-25 
TEST PRODUCT: 
Emicizumab (RO5534262) 
MEDICAL MONITOR: 
Dr. 
 MD, MBA 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor.  
 






 
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the Schedule of Activities (Appendix 1  
Schedule of Activities   
). 
Drugs intended to control breakthrough bleeds (e.g. rFVII, FVIII, activated prothrombin complex concentrate 
[aPCC]) or bleeds during surgeries should be used at the lowest dose expected to achieve hemostasis. Given that 
circulating emicizumab may increase the patient’s coagulation potential, the doses required to achieve 
hemostasis may be lower than doses used prior to starting emicizumab. Investigators shall discuss at the start of 
the study with patients recommended doses of any additional coagulation factors used, following the guidance 
below.  
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided if possible, and 
recombinant activated human Factor VII (rFVIIa) should be the first option used to treat, starting with no more 
than 90 µg/kg as an initial dose. If aPCC needs to be used, no more than 50 IU/kg should be administered as an 
initial dose and doses of > 100 U/kg/24 hours or more should be avoided, as cases of TMA and thrombotic events 
were reported when on average a cumulative amount of > 100 U/kg/24 hours aPCC was administered for 24 
hours or more. Investigators should provide or remind patients of the exact dose and schedule of bypassing 
agents or FVIII required to treat any bleed. 
When a bleed has occurred, patients (or their legally authorized representative) will be required to 
report bleed information on an ePRO device where possible, including site of bleed, type of bleed, time of 
each individual bleed (day, start and stop time), and treatment for bleed (e.g., other than emicizumab 
in case of breakthrough bleeds). The reason for the use of rFVIIa will be documented (e.g., bleeding, 
preventative dose before activity). Thorough documentation of the treatments for bleeds and/or 
surgeries will be requested, including agent, start time, dose, route of administration, and number of 
infusions needed to treat the bleed. Local and central laboratory assessments are required to monitor 
the risk for thromboembolic events or microangiopathic hemolytic anemia or TMA, as per the Schedule of 
Activities (Appendix 1 
 
Schedule of Activities   
), if bypassing agents are used to treat a breakthrough bleed. 
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 a potential increase in emicizumab dose to 3 mg/kg/week 
and additional laboratory evaluations (e.g., coagulation tests), as well as to re-evaluate the patient’s 
individual benefit-risk for continuing treatment. 
An independent Data Monitoring Committee (iDMC) will be responsible for monitoring safety throughout the 
duration of the study. 
Number of Patients 
This global study will enroll approximately 200 patients with congenital hemophilia A who have 
persistent inhibitors against FVIII at enrollment. The patients are expected to be enrolled at 
approximately 85 sites globally. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. As per the investigator’s judgement, a willingness and ability to comply with scheduled visits, 
treatment plans, laboratory tests, and other study procedures, including the patient-reported 
outcome (PRO) questionnaires and bleed diaries through the use of an electronic device or paper 
3. Aged 12 years or older at the time of informed consent 
4. Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII  
5. Documented treatment with bypassing agents or FVIII concentrates in the last 6 months (on-
demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day before starting 
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6. Adequate hematologic function, defined as platelet count ≥ 100,000/μL and hemoglobin ≥ 8 g/dL 
(≥ 4.97 mmol/L) at the time of screening 
7. Adequate hepatic function, defined as total bilirubin ≤ 1.5 × the upper limit of normal (ULN) 
(excluding 
Gilbert’s 
syndrome) 
and 
aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 3 ×ULN at the time of screening; no clinical signs or known 
laboratory/radiographic evidence consistent with cirrhosis 
8. Adequate renal function, defined as serum creatinine ≤ 2.5 × ULN and creatinine clearance by 
Cockcroft-Gault formula ≥ 30 mL/min 
9. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use a highly effective contraceptive method with a failure rate of < 1% per year 
during the treatment period and for at least five elimination half-lives (24 weeks) after the last 
dose of emicizumab: 
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus) 
• Examples of highly effective contraceptive methods with a failure rate of < 1% per year 
include proper use of combined oral or injected hormonal contraceptives, bilateral tubal 
ligation, male sterilization, hormone-releasing intrauterine devices, and copper intrauterine 
devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a 
cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods 
must always be supplemented with the use of a non-lipid-based spermicide 
• The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Inherited or acquired bleeding disorder other than hemophilia A 
2. Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy 
(prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to 
enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-hour 
washout period prior to the first emicizumab administration 
3. History of illicit drug or alcohol abuse within 12 months prior to screening, as per the investigator’s 
judgment 
4. High risk for TMA (e.g., have a previous medical or family history of TMA), as per the 
investigator’s judgment 
5. Previous (in the past 12 months) or current treatment for thromboembolic disease (with the 
exception of previous catheter-associated thrombosis for which antithrombotic treatment is not 
currently ongoing) or current signs of thromboembolic disease 
6. Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or 
thrombosis 
7. History of a clinically significant hypersensitivity reaction associated with monoclonal antibody 
therapies or components of the emicizumab injection 
8. Known human immunodeficiency virus (HIV) infection with CD4 count < 200 cells/μL within 
6 months prior to screening 
9. Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use 
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10. 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 
11. Receipt of: 
• Emicizumab in a prior investigational study 
• An investigational drug to treat or reduce the risk of hemophilic bleeds within five half-lives of 
last drug administration 
• A non-hemophilia-related investigational drug within last 30 days or five half-lives, whichever 
is shorter 
• Any concurrent investigational drug. 
12. Pregnancy or lactation, or intent to become pregnant during the study 
13. Positive serum pregnancy test result within 7 days prior to initiation of emicizumab (females only) 
End of Study and Length of Study 
The approximate length of the entire study from the first patient enrolled to the last patient, last visit 
(LPLV; see below) is approximately 3 years. For each individual patient, the study is expected to last 
approximately 2 years (patients will receive 3 mg/kg/week emicizumab for the first 4 weeks followed 
by 1.5 mg/kg/week emicizumab for the remainder of the 2-year treatment period).  Patients who 
discontinue emicizumab prior to the completion of the 2-year treatment period will undergo a Safety Follow-up 
Visit 24 weeks after the patient’s last emicizumab dose or at 2 years after emicizumab treatment start, 
whichever occurs first.  
The end of this study is defined as the date when the last remaining patient has completed the last 
visit (i.e., LPLV). The study will end when all patients have been treated with emicizumab for 2 years, 
or earlier, if one of the following is documented: 
Withdrawal of consent 
OR 
Completed the Safety Follow-up Visit 24 weeks after discontinuing emicizumab 
OR 
Lost to follow-up 
OR 
Death. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Emicizumab will be administered at a dose of 3 mg/kg/week subcutaneously for 4 weeks when 
initiating treatment, followed by 1.5 mg/kg/week subcutaneously for the remainder of the 2-year 
treatment period. There will be an option to increase the dose to 3 mg/kg/week in cases of insufficient 
control of bleeds on the 1.5 mg/kg/week emicizumab dose. If the investigator believes that a specific 
patient warrants dose up-titration following the occurrence of, for example, at least two spontaneous 
bleeds, significant bleeds, or a traumatic bleed out of proportion to the degree of injury, they must 
discuss the case with the Medical Monitor for consideration and potential approval. 
To support home administration of the drug, patients/caregivers will be required to complete in-person, 
instructional training on how to administer emicizumab as a subcutaneous (SC) injection. 
Patients/caregivers will be taught to perform the injections utilizing the Instructions for Use document. 
In addition, the healthcare provider (HCP) is to inform the patient/caregiver of the volumetric dose to be 
administered and the dosing frequency. The patients/caregivers will observe at least one SC injection 
performed by a HCP and will need to successfully administer at least one SC injection under an 
HCP’s supervision prior to starting home administration. The patient/caregiver will also have the 
opportunity to ask any questions to the HCP before starting home administration. The first three weekly 
treatments will be administered in a monitored setting, such as an infusion center, clinic, or hospital, in 
conjunction with emicizumab PK and pharmacodynamic (PD) assessments. Patients will be observed 


 
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for a minimum of 60 minutes after the first three doses. Patients/caregivers will be instructed on how 
to recognize signs/symptoms of hypersensitivity (including anaphylaxis) and obtain emergency care in 
the event of such reactions occurring. Each site will have the discretion to provide additional training 
or include additional observation (e.g., after the third or fifth doses), if deemed appropriate. If, despite 
additional training, the investigator determines that the patient/caregiver is unable to inject 
emicizumab, a trained and proficient caregiver or HCP should be identified to administer the SC 
injections. Patients/caregivers will be provided with contact information for the clinic in case they have 
questions related to self-administration between visits. 
Compliance in the home setting is to be monitored at each site by reviewing reported hemophilia 
medication use and recording collected used and unused vials. 
Statistical Methods 
Primary Safety Analyses 
The primary objective of this study is to evaluate the overall safety and tolerability of prophylactic 
administration of emicizumab in patients with congenital hemophilia A who have persistent inhibitors 
against FVIII at enrollment. Of primary interest in this study are the incidence and severity of all 
adverse events, including thromboembolic events, microangiopathic hemolytic anemia or TMA, systemic 
hypersensitivity, anaphylaxis, and anaphylactoid events. 
All adverse events will be assessed according to the World Health Organization (WHO) toxicity 
grading scale. The incidence, type, and grade of adverse events will be summarized according to the 
primary system-organ class (SOC) and, within each SOC, by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. For each adverse event, data will be provided on the timing (start 
and stop date, time of onset in comparison with last dose of emicizumab received, and doses of 
emicizumab received), severity, relationship to emicizumab, outcome, and effect on therapy. The data 
may be presented together with two-sided 95% Clopper-Pearson confidence intervals (CIs) if 
appropriate. 
In addition, as part of the safety evaluation, additional assessments will be summarized descriptively 
as follows: 
1. Cumulative emicizumab doses, dose modifications (delays and interruptions), and duration of 
exposure 
2. Compliance with respect to emicizumab intake (planned vs. received) 
3. Changes from baseline in physical examination findings 
4. Vital signs over time: 
• 
Vital signs will be analyzed using descriptive statistics for continuous variables and presented 
graphically over time with associated 95% CIs. 
5. Laboratory parameters (hematology and chemistry): 
• 
These parameters will be presented in shift tables of WHO toxicity grade at baseline versus 
worst grade during the treatment period. Selected laboratory parameters will be summarized 
in terms of mean, standard deviation, minimum, and maximum. Laboratory parameters will 
also be presented graphically over time. 
All safety variables will be analyzed for the safety population. For each variable, the number of 
available observations will be reported. The safety population includes all patients who have received 
at least one dose of emicizumab. 
The primary safety analysis will occur at the end of the study. 
The iDMC will evaluate the study data, including the emerging safety results, at periodic reviews and 
recommend to the Sponsor whether the protocol should be amended or the study should be stopped early. All 
summaries and analyses will be prepared by the Study Management Team (SMT) statistician and presented for 
iDMC review. Members of the iDMC will be external to the Sponsor and will follow a charter that outlines 
their roles and responsibilities. 
A detailed description of the statistical methods that will be used for the primary and secondary 
analyses will be provided in the Statistical Analysis Plan (SAP). 


 
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Determination of Sample Size 
A sample size of approximately 200 patients is planned for this study. 
For the purpose of the sample size calculation, the incidence of adverse events was chosen as the 
safety endpoint of primary interest. 
If the observed incidence of adverse events is between 2.5% and 15%, the precision for the estimated 
incidence rate is presented below according to the 95% Clopper-Pearson CIs (Table 2). 




 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABR 
annualized bleeding rate 
ADA 
anti-drug antibody 
ALT 
alanine aminotransferase 
aPCC 
activated prothrombin complex concentrate 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCτ 
area under the curve during the dosage interval 
BU 
Bethesda unit 
BUN 
blood urea nitrogen 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
contract research organization 
Ctrough 
concentration at the end of the dosage interval 
CTX 
C-terminal telopeptide of collagen 1 
CVAD 
central venous access device 
CWA 
clot waveform analysis 
cyFcγR 
cynomolgus monkey Fcγ receptor 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECL 
electrochemiluminescence 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
ELISA 
enzyme linked immunosorbent assay 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL Five-Dimension-Five Levels Questionnaire 
EQ-VAS 
EuroQoL visual analogue scale 
E.U. 
European Union 
FDA 
Food and Drug Administration 
FEIBA 
Factor eight inhibitor bypassing activity 
FIX 
Factor IX 
FIXa 
activated Factor IX 
FIX:Ag 
Factor IX antigen 
FVIIa 
activated Factor VII 


 
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Abbreviation 
Definition 
FVIII 
Factor VIII 
FVIII:Ag 
Factor VIII antigen 
FX 
Factor X 
FX:Ag 
Factor X antigen 
Haem-A-QoL 
Hemophilia Adult Quality of Life Questionnaire 
Haemo-QoL 
Hemophilia Quality of Life 
Haemo-QoL-SF 
Hemophilia Quality of Life Short Form 
HCP 
healthcare provider 
hFcγR 
human Fcγ receptor 
HIV 
human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
ICH 
International Conference on Harmonisation 
iDMC 
independent Data Monitoring Committee 
IFU 
Instructions for Use 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
IND 
Investigational New Drug  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
ITI 
immune tolerance induction 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice or web-based response system 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
MABEL 
minimal anticipated biological effect level 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIS 
non-interventional study 
NOAEL 
no observed adverse effect level 
OPG 
osteoprotegerin 
P1NP 
procollagen type 1 amino-terminal propeptide 
PD 
pharmacodynamic(s) 
pdFVIII 
plasma-derived Factor VIII 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcome 


 
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Abbreviation 
Definition 
PT 
prothrombin time 
RANK-L 
receptor activator of nuclear factor kappa-B ligand 
RBC 
red blood cell 
rFVIIa 
recombinant activated human Factor VII 
rFVIII 
recombinant Factor VIII 
SAD 
single ascending dose 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SMT 
Study Management Team 
SOC 
system-organ class 
SSC 
Scientific and Standardization Committee 
t1/2 
terminal plasma half-life 
TMA 
thrombotic microangiopathy 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
U.S. 
United States 
VAS 
visual analog scale 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HEMOPHILIA A WITH INHIBITORS 
Hemophilia A is a rare bleeding disorder that is attributable to a congenital absence or 
hypofunctioning of Factor VIII (FVIII) (Acharya 2013; Witmer and Young 2013). The gene 
that encodes FVIII is located on the X chromosome. Genetic defects are expressed through 
X-linked recessive inheritance or de novo FVIII mutations, and more than 99% of hemophilia 
patients are males. The prevalence of hemophilia A is approximately 1 in 5,000 live-born 
males or 1 out of every 10,000 live births (CDC 2016; Franchini and Mannucci 2013; 
NIH 2013). No racial differences have been reported, and the numbers of patients registered 
in 2014 in various regions included 4,870 in Japan, 21,052 in North America, and 11,029 in 
just two European nations (United Kingdom and France) (World Federation of Hemophilia 
2014). 
Hemophilia A is most commonly caused by an inherited FVIII gene mutation within the Xq28 
region of the X chromosome. It occurs almost exclusively in males who have one defective 
copy of the relevant gene on their X chromosome. As an affected male will transmit a normal 
Y chromosome to all his sons and an abnormal X chromosome to all his daughters, his sons 
will not be affected and all of his daughters will be carriers. For female carriers, with each 
birth there is a 50% chance to transmit the disorder to male infants and a 50% chance for 
female infants to be a carrier. Females who are carriers of hemophilia A may experience 
bleeding symptoms similar to those seen in men with mild hemophilia A, as approximately 
10% of carriers have a FVIII activity that is less than 35% (Plug et al. 2006). Rarely, women 
have more severe bleeding symptoms requiring treatment and may develop FVIII inhibitors. 
Approximately 30% of patients with hemophilia A do not have a family history of the disorder; 
these cases arise from spontaneous FVIII gene mutations. 
The main bleeding sites are intra-articular, intramuscular, subcutaneous (SC), intraoral, 
intracranial, gastrointestinal, and intranasal (Karaman et al. 2015; Srivastava et al. 2013). 
Repeated intra-articular bleeding is a major factor that decreases health-related quality of life 
(HRQoL) in patients with hemophilia A, because it may progress to hemophilic arthropathy 
with walking difficulties, and joint replacement surgery may eventually be necessary. 
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 hemophilia A is classified in accordance with endogenous FVIII 
activity in the blood. Patients with FVIII activity of less than 1% have severe disease, those 
with activity between 1% and 5% have moderate disease, and those with activity greater 
than 5% and less than 40% have mild disease. Patients who have severe hemophilia who 
do not initiate and/or comply with rigorous FVIII prophylaxis regimens, or do not have access 
to FVIII products, experience bleeding episodes several times a month, which is much more 
frequent than in patients with moderate or mild disease. In addition, patients with severe 
hemophilia have a high frequency of spontaneous bleeding. Hence, the maintenance of 
plasma FVIII activity at 1% or higher is important to prevent the onset of recurrent bleeding 
episodes, reduce comorbidities such as arthropathy, and improve HRQoL in patients with 
severe hemophilia A (Srivastava et al. 2013). 


 
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The standard therapy for patients with hemophilia A is intravenous (IV) FVIII replacement 
therapy with recombinant Factor VIII (rFVIII) products or plasma-derived Factor VIII (pdFVIII) 
concentrates. FVIII replacement treatment regimens can be broadly categorized into two 
types: episodic or on-demand therapy (in which FVIII concentrates are administered in 
response to the occurrence of bleeding symptoms) and prophylactic (in which they are 
administered on a scheduled basis to prevent the onset of bleeding symptoms). Prophylaxis 
has been shown to markedly reduce the bleed rate in adult patients with severe hemophilia 
A (Manco-Johnson et al. 2013; Valentino et al. 2012). Prophylactic therapy aims to maintain 
FVIII activity levels above 1% or higher and effectively prevents the onset or progression of 
hemophilic arthropathy by providing a minimum concentration of FVIII to avert spontaneous 
bleeding, particularly in the case of repeated bleeding into joints. The treatment regimens 
used to achieve optimal prevention of bleeding events vary on an individual basis; some 
patients will need trough FVIII levels of 1%, whereas others require higher trough FVIII levels 
to achieve the desired therapeutic outcome (Ahnström et al. 2004; Collins et al. 2010). 
Current standard prophylactic regimens commonly use infusion therapy administered three 
times weekly; other regimens require every other day administration, depending on the 
patient’s needs (Shapiro 2013). In developed countries, the availability and overall utilization 
of FVIII prophylaxis has increased in recent years due to the therapeutic advantages 
conferred by this type of therapy and expansion of the rFVIII concentrate supply (Geraghty 
et al. 2006). In such countries, the current standard of care for children with severe 
hemophilia A is primary prophylaxis, which involves regular FVIII infusions that are started 
following their first bleed, or by 2 years of age, with the aim of avoiding the development of 
any joint abnormality in the future (Astermark 2003; Manco-Johnson et al. 2007). 
The required adherence to demanding therapeutic regimens, that involve frequent morning 
infusions to achieve adequate hemostatic coverage during periods of highest activity, 
reduces patient compliance thereby making these regimens less effective and compromising 
their cost-benefit ratio (Thornburg 2010). Major issues with current regimens are the need for 
adequate venous access and patient/family compliance with regular prophylaxis, especially 
in the very young pediatric population. In this population, central venous access devices 
(CVADs) have been used to overcome technical difficulties. Although CVADs make 
prophylaxis feasible in young children, they are associated with complications, including 
mechanical failure, dehiscence of the skin over the reservoir, infection, and thrombosis 
(Ewenstein et al. 2004). In addition, significant healthcare provider (HCP) efforts are required 
to manage optimal treatment solutions and to overcome identified issues (Schrijvers et al. 
2013). Thus, both the disease and potential therapeutic options have the potential to affect 
HRQoL, the latter through limitations on daily activities. 
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 a high-titer 
inhibitor (≥ 5 Bethesda units [BU]/mL) following a re-challenge with FVIII administration 
(high-responding inhibitor), the only hemostatic options currently available are pro-
thrombotic coagulation factors that augment other parts of the coagulation cascade (i.e., 
“bypassing agents”). Bypassing products include Factor eight inhibitor bypassing activity 
(FEIBA), an activated prothrombin complex concentrate (aPCC; FEIBA will be referred to as 


 
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aPCC throughout this document), and NovoSeven® (recombinant activated human Factor 
VII [rFVIIa]; NovoSeven® will be referred to as rFVIIa throughout this document) (Srivastava 
et al. 2013). Both of these products have been used as prophylactic therapies to prevent 
bleeding in patients with inhibitors against FVIII. However, in most countries, the only 
available product for this indication is the aPCC FEIBA. 
aPCCs may be associated with side effects, such as thromboembolic events, 
hypersensitivity reactions, myocardial infarction, and disseminated intravascular coagulation 
(Bui et al. 2002; Dentali et al. 2011; Tjønnfjord 2004; Wójcik et al. 2009). Both aPCC and 
rFVIIa are administered intravenously, with aPCC prophylaxis requiring every other day 
dosing and rFVIIa requiring daily (or more frequent) dosing. 
The development of effective prophylactic treatment options with less frequent dosing 
requirements is a high, unmet medical need in the population of patients with hemophilia A 
with FVIII inhibitors. Reducing the time and burden associated with frequent IV dosing and 
the impact of the disease on aspects of physical health and other areas of functioning and 
well-being, while promoting increased efficacy, may further improve HRQoL. This hypothesis 
is supported by a study in which patients receiving a prophylactic treatment with FEIBA had 
improved HRQoL than those who received episodic therapy (i.e., administered following 
bleeds) with FEIBA (Gringeri et al. 2013). Therefore, despite major therapeutic advances in 
the treatment of hemophilia A, opportunities still remain to optimize and transform therapy, in 
particular for patients with inhibitors. 
1.2 
BACKGROUND ON EMICIZUMAB 
Emicizumab (also known as ACE910, CH5534262, and RO5534262) is a recombinant, 
humanized, bispecific, immunoglobulin G4 (IgG4) monoclonal antibody that binds with 
moderate affinity to activated Factor IX (FIXa) and Factor X (FX), thereby 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. Emicizumab therefore has no potential to induce or enhance the 
development of direct inhibitors to FVIII or other coagulation factors. In addition, emicizumab 
offers the possibility of SC administration, removing the need for venous access. Finally, 
because of the expected pharmacokinetic (PK) properties of this antibody, markedly 
extending the dosing interval to once weekly or even more, this compound has the potential 
to improve the treatment of patients with hemophilia A with and without FVIII inhibitors who 
are in need of effective, safe, and convenient prophylactic therapy. 
1.2.1 
Preclinical Experience 
As mentioned above, emicizumab binds with moderate affinity in the low μM range to FIXa 
and FX and mimics the co-factor activity of FVIII. Preclinical studies have shown that 
mimicking FVIII activity promotes the activation of FX by FIXa and subsequent activation of 
downstream coagulation factors, considerable increases in thrombin generation, and the 
achievement of hemostasis at the site of bleeding in patients with hemophilia A who have 
hypofunctional levels of, or entirely lack, FVIII, irrespective of the presence of FVIII inhibitors 
(Sampei et al. 2013). Preclinical studies investigating emicizumab binding to cynomolgus 
monkey Factor IX (FIX) and FX found that similar affinities were observed in both humans 
and monkeys. Mechanistic in vitro studies were conducted in human and cynomolgus FVIII-


 
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neutralized plasma and in various coagulation factor-specific assay testing systems. These 
studies revealed that emicizumab shortened activated partial thromboplastin time (aPTT) 
and promoted thrombin generation. 
Binding experiments of emicizumab to a panel of human Fcγ receptors (hFcγRs) and 
cynomolgus monkey Fcγ receptors (cyFcγRs) showed that comparable binding to hFcγR 
and to cyFcγR was observed with emicizumab and two commercial therapeutic antibodies, 
namely rituximab and natalizumab. Likewise, binding of emicizumab to the human and 
cynomolgus monkey neonatal Fc receptor was comparable to that of natalizumab. 
In vivo pharmacology experiments were conducted using a hemophilia A cynomolgus 
monkey model where endogenous FVIII levels were neutralized by a FVIII specific 
monoclonal antibody. This model mimics the essential characteristics of patients with 
hemophilia A and was used to test in vivo pharmacodynamics (PD) and efficacy of 
emicizumab. In a needle−induced trauma investigation, the SC and IV administration of 
emicizumab inhibited the decrease in hemoglobin level compared with the control group and 
also significantly reduced the area of bruising on the skin surface. SC administration of high 
dose (200 mg/kg) emicizumab demonstrated pro-coagulant activity, with a significant 
reduction in bleeding tendency. In addition, increased levels of aPTT (due to FVIII 
neutralization) were completely normalized by 200 mg/kg emicizumab compared to 
untreated 
controls. 
In 
a 
cynomolgus 
monkey 
FVIII−neutralized 
hemophilia 
A 
spontaneous−bleeding investigation, emicizumab prevented intra-articular bleeding and 
other bleeding symptoms characteristic of hemophilia A following repeated weekly SC doses 
of 1 mg/kg/week subsequent to a single SC starting dose of 3.97 mg/kg. Overall, no 
increased bleeding tendency has been observed in any of the cynomolgus monkey studies. 
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 was evaluated in the presence of emicizumab, FVIII, or bypass agents 
activated Factor VII (FVIIa). Emicizumab did not induce more thrombus formation than that 
seen with FVIIa and FVIII. 
Overall, the preclinical pharmacology program is considered to have fully characterized the 
preclinical profile of emicizumab. The conducted in vitro and in vivo studies demonstrated 
the mode of action of emicizumab and provided supportive data on efficacious dose levels, 
through the use of a relevant hemophilia A disease model, which were subsequently used 
for dose extrapolation to humans. 
The PK/toxicokinetics of emicizumab were assessed in cynomolgus monkeys after single 
and multiple doses were administered IV and through the intended clinical SC route. After a 
single IV dose of 6 mg/kg emicizumab to male cynomolgus monkeys, the plasma clearance 
was 3.69 mL/day/kg and the terminal plasma half-life (t1/2) of emicizumab was 19.4 days. 
The volume of distribution at steady state (Vss) was 98.1 mL/kg, which is approximately twice 
the plasma volume in monkeys, suggesting that emicizumab has low tissue penetration. A 
single SC administration study (dose levels: 0.06, 0.6, and 6 mg/kg) indicated that 
emicizumab exhibited slow (time to maximum plasma concentration [tmax]: 3.0−5.3 days) and 
complete absorption (bioavailability [BA]: 102% at 6 mg/kg). 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 


 
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(AUC), increased in an approximately dose proportional manner. No differences in PK 
parameters were observed between sexes. 
The formation of anti-emicizumab antibodies (which is expected with humanized monoclonal 
antibodies) was observed in a subset of the cynomolgus monkeys treated with repeated 
doses of emicizumab. In addition, a few animals also developed neutralizing antibodies. The 
formation of anti-emicizumab antibodies and neutralizing antibodies in cynomolgus monkeys 
is not thought to be predictive of the response observed in humans. 
Acute and repeat-dose toxicity, including local tolerance assessments, were evaluated in 
cynomolgus monkeys in 4-, 13-, and 26-week SC dose toxicity studies (doses up to 
30 mg/kg weekly) and a 4-week IV dose toxicity study (doses up to 100 mg/kg weekly). No 
toxicologically relevant changes attributable to the SC or IV administration of emicizumab 
were observed; the no observed adverse effect level (NOAEL) was the highest tested dose 
in each toxicity study. 
Refer to the emicizumab Investigator's Brochure for additional details on the preclinical 
studies with emicizumab. 
1.2.2 
Clinical Experience 
Currently available experience with emicizumab in humans includes data from two completed Phase I 
studies (ACE001JP and JP29574), one ongoing Phase I/II study (ACE002JP) extension in hemophilia 
A patients, and two ongoing Phase III studies in hemophilia A patients with inhibitors (adult patients 
- BH29884; pediatric patients – BH29992). 
The clinical development program in adult and pediatric patients with hemophilia A (both with and 
without FVIII inhibitors) is ongoing for emicizumab. Refer to the emicizumab Investigator's Brochure 
for details on the preclinical and clinical studies. 
1.2.2.1 
Studies ACE001JP and ACE002JP 
ACE001JP was a single study conducted in three parts, which included 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 PD response 
of SC-administered emicizumab in adult Japanese and Caucasian men and to evaluate for 
racial differences, if any, in their PK and PD response. A total of 64 healthy male volunteers 
were enrolled in Parts A and B. In Part C, the objective was to investigate the tolerability, 
safety, PK, and PD response of SC-administered emicizumab in patients 1259 years of age 
with congenital hemophilia A who had previous documentation of bleeds and/or coagulation 
factor treatment in the last 6 months. A total of 18 patients were enrolled in Part C. 
Patients who participated in Part C of Study ACE001JP were offered the opportunity to 
continue in the extension study (ACE002JP). 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.  
After administration of emicizumab to patients with hemophilia A, annualized bleeding rates (ABRs) 
decreased in all patients in Studies ACE001JP and ACE002JP compared with the pre-treatment 
period, regardless of whether or not they had FVIII inhibitors, with the exception of one patient in the 


 
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3 mg/kg/week group who was previously treated with FVIII prophylaxis and had a baseline ABR of 0 
(in this patient, the ABR was maintained at 0 while receiving emicizumab). Among all patients, 
percentage reduction in ABR ranged from 22.8% to 100% in the 0.3 mg/kg/week group, from 57.5% 
to 100% in the 1 mg/kg/week group, and from 90.1% to 100% in the 3 mg/kg/week group. 
The safety data from completed studies of healthy male volunteers (Japanese and Caucasian) in 
ACE001JP Parts A and B (n=48) showed that emicizumab was well tolerated and the incidence of 
adverse events was similar in the emicizumab dosing groups and the placebo group. Moreover, no 
racial differences or dose-dependent increases in the incidence of adverse events were observed. There 
were no serious adverse events, adverse events leading to discontinuation, or deaths in either study.  
From ACE001JP Part C and its ongoing extension ACE002JP (as of the cut-off date 15 February 
2016), most adverse events were of mild or moderate intensity, except for 2 severe adverse events 
(appendicitis and mesenteric hematoma). The majority of the adverse events were not considered 
related to emicizumab (see the Emicizumab Investigator’s Brochure). 
1.2.2.2 
JP29574 
Completed Study JP29574 included 5 groups of 12 healthy Japanese volunteers. This study 
investigated the relative bioavailability between Phase I/II 80 mg/mL formulation and Phase III 150 
mg/mL formulation materials and among three different sites of injection, as well as the absolute 
bioavailability. Results showed no significant difference in the incidence of adverse events observed by 
formulation, injection site, or administration route.  
1.2.2.3 
Studies BH29884 and BH29992 
The HAVEN 1 study (BH29884; NCT02622321) was a randomized, multicenter, open-label, clinical 
trial in 109 adult and adolescent males (aged 12 to 75 years and > 40 kg) with hemophilia A with 
FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with 
bypassing agents. Patients received weekly emicizumab prophylaxis (Arms A, C, and D), 3 mg/kg 
once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis 
(Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on emicizumab 
prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). 
During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once 
weekly. 
Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized 
in a 2:1 ratio to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B), with 
stratification by prior 24-week bleed rate (< 9 or ≥ 9). Patients randomized to Arm B could switch to 
emicizumab prophylaxis after completing at least 24 weeks without prophylaxis. 
Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C 
to receive emicizumab prophylaxis. Seven patients previously treated with episodic (on-demand) 
bypassing agents who had participated in a non-interventional study (NIS) prior to enrollment, but 
were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D 
to receive emicizumab prophylaxis. 
Efficacy was evaluated based on the ABR requiring treatment with coagulation factors (minimum of 
24 weeks or date of discontinuation) among patients previously treated with episodic bypassing 












 
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The immunogenicity of emicizumab was evaluated using an enzyme-linked immunosorbent assay 
(ELISA) or an electrochemiluminescence (ECL) assay. No patients tested positive for anti-
emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-
emicizumab antibodies in the dose-finding trial (n = 18). The anti-emicizumab antibody positive rate 
may be under-reported due to the limitation of the assay (US Prescribing Information). 
1.2.2.6 
Peri-Operative Management of Patients on Emicizumab 
The safety and efficacy of emicizumab has not been specifically tested in patients undergoing 
procedures or surgeries. Limited data are available from pivotal clinical trials, where hemophilia A 
patients with inhibitors receiving emicizumab prophylaxis underwent procedures and surgeries, 
either with or without the additional use of bypassing agents. The use of bypassing agents was at the 
investigator's discretion. 
Procedures/surgeries that were performed without peri-operative bypassing agent use and did not 
result in a bleed included skin biopsy, tooth extraction or restoration, esophagogastroduodenoscopy 
with biopsy, ultrasound fluid aspiration, and port or central line removal. Other procedures/surgeries 
which were performed with peri-operative bypassing agent use (preventive and/or treatment for bleeds) 
included central line catheter placement, tooth extractions and appendectomy. One hip replacement 
was performed with peri-operative bypassing agent (rFVIIa) and FVIII use (preventive and treatment 
for bleed) as well as tranexamic acid.  
No emicizumab dose adjustments are recommended for patients undergoing procedures or 
surgeries. Thorough documentation of surgeries will be requested. 
The available data are insufficient to provide specific dosing guidance for the use of bypassing agents 
or FVIII in peri-operative settings. If bypassing agents or FVIII are required in the peri-operative 
period, please refer to the dosing guidance for those concomitant medications in Section 4.4 and in the 
emicizumab Investigator’s Brochure. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
For patients with hemophilia A who are diagnosed with inhibitors, permanent eradication of 
these inhibitors is currently the ultimate aim of therapy. This can be achieved by means of 
intensive FVIII administration over many months with immune tolerance induction (ITI), 
which is successful in approximately 60%−80% of treated patients with inhibitors (Hay and 
DiMichele 2012; Santagostino et al. 2009). However, effective hemostatic management may 
be challenging during the time interval required to achieve ITI success. Furthermore, ITI is 
not viewed as a viable option for patients with inhibitors in many countries, owing to its high 
cost, the scarce local supply of FVIII concentrates, practical issues and potential 
complications associated with CVADs, and the psychological stress on patients and their 
families of this highly demanding therapeutic endeavor. Finally, even with successful 
implementation, ITI will fail to eradicate inhibitors in a sizeable proportion (21%−47%) of 
treated patients (Mariani et al. 2003). 
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 that of FVIII 
concentrates. In addition, as opposed to the 8−12-hour t1/2 and 15−20-minute infusion time 


 
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of FVIII, rFVIIa has a short t1/2 of only 2−3 hours and aPCC requires a 25−50-minute infusion 
(with a t1/2 of 4−7 hours). rFVIIa therefore requires frequent and aPCC requires extended IV 
infusions. In practice, some patients with inhibitors will have bleeds that respond better to 
rFVIIa while other patients will respond better to aPCC. Several publications evaluating the 
efficacy of prophylactic therapy in adults and children with the bypassing agents rFVIIa 
(Konkle et al. 2007) and aPCC (Antunes et al. 2014; Ettingshausen and Kreuz 2010; 
Leissinger et al. 2011, 2007) indicated that these treatments decreased bleeding rates 
compared with episodic treatment. Following the clinical results obtained, aPCC was 
approved by the Food and Drug Administration (FDA) as a prophylactic treatment in inhibitor 
patients in December 2013. Despite this, the use of prophylactic bypassing agents has yet to 
be established as the standard of care. 
Given the hemostatic management challenges in adults and children with inhibitors, there is 
a clinical need for therapeutics that have a lower treatment burden, more reliable efficacy, 
and an extended t1/2 that can be used for preventing bleeding in patients with hemophilia A.  
In the Phase I/II study (ACE001JP) 18 Japanese patients with hemophilia A, either with or 
without inhibitors, were treated with emicizumab at three different dosing regimens (0.3 
mg/kg/week, 1 mg/kg/week, or 3 mg/kg/week). During the course of emicizumab 
administration, the ABR significantly decreased in all patients compared with the ABR prior 
to study enrollment, regardless of whether or not the patient had inhibitors, with the 
exception of one patient without inhibitors in the 3 mg/kg/week group (see Section 1.2.2). 
Emicizumab has been well tolerated in patients in the Phase I/II studies (cut-off date 15th 
February 2016). The majority of adverse events have been mild in intensity, with the most 
common being ISRs. The majority of the adverse events have not been considered to be 
related to emicizumab. In these studies, no thromboembolic or systemic hypersensitivity 
adverse events have been observed. However, as of April 2017, three cases of TMA, and 
three thromboembolic events in two patients, have been observed in the ongoing Phase III 
Study BH29884 in patients who received emicizumab as well as bypassing agents for the 
treatment of breakthrough bleeds. Four of these patients have fully recovered and the fifth 
patient died (death due to serious adverse event of rectal haemorrhage unrelated to emicizumab, with 
the TMA related to emicizumab and aPCC) (see Sections 0 and 0). 
Given the unmet need to develop novel therapeutics for use in hemophilia A patients with 
inhibitors and the positive risk-benefit assessment observed, a Phase IIIb safety study with 
emicizumab is warranted in this patient population. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety and tolerability of emicizumab in patients with congenital 
hemophilia A who have persistent inhibitors against FVIII at enrollment. Specific objectives 
and corresponding endpoints for the study are outlined below (Table ). 






 
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study with patients recommended doses of any additional coagulation factors used, following the 
guidance below.  
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided if 
possible, and rFVIIa should be the first option used to treat, starting with no more than 90 µg/kg as 
an initial dose. If aPCC needs to be used, no more than 50 IU/kg should be administered as an initial 
dose and doses of > 100 U/kg/24 hours or more should be avoided, as cases of TMA and thrombotic 
events were reported when on average a cumulative amount of > 100 U/kg/24 hours aPCC was 
administered for 24 hours or more. Investigators should provide or remind patients of the exact dose 
and schedule of bypassing agents or FVIII required to treat any bleed. 
When a bleed has occurred, patients (or their legally authorized representative) will be 
required to report bleed information on an ePRO device where possible, including site of bleed, 
type of bleed, time of each individual bleed (day, start and stop time), and treatment for 
bleed (e.g., other than emicizumab in case of breakthrough bleeds). The reason for the use 
of rFVIIa will be documented (e.g., bleeding, preventative dose before activity). Thorough 
documentation of the treatments for bleeds and/or surgeries will be requested, including agent, 
start time, dose, route of administration, and number of infusions needed to treat the bleed. 
Local and central laboratory assessments are required to monitor the risk for 
thromboembolic events or microangiopathic hemolytic anemia or TMA, as per the Schedule of 
Activities (Appendix 1  
Schedule of Activities   
), if bypassing agents are used to treat a breakthrough bleed. 
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 a potential increase in emicizumab dose to 
3 mg/kg/week and additional laboratory evaluations (e.g., coagulation tests), as well as to re-
evaluate the patient’s individual benefit-risk for continuing treatment. 
An independent Data Monitoring Committee (iDMC) will be responsible for monitoring safety the 
duration of the study. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The approximate length of the entire study from the first patient enrolled to the last patient, 
last visit (LPLV; see below) is approximately 3 years. For each individual patient, the study is 
expected to last approximately 2 years (patients will receive 3 mg/kg/week emicizumab for 
the first 4 weeks followed by 1.5 mg/kg/week emicizumab for the remainder of the 2-year 
treatment period). Patients who discontinue emicizumab prior to the completion of the 2-year 
treatment period will undergo a Safety Follow-up Visit 24 weeks after the patient’s last emicizumab 
dose or at 2 years after emicizumab treatment start, whichever occurs first. 
The end of this study is defined as the date when the last remaining patient has completed 
the last visit (i.e., LPLV). The study will end when all patients have been treated with 
emicizumab for 2 years, or earlier, if one of the following is documented: 
Withdrawal of consent 
OR 




 
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In study BH29884, the ABR was 2.9 events (95% CI, 1.7 to 5.0) among participants who were 
randomly assigned to emicizumab prophylaxis (Group A, 35 participants) versus 23.3 events (95% 
CI, 12.3 to 43.9) among those assigned to no prophylaxis (Group B, 18 participants), representing a 
significant difference of 87% in favor of emicizumab prophylaxis (p<0.001). A total of 22 participants 
in Group A (63%) had zero bleeding events, as compared with 1 participant (6%) in Group B. 
Among 24 participants in Group C who had participated in a NIS, emicizumab prophylaxis resulted 
in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent 
prophylaxis (p<0.001) (Oldenburg et al. 2017). 
The exposure-response relationship for emicizumab was quantitatively characterized and 
simulations suggested that the trough concentration of emicizumab needed for almost 
complete inhibition of bleeding onset is ≥ 45 µg/mL. On the basis of population PK modeling, 
a median trough plasma concentration of 45 μg/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. In light of this finding, the loading dose of 3 mg/kg emicizumab per week for 4 
weeks was chosen in order to rapidly achieve the effective trough concentration of 45 μg/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 μg/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) will, therefore, be investigated in this study. 
A study duration of approximately 2 years for each individual patient has been chosen in 
order to thoroughly assess the long-term safety of prophylactic use of emicizumab. 
3.3.2 
Rationale for Patient Population 
Patients with congenital hemophilia A who have persistent inhibitors against FVIII at enrollment 
will comprise the primary population for this Phase IIIb study investigating the safety, 
tolerability, efficacy, immunogenicity, and PK of prophylactic administration of emicizumab. 
Patients may have received episodic or prophylactic treatment before enrollment; at least 
one documented treatment with bypassing agents or FVIII concentrates is required within 
the last 6 months to indicate the need for prophylactic emicizumab treatment. 
Based on current treatment algorithms for patients with hemophilia A with inhibitors 
(Kempton and White II 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. As clinical safety data relating to the concomitant use 
of prophylactic emicizumab during ITI are not available at this time, patients currently 
receiving ITI will not be eligible for this study.  Patients receiving ITI therapy will be eligible 
following the completion of a 72-hour washout period prior to the first emicizumab administration.  
Owing to the fact that the presence or amount of FVIII inhibitors in their plasma does not 
impact the efficacy of emicizumab, patients’ inhibitor titers at the time of study entry will not 
influence their study eligibility. 


 
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3.3.3 
Rationale for Control Group 
This study involves the use of a single-arm study design and therefore a control group will 
not be used. The primary endpoint of this study is to evaluate the overall safety and 
tolerability of prophylactic administration of emicizumab in patients with congenital hemophilia 
A who have persistent inhibitors against FVIII. As hemophilia A is a rare disease (Acharya 2013) 
and the study is designed to investigate the broad safety profile of emicizumab, 
approximately 200 patients will be enrolled. Given the size of the patient population, a single-
arm study design without a control group is considered an appropriate method to capture the 
safety data that will be observed following the use of emicizumab. This type of study design 
has been used extensively in previous clinical studies involving patients with rare diseases 
(Bell and Tudur Smith 2014). 
3.3.4 
Rationale for Biomarker Assessments 
The identity of effective PD, safety, and bone and joint biomarkers has not been fully 
elucidated and further testing is required to determine which assays and technical conditions 
are most suitable for use with emicizumab treatment. Plasma and serum samples will be 
collected for PD, safety, and bone and joint biomarker assessments at specific clinic visits in 
order to obtain evidence of the biologic activity of emicizumab in patients (see Appendix 2
 
 
Schedule of Biomarker Samples 
). 
The PD biomarkers include, but are not limited to, coagulation assays such as aPTT and 
FVIII activity assays. The results of the Phase I/II study have shown that a dose-response 
relationship was apparent between aPTT and emicizumab concentration (for more 
information, see the Investigator’s Brochure). The aPTT assay will be run in a modified form 
to ensure that the assay range covers all levels of emicizumab exposure. In addition, clot 
waveform analysis (CWA) may be run as an exploratory PD coagulation assay. 
The safety biomarkers will be used to monitor patient safety throughout the study and may 
include, but are not limited to, D-dimer. 
Exploratory safety coagulation system biomarkers will include Factor VIII antigen (FVIII:Ag), 
Factor IX antigen (FIX:Ag), and Factor X antigen (FX:Ag) to assess whether drug treatment 
causes alterations in the circulating levels of the coagulation factors that are the binding 
targets for emicizumab. Measurement of other coagulation or hemophilia-related factors may 
also be conducted. 
The bone and joint biomarkers will include exploratory biomarkers of bone turnover and joint 
health. The selection of bone and joint biomarkers that will be tested will be based on 
findings from biomarker analyses in other emicizumab trials (see Appendix 2 
 
Schedule of Biomarker Samples 
). 
Residual blood and/or, plasma, and serum from collected biomarker samples may be stored 
for up to 5 years after the final Clinical Study Report has been completed and may be used for 
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vitro diagnostic assay(s) related to emicizumab plasma concentration, FVIII inhibitor titre 
and/or coagulation activity.   
3.3.5 
Rationale for Pharmacokinetic Sample Collection Schedule 
PK samples will be collected throughout the 2-year study period in order to further investigate 
the PK of emicizumab (see the Schedule of Activities; Appendix 1  
Schedule of Activities   
). 
3.3.6 
Rationale for Immunogenicity Sample Collection 
Immunogenicity will be monitored by investigating the incidence and clinical significance of 
antibodies to emicizumab at specified time points (see the Schedule of Activities; Appendix 1
 
 
Schedule of Activities   
). The emergence of anti-drug antibodies (ADAs) has been previously observed in clinical 
studies involving monoclonal antibodies of the IgG4 class (Lundkvist et al. 2012; Vennegoor 
et al. 2013). 
3.3.7 
Rationale for Disease Response–based Endpoints 
The secondary objective of this study is to evaluate the efficacy of prophylactic 
administration of emicizumab. This objective will be achieved by investigating the number of 
bleeds over time under emicizumab treatment, assessing HRQoL, and evaluating health status 
according to EQ-5D-5L and patient preference for the emicizumab regimen compared with the 
previous regimen. As mentioned in Section 0, this analysis will occur when all patients have 
completed 2 years of treatment or have withdrawn, whichever occurs sooner. In order to 
obtain comprehensive data on each bleed, patients will be asked to report bleed information 
on an ePRO device where possible, including site of bleed, type of bleed, time of each individual 
bleed (day, start and stop time), and treatment for bleed. 
Conducting the efficacy analysis after 2 years of therapy is supported by the results of 
previous clinical studies that have demonstrated the benefits of long-term prophylactic 
therapy in patients with hemophilia (Gringeri et al. 2011; Khawaji et al. 2012; Manco-
Johnson et al. 2007). The results of these studies showed that prophylactic treatment could 
effectively prevent joint damage, decrease the frequency of joint and other hemorrhages, 
and lead to improvements in the patients’ HRQoL. 
3.3.8 
Rationale for Primary Endpoint Selection 
As stated in Section 0, the primary objective of this study is to evaluate the overall safety and 
tolerability of prophylactic administration of emicizumab. In order to achieve this objective, 
the incidence and severity of all adverse events, including adverse events of special interest, 
will be captured on an ongoing basis, as they occur during the study. Physical examinations, 
vital signs, and laboratory values will be assessed as per the Schedule of Activities 
(Appendix 1  
Schedule of Activities   


 
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). 
The bypassing agents that are currently used for treating patients with hemophilia A are 
associated with specific side effects, such as thromboembolic events, hypersensitivity 
reactions, myocardial infarction, and disseminated intravascular coagulation (Bui et al. 2002; 
Dentali et al. 2011; Tjønnfjord 2004; Wójcik et al. 2009). In addition, these agents are 
administered according to a frequent dosing schedule, which may reduce patient compliance 
thereby making these regimens less effective and compromising their cost-benefit ratio 
(Thornburg 2010). Therefore, there currently exists an unmet need to develop novel 
therapeutics for use in hemophilia A patients with inhibitors. This study will provide long-term 
safety data on the prophylactic use of emicizumab. 
3.3.9 
Rationale for Interim Analyses 
Owing to the long-term nature of this study, interim analyses will be conducted in order to obtain 
accurate information on the safety, efficacy, immunogenicity, and PK of prophylactic emicizumab at 
specific points throughout the study. The first interim analysis will be performed once 
approximately 100 patients have received treatment with emicizumab for at least 24 weeks. A 
second interim analysis will be performed when approximately 100 patients have received 
treatment with emicizumab for at least 52 weeks. The data from these analyses will 
subsequently be presented to the iDMC in order to enable them to effectively monitor the 
study. 
3.3.10 
Rationale for Patient-reported Outcome (PRO) Assessments 
During the study, electronic capture of HRQoL, health status (EQ-5D-5L) will be obtained 
using an ePRO device. Patient preference data (EmiPref) will be collected on paper forms. 
HRQoL is an important outcome in the care of patients with hemophilia (Brown et al. 2009). 
HRQoL in hemophilic patients is multifaceted and is affected by disease symptoms (e.g., 
pain, bleeding), treatment (prophylactic, on demand, side effects), limitations on daily 
functioning, anxiety / depression, and time spent in hospital. 
The goal of measuring HRQoL is to quantify any treatment benefits from the patient 
perspective. Previous studies that have used the Hemophilia Quality of Life questionnaire 
(Haemo-QoL), a measure of HRQoL parameters affected by hemophilia in children and 
adolescents, have reported improvements in physical health, feelings, view of self, family 
relations, friend relations, perceived support, relation with others, participation in sports, 
dealing with hemophilia, views of treatment, views of the future, and relationships 
(Santagostino et al. 2014). Improvements in physical health, feelings, view of self, and 
participation in work have also been observed on the adult version of the measure, the 
Haem-A-QoL (Stasyshyn et al. 2014). 
The HRQoL measures employed in the current study will be used to investigate the impact 
of prophylactic administration of emicizumab in adolescents and adults with hemophilia A. In 
addition, the measures will be used to evaluate the longitudinal changes in HRQoL with 
emicizumab compared with the previous treatment regimen that the patients received. 
The EQ-5D-5L is a standardized, preference-based measure of generic health status that is 
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of health: mobility, ability to self-care, ability to undertake usual activities, pain / discomfort, 
and anxiety / depression. The EQ-5D-5L also assesses current overall health. The goal of 
measuring EQ-5D-5L is to assess the impact of treatment with emicizumab over time on 
overall health and the different health dimensions. Data from the EQ-5D-5L can also be used 
to inform pharmacoeconomic evaluations.  
The study will also evaluate patient preference for treatment (EmiPref). Previous studies 
have noted that patients express preference for treatments that do not have negative effects 
(e.g., pain that results from infusions), are not time-consuming, are not associated with high 
treatment burden, and have a goal of achieving a “normal life” (Cimino et al. 2014). The 
inclusion of a fit-for-purpose preference survey after the completion of 3 months of 
emicizumab treatment will provide information on whether SC emicizumab is preferred to the 
previous treatment and explore the potential underlying reasons for any findings. This 
assessment will be performed after 3 months as the patients will have gained sufficient 
experience with emicizumab and SC injection, while still being reliably able to recall their 
experience with their prior therapy. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
This global study will enroll approximately 200 patients with congenital hemophilia A who 
have persistent inhibitors against FVIII at enrollment. The patients are expected to be enrolled 
at approximately 85 sites globally. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. As per the investigator’s judgement, a willingness and ability to comply with scheduled 
visits, treatment plans, laboratory tests, and other study procedures, including the PRO 
questionnaires and bleed diaries through the use of an electronic device or paper 
3. Aged 12 years or older at the time of informed consent 
4. Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII 
5. Documented treatment with bypassing agents or FVIII concentrates in the last 6 months 
(on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day 
before starting emicizumab. 
6. Adequate hematologic function, defined as platelet count ≥ 100,000/μL and hemoglobin 
≥ 8 g/dL (≥ 4.97 mmol/L) at the time of screening 
7. Adequate hepatic function, defined as total bilirubin ≤ 1.5 × the upper limit of normal 
(ULN) (excluding Gilbert’s syndrome) and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 3 ×ULN at the time of screening; no clinical signs or known 
laboratory/radiographic evidence consistent with cirrhosis 
8. Adequate renal function, defined as serum creatinine ≤ 2.5 × ULN and creatinine 
clearance by Cockcroft-Gault formula ≥ 30 mL/min 


 
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9. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a highly effective contraceptive method with a failure 
rate of < 1% per year during the treatment period and for at least five elimination half-
lives (24 weeks) after the last dose of emicizumab: 
• 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus) 
• 
Examples of highly effective contraceptive methods with a failure rate of < 1% per 
year include proper use of combined oral or injected hormonal contraceptives, 
bilateral tubal ligation, male sterilization, hormone-releasing intrauterine devices, 
and copper intrauterine devices. Alternatively, two methods (e.g., two barrier 
methods such as a condom and a cervical cap) may be combined to achieve a 
failure rate of < 1% per year. Barrier methods must always be supplemented with 
the use of a non-lipid-based spermicide 
• 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Inherited or acquired bleeding disorder other than hemophilia A 
2. Ongoing (or plan to receive during the study) ITI therapy (prophylaxis regimens with FVIII 
and/or bypassing agents must be discontinued prior to enrollment). Patients receiving ITI 
therapy will be eligible following the completion of a 72-hour washout period prior to the 
first emicizumab administration 
3. History of illicit drug or alcohol abuse within 12 months prior to screening, as per the 
investigator’s judgment 
4. High risk for TMA (e.g., have a previous medical or family history of TMA), as per the 
investigator’s judgment 
5. Previous (in the past 12 months) or current treatment for thromboembolic disease (with 
the exception of previous catheter-associated thrombosis for which antithrombotic 
treatment is not currently ongoing) or current signs of thromboembolic disease 
6. Other conditions (e.g., certain autoimmune diseases) that may increase the risk of 
bleeding or thrombosis 
7. History of clinically significant hypersensitivity reaction associated with monoclonal 
antibody therapies or components of the emicizumab injection 
8. Known human immunodeficiency virus (HIV) infection with CD4 count < 200 cells/μL 
within 6 months prior to screening 
9. Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or 
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10. 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 
11. Receipt of: 
• 
Emicizumab in a prior investigational study 
• 
An investigational drug to treat or reduce the risk of hemophilic bleeds within five 
half-lives of last drug administration 
• 
A non-hemophilia-related investigational drug within last 30 days or five half-lives, 
whichever is shorter 
• 
Any concurrent investigational drug. 
12. Pregnancy or lactation, or intent to become pregnant during the study 
13. Positive serum pregnancy test result within 7 days prior to initiation of emicizumab 
(females only) 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Study MO39129 is a single-arm, open-label study and therefore no treatment blinding will 
occur during this study. 
4.3 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is emicizumab. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Emicizumab 
Emicizumab drug product will be supplied by the Sponsor as a sterile colourless to pale 
yellow liquid for SC injection in a single-dose 3-mL glass vial containing 1 mL of emicizumab. 
The recommended storage condition for emicizumab drug product is between 2°C and 8°C 
(36°F to 46°F), and protected from light. Vials should not be frozen or shaken. 
Each single-use vial contains 150 mg/mL emicizumab in a histidine-aspartic acid buffered 
solution (approximately pH 6.0), which contains arginine and Poloxamer 188. For information 
on the formulation and handling of emicizumab, see the Investigator's Brochure. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Emicizumab 
Emicizumab will be administered at a dose of 3 mg/kg/week subcutaneously for 4 weeks 
when initiating treatment, followed by 1.5 mg/kg/week subcutaneously for the remainder of 
the 2-year treatment period. There will be an option to increase the dose to 3 mg/kg/week in 
cases of insufficient control of bleeds on the 1.5 mg/kg/week emicizumab dose. If the 
investigator believes that a specific patient warrants dose up-titration following the 
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traumatic bleed out of proportion to the degree of injury, they must discuss the case with the 
Medical Monitor for consideration and potential approval. 
Recommended injection sites include the front of middle of the patient’s thighs, or the lower part of 
the patient’s abdomen below the navel.  Avoid injecting within a 2” radius around the navel. If a 
caregiver is giving the injection, the outer area of the upper arms may also be used. For additional 
information re the administration of emicizumab, refer to the Instructions for Use (IFU) document. 
If a patient has a systemic hypersensitivity reaction or a severe adverse reaction that may be 
attributable to emicizumab, subsequent doses should be withheld until the situation is 
discussed with the Medical Monitor and approval to resume dosing is provided. Should 
certain, unanticipated events occur during the study that require treatment with multiple daily 
administrations of bypassing agents or FVIII concentrates for multiple days (e.g., 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. In order to be eligible for inclusion in the study, prophylaxis regimens 
with FVIII and/or bypassing agents must be discontinued prior to enrollment. Any other 
emicizumab dose adjustment request will require discussion of the clinical case with, and 
approval from, the Medical Monitor. 
Study site HCPs will be initially trained on how to properly prepare emicizumab and 
administer the correct calculated dose subcutaneously as described in the IFU document. 
To support home administration of the drug, patients/caregivers will be required to complete 
in-person, instructional training on how to administer emicizumab as a SC injection. 
Patients/caregivers will also be taught how to perform the injections through the use of the 
IFU document. In addition, the HCP is to inform the patient/caregiver of the volumetric dose 
to be administered and the dosing frequency. The patients/caregivers will observe at least 
one SC injection performed by a HCP and will need to successfully administer at least one 
SC injection under an HCP’s supervision prior to starting home administration. The 
patient/caregiver will also have the opportunity to ask any questions to the HCP before 
starting home administration. The first three weekly treatments will be administered in a 
monitored setting, such as an infusion center, clinic, or hospital, in conjunction with 
emicizumab PK and PD assessments. Patients will be observed for a minimum of 
60 minutes after the first three doses. Patients/caregivers will be instructed on how to 
recognize signs/symptoms of hypersensitivity (including anaphylaxis) and obtain emergency 
care in the event of such reactions occurring. Each site will have the discretion to provide 
additional training or include additional observation (e.g., after the third or fifth doses), if 
deemed appropriate. If, despite additional training, the investigator determines that the 
patient/caregiver is unable to inject emicizumab, a trained and proficient caregiver or HCP 
should be identified to administer the SC injections. Patients/caregivers will be provided with 
contact information for the clinic in case they have questions related to self-administration 
between visits. 
In order to minimize the number of injections for patients in certain weight categories, the 
administration of a single injection of up to 2 mL drug product solution may be permitted. 
This administration will require the combination of emicizumab drug product solution from up 
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needle for each vial. The detailed procedure for vial pooling will be described in the IFU 
document. If the patient’s dose is > 2 mL, a second injection will be required.  
Medication administration errors during training will be documented in the electronic Case 
Report Form (eCRF). If necessary, patients or their HCP may choose to continue 
administration of emicizumab within the clinic. Compliance in the home setting is to be 
monitored at each site by reviewing reported hemophilia medication use and recording 
collected used and unused vials. 
If the patient forgets or cannot administer emicizumab on the scheduled dosing day, 
emicizumab should be administered as soon as possible before the day of the next scheduled dose, 
and then the patient should resume the usual weekly dosing schedule. Do not double doses to make up 
for a missed dose.  All four loading doses of 3 mg/kg should be taken, even if this is done over a period 
or more than four weeks.  
Any overdose or incorrect administration of emicizumab should be noted on the Study Drug 
Administration eCRF. Adverse events associated with an overdose or incorrect 
administration of emicizumab should be recorded on the Adverse Event eCRF. Section 0 
summarizes available safety data related to overdosing of emicizumab. 
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 the signs/symptoms of 
thromboembolic events or allergic/anaphylactic/anaphylactoid reactions and how to obtain 
emergency care. In addition, alert cards are designed to notify non-study HCPs that 
emicizumab will interfere with certain coagulation laboratory tests (see the Investigator’s 
Brochure for more information) and that the investigator should be contacted for assistance 
in interpreting the test results. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided 
in Section 5.1.1. 
4.3.3 
Investigational Medicinal Product Accountability 
Emicizumab, the only IMP in the study, will be provided by the Sponsor. Accountability for 
each vial is required and the study site will acknowledge the receipt of IMP using the 
interactive voice or web-based response system (IxRS) to confirm shipment condition and 
content. Any damaged shipments will be replaced. 
Used and unused emicizumab vials will be returned by the patients to the study site and 
appropriately accounted for. Used emicizumab vials will then be disposed of at the study site 
according to institutional standard operating procedures. 
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. 


 
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4.3.4 
Continued Access to Emicizumab 
The Sponsor will offer continued access to emicizumab to study patients who have shown a 
demonstrable benefit from emicizumab treatment during this study (as measured by 
sustained clinical response and/or improvement in clinical symptoms).  
Continued Access to emicizumab will be provided free of charge, through either an Open 
Label Extension trial, a Post-Trial Access Program, local Patient Support Programs, or other 
local access mechanisms according to each country regulation, as described per Global 
procedural document: Continued Access to Roche Investigational Medicinal Product (SOP-
0112895), in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, and the Declaration of Helsinki in its 2013 issue. 
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 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment for 
hemophilia A 
• 
Provision of study drug is not permitted under the laws and regulations of the patient's 
country. 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
from 4 weeks prior to initiation of emicizumab to the Study Completion/Early Termination Visit 
(or to the Safety Follow-up Visit, if applicable). All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
Any hemostatic medications (e.g. bypassing agents) and other medications used to treat or prevent 
bleeds in the 6-month period prior to starting emicizumab treatment will also be collected (see 
Section 4.5.5).  
4.4.1 
Permitted Therapy  
Concomitant use of the following drugs and therapies will be permitted: 
• 
Drugs to treat existing conditions at time of study entry, as long as allowed based on eligibility 
criteria (Section 4.1.1 and Section 4.1.2). 
• 
During the study, any medication to treat or prevent any medical condition as deemed 
necessary by the treating physician. If prohibited treatment (see Section 4.4.2) is prescribed or 


 
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considered medically necessary, the Medical Monitor should be consulted to discuss any changes 
in the benefit-risk profile and determine whether the patient should continue on the study.  
• 
Any over-the-counter medication used to treat the symptoms of hemophilia 
• 
Supplementary vitamins and minerals. 
• 
Drugs and therapies to treat adverse events and the use of topical antiseptics, anesthetics, eye 
drops, etc., that are not considered to enter the bloodstream and result in systemic exposure 
Concomitant use of the following hemostatic treatments will be permitted: 
• 
Drugs intended to control breakthrough bleeds (e.g. rFVII, FVIII, aPCC) or bleeds during 
surgeries should be used at the lowest dose expected to achieve hemostasis. Given that circulating 
emicizumab may increase the patient’s coagulation potential, the doses required to achieve 
hemostasis may be lower than doses used prior to starting emicizumab. At the start of the study, 
Investigators shall discuss with patients the recommended doses of any additional coagulation 
factors used, given the guidance below.  
• 
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided 
if possible, and rFVIIa should be the first option used to treat, starting with no more than 90 
µg/kg as an initial dose. If aPCC needs to be used, no more than 50 IU/kg should be administered 
as an initial dose and doses of > 100 U/kg/24 hours or more should be avoided, as cases of TMA 
and thrombotic events were reported when on average a cumulative amount of > 100 U/kg/24 
hours aPCC was administered for 24 hours or more. Investigators should provide or remind 
patients of the exact dose and schedule of bypassing agents or FVIII required to treat any bleed. 
o Caution should be taken if anti-fibrinolytics are used in conjunction with rFVIIa in patients 
receiving emicizumab 
• 
Other bypassing agents: 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 mg/kg of Byclot®). For patients receiving Byclot® prior to study entry, a 
washout period of 72 hours prior to the first emicizumab dose is required 
The exact dose and schedule of FVIII or bypassing agents should 
be discussed with the patient at study entry and throughout the 
study. Repeated dosing of FVIII, rFVIIa, aPCC, or other bypassing 
agents should be performed only under medical supervision and 
consideration should be given to verifying the 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 Activities 
(see Section 4.5.6.9Appendix 1 
 
Schedule of Activities   
• 
). 


 
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4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• 
Use of systemic immunomodulators (e.g., rituximab, interferon) other than antiretroviral 
therapy 
• 
Use of other investigational drugs 
• 
Use of aPCC for short-term prophylaxis 
o Use of aPCC for any reason should be avoided if possible during the study but use of 
aPCC to treat breakthrough bleeds is permitted (as described in Section 4.4.1) if 
rFVIIa is not available or not an option for medical reasons (see Section 0). 
• 
Use of ITI therapy (prophylactic regimens with FVIII and/or bypassing agents): 
o However, short-term prophylaxis around the time of surgery is permitted as deemed 
needed by the investigator (see Section 4.4.1).   FEIBA can not be used prophylactically.  
• 
Use of anti-fibrinolytics in conjunction with aPCC or Byclot® 
If prohibited therapy is administered for any reason, it should be recorded on the eCRF. If 
prohibited treatment is prescribed or considered medically necessary, the Medical Monitor 
should be consulted to discuss any changes in the benefit-risk profile and determine whether 
the patient should continue on the study. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 
 
Schedule of Activities   
 for the Schedule of Activities to be performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or evaluations. Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the study 
site. For adolescents (i.e., patients who are 12−17 years of age), an Informed Assent Form 
will be completed instead. Parents or caregivers of adolescents will also complete an 
Informed Consent Form. 
The enrollment form will be completed after informed consent and/or assent is obtained. 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. 
4.5.2 
Medical History and Demographic Data   
Medical history includes hemophilia-related history, clinically significant diseases, 
procedures (including prior surgeries), use of alcohol and drugs of abuse within the past year, 
and medication allergies. In particular, sites should record whether the patient has any 
history of prior ITI, anaphylaxis, or known thrombophilia. It should also include all medication 
taken in the 4 weeks prior to screening (including prescription drugs, over-the-counter drugs, 
and herbal/homeopathic remedies and therapies). 






 
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4.5.6.3 
HIV and Hepatitis Serology 
The specific tests utilized for hepatitis and HIV testing are per local standard of care. As this patient 
population is at high risk for HIV, hepatitis A, B and C, sites should consider testing for these. While 
the specific serological tests used is at the discretion of the Investigator, this is with the understanding 
that the status of that participants’ hepatitis or HIV is confidently known at time at enrollment.  HIV 
and hepatitis serology tests will be conducted at the local laboratory. 
4.5.6.4 
Anti-FVIII Antibodies 
For the assessment of anti-FVIII antibodies (inhibitors), functional assays that utilize a clotting 
readout (classic Bethesda or Nijmegen assay) cannot be used for patients on emicizumab therapy as 
emicizumab drives clotting even in the presence of FVIII inhibitors, causing a false-negative test 
result (see Section 5.1.3). After the first dose, local measurement of FVIII inhibitors, if indicated, 
requires use of an ELISA-based test or a chromogenic Bethesda assay. 
At the discretion of the local investigator, any additional urgent requests to assess FVIII inhibitors 
will need to be sent to the central laboratory (see Appendix 2 
 
Schedule of Biomarker Samples 
 for additional information).  
Plasma samples for anti-FVIII antibodies will be analysed at the central laboratory.  
4.5.6.5 
Anti-emicizumab Antibodies 
Plasma samples are required for immunogenicity assessments to detect anti-emicizumab antibodies.  
Additional samples to detect anti-emicizumab antibodies may also be drawn at the time of 
hypersensitivity events or following suspected loss of efficacy. Samples will be analysed at the central 
laboratory. 
4.5.6.6 
Pharmacokinetics   
Plasma samples are required for PK assessments. On days where PK samples are to be collected, the 
emicizumab injection will be performed in the clinical unit.  One single pre-dose sample is required on 
the applicable visits.  Samples will be analysed by the central laboratory.   
4.5.6.7 
Biomarkers 
4.5.6.7.1 
Safety Biomarkers 
Plasma samples for safety biomarker assessment must be citrate plasma.  Tests may include, but are 
not limited to, D-dimer. Samples will be analysed by the central laboratory.  See Appendix 2. 
4.5.6.7.2 
Safety Coagulation System Biomarkers 
Plasma samples for safety coagulation system biomarker assessment must be citrate plasma.  Tests 
include FVIII:Ag, FIX:Ag and FX:Ag. Samples will be analysed by the central laboratory.  See 
Appendix 2. 


 
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4.5.6.7.3 
PD Biomarkers 
Plasma samples for PD biomarker assessment must be citrate plasma.  Tests will include, but are not 
limited to FVIII activity and modified aPTT (one stage). Additional plasma samples will be collected 
for future exploratory research, which may include tests such as CWA and others (see Appendix 2). 
Samples will be analysed by the central laboratory.   
4.5.6.7.4 
Bone and Joint Biomarkers 
Serum and plasma ethylenediaminetetraacetic acid (EDTA) samples for bone and joint biomarkers 
must be collected after fasting (no food or drink other than water for at least 8 hours prior to the blood 
draw). Ideally these samples should be collected in the morning (before noon), in order to control for 
diurnal variation. Please consult the Central Laboratory Services Manual for details. The selection of 
exploratory bone and joint biomarkers to be tested will build on findings from biomarker analyses in 
other emicizumab trials and may include C-terminal telopeptide of collagen 1 (CTX-1), 
osteoprotegerin (OPG), procollagen type 1 amino-terminal propeptide (P1NP), and soluble receptor 
activator of nuclear factor kappa-B ligand (RANK-L) (see Appendix 2 
 
Schedule of Biomarker Samples 
). Samples will be analysed by the central laboratory.   
4.5.6.8 
Extra Testing with Use of Bypass Agents 
In the event of a breakthrough bleed that is treated with bypassing agents, it is 
recommended that the following laboratory tests will be performed within 2448 hours of 
initial bypassing agent use (these tests will be conducted so that the investigator can monitor 
the patient for potential thromboembolic events and microangiopathic hemolytic anemia or 
TMA). These tests include:  
• 
Platelet count 
• 
Serum creatinine 
• 
LDH 
• 
Schistocytes 
• 
A plasma sample should also be provided for central laboratory monitoring of 
prothrombin fragment F1+2, fibrinogen and D-dimer. 
Ideally, samples for these tests should be analysed at the central laboratory.  Exceptionally in urgent 
situations where results are required quickly, local laboratory testing can be used, with results 
recorded in the eCRF. 
For patients who require multiple doses of bypassing agents, laboratory monitoring should 
be performed every 2448 hours until 2448 hours after the last dose of bypassing agents is 
administered to treat a specific bleed. All laboratory results which are required as part of the 
patient’s safety assessment should be recorded in the unscheduled visit eCRFs. 
4.5.6.9 
Sampling Procedures and Sample Storage, Shipment and Destruction 
For sampling procedures, storage conditions, and shipment instructions, see the Central 
Laboratory Services Manual. 


 
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Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 
• 
Plasma or serum samples, as applicable, collected for anti-FVIII antibody, PD biomarker, 
safety biomarker, safety coagulation system biomarker, bone and joint biomarker 
assessments and other future exploratory research will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analyzed, unless the patient specifically requests that the samples be destroyed 
or local laws require destruction of the samples. 
Data arising from sample analysis will be subject to the confidentiality standards described in 
Section 8.4. 
4.5.7 
Bleed Assessments 
Patients will be trained on how to record their bleeds and hemophilia medication use using an ePRO 
device where possible. When bleeds occur, patients will need to record the site of bleed, type of 
bleed, time of each individual bleed (day, start and stop time), and treatment for bleed. At 
least once a week, patients will need to record any hemophilia medication use (including emicizumab) 
and information regarding any bleeding events. Investigator review of patient-reported 
bleed/medication records with the patient/caregiver will occur for completeness and 
accuracy throughout the study.  
4.5.7.1 
Definition of a Bleed 
For the purposes of the efficacy analyses, a standardized definition of bleed, adapted from 
the standard criteria defined by the FVIII and FIX Subcommittee of the Scientific and 
Standardization Committee (SSC) of the International Society on Thrombosis and 
Haemostasis (ISTH), that is similar to the definition used in a recent clinical investigation, 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 reported bleeds 
(irrespective of treatment with coagulation factors) will be applied for a separate analysis. 
• 
Bleeds starting from the first sign of a bleed and ending 72 hours after the last treatment 
for the bleed, which have 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. 
• 
In case of trauma with multiple different locations of bleed, this will be considered as one 
bleed for the analyses. However, all data will be collected, including the various locations 
of the different bleeds. 
• 
Any bleed with a different etiology is considered a separate bleed regardless of time from 
last injection. 


 
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4.5.7.2 
Definition of a Target Joint 
A target joint is defined as: 
• 
A major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated 
bleeds occur (frequency of at least three bleeds into the same joint over the last 24 
weeks prior to study entry). 
4.5.7.3 
Bleed Sites 
The bleed sites are defined as follows: 
• 
Joint bleeds, which are defined as having an unusual sensation (“aura”) in the joint in 
combination with any of the following: 
o Increasing swelling or warmth of the skin over the joint 
o Increasing pain 
o Progressive loss of range of motion or difficulty in using the limb as compared with 
baseline. 
• 
Muscle bleeds 
• 
Other bleeds. 
4.5.7.4 
Definitions of Bleed Types 
Bleed assessments will be separated into spontaneous bleeds, traumatic bleeds, and bleeds 
related to procedures. 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. The definitions for the different type of bleeds are as follows: 
• 
Spontaneous bleeds. Bleeds will be classified as spontaneous if a patient records a 
bleed when there is no known contributing factor such as definite trauma, antecedent 
“strenuous” activity, “overuse”, or procedure/surgery. The determination of what 
constitutes “strenuous” or “overuse” will be at the discretion of the patient. For example, 
light jogging may be considered “non-strenuous” while sprinting may be considered 
“strenuous”; lifting of weights for a short period of time may be considered “moderate 
use” while repetitive weightlifting may be considered “overuse” 
• 
Traumatic bleeds. Bleeds should be classified as traumatic if a patient records a bleed 
when there is a known or believed reason for the bleed. For example, if a patient were to 
exercise “strenuously” and then have a bleed in the absence of any obvious injury, the 
bleed would be recorded as a traumatic bleed because, although no injury occurred, 
there was antecedent “strenuous” activity. Bleeds with preceding injuries would certainly 
be classified as traumatic. In addition, bleeds related to surgery, such as hematomas 
resulting from any surgeries, will also be classified as traumatic bleeds. Bleeds related to 
surgeries will not be associated with any trauma except surgery-induced trauma 
• 
Bleeds related to procedures. This category would include hematomas resulting from 
any invasive procedure (e.g., tooth extractions, venepuncture, or SC drug 
administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial blood 
gas determination, or any endoscopy with biopsy, etc.) or surgeries. Any instances of 
these bleeds would not be counted as bleeds in the context of the study, but the relevant 


 
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data will be collected. Bleeds related to procedures will not be associated with any 
trauma except procedure-induced trauma. 
4.5.8 
Surgical Events 
Thorough documentation on surgical events will be requested, including type of surgery or 
procedures, treatments, outcomes, etc.  
4.5.9 
Patient-Reported Outcomes 
The PRO data that will be collected during this study include bleed/medication assessments 
(see Section 4.5.7) and HRQoL, health status (EQ-5D-5L), and treatment preference 
(EmiPref) questionnaires. 
The PRO questionnaire data will be collected to document the treatment benefit of 
emicizumab. The questionnaires, translated into the local language as required, will be 
completed in their entirety at specified timepoints during the study. To ensure instrument 
validity and that data standards meet health authority requirements, questionnaires will be 
self-administered before the patient/caregiver receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of 
emicizumab, unless otherwise specified. 
4.5.9.1 
HRQoL Assessments 
The Haem-A-QoL (version AU 3.0; UK English) and the Hemophilia Quality of Life Short Form 
(Haemo-QoL-SF) (version AU 2.0; UK English) will be completed electronically and used to 
measure HRQoL in adults and adolescents, respectively. Paper versions of the questionnaires 
are also available in case of ePRO outage or if an ePRO device is otherwise unavailable.  
The Haem-A-QoL was designed for adult patients with hemophilia. It consists of 46 items 
comprising 10 dimensions (physical health, feelings, view of yourself, sports and leisure, 
work and school, dealing with hemophilia, treatment, future, family planning, and 
partnerships and sexuality) and a scale representing total score. Items are rated according 
to five response options, although for some items there is also a ‘not applicable’ option 
(Mackensen and Gringeri 2010; Wyrwich et al. 2015). 
The Haemo-QoL has been developed as a series of age-related questionnaires to measure 
HRQoL in children and adolescents with hemophilia (Bullinger et al. 2002; Pollak et al. 2006; 
Von Mackensen and Bullinger 2004). These questionnaires include a 77-item long form, a 
35-item short form, and an 8-item index form. Long versions for three different age groups 
contain 21−77 items and cover 8−12 dimensions of HRQoL. Furthermore, two age-specific 
short form measures containing 16 and 35 items have been developed. The short version for 
older children (8−16 years) containing 35 items was selected for this study. This version 
covers nine dimensions considered relevant for the children’s HRQoL (physical health, 
feelings, view of yourself, family, friends, other people, sports, dealing with hemophilia, and 
treatment). Items are rated with respect to five response options: never, rarely, sometimes, 
often, and all the time. 


 
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4.5.9.2 
Health Status Assessments (EQ-5D-5L) 
The EQ-5D-5L (version 2; UK English) is a generic, self-report, preference-based health utility 
measure that consists of six questions that are completed electronically and is used to assess 
health status and inform pharmacoeconomic evaluations. Paper versions of the questionnaires 
are also available in case of ePRO outage or if an ePRO device is otherwise unavailable. The EQ-5D-
5L consists of two components. The first part, health state classification, contains five 
dimensions of health: mobility, self-care, usual activities, pain / discomfort, and anxiety / 
depression (Herdman et al. 2011; Janssen et al. 2013). Published weights are available that 
permit the creation of a single summary score. Overall scores range from 0 to 1, with low 
scores representing a higher level of dysfunction. The second part is a 0 to 100-point visual 
analog scale (VAS), which assesses current health status and higher scores are reflective of 
better health. 
4.5.9.3 
Treatment Preference Questionnaire 
Patient preference will be assessed through a paper version of the EmiPref questionnaire 
(Appendix 3), which asks patients to specify the treatment they would prefer to continue to 
receive after receiving treatment with their previous episodic or prophylactic regimen and SC 
emicizumab. Patients who express a preference are then asked to identify the reasons 
which may have influenced their decision and indicate the top three reasons for their choice. 
Patients will complete this questionnaire after 3 months of treatment with emicizumab. 
4.6 
PATIENT, TREATMENT, STUDY AND SITE DISCONTINUATION 
Patients who discontinue emicizumab prior to the completion of the 2-year treatment period will 
undergo a Safety Follow-up Visit 24 weeks after the patient’s last emicizumab dose or at 2 years after 
emicizumab treatment start, whichever occurs first (see Appendix 1 
 
Schedule of Activities   
). 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient’s inability or unwillingness to comply with protocol requirements 
• 
Non-compliance despite appropriate education measures taken by the clinical site. 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. However, patients will not be followed for any reason after consent has been 
withdrawn. Patients who withdraw from the study will not be replaced. 


 
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4.6.2 
Study Treatment Discontinuation 
Patients must discontinue emicizumab if they experience any of the following: 
• 
Pregnancy 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize the patient’s 
safety if he or she continues to receive emicizumab 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Requirement of another medication not permitted per protocol 
The primary reason for emicizumab discontinuation should be documented on the appropriate 
eCRF. Patients who discontinue emicizumab prematurely will not be replaced. Patients who 
become pregnant should immediately discontinue treatment and be managed according to 
local guidelines. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients 
• 
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 data not checked by investigator/co-
investigator for > 8 weeks) 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled). 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Emicizumab is not approved in all countries, and clinical development is still ongoing. The 
safety plan for patients in this study is based on clinical experience with emicizumab in 
completed and ongoing studies. The anticipated important safety risks for emicizumab are 
outlined below. Please refer to the emicizumab 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 high risk for toxicities. Patients 


 
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will undergo safety monitoring during the study, including assessment of the nature, 
frequency, and grade 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, ISRs have been observed in some patients 
with hemophilia A. These local ISRs included injection-site erythema, injection-site 
hematoma, injection-site rash, injection-site discomfort, injection-site pain, and injection-site 
pruritus. All local ISRs were of mild intensity. Further details on the observed ISRs are 
available in the Investigator’s Brochure. To minimize the risk for ISRs, emicizumab should be 
injected subcutaneously using separate injection sites as described in Sections 0 and 0 and 
the IFU document. 
5.1.1.2 
Hypercoagulation and Thromboembolic Events 
As of April 2017, there have been two serious thrombotic events reported in two patients who 
were treated with bypassing agents while receiving emicizumab prophylaxis in Study BH29884.  
• 
One patient self-administered greater than 200 units/kg/day of aPCC for two consecutive 
days and developed cavernous sinus thrombosis. Treatment with emicizumab was 
interrupted, no further aPCC was administered, and the clot resolved without 
anticoagulation in approximately 2.5 weeks. Emicizumab was restarted after 
approximately 10 days after the resolution of the serious adverse event without recurrence.  
• 
The second patient developed severe skin necrosis (both legs) and contemporaneous 
superficial vein thrombosis in the right leg after self-administering two consecutive doses 
of 100 units/kg/day of aPCC. The patient recovered on supportive therapy (no 
anticoagulation). For more details please refer to the emicizumab Investigator’s Brochure. 
All thromboembolic events should be reported as adverse events of special interest (see 
Section 5.2.3), and also as serious adverse events if it meets criteria as described in Section 5.2.2.  
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 should thromboembolism be suspected. 
5.1.1.3 
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, central nervous system. As of April 2017, three 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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• 
The first patient self-administered two doses of aPCC 94 units/kg in 2 days to treat his left 
knee hemarthrosis. The next day, he started experiencing icterus and severe back pain 
and the patient self-administered two doses of rFVIIa 85 µg/kg and two doses of aPCC 
94 units/kg. Then the patient presented with thrombocytopenia, hyperbilirubinemia, and 
acute renal failure with schistocytes on peripheral blood smears. The patient was 
diagnosed with TMA and treated with plasmapheresis, hemodialysis, and supportive 
care and his condition improved and resolved after 16 days. The patient discontinued 
treatment with emicizumab 
• 
The second patient self-administered five doses of aPCC 74 units/kg over three 
consecutive days before the serious adverse event onset. The patient had abdominal 
pain and emesis, acute renal failure, thrombocytopenia, elevated LDH, and a low 
haptoglobin with schistocytes on peripheral blood smears. The patient was diagnosed 
with TMA and recovered without plasmapheresis or hemodialysis after 18 days. The 
patient restarted treatment with emicizumab after resolution of the serious adverse event 
without recurrence of TMA. 
• 
The third patient presented at the hospital complaining of rectal bleeding, postural dizziness, and 
exertional dyspnea. Of note, 
 
. Multiple doses of rFVIIa were administered and various interventions 
(hemostatic powder application, absorbable hemostat packing, and embolization of rectal arteries) 
were used in an attempt to control bleeding. Despite these measures, the patient continued to have 
rectal hemorrhage. The patient’s bypassing agent treatment was then changed to aPCC and 
temporary cessation of bleeding was achieved. Subsequently, the patient developed a serious 
adverse event of TMA following concomitant bypassing agent treatment. Emicizumab 
prophylaxis and aPCC were discontinued and therapeutic plasma exchange with albumin was 
provided. Three days later, investigators assessed the patient’s TMA to be improving based on 
laboratory assessments (LDH and platelet count). However, the patient experienced recurrent 
rectal hemorrhage. Surgery and arterial embolization were no longer deemed to be feasible and the 
patient was placed on comfort care before passing away the same day. The investigator assessed 
the patient death as related to the serious adverse event of rectal hemorrhage and unrelated to 
emicizumab, and the TMA as related to emicizumab and aPCC. For more details please refer to 
the Emicizumab Investigator’s Brochure. 
These events should be reported as adverse events of special interest (see Section 5.2.3), and also as 
serious adverse events if it meets criteria as described in Section 5.2.2. 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. 
5.1.1.4 
Hypersensitivity 
Since emicizumab is a biological product, acute systemic hypersensitivity reactions, 
including anaphylactic/anaphylactoid reactions, may occur. In Study ACE001JP, no severe 
hypersensitivity reactions or anaphylactic/anaphylactoid reactions have been observed. 








 
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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 unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as described in Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram 
[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 the patient’s pre-
study disease state (the bleed will also be recorded in the patient’s bleed/medication 
records). 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 in 
the patient’s bleed/medication records. 
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; see Section 5.3.3); the 


 
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event itself may be of relatively minor medical significance (such as Grade 3 headache 
without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). 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 4) 
• 
Thromboembolic events 
• 
Microangiopathic hemolytic anemia or TMA (e.g. hemolytic uremic syndrome). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 0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 0). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record and on the Adverse Event eCRF. 




 
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• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions 
An adverse event that occurs during or within 24 hours after emicizumab administration and 
in the investigator’s opinion is judged to be related to emicizumab injection should be 
captured as an “injection-site reaction” on the Adverse Event eCRF. An injection-site 
reaction that is localized should be marked as a “local injection-site reaction.” Associated 
signs and symptoms (e.g., injection-site erythema or injection-site rash) should be recorded 
on the dedicated Injection-Site Reaction eCRF. Systemic reactions should be recorded 
separately on the Adverse Event eCRF. The dedicated Injection-Site Reaction eCRF should 
only be used to capture the individual signs/symptoms for local injection-site reactions. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than injection reactions (see Section 0), a diagnosis (if known) 
should be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual 
event should be recorded on the Adverse Event eCRF. If a diagnosis is subsequently 
established, all previously reported adverse events based on signs and symptoms should be 
nullified and replaced by one adverse event report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
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5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary adverse event that is separated 
in time from the initiating event should be recorded as an independent event on the Adverse 
Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be reported on the eCRF 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
• 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF, if it is unclear 
as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the time 
the event is first reported. If a persistent adverse event becomes more severe, the most 
extreme severity should also be recorded on the Adverse Event eCRF. If the event becomes 
serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions). The 
Adverse Event eCRF should be updated by changing the event from "non-serious" to 
"serious," providing the date that the event became serious, and completing all data fields 
related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints and 
subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
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 
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• 
Is clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the adverse event. For example, an elevated serum potassium level of 7.0 
mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for details on 
recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF. 
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 


 
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defined by Hy's law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 x baseline value in combination with total 
bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical 
jaundice. 
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 emicizumab, 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 A. 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of death 
later becomes available (e.g., after autopsy), "unexplained death" should be replaced by the 
established cause of death. The term "sudden death" should not be used unless combined 
with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of hemophilia A, "hemophilia A progression" should 
be recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as described 
in Section 5.6. 
5.3.5.9 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present during the study Screening Period. Such 
conditions should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
A pre-existing 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 pre-
existing condition has changed by including applicable descriptors (e.g., "more frequent 
headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Hemophilia A  
Medical occurrences or symptoms of deterioration that are anticipated as part of hemophilia 
A should be recorded as an adverse event if judged by the investigator to have unexpectedly 
worsened in severity or frequency or changed in nature at any time during the study. When 


 
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recording an unanticipated worsening of hemophilia A on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors (e.g., "accelerated hemophilia A"). 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) or 
prolonged hospitalization should be documented and reported as a serious adverse event 
(per the definition of serious adverse event in Section 5.2.2), except as outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration) 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
o 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 
o 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: 
• 
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 emicizumab 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 information about overdose is currently available. Accidental overdose may result in 
enhanced procoagulant effects of emicizumab. As with any medication overdose, patients 
may be more susceptible to both known and unknown risks and should be closely monitored 
as appropriate by the investigator.  
5.3.5.13 
Patient-Reported Outcome Data 
The PRO measurements are described in Section 4.5.8. The methods for collecting and 
analyzing PRO data are different from those used for observed or volunteered adverse 
events. Owing to these differences, PRO data will not be reported as adverse events and no 
attempt will be made to resolve any noticeable discrepancies between PRO data and 
observed or volunteered adverse events. All adverse events will be reported by the 


 
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investigator on the Adverse Event eCRF. The PRO data will be presented in separate tables, 
figures, and data listings from the adverse event data, and will be included in the appropriate 
section of the final study report. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR 
TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report such 
events to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the investigator learns of the event. The following is a list of events 
that the investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to emicizumab: 
• 
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 Institutional Review Board/Ethics Committee (IRB/EC). 
5.4.1 
Emergency Medical Contacts 
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 
Responsible individual, and track all calls. The Emergency Medical Call Center Help Desk 
will be available 24 hours per day, 7 days per week. Toll-free numbers for the Help Desk, as 
well as Medical Monitor and Medical Responsible individual 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 emicizumab, 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 
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(i.e., no more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of emicizumab, serious adverse events and adverse events of special interest 
will be reported until the last scheduled study visit (see Section 5.3.1). 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 using the fax 
number or email address provided to investigators. Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the patient has completed 
the 2-year treatment period are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last dose 
of emicizumab. A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. Pregnancy should not be recorded on 
the Adverse Event eCRF. The investigator should discontinue emicizumab and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth 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 (for both the 1.5 and 3.0 mg/kg per week dosing regimens) is 
greater than 10-fold (Banholzer et al. 2012). At this time, very little emicizumab is thought to 
transfer into semen, and there are no known reproductive risks to female partners of male 
patients treated with emicizumab. Therefore, contraception use by male patients is not 


 
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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 
emicizumab 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 trial-related procedures until a final 
outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented on 
the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. At 
the time of pregnancy outcome, reporting instructions provided in Section 0 should be 
followed. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a monitoring 
visit to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that occurs after the end of the adverse event reporting period (defined as the end of 
the 2-year treatment period), 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 


 
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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 using 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 against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health authorities 
based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will assess 
the expectedness of these events using the following reference document: 
• 
Emicizumab Investigator's Brochure. 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary analysis population is all patients who have received at least one dose of 
emicizumab (safety population). The intent-to-treat (ITT) population includes all enrolled 
patients.  
No formal statistical hypothesis tests will be performed and all analyses are considered 
descriptive.  
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 200 patients is planned for this study. 
For the purpose of the sample size calculation, the incidence of adverse events was chosen 
as the safety endpoint of primary interest. 
If the observed incidence of adverse events is between 2.5% and 15%, the precision for the 
estimated incidence rate is presented below according to the 95% Clopper-Pearson 
confidence intervals (CIs) (Table 14). 




 
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and effect on therapy. The data may be presented together with two-sided 95% Clopper-
Pearson CIs if appropriate. 
In addition, as part of the safety evaluation, additional assessments will be summarized 
descriptively as follows: 
• 
Cumulative study medication doses, dose modifications (delays and interruptions), and 
duration of exposure 
• 
Compliance with respect to emicizumab intake (planned vs. received) 
• 
Changes from baseline in physical examination findings 
• 
Vital signs over time: 
o Vital signs will be analyzed using descriptive statistics for continuous variables and 
presented graphically over time with associated 95% CIs. 
• 
Laboratory parameters (hematology and chemistry): 
o These parameters will be presented in shift tables of WHO toxicity grade at baseline 
versus worst grade during the treatment period. Selected laboratory parameters will 
be summarized in terms of mean, standard deviation, minimum, and maximum. 
Laboratory parameters will also be presented graphically over time, if appropriate. 
All safety variables will be analyzed for the safety population. For each variable, the number 
of available observations will be reported. The safety population includes all patients who 
have received at least one dose of emicizumab. 
The primary safety analysis will occur at the end of the study. 
The iDMC (see Section 0) will evaluate the study data, including the emerging safety results, 
at periodic reviews and recommend to the Sponsor whether the protocol should be amended or 
the study should be stopped early. All summaries and analyses will be prepared by the Study 
Management Team (SMT) statistician and presented for iDMC review. Members of the iDMC 
will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities. 
A detailed description of the statistical methods that will be used for the primary analyses will 
be provided in the Statistical Analysis Plan (SAP). 
6.5 
EFFICACY ANALYSES 
The efficacy analyses will involve evaluating the number of bleeds over time, the HRQoL of 
patients, the health status of patients according to EQ-5D-5L scores, and assessing patient 
preference for the emicizumab regimen compared with the previous regimen used. 
The definition of a bleed is described in Section 4.5.7.1. Patients will be asked to record any 
hemophilia medication use (including emicizumab) and information regarding any bleeding events. 
The patients should record this information at least every week even if they do not 
experience a bleed. The number of bleeds will be compared with patients’ bleed rate prior to 
study entry and will be summarized descriptively. 
HRQoL (using the Haem-A-QoL or the Haemo-QoL-SF), health status (using the EQ-5D-5L), 
and patient treatment preference will be assessed as per the Schedule of Activities 
(Appendix 1  
Schedule of Activities   


 
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). 
Adherence with the HRQoL, health status, and patient treatment preference measures will 
be summarized. 
As different HRQoL measures (Haem-A-QoL and the Haemo-QoL-SF) will be used for adult 
and adolescent patients, all calculations and analyses will be conducted separately for each 
patient population. Scale scores for the Haem-A-QoL and Haemo-QoL-SF will be calculated 
and summarized descriptively. The HRQoL scale scores for all patients will be evaluated 
after 6 months of treatment, a timepoint which is consistent with other recent registrational 
studies in hemophilia (Lentz et al. 2013; Mahlangu et al. 2014; Powell et al. 2013) and 
analyses of this type of data (Santagostino et al. 2014; Wyrwich et al. 2015). Paired t-tests 
will be used to compare the on-treatment scores with the baseline scale scores for each 
HRQoL measure. Within-patient changes from baseline for the different HRQoL scale scores 
will also be calculated for each of the on-treatment timepoints. The proportion of patients 
who report changes that exceed clinically meaningful thresholds will be reported. 
For each of the EQ-5D-5L assessments, the number and percentage of patients in each of 
the five categories for each question will be evaluated. Changes in the EQ-5D-5L index utility 
score from baseline will also be reported. In addition, summary statistics including mean, 
standard deviation, median, minimum, and maximum will be calculated according to the 
patients’ health state using the EuroQoL visual analogue scale (EQ-VAS). The proportion of 
patients who report changes that exceed the clinically meaningful threshold on the EQ-5D-
5L index and the EQ-VAS scores will be reported. 
Summary statistics on patient preference for the emicizumab regimen compared with the 
previous regimen used will be presented. 
A detailed description of the statistical methods that will be used for the secondary analyses 
will be provided in the SAP. 
6.6 
IMMUNOGENICITY ANALYSES 
Data on the impact of immunogenicity (anti-emicizumab antibodies) on safety, efficacy, 
and/or PK will be summarized using standard language/terminology (Shankar et al. 2014). 
The immunogenicity analyses will include patients with at least one pre-dose and one post-
dose anti-emicizumab antibody assessment. The numbers and proportions of antibody-
positive patients and antibody-negative patients during the treatment period will be 
summarized. Patients are considered to be antibody-positive if they are negative at baseline 
but develop an anti-emicizumab antibody response following emicizumab administration 
(treatment-induced antibody response), or if they are positive at baseline and the titer of one 
or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer 
of the baseline sample (treatment-enhanced antibody response). Patients are considered to 
be antibody-negative if they are negative at baseline and all post-baseline samples are 
negative, or if they are positive at baseline but do not have any post-baseline samples with a 
titer that is at least 4-fold greater than the titer of the baseline sample (treatment unaffected). 
The relationship between anti-emicizumab antibody status and safety, efficacy, and PK 
endpoints will be analyzed and reported descriptively via subgroup analyses. 


 
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A detailed description of the statistical methods that will be used for the secondary analyses 
will be provided in the SAP. 
6.7 
PHARMACOKINETIC ANALYSES 
For all patients, pre-dose (concentration at the end of the dosage interval [Ctrough]) plasma 
concentrations of emicizumab will be presented descriptively for each timepoint. Data 
presented will include 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 
for emicizumab following SC administration. Population PK parameters, such as clearance 
and volume of distribution, will be estimated, and the influence of various covariates, such as 
age, gender, and body weight, on these parameters will be investigated graphically. 
Secondary PK parameters, such as AUC, will be derived from individual post-hoc 
predictions. Results may be pooled with data from previous Phase I-III studies. If conducted, 
these analyses will be presented in a dedicated report. 
6.8 
BIOMARKER ANALYSES 
Data from PD, safety biomarker, safety coagulation system biomarker, and bone and joint 
biomarker assessments will be presented using summary statistics, including arithmetic and 
geometric means, median, range, standard deviations, and coefficients of variation. 
6.9 
INTERIM ANALYSES 
6.9.1 
Planned Interim Analyses 
The first interim analysis will be performed once approximately 100 patients have received 
treatment with emicizumab for at least 24 weeks. A second interim analysis will be 
performed when approximately 100 patients have received treatment with emicizumab for at 
least 52 weeks. The data from these analyses will subsequently be presented to the iDMC in 
order to enable them to effectively monitor the study (see Section 0). 
Details regarding the planned interim analyses will be provided in the SAP and iDMC charter. 
6.9.2 
Optional Interim Analysis 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up 
to two additional interim efficacy analyses (i.e., beyond what is specified in Section 0). The 
decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analysis. Any 
interim analyses will be performed and interpreted by members of the Sponsor study team 
and appropriate senior management personnel. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study. A contract research organization 
(CRO) will be responsible for data management of this study, including quality checking of 


 
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the data. Data entered manually will be collected using EDC through use of eCRFs. Sites 
will be responsible for data entry into the EDC system. In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve electronically in 
the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. Central laboratory data and ePRO data will be sent directly to the 
either the Sponsor or the vendor using the Sponsor's standard procedures to handle and 
process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including approval 
of the CRO’s data management plans and specifications. Data will be periodically 
transferred electronically from the CRO to the Sponsor, and the Sponsor’s standard 
procedures will be used 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 at the CRO and records retention for the study data will be 
consistent with the CRO’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 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
PRO data will be collected electronically through the use of electronic devices provided by 
an ePRO vendor (HRQoL and EQ-5D-5L) or using a paper questionnaire (EmiPref). Paper 
versions of the questionnaires are also available in case of ePRO outage or if an ePRO device is 
otherwise unavailable. The electronic device is designed for entry of data in a manner that is 
attributable, secure, and accurate, in compliance with electronic records: 21 Code of Federal 
Regulations, Part 11. The PRO data from the device will be transmitted electronically to the 
eCRF in real time. Only identified and trained users may view the data, and their actions (if 
any) will become part of the audit trail. The Sponsor will have view-only access to PRO data. 
The Sponsor will receive all data (including requested meta-data) entered by the patients on 
the ePRO devices and all relevant study documentation. 
Once the study is complete, the ePRO data, audit trail, and trial and system documentation 
will be archived. The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data. Acknowledgement of receipt of the compact disc is required. 


 
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In addition, the Sponsor will receive all patient data in a machine-readable format on a 
compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical 
and office charts, laboratory notes, memoranda, PROs, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions that 
are certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, 
laboratories, and medico-technical departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly 
into the eCRFs (i.e., no prior written or electronic record of the data) and considered source 
data. 
Source documents that are required to verify the validity and completeness of data entered 
into the eCRFs must not be obliterated or destroyed and must be retained per the policy for 
retention of records described in Section 0. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The study site must also allow inspection by 
applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve as 
the source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research. An acceptable 
computerized data collection system allows preservation of the original entry of data. If 
original data are modified, the system should maintain a viewable audit trail that shows the 
original data as well as the reason for the change, name of the person making the change, 
and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including eCRFs, ePRO data, 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. 


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


 
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Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each 
patient’s study file or in the site file and must be available for verification by study monitors at 
any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators 
must comply with requirements for reporting serious adverse events to the local health 
authority and IRB/EC. Investigators may receive written IND safety reports or other 
safety-related communications from the Sponsor. Investigators are responsible for ensuring 
that such reports are reviewed and processed in accordance with health authority 
requirements and the policies and procedures established by their IRB/EC, and archived in 
the site’s study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names 
are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
The aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication (see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, representatives, 
and collaborators, and the IRB/EC for each study site, as appropriate. 


 
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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, subjects’ medical records, and eCRFs. The investigator will permit national and 
local health authorities; Sponsor monitors, representatives, and collaborators; and the 
IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The IxRS system will be used to confirm the shipment condition and content of the IMP (see 
Section 0). A central laboratory will be used to conduct all laboratory assessments (see 
Section 0). A CRO will be responsible for data management of this trial (see Section 7.1). An 
iDMC will review the safety, efficacy, immunogenicity, and PK data collected during the 
study (see Section 0). The procedures that will be used by the iDMC will be detailed in an 
iDMC charter. 
9.4.1 
Independent Data Monitoring Committee 
An iDMC will be assembled to review the safety data collected during the study. The iDMC 
members will consist of, at minimum, independent hemostasis/thrombosis experts and a 
statistician, none of whom will be otherwise involved in the conduct of study. All analyses for 
review by the iDMC will be prepared by the SMT statistician. Monitoring and analysis of all 


 
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significant safety events will be performed on a continuous basis. A first interim analysis of 
the study data will be performed once approximately 100 patients have received treatment 
with emicizumab for at least 24 weeks (see Section 0), and a second interim analysis will be 
performed when approximately 100 patients have received treatment with emicizumab for at 
least 52 weeks. Thereafter, the iDMC will meet at a frequency determined by the iDMC and 
the Sponsor according to the emerging data. 
The SMT statistician will perform analyses and provide tables and listings to support the 
study reviews by the iDMC. The safety data that will be provided will include demographic 
data, adverse events (the incidence and severity of all adverse events, including 
thromboembolic events, microangiopathic hemolytic anemia or TMA, systemic hypersensitivity, 
anaphylaxis, and anaphylactoid events), medication dose information, physical examination 
findings, vital sign data, and laboratory abnormalities (hematology and chemistry). If 
available, the efficacy data that will provided will include the number of bleeds over time, 
ABR data, the HRQoL of patients, the health status of patients according to EQ-5D-5L 
scores, and patient preference for the emicizumab regimen compared with the previous 
regimen used. Further information will be provided on request. 
Following each meeting, the iDMC will recommend to the Sponsor whether the study should 
continue according to the protocol or may suggest changes to the protocol based on the 
outcome of the data review. In exceptional cases, the iDMC may recommend stopping the 
study for safety reasons. 
The meeting schedule and all other iDMC-related activities will be specified in a separate 
iDMC charter. All closed meetings will be summarized in written minutes available only to 
iDMC members. These minutes will be kept by the iDMC chair until the end of the study. The 
recommendations can be communicated to the Sponsor verbally but have to be confirmed in 
writing according to a pre-defined timeframe.  
The final decision of acting upon the recommendations from the iDMC will rest with the 
Sponsor. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all requirements for 
publication of study results. For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Information.  
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application has 
been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within 6 months after the availability of the respective 
Clinical Study Report. In addition, for all clinical trials in patients involving an IMP for which a 
marketing authorization application has been filed or approved in any country, the Sponsor 
aims to publish results from analyses of additional endpoints and exploratory data that are 
clinically meaningful and statistically sound. 


 
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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not 
yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. Any formal publication of the study in 
which contribution of Sponsor personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the 
use of data from this study will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
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). 
9.7 
STUDY PARTICIPANT SURVEY 
Consenting patients may be asked about their study experience via a short study-specific survey.   
Survey questions will ask the patient to rate their study experience on a scale of 1-5 on topics that 
include the following: information provided prior to the study, the consent and enrolment process, 
study participation, study results and feeling appreciated as a study patient.   
Patients will be asked to complete the survey at the end of the study. The goal of this survey is to 
identify areas where Roche is performing well and areas where improvement may be required.   
Information will be provided to the Sponsor securely and on an anonymous basis and consent to the 
survey is totally voluntary and does not affect patient’s enrolment to the study.  
 


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10.
REFERENCES
Acharya SS. Rare bleeding disorders in children: identification and primary care 
management. Pediatrics 2013;132:882–92. 
Ahnström J, Berntorp E, Lindvall K, Björkman S. A 6-year follow-up of dosing, coagulation 
factor levels and bleedings in relation to joint status in the prophylactic treatment of 
haemophilia. Haemophilia 2004;10:689–97. 
Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis and 
on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. 
Haemophilia 2014;20:65–72. 
Astermark J. When to start and when to stop primary prophylaxis in patients with severe 
haemophilia. Haemophilia 2003;9 (suppl 1):32–7. 
Banholzer ML, Buergin H, Wandel C, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partners. J Transl Med 
2012;10:129. 
Bell SA, Tudur Smith C. A comparison of interventional clinical trials in rare versus non-rare 
diseases: an analysis of ClinicalTrials.gov. Orphanet J Rare Dis 2014;9:170. 
Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. 
Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 
2014;12:1935–9. 
Brown TM, Lee WC, Joshi AV, Pashos CL. Health-related quality of life and productivity 
impact in haemophilia patients with inhibitors. Haemophilia 2009;15:911–7. 
Bui JD, Despotis GD, Trulock EP, Patterson GA, Goodnough LT. Fatal thrombosis after 
administration of activated prothrombin complex concentrates in a patient supported by 
extracorporeal membrane oxygenation who had received activated recombinant factor VII. J 
Thorac Cardiovasc Surg 2002;124:852–4. 
Bullinger M, Von Mackensen S, Fischer K, et al. Pilot testing of the “Haemo-QoL” quality of 
life questionnaire for haemophiliac children in six European countries. Haemophilia 2002;8 
(suppl 2):47–54. 
CDC. Centers for Disease Control and Prevention: Hemophilia Data & Statistics. Available
from: https://www.cdc.gov/ncbddd/hemophilia/data.html. Last accessed: 17 August 2016
Cimino E, Linari S, Malerba M, Halimeh S, Biondo F, Westfeld M. Patient preference and 
ease of use for different coagulation factor VIII reconstitution device scenarios: a cross-
sectional survey in five European countries. Patient Prefer Adherence 2014;8:1713–20. 
Collins PW, Björkman S, Fischer K, et al. Factor VIII requirement to maintain a target plasma 
level in the prophylactic treatment of severe hemophilia A: influences of variance in 
pharmacokinetics and treatment regimens. J Thromb Haemost 2010;8:269–75. 
Dentali F, Marchesi C, Pierfranceschi MG, et al. Safety of prothrombin complex concentrates 
for rapid anticoagulation reversal of vitamin K antagonists: A meta-analysis. Thromb 
Haemost 2011;106:429–38. 


 
Emicizumab — F. Hoffmann-La Roche Ltd 
155 / Protocol MO39129, Version 3 
Ettingshausen CE, Kreuz W. Early long-term FEIBA prophylaxis in haemophilia A patients 
with inhibitor after failing immune tolerance induction: A prospective clinical case series. 
Haemophilia 2010;16:90–100. 
Ewenstein BM, Valentino LA, Journeycake JM, et al. Consensus recommendations for use 
of central venous access devices in haemophilia. Haemophilia 2004;10:629–48. 
Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013;27:179–84. 
Geraghty S, Dunkley T, Harrington C, Lindvall K, Maahs J, Sek J. Practice patterns in 
haemophilia A therapy – global progress towards optimal care. Haemophilia 2006;12:75–81. 
Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci PM. A randomized clinical 
trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 
2011;9:700–10. 
Hay CRM, DiMichele DM. The principal results of the International Immune Tolerance Study: 
a randomized dose comparison. Blood 2012;119:1335–44. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-
level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727–36. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res 
2013;22:1717–27. 
Karaman K, Akbayram S, Garipardıç M, Öner AF. Diagnostic evaluation of our patients with 
hemophilia A: 17-year experience. Turk Arch Pediatr 2015;50:96–101. 
Kempton CL, White II GC. How we treat a hemophilia A patient with a factor VIII inhibitor. 
Blood 2009;113:11–7. 
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult patients 
with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. Eur J 
Haematol 2012;88:329–35. 
Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of 
recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J 
Thromb Haemost 2007;5:1904–13. 
Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in 
hemophilia with inhibitors. N Engl J Med 2011;365:1684–92. 
Leissinger CA, Becton DL, Ewing NP, Valentino LA. Prophylactic treatment with activated 
prothrombin complex concentrate (FEIBA®) reduces the frequency of bleeding episodes in 
paediatric patients with haemophilia A and inhibitors. Haemophilia 2007;13:249–55. 
Lentz SR, Misgav M, Ozelo M, et al. Results from a large multinational clinical trial 
(guardianTM1) using prophylactic treatment with turoctocog alfa in adolescent and adult 
patients with severe haemophilia A: safety and efficacy. Haemophilia 2013;19:691–7. 
Lundkvist M, Engdahl E, Holmén C, et al. Characterization of anti-natalizumab antibodies in 
multiple sclerosis patients. Mult Scler J 2012;19:757–64. 


Emicizumab — F. Hoffmann-La Roche Ltd 
156 / Protocol MO39129, Version 3 
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion 
protein in severe hemophilia A. Blood 2014;123:317–25. 
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to 
prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535–44. 
Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, controlled, parallel-group 
trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant 
factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013;11:1119–
27. 
Mariani G, Siragusa S, Kroner BL. Immune tolerance induction in hemophilia A: a review. 
Semin Thromb Hemost 2003;29:069–76. 
NIH. National Institutes of Health: National Heart, Lung, and Blood Institute. What Is 
Hemophilia? Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia. 
Last accessed: 17 August 2016 
Oldenburg J, Mahlangu JN, Kim B, et al.  Emicizumab prophylaxis in hemophilia A with 
inhibitors.  NEJM 2017;277(9):809-18. 
Plug I, Mauser-Bunschoten EP, Bröcker-Vriends AHJT, et al. Bleeding in carriers of 
hemophilia. Blood 2006;108:52–6. 
Pollak E, Mühlan H, Von Mackensen S, Bullinger M. The Haemo-QoL Index: developing a 
short measure for health-related quality of life assessment in children and adolescents with 
haemophilia. Haemophilia 2006;12:384–92. 
Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion 
protein in hemophilia B. N Engl J Med 2013;369:2313–23. 
Sampei Z, Igawa T, Soeda T, et al. Identification and multidimensional optimization of an 
asymmetric bispecific igg antibody mimicking the function of factor viii cofactor activity. 
PLOS ONE 2013;8:e57479. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: Summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006;117:391–7. 
Santagostino E, Morfini M, Auerswald GK-H, et al. Paediatric haemophilia with inhibitors: 
existing management options, treatment gaps and unmet needs. Haemophilia 2009;15:983–
9. 
Santagostino E, Lentz SR, Busk AK, 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;20:527–34. 
Schrijvers LH, Uitslager N, Schuurmans MJ, Fischer K. Barriers and motivators of adherence 
to prophylactic treatment in haemophilia: a systematic review. Haemophilia 2013;19:355–61. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical immunogenicity 
of 
therapeutic 
proteins 
and 
peptides—harmonized 
terminology 
and 
tactical 
recommendations. AAPS J 2014;16:658–73. 


Emicizumab — F. Hoffmann-La Roche Ltd 
157 / Protocol MO39129, Version 3 
Shapiro AD. Long-lasting recombinant factor VIII proteins for hemophilia A. Hematol Am Soc 
Hematol Educ Program 2013;2013:37–43. 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of 
hemophilia. Haemophilia 2013;19:e1–47. 
Stasyshyn O, Antunes S, Mamonov V, et al. Prophylaxis with anti-inhibitor coagulant 
complex improves health-related quality of life in haemophilia patients with inhibitors: results 
from FEIBA NF Prophylaxis Study. Haemophilia 2014;20:644–50. 
Thornburg CD. Prophylactic factor infusions for patients with hemophilia: challenges with 
treatment adherence. J Coagul Disord 2010;2:1–6. 
Tjønnfjord GE. Activated prothrombin complex concentrate (FEIBA®) treatment during 
surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience. 
Haemophilia 2004;10 (suppl 2):41–5. 
Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis 
regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia 
A management. J Thromb Haemost 2012;10:359–67. 
Vennegoor A, Rispens T, Strijbis EM, et al. Clinical relevance of serum natalizumab 
concentration and anti-natalizumab antibodies in multiple sclerosis. Mult Scler J 
2013;19:593–600. 
Von Mackensen S, Bullinger M. Development and testing of an instrument to assess the 
quality of life of children with haemophilia in europe (haemo-qol). Haemophilia 2004;10 
(suppl 1):17–25. 
Von Mackensen SV, Gringeri A. Quality of life in hemophilia. In: Preedy VR, Watson RR, editors. 
Handbook of disease burdens and quality of life measures. New York: Springer, 2010:1895–920. 
Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. 
Ther Adv Hematol 2013;4:59–72. 
Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII 
inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J 
Emerg Med 2009;2:217–25. 
World Federation of Hemophilia. Annual Global Survey Data 2014. Available from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx. 
Last 
accessed: 16 August 2016 
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of life 
change using the Haem-A-QoL. Haemophilia 2015;21:578–84. 








Appendix 1  
Schedule of Activities (cont.) 
Emicizumab — F. Hoffmann-La Roche Ltd 
161 / Protocol MO39129, Version 3 
4 weeks prior to screening (including prescription drugs, over-the-counter drugs, and herbal/homeopathic remedies and therapies). Any hemostatic medications (e.g. 
bypassing agents) and other medications used to treat or prevent bleeds in the 6-month period prior to starting emicizumab treatment will also be collected. Demographic 
data will include age, sex, and self-reported race and ethnicity. 
f.
A complete physical examination will be performed during Screening and should include, but not necessarily be limited to, an evaluation of the head, eyes, ears,
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological systems. Any abnormality identified during
screening should be recorded on the General Medical History and Baseline Conditions eCRF.  Targeted physical examinations (i.e., joints for bleeds, evidence of
arthropathy; skin for bruises, hematomas and ISRs; other organ systems as clinically indicated) should be conducted at subsequent visits or as clinically
indicated. New or worsened clinically significant abnormalities from screening should be recorded as adverse events, if appropriate, on the Adverse Event eCRF.
g.
Vital signs include measurement of body temperature (oral, rectal, axillary, or tympanic), heart and respiratory rates, blood pressure and weight.  On treatment
days, measurement should occur prior to emicizumab administration. Height will be measured and recorded only during Screening and 6 and 12 months after
starting emicizumab. Additional vital signs assessments may also be taken anytime as unscheduled assessments as judged by the investigator. In addition, vital signs
may be taken to help monitor for hypersensitivity reactions during or after injections at the investigator's discretion, although these data should not be entered
into the eCRF.
h.
The definition of concomitant medications, as well as permitted and prohibited medications is described in Section 4.4.  Concomitant medications used by a patient
from 4 weeks prior to initiation of emicizumab to the Study Completion/Early Termination Visit (or to the Safety Follow-up Visit, if applicable) should be reported to the
investigator and recorded on the Concomitant Medications eCRF.  Treatments for bleeds (i.e., bypassing agents and other medications to treat bleeds), will be collected in
the bleed records.
i.
Hematology and blood chemistry assessments will include a complete blood count with differential and serum chemistries (see Section 4.5.6.1). Laboratory
assessments completed during Screening do not have to be repeated at Week 1, if the period between Screening and Week 1 is ≤ 5 days and there has
been no change in the patient’s health status as assessed by the investigator. Samples will be sent to the central laboratory for analysis.
j.
Pregnancy tests: Female patients of childbearing potential (including those who have had a tubal ligation) will be required to have a negative serum
pregnancy test result during Screening and again within 7 days prior to the first dose of emicizumab. Urine pregnancy tests will be performed throughout
the study treatment period. Pregnancy testing will be conducted at the local laboratory.
k.
The specific tests utilized for hepatitis and HIV serology testing are per local standard of care. As this patient population is at high risk for HIV, hepatitis A, B and C,
sites should consider testing for these. While the specific serological tests used is at the discretion of the Investigator, this is with the understanding that the status of that
participants’ hepatitis or HIV is confidently known at time at enrollment. HIV and hepatitis serology tests will be conducted at the local laboratory.
l.
For the assessment of anti-FVIII antibodies (inhibitors), functional assays that utilize a clotting readout (classic Bethesda or Nijmegen assay) cannot be used for
patients on emicizumab therapy as emicizumab drives clotting even in the presence of FVIII inhibitors, causing a false-negative test result (see Section 5.1.3). After the
first dose, local measurement of FVIII inhibitors, if indicated, requires use of an ELISA-based test or a chromogenic Bethesda assay.  At the discretion of the local
investigator, any additional urgent request to assess FVIII inhibitors will need to be sent to the central laboratory (see Appendix 2 for additional information). Plasma
samples for anti-FVIII antibodies will be analysed at the central laboratory
m. Plasma samples are required for immunogenicity assessments to detect anti-emicizumab antibodies.  Additional samples to detect anti-emicizumab
antibodies may also be drawn at the time of hypersensitivity events or following suspected loss of efficacy. Samples will be analysed at the central laboratory.


Appendix 1  
Schedule of Activities (cont.) 
Emicizumab — F. Hoffmann-La Roche Ltd 
162 / Protocol MO39129, Version 3 
n.
ePRO bleed / medication recording: At the Week 1 visit, patients will be trained on how to record their bleeds and hemophilia medication use on the ePRO
device where possible. Data that need to be recorded will include the site of bleed, type of bleed, time of each individual bleed (day, start and stop time), and
treatment for bleed. At least once a week, patients will need to record any hemophilia medication use (including emicizumab) and information regarding any bleeding
events. Investigator review of patient-reported bleed/medication records with the patient/caregiver will occur for completeness and accuracy at all of the
visits during the treatment period, at study completion, at any unscheduled visits (if required), and at the Early Termination Visit (if required).
o.
Thorough documentation on surgical events will be requested, including type of surgery or procedures, treatments, outcomes, etc.
p.
Adverse events:  After informed consent has been obtained but prior to initiation of emicizumab, only serious adverse events caused by a protocol-mandated
intervention should be reported. Injection-site reaction adverse events will be collected on the injection site reaction form.
q.
Management of emicizumab: Drug dispensation will not occur at the Study Completion Visit or the Early Termination Visit (if required). Patients will only
receive emicizumab during an unscheduled visit if drug dispensation is required at this time.
r.
HRQoL and EQ-5D-5L: Patients will be requested to complete Haem-A-QoL (adults age: ≥ 18 years) or the Haemo-QoL-SF (adolescents ages:
12−17 years) questionnaire and the EQ-5D-5L questionnaire. Questionnaires will be self-administered electronically before the patient/caregiver receives any
information on disease status, prior to the performance of non-PRO assessments, and prior to emicizumab administration (if on a treatment day). Paper versions of the
questionnaires are also available in case of ePRO outage or if an ePRO device is otherwise unavailable.
s.
EmiPref:  At the 3-month assessment, patients will be prompted to complete a paper version of the EmiPref questionnaire (Appendix 3). The questionnaire will
be self-administered before the patient/caregiver receives any information on disease status, prior to the performance of non-PRO assessments, and prior to emicizumab
administration (if on a treatment day).
t.
On treatment days, blood collection should occur within 2 hours prior to emicizumab administration unless otherwise specified. Unless otherwise specified, additional
analysis will be performed at a local laboratory, as per the investigator’s discretion.  Any additional laboratory results which are required as part of the patient’s safety
assessment should be recorded in the unscheduled visit eCRFs.  Central labs are part of the non-eCRF data which will be sent to the Sponsor directly by the central lab
vendor.
u.
Plasma samples are required for PK assessments.  On days where samples are to be collected, the emicizumab injection will be performed in the clinical unit.  One
single pre-dose sample is required on the applicable visits. Samples will be analysed by the central laboratory.
v.
Plasma samples for safety biomarkers must be citrate plasma. Tests may include, but are not limited to, D-dimer.  Samples will be analysed by the central laboratory.
See Appendix 2.
w.
Plasma samples for safety coagulation system biomarker assessments must be citrate plasma. Tests include FVIII:Ag, FIX:Ag and FX:Ag. Samples will be
analysed by the central laboratory.  See Appendix 2.
x.
Plasma samples for PD biomarker assessments must be citrate plasma.  Tests will include, but are not limited to, FVIII activity and modified aPTT (one stage).
Time windows for sample collection are specified in Appendix 2
Schedule of Biomarker Samples
y.
. Additional plasma samples will be collected for future exploratory research, which may include tests such as clot waveform analysis (CWA) and others
(see Appendix 2
Schedule of Biomarker Samples
z.
).  Samples will be analysed by the central laboratory.


Appendix 1  
Schedule of Activities (cont.) 
Emicizumab — F. Hoffmann-La Roche Ltd 
163 / Protocol MO39129, Version 3 
aa. Serum and plasma EDTA samples for bone and joint biomarkers must be collected after fasting (no food or drink other than water for at least 8 hours 
prior to the blood draw). Ideally these samples should be collected in the morning (before noon), in order to control for diurnal variation. Please consult 
the Central Laboratory Services Manual for details. The selection of exploratory bone and joint biomarkers to be tested will build on findings from 
biomarker analyses in other emicizumab trials and may include CTX-1, OPG, P1NP, and soluble RANK-L (see Appendix 2  
Schedule of Biomarker Samples 
bb. ). Samples will be analysed by the central laboratory. 
cc. Additional laboratory assessments:  In the event of a breakthrough bleed that is treated with bypassing agents, it is recommended that the following laboratory tests
will be performed within 2448 hours of initial bypassing agent use (these tests will be conducted so that the investigator can monitor the patient for potential
thromboembolic events and microangiopathic hemolytic anemia or TMA). These tests include platelet count, serum creatinine, LDH and schistocytes. A plasma sample
should also be provided for central laboratory monitoring of prothrombin fragment F1+2, fibrinogen and D-dimer. Samples for these tests should ideally be
analysed at the central laboratory.  Exceptionally in urgent situations where results are required quickly, local laboratory testing can be used, with results recorded in
the eCRF. For patients who require multiple doses of bypassing agents, laboratory monitoring should be performed every 2448 hours until 2448 hours after the last
dose of bypassing agents is administered to treat a specific bleed. If applicable, laboratory results should be recorded in the unscheduled visit eCRFs.




Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples (cont.) 
Emicizumab — F. Hoffmann-La Roche Ltd 
165 / Protocol MO39129, Version 3 
d. Serum and plasma EDTA samples for bone markers must be collected after fasting (no food or 
drink other than water for at least 8 hours prior to the blood draw). Ideally these samples should 
be collected in the morning (before noon), in order to control for diurnal variation. Please consult 
the Central Laboratory Services Manual for details. 
e. The selection of exploratory bone and joint biomarkers to be tested will build on findings from 
biomarker analyses in other emicizumab trials. Biomarkers that have been tested in these trials 
include CTX-1, OPG, P1NP, and soluble RANK-L. 
 


Emicizumab — F. Hoffmann-La Roche Ltd 
166 / Protocol MO39129, Version 3 
Appendix 33  
EmiPref Patient Preference Questionnaire 
(Paper Version, United Kingdom / English) 
Instructions: You have been treated with intravenous (IV) Factor VIII or bypassing agent 
(your old hemophilia treatment) and prophylactic subcutaneous (SC) emicizumab (the new 
study drug treatment). Please complete the following questions based on your experience 
with these treatments.  
There are no right or wrong answers and your responses will not influence your continued 
participation in the study or treatment with emicizumab.  
1. Which of the treatments would you prefer to take as the treatment for your hemophilia?
(Mark ONLY one response)
Prefer my old hemophilia treatment (IV) 
Prefer the new study drug treatment (SC) 
Have no preference 
If you indicated a preference, please complete question 2. 
If you did not have a preference, you do not need to complete questions 2. 


Appendix 3 
EmiPref Patient Preference Questionnaire 
(cont.) 
Emicizumab — F. Hoffmann-La Roche Ltd 
167 / Protocol MO39129, Version 3 
 
2. Below are some factors that may have influenced your treatment preference. Please 
indicate which factors had an influence on YOUR preference. Please indicate YES (this 
influenced my preference) or NO (this did not influence my preference) for each item.  
On those you said YES to, please rank the top 3 in order of importance (1 being the  
“most important” reason for your preference). 
 
Yes 
No 
Importance 
rank 
Route of administration (IV or SC) was easier 
 
 
 
Pain associated with treatment was less 
 
 
 
Worry about finding a vein was less 
 
 
 
Concern over port use/infection was less 
 
 
 
Administration was easier 
 
 
 
Able to keep treatment at room temperature 
 
 
 
Time to administer treatment was shorter 
 
 
 
The frequency of treatments was lower 
 
 
 
Effect on other activities (work, school, sports, 
social interactions) was less 
 
 
 
Impact on family members and friends was less 
 
 
 
Worries about having a bleed were less 
 
 
 
Quality of life, in general, was better 
 
 
 
It was easier to take every dose my doctor 
recommended 
 
 
 
Made me feel more ‘normal’ 
 
 
 
 
3. Please add any additional information about your experience with the study drug (SC 
emicizumab). 
 


Emicizumab — F. Hoffmann-La Roche Ltd 
168 / Protocol MO39129, Version 3 
Appendix 44  
Clinical Criteria for Diagnosing Anaphylaxis 
These criteria are taken from a summary report from the second symposium on the definition 
and management of anaphylaxis, conducted by the National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network.1 Anaphylaxis is highly likely when 
any one of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips,
tongue/uvula)
AND AT LEAST ONE OF THE FOLLOWING:
•
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced
peak expiratory flow, hypoxemia)
•
Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g.,
hypotonia, syncope, incontinence).
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
•
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen
lips-tongue-uvula)
•
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced
peak expiratory flow, hypoxemia)
•
Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope,
incontinence)
•
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting).
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to
several hours):
•
Infants and children: low systolic blood pressure (age specific) or greater than 30%
decrease in systolic blood pressure [a]
•
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. 
a.
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 Single-Arm, Multicenter Phase IIIB Clinical Trial to Evaluate the 
Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A 
Patients With Inhibitors 
NCT Number: NCT03191799 
Document Dates: SAP Version 3: 05-November-2020 
 
 


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 MO39129 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A SINGLE-ARM, MULTICENTER PHASE IIIB 
CLINICAL TRIAL TO EVALUATE THE SAFETY AND 
TOLERABILITY OF PROPHYLACTIC EMICIZUMAB 
IN HEMOPHILIA A PATIENTS WITH INHIBITORS 
PROTOCOL NUMBER: 
MO39129 
STUDY DRUG: 
Emicizumab (RO5534262) 
VERSION NUMBER: 
3.0 (Protocol Version 3 of 09 March 2018) 
EUDRACT NUMBER: 
2016-004366-25 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel 
(Versions 2.0 and 3.0) 
 (Version 1.0) 
 (Version 
1.0) 
 
DATE FINAL: 
5 November 2020 
 
 


Emicizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan MO39129 
STATISTICAL ANALYSIS PLAN HISTORY 
 
SAP Version / Date 
Description 
Version 1.0 / 11 June 2018 
Initial version. 
Version 2.0 / 6 December 
2018 
• Revision based on protocol amendment v3.0 dated 
09MAR2018: population for patients with surgery 
on-study added (Section 4.2.5) and analyses on 
patients with surgeries on-study added (Sections 
4.4 and 4.9.4). 
• Population for efficacy analyses updated to ITT 
instead of Safety (Section 4.6), for consistency with 
protocol. 
• Clarifications added on the study periods (before 
up-titration, after up-titration, both) to be included in 
the analyses. 
• Updates done for consistency with Haven-1 and 
Haven-4 studies: Definition of efficacy period 
(Section 4.1); Definition of prior / concomitant 
medications (Section 4.5). 
• Addition of analyses done for Haven-1 and Haven-4 
studies: Compliance analyses for questionnaires 
(Section 4.6.1.7); Analysis of the number of days 
hospitalized (Section 4.6.8). 
• Updates to the analysis of adverse events (Section 
4.9.2): clarification of the reporting period, list of 
AESIs revised as per protocol.  
• Details on the PK analysis removed as it will be 
described in a separate SAP. 
Version 3.0 / 5 November 
2020 
• Definition of treated joint bleeds revised for 
consistency with Haven-1 and Haven-4 studies: 
aura criterion removed (Section 2.2.2.7) 
• Definition of positive ATA patients updated for 
consistency with Haven-1 and Haven-4 studies 
(Section 4.8) 
• Definition of TEAEs clarified (Section 4.9.2) 
• Section on analysis of surgeries revised (Section 
4.9.4) 
• Section on analysis of biomarkers revised (Section 
4.10) 
• Analyses on impact of COVID-19 added (Section 
4.3 and 4.9.2) 
• Details on the PK analysis added (Section 4.7) 


Emicizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan MO39129 v3.0 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 9 
1.1 
Background on Hemophilia A with Inhibitors ........................... 9 
1.2 
Background on Emicizumab .................................................... 9 
2. 
STUDY DESIGN ......................................................................................... 10 
2.1 
Protocol Synopsis .................................................................. 11 
2.2 
Objectives and Endpoints ...................................................... 12 
2.2.1 
Adverse Events of Special Interest ........................................ 12 
2.2.2 
Bleed Assessments ............................................................... 12 
2.2.2.1 Definition of a Bleed ............................................................. 13 
2.2.2.2 Treated bleeds ..................................................................... 13 
2.2.2.3 72-Hour rule ......................................................................... 13 
2.2.2.4 All bleeds .............................................................................. 13 
2.2.2.5 Bleed Sites ........................................................................... 14 
2.2.2.6 Definitions of Cause/Classification of Bleeds ....................... 14 
2.2.2.7 Treated Joint Bleeds ............................................................ 15 
2.2.2.8 Treated Target Joint Bleeds ................................................. 15 
2.2.2.9 Treated Spontaneous Bleeds ............................................... 15 
2.2.3 
HRQoL Assessments ............................................................ 15 
2.2.4 
Health Status Assessments (EQ-5D-5L) ............................... 16 
2.2.5 
Treatment Preference Questionnaire .................................... 16 
2.3 
Determination of Sample Size ............................................... 17 
2.4 
Analysis Timing ..................................................................... 17 
3. 
STUDY CONDUCT ..................................................................................... 17 
3.1 
Randomisation Issues ........................................................... 17 
3.2 
Independent Review Facility .................................................. 17 
3.3 
Data Monitoring ..................................................................... 18 
4. 
STATISTICAL METHODS .......................................................................... 18 
4.1 
Reporting Periods .................................................................. 18 
4.2 
Analysis Populations ............................................................. 20 
4.2.1 
Primary Population (Safety Population) ................................. 20 
4.2.2 
Intend-To-Treat Population .................................................... 20 


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4.2.3 
Pharmacokinetic-Evaluable Population(PK 
Population) 20 
4.2.4 
Up-Titrated Population ........................................................... 20 
4.2.5 
Surgery Population ................................................................ 20 
4.3 
Analysis of Study Conduct ..................................................... 20 
4.4 
Baseline and demographic characteristics ............................ 21 
4.5 
Previous and concomitant medications ................................. 22 
4.6 
Efficacy Analysis .................................................................... 23 
4.6.1 
Efficacy endpoints ................................................................. 23 
4.6.1.1 Bleeds .................................................................................. 23 
4.6.1.2 Number of Bleeds/ABR categories ....................................... 23 
4.6.1.3 Cause, type and location of bleed ........................................ 24 
4.6.1.4 Type of trauma ..................................................................... 24 
4.6.1.5 Time of bleed ....................................................................... 24 
4.6.1.6 Use of non-Emicizumab hemophilia treatments ................... 24 
4.6.1.7 Bleed and Medication Questionnaire 
Compliance ........................................................................................ 24 
4.6.2 
HRQoL (Haem-A-QoL and Haemo-QoL-SF) ......................... 25 
4.6.3 
EQ-5D-5L .............................................................................. 25 
4.6.4 
Patient preference ................................................................. 26 
4.6.5 
Exploratory Efficacy Endpoints .............................................. 27 
4.6.6 
Sensitivity Analyses ............................................................... 27 
4.6.7 
Subgroup Analyses ............................................................... 28 
4.6.8 
Number of Days Hospitalized ................................................ 28 
4.7 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 28 
4.8 
Immunogenicity Analyses ...................................................... 29 
4.9 
Safety Analyses ..................................................................... 29 
4.9.1 
Exposure of Study Medication ............................................... 30 
4.9.1.1 Administration problems ....................................................... 30 
4.9.1.2 Exposure to Anti-coagulant factors by bleed ........................ 30 
4.9.2 
Adverse Events ..................................................................... 30 
4.9.2.1 Adverse events of special interest ........................................ 33 
4.9.3 
Deaths ................................................................................... 33 


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4.9.4 
Surgeries ............................................................................... 33 
4.9.5 
Laboratory Data ..................................................................... 34 
4.9.6 
Vital Signs .............................................................................. 34 
4.10 
Biomarker .............................................................................. 35 
4.11 
Missing Data .......................................................................... 36 
4.12 
Interim Analyses .................................................................... 37 
5. 
REFERENCES ........................................................................................... 38 
APPENDIX 1 
 PROTOCOL SYNOPSIS ...................................................... 39 
APPENDIX 2 
 SCHEDULE OF ACTIVITIES ................................................ 46 
APPENDIX 3 
 HRQOL QUESTIONNAIRES : DETAILS ON 
RECODING, SCALES AND HANDLING OF MISSING DATA .................... 52 
Recoding and Scales .......................................................................... 52 
Missing items ...................................................................................... 53 
 
 


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LIST OF TABLES 
Table 1: Clopper-Pearson 95% CIs for the Incidence of AEs (Based on 
N=200) ........................................................................................ 17 
Table 2: List of analyzed biomarkers .................................................................. 35 
Table 3: List of outputs to be generated for biomarkers and FVIIi inhibitor 
titers ............................................................................................ 36 
 
 
LIST OF FIGURES 
Figure 1 – Study Design ..................................................................................... 10 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABR 
annualized bleeding rate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPCC 
activated prothrombin complex concentrate 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibodies 
BMI 
body mass index 
BMQ 
Bleed and Medication Questionnaire 
BSA 
body surface area 
BU 
Bethesda unit 
CI 
confidence interval 
CSP 
clinical study protocol 
CVAD 
central venous access device 
CWA 
clot waveform analysis 
eCRF 
electronic Case Report Form 
ELISA 
enzyme linked immunosorbent assay 
EmiPref  
Patient Preference Questionnaire regarding the 
treatment with Emicizumab 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL Five-Dimension-Five Levels Questionnaire 
EQ-VAS 
EuroQoL visual analogue scale 
FEIBA 
factor eight inhibitor bypassing activity 
FIX 
Factor IX 
FIXa 
activated Factor IX 
FIX:Ag 
Factor IX antigen 
FVIIa 
activated Factor VII 
FVIII 
Factor VIII 
FVIII:Ag 
Factor VIII antigen 
FX 
Factor X 
FX:Ag 
Factor X antigen 
Haem-A-QoL 
Hemophilia Adult Quality of Life Questionnaire 
Haemo-QoL 
Hemophilia Quality of Life 


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Abbreviation 
Definition 
Haemo-QoL-SF 
Hemophilia Quality of Life Short Form 
HCP 
healthcare provider 
HIV 
human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
iDMC 
independent Data Monitoring Committee 
IgG 
immunoglobulin G 
IND 
investigational new drug  
INR 
international normalized ratio 
ISR 
ISTH 
injection site reactions 
International Society on Thrombosis and Haemostasis 
ITI 
immune tolerance induction 
ITT 
intent-to-treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
LPLV 
last patient, last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
rFVIIa 
recombinant activated human Factor VII 
rFVIII 
recombinant Factor VIII 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SMQ 
standardised MedDRA queries 
SOC 
system-organ class 
SSC 
scientific and standardization committee 
TE 
thromboembolic event 
TMA 
thrombotic microangiopathy 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WHO 
World Health Organization 
 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON HEMOPHILIA A WITH INHIBITORS 
Hemophilia A is a rare bleeding disorder that is attributable to a congenital absence or 
hypofunctioning of Factor VIII (FVIII) (Acharya 2013; Witmer and Young 2013). The gene 
that encodes FVIII is located on the X chromosome. Genetic defects are expressed 
through X-linked recessive inheritance or de novo FVIII mutations, and more than 99% of 
hemophilia patients are males. The prevalence of hemophilia A is approximately 1 in 5,000 
live-born males or 1 out of every 10,000 live births (CDC 2016; Franchini and Mannucci 
2013; NIH 2016). No racial differences have been reported, and the numbers of patients 
registered in 2014 in various regions included 4,870 in Japan, 21,052 in North America, 
and 11,029 in just two European nations (United Kingdom and France) (World Federation 
of Hemophilia 2014). 
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 hemophilia A is classified in accordance with 
endogenous FVIII activity in the blood. Patients with FVIII activity of less than 1% have 
severe disease, those with activity between 1% and 5% have moderate disease, and 
those with activity greater than 5% and less than 40% have mild disease. Patients who 
have severe hemophilia who do not initiate and/or comply with rigorous FVIII prophylaxis 
regimens, or do not have access to FVIII products, experience bleeding episodes several 
times a month, which is much more frequent than in patients with moderate or mild 
disease. In addition, patients with severe hemophilia have a high frequency of 
spontaneous bleeding. Hence, the maintenance of plasma FVIII activity at 1% or higher is 
important to prevent the onset of recurrent bleeding episodes, reduce comorbidities such 
as arthropathy, and improve Health Related Quality of Life (HRQoL) in patients with 
severe hemophilia A (Srivastava et al. 2013). 
1.2 
BACKGROUND ON EMICIZUMAB 
Emicizumab (also known as ACE910, CH5534262, and RO5534262) is a recombinant, 
humanized, bispecific, immunoglobulin G4 (IgG4) monoclonal antibody that binds with 
moderate affinity to activated Factor IX (FIXa) and Factor X (FX), thereby 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. Emicizumab therefore has no potential to induce or enhance the 
development of direct inhibitors to FVIII or other coagulation factors. In addition, 
emicizumab offers the possibility of subcutaneous (SC) administration, removing the need 
for venous access. Finally, because of the expected pharmacokinetic (PK) properties of 
this antibody, markedly extending the dosing interval to once weekly or even more, this 
compound has the potential to improve the treatment of patients with hemophilia A with 
and without FVIII inhibitors who are in need of effective, safe, and convenient prophylactic 
therapy.  
In the Phase I/II study (ACE001JP) 18 Japanese patients with hemophilia A, either with 
or without inhibitors, were treated with emicizumab at three different dosing regimens (0.3 
mg/kg/week, 1 mg/kg/week, or 3 mg/kg/week). During the course of emicizumab 
administration, the Annualized Bleeding Rate (ABR) significantly decreased in all patients 
compared with the ABR prior to study enrollment, regardless of whether or not the patient 


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had inhibitors, with the exception of one patient without inhibitors in the 3 mg/kg/week 
group (see Section 1.2.2 of the protocol).  
Emicizumab has been well tolerated in patients in the Phase I/II studies (cut-off date 15th 
February 2016). The majority of adverse events have been mild in intensity, with the most 
common being injection-site reactions (ISRs). The majority of the adverse events have not 
been considered to be related to emicizumab. In these studies, no thromboembolic or 
systemic hypersensitivity adverse events have been observed. However, as of April 2017, 
three cases of thrombotic microangiopathy (TMA), and three thromboembolic events in 
two patients, have been observed in the ongoing Phase III Study BH29884 in patients who 
received emicizumab as well as bypassing agents for the treatment of breakthrough 
bleeds. Four of these patients have fully recovered and the fifth patient died (death due to 
serious adverse event of rectal haemorrhage unrelated to emicizumab, with the TMA 
related to emicizumab and aPCC) (see Sections 5.1.1.2 and 5.1.1.3 of the protocol).  
Given the unmet need to develop novel therapeutics for use in hemophilia A patients with 
inhibitors and the positive risk-benefit assessment observed, a Phase IIIb safety study 
with emicizumab is warranted in this patient population.  
 
2. 
STUDY DESIGN 
This single-arm, multicenter, open label Phase IIIb clinical study will enroll patients aged 
12 years or older with congenital hemophilia A who have persistent inhibitors against FVIII 
at enrollment. Approximately 200 patients with inhibitors will be enrolled globally. Patients 
will receive prophylactic emicizumab at 3 mg/kg/week subcutaneously for 4 weeks, 
followed by 1.5 mg/kg/week subcutaneously for the remainder of the 2-year treatment 
period (Figure 1). 
Figure 1 – Study Design 
 
The primary objective of this study is to evaluate the overall safety and tolerability of 
prophylactic administration of emicizumab in patients with congenital hemophilia A who 
have persistent inhibitors against FVIII at enrollment. In order to achieve this objective, all 
adverse events, including adverse events of special interest, will be captured on an 
ongoing basis, as they occur during the study. Physical examinations, vital signs, and 
laboratory values will be assessed as per the Schedule of Activities (Appendix 2: Schedule 
of Activities). 
 


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The secondary objective of this study is to evaluate the efficacy of prophylactic 
administration of emicizumab. As part of this objective, the number of bleeds over time will 
be recorded for all of the enrolled patients. 
The final analysis will be conducted when all patients have completed 2 years of treatment 
or have withdrawn, whichever occurs sooner. Patients, or their legally authorized 
representative, will be asked to report bleed information on an electronic patient-reported 
outcome (ePRO) device where possible, including site of bleed, type of bleed, time of each 
individual bleed (day, start and stop time), and treatment for bleed. HRQoL will be 
assessed and the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) will be 
completed prior to the first emicizumab administration (Week 1), at the Month 3, 6, 12, 
and 18 assessments, and at study completion as outlined in the Schedule of Activities 
(Appendix 2: Schedule of Activities). Additional secondary endpoints include assessing 
patient preference for the emicizumab regimen compared with the previous regimen using 
a questionnaire (EmiPref). 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1. For additional details, see the Schedule of 
Assessments in Appendix 2: Schedule of Activities. 


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2.2 
OBJECTIVES AND ENDPOINTS 
• 
To evaluate the overall safety and tolerability of prophylactic administration of 
emicizumab (primary objective): Incidence and severity of all adverse events 
(AEs), including AEs of special interest, AEs leading to discontinuation and SAEs 
will be analyzed. Additionally, changes in physical examination findings, vital signs 
and laboratory parameters will be presented. 
• 
To evaluate the efficacy of prophylactic administration of emicizumab (secondary 
objective): the number of bleeds over time, the HRQoL of patients according to 
Haem-A-QoL (≥18 y) or Haemo-QoL-SF (ages 12−17) scores, the health status of 
patients according to EQ-5D-5L scores over time and the patient preference for 
the emicizumab regimen compared with the previous regimen used are shown. 
• 
To evaluate the immunogenicity of emicizumab (immunogenicity objective): the 
occurrence and clinical significance of anti-emicizumab antibodies are assessed. 
• 
Emicizumab PK data (pharmacokinetic objective) at defined time points are 
analyzed. 
2.2.1 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) 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 Protocol 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 Protocol Appendix 4). 
• 
Thromboembolic events. 
• 
Microangiopathic hemolytic anemia or TMA (e.g. hemolytic uremic syndrome). 
2.2.2 
Bleed Assessments  
Patients will be trained on how to record their bleeds and hemophilia medication use using 
an ePRO device. When bleeds occur, patients will need to record the site of bleed, type 
of bleed, time of each individual bleed (day, start and stop time), and treatment for bleed. 
At least once a week, patients will need to record any hemophilia medication use (including 
emicizumab) and information regarding any bleeding events. Investigator review of 
patient-reported bleed/medication records with the patient/caregiver will occur for 
completeness and accuracy throughout the study.  
 


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2.2.2.1 
Definition of a Bleed  
For the purposes of the efficacy analyses, a standardized definition of bleed, adapted from 
the standard criteria defined by the FVIII and FIX Subcommittee of the Scientific and 
Standardization Committee (SSC) of the International Society on Thrombosis and 
Haemostasis (ISTH), that is similar to the definition used in a recent clinical investigation, 
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 reported bleeds 
(irrespective of treatment with coagulation factors) will be applied for a separate analysis.  
2.2.2.2 
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” (see 
Haemophilia Medication Record) irrespective of the time between the treatment and the 
preceding bleed. Note, a bleed occurring at the same time as a treatment, counts as a 
treated bleed.  A bleed and the first treatment thereafter are considered to be pairs (i.e., 
one treatment belongs to one bleed only), with the following exception:  if multiple bleeds 
occur on the same calendar day, the subsequent treatment is considered to apply for each 
of these multiple bleeds. 
Bleeds due to surgery/procedure will not be included in the primary analysis. In addition, 
treatments reported as “Treatment for bleed” directly following a bleed due to 
surgery/procedure are excluded. 
2.2.2.3 
72-Hour rule  
Two bleeds of the same type (e.g., “joint,” “muscle,” or “other”) and the same etiology and 
at the same anatomical location are considered to be one bleed if the second occurs within 
72 hours from the last treatment for the first bleed. Any bleed with a different etiology is 
considered a separate bleed regardless of time from last injection. The last treatment is 
defined as the last treatment before a new bleed occurs, either in the same or in a different 
location.  This is in-line with the above definition that bleeds and treatments are considered 
to be pairs. 
If the bleed location is other/other, other/other is used as the bleed location and not the 
exact location entered on the separate eCRF page. 
In case of trauma with multiple different locations of bleed, this will be considered as one 
bleed for the analyses. However, all data will be collected, including the various locations 
of the different bleeds.  
A listing of all bleeds is produced. The listing includes all bleed and hemophilia medication, 
except emicizumab, information entered on the Bleed Record, with an indicator which 
bleeds are included in the primary analysis and which do not count as separate bleeds 
due to the 72h rule. 
2.2.2.4 
All bleeds 
 “All bleeds” 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 in the primary analysis.  


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The 72-hour rule will be applied to the “All bleeds” endpoint. For treated bleeds, it will be 
implemented exactly as defined in Section2.2.2.2. For non-treated bleeds (not followed by 
any treatments with coagulation factors before the recording of a subsequent bleed), it will 
be implemented by calculating the interval of 72 hours from the bleed itself. Non-Treated 
bleeds are bleeds not covered by the definition of treated bleeds for the primary endpoint. 
To clarify, one bleed can be a composition of treated and non-treated bleeds. 
 
Examples: 
RE - 2h – T* – 75h – RE – 2h - T -> 2 bleeds (*72h calculated from last treatment) 
RE* - 75h – RE – 2h - T -> 2bleeds (*72h calculated from bleed because there is no treatment) 
RE – 70h – RE – 2h - T -> 1 bleed 
RE - 50h – RE – 30h – RE -> 1 bleed 
RE – 30h – RE - 25h – LE -> 2 bleeds  
RE – 2h – T – 3h – T* – 35h – RE– 2h – LE** – 45h – LE- 70h - RE -2h -T -> 3 bleeds (*72h 
calculated from last treatment, ** calculated from previous bleed due to no treatment) 
RE=right elbow bleed, LE=left elbow bleed, T=treatment for bleed 
2.2.2.5 
Bleed Sites  
The bleed sites are defined as follows:  
• 
Joint bleeds, which are defined as having an unusual sensation (“aura”) in the joint 
in combination with any of the following:  
o Increasing swelling or warmth of the skin over the joint  
o Increasing pain  
o Progressive loss of range of motion or difficulty in using the limb as 
compared with baseline.  
• 
Muscle bleeds  
• 
Other bleeds.  
2.2.2.6 
Definitions of Cause/Classification of Bleeds 
Bleed assessments will be separated into spontaneous bleeds, traumatic bleeds, and 
bleeds related to procedures. 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. The definitions for the different type of bleeds are 
as follows:  
• 
Spontaneous bleeds. Bleeds will be classified as spontaneous if a patient records 
a bleed when there is no known contributing factor such as definite trauma, 
antecedent 
“strenuous” 
activity, 
“overuse”, 
or 
procedure/surgery. 
The 
determination of what constitutes “strenuous” or “overuse” will be at the discretion 
of the patient. For example, light jogging may be considered “non-strenuous” while 
sprinting may be considered “strenuous”; lifting of weights for a short period of time 
may be considered “moderate use” while repetitive weightlifting may be considered 
“overuse”. 
• 
Traumatic bleeds. Bleeds should be classified as traumatic if a patient records a 
bleed when there is a known or believed reason for the bleed. For example, if a 
patient were to exercise “strenuously” and then have a bleed in the absence of any 


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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. In addition, bleeds 
related to surgery, such as hematomas resulting from any surgeries, will also be 
classified as traumatic bleeds. Bleeds related to surgeries will not be associated 
with any trauma except surgery-induced trauma. 
• 
Bleeds related to procedures. This category would include hematomas resulting 
from any invasive procedure (e.g., tooth extractions, venipuncture, or SC drug 
administrations) or invasive diagnostic procedures (e.g., lumbar puncture, arterial 
blood gas determination, or any endoscopy with biopsy, etc.) or surgeries. Any 
instances of these bleeds would not be counted as bleeds in the context of the 
study, but the relevant data will be collected. Bleeds related to procedures will not 
be associated with any trauma except procedure-induced trauma.  
2.2.2.7 
Treated Joint Bleeds  
Joint bleeds are defined as bleeds where the bleed type is “joint” and at least one of the 
following symptoms has been observed: increased swelling or warmth of the skin over the 
joint, increased pain in the joint or decreased range of motion, or difficulty moving the joint 
compared to baseline.  
For the analysis, all treated bleeds that fulfill the above joint bleeds definition will be 
included and then the 72-hour rule will be applied. Bleeds due to procedure/surgery will 
be excluded.  
In case multiple bleeds are counted as one bleed (72h rule), all of these bleeds needs to 
fulfill the above rule.  
Additional analyses will be performed for joint bleeds where the bleed site is “joint”, 
regardless of any accompanying reported symptom. 
 
2.2.2.8 
Treated Target Joint Bleeds  
Target joints are major joints in which repeated bleeds occur (i.e.,  3 bleeds in 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 (see 
Section 4.1) are defined by first selecting the bleeds that fulfill the definition of a treated 
joint bleed (see Section 2.2.2.7) 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. 
2.2.2.9 
Treated Spontaneous Bleeds  
For the analysis all treated bleeds that fulfil the above spontaneous bleeds definition 
(section 2.2.2.6) will be included and then the 72-hour rule will be applied. 
 
2.2.3 
HRQoL Assessments  
The Haem-A-QoL (version AU 3.0; UK English) and the Hemophilia Quality of Life Short 
Form (Haemo-QoL-SF) (version AU 2.0; UK English) will be completed electronically and 


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used to measure HRQoL in adults and adolescents, respectively. Paper versions of the 
questionnaires are also available in case of ePRO outage or if an ePRO device is 
otherwise unavailable. 
The Haem-A-QoL was designed for adult patients with hemophilia. It consists of 46 items 
comprising 10 dimensions (physical health, feelings, view of yourself, sports and leisure, 
work and school, dealing with hemophilia, treatment, future, family planning, and 
partnerships and sexuality) and a scale representing total score. Items are rated according 
to five response options, although for some items there is also a ‘not applicable’ option 
(Mackensen and Gringeri 2010; Wyrwich et al. 2015).  
The Haemo-QoL has been developed as a series of age-related questionnaires to 
measure HRQoL in children and adolescents with hemophilia (Bullinger et al. 2002; Pollak 
et al. 2006; Von Mackensen and Bullinger 2004). These questionnaires include a 77-item 
long form, a 35-item short form, and an 8-item index form. Long versions for three different 
age groups contain 21−77 items and cover 8−12 dimensions of HRQoL. Furthermore, two 
age-specific short form measures containing 16 and 35 items have been developed. The 
short version for older children (8−16 years) containing 35 items was selected for this 
study. This version covers nine dimensions considered relevant for the children’s HRQoL 
(physical health, feelings, view of yourself, family, friends, other people, sports, dealing 
with hemophilia, and treatment). Items are rated with respect to five response options: 
never, rarely, sometimes, often, and all the time.  
2.2.4 
Health Status Assessments (EQ-5D-5L)  
The EQ-5D-5L (version 2; UK English) is a generic, self-report, preference-based health 
utility measure that consists of six questions that are completed electronically and is used 
to assess health status and inform pharmacoeconomic evaluations. Paper versions of the 
questionnaires are also available in case of ePRO outage or if an ePRO device is 
otherwise unavailable. The EQ-5D-5L consists of two components. The first part, health 
state classification, contains five dimensions of health: mobility, self-care, usual activities, 
pain / discomfort, and anxiety / depression (Herdman et al. 2011; Janssen et al. 2013). 
Published weights are available that permit the creation of a single summary score. 
Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction. 
The second part is a 0 to 100-point visual analog scale (VAS), which assesses current 
health status and higher scores are reflective of better health. 
2.2.5 
Treatment Preference Questionnaire 
Patient preference will be assessed through a paper version of the EmiPref questionnaire 
(see Protocol Appendix 3), which asks patients to specify the treatment they would prefer 
to continue to receive after receiving treatment with their previous episodic or prophylactic 
regimen and SC emicizumab. Patients who express a preference are then asked to 
identify the reasons which may have influenced their decision and indicate the top three 
reasons for their choice. Patients will complete this questionnaire after 3 months of 
treatment with emicizumab. 
 
 




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3.3 
DATA MONITORING 
The iDMC will review safety data on a regular basis until all patients have been enrolled 
and have completed treatment. All analyses for review by the iDMC will be prepared by 
the study statistician. Analyses of safety events will be conducted after approximately 100 
patients have completed 24 weeks in the study and again after approximately 100 patients 
have completed 52 weeks in the study. Thereafter, the iDMC will meet at a frequency 
determined by the iDMC and the Sponsor according to the emerging safety profile.  
Further details are specified in a separate iDMC charter. 
4. 
STATISTICAL METHODS 
No formal statistical hypothesis tests will be performed and all analyses are considered 
descriptive. 
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate). Continuous data will be summarized using descriptive 
statistics (N, mean, standard deviation, median, lower quartile, upper quartile, minimum 
and maximum). Other analysis methods will be specified (below) where applicable. 
4.1 
REPORTING PERIODS 
The following definitions are used to allocate data to study periods. The same definitions 
are used for all outputs, e.g. AEs, laboratory data, patient disposition, efficacy and quality 
of life, unless otherwise specified.  
 
Original Study Day 1:  
Original study day 1 is defined as the day of the first emicizumab dose.  
For patients who withdrew before week 1 and have neither received emicizumab nor have 
an entry in the electronic handheld device or site data entry system, original study day 1 
is the date of enrollment, defined as week 1 visit, if available, or the date of informed 
consent. 
 
Up-titration Study Day 1: 
Emicizumab is administered at a dose of 3 mg/kg/week for 4 weeks when initiating 
treatment, followed by 1.5 mg/kg/week for the remainder of treatment period. It is possible 
to increase the dose to 3 mg/kg/week if protocol defined criteria are met. For all patients 
whose emicizumab dose was up-titrated to 3 mg/kg/week, up-titration study day 1 is 
defined as the day of the first higher emicizumab dose (based on eCRF). Up-titration study 
day 1 is defined for up-titrated patients only. 
 
Study Day: 
Study day (original or up-titration respectively) of an event/assessment is defined as the 
date of the event/assessment minus the date of Study Day 1 (original or up-titration 
respectively). If the result is a positive number or zero, add one day. In other words, there 
is no day zero. 
 
Before therapy:  
All events/assessments that occur before the original study day 1 are considered to have 
occurred before therapy and have a negative study day. AEs occurring at the original study 


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day 1 are assumed to have occurred after therapy started. For handling of laboratory 
assessment, see definition of baseline. 
 
Baseline:  
Baseline assessment is the last valid assessment before or on original study day 1. As 
defined in the protocol, for all laboratory and immunogenicity assessments at the original 
study day 1, it is assumed that the assessment was done before the emicizumab intake.  
Baseline assessments that are measured only once at screening or week 1 and are not 
affected by treatment should be considered irrespective of the study day (e.g. gender, 
height, hemophilia history). 
For Haem-A-QoL, Heamo-QoL-SF and EQ-5D-5L, the Week 1 questionnaire is 
considered to be the baseline irrespective of the collection date/time.  
 
Up-titration Baseline: 
For patients who are up-titrated, baseline for this period is defined as the last valid 
assessment done before or on Up-titration study day 1.  
 
Treatment period:  
Treatment period is defined as the time between original study day 1 and last emicizumab 
injection. For a patient who has not withdrawn from/completed treatment, the end of 
treatment period is actually defined as the date of the clinical cutoff. 
 
Before up-titration: 
The period before up-titration starts on the date of the original study day 1and ends one 
day before Up-titration study day 1 or, in case of no Up-titration, either the date of study 
withdrawal or the cut-off date, whichever comes first. 
 
After Up-Titration: 
For patients who are up-titrated, the period after up-titration starts on the up-titration study 
day 1 and ends on the date of study withdrawal or the cut-off date, whichever comes first. 
 
Follow-up:  
Follow-up period starts on the day after the end of the treatment period. Follow-up period 
ends on the day of withdrawal, completion of follow-up, or at the end of the study as 
defined in the protocol.  Only patients who have an assessment during this time period 
are considered as having entered follow-up. 
 
Observation time: 
Observation time is the time between date of enrollment and the day of death or the last 
actual assessment in the database (=last date known to be alive). At the time of a 
database cutoff for patients who have not withdrawn from the study, the cutoff date will be 
used instead of the last assessment date.  
 
Efficacy periods: 
The start of the efficacy period for each individual starts on the date of first emicizumab 
treatment. The end of the efficacy period is defined as the date of the clinical cutoff or the 
date of withdrawal from/completion of the treatment 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 enrollment. 
For patients whose dose is up-titrated, the efficacy period ends one day prior to the first 
day on the up-titrated dose (Efficacy period 1). 


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For patients whose dose is up-titrated, the bleeds occurring during the administration of 
the up-titrated dose are analyzed separately.  The efficacy period on the up-titrated dose 
starts with the first day on this dose and ends on the day of the clinical cutoff or the date 
of withdrawal from/completion of treatment (Efficacy period 2).  
 
 
For statistical evaluations (e.g. descriptive summaries) of post-baseline data summarized 
by visit, only measurements at scheduled visits are considered. If a measurement is 
repeated at a scheduled visit (or time point), then only the latest retest result will be used 
in calculation of the statistical summary.  All data – including unscheduled measurements 
– will be included in the listings.  
If a time interval was calculated in minutes, hours or days and needs to be converted into 
months or years the following conversion factors will be used: 
1 year = 365.25 days 
1 month = 30.4375 days 
4.2 
ANALYSIS POPULATIONS 
4.2.1 
Primary Population (Safety Population) 
The primary analysis population is all patients who have received at least one dose of 
study medication (safety population). 
4.2.2 
Intend-To-Treat Population 
The intent-to-treat (ITT) population includes all enrolled patients (enrolled patients are 
defined as patient who signed the informed consent). 
4.2.3 
Pharmacokinetic-Evaluable Population (PK Population) 
The PK population includes all patients who have received at least one dose of 
emicizumab and have at least one post-baseline concentration result. 
4.2.4 
Up-Titrated Population  
This population includes patients who have received at least one dose up-titrated to 3 
mg/kg. 
4.2.5 
Surgery Population  
This population includes patients who received at least one dose of emicizumab and have 
at least one surgical surgery during study conduct (i.e. while receiving emicizumab). 
 
4.3 
ANALYSIS OF STUDY CONDUCT 
A clear account of all patients who enrolled in the study and who entered, discontinued, 
and completed the initial and maintenance phases of the study will be displayed. 
The reasons for premature discontinuation from study treatment and the reasons for study 
withdrawal will be described in listings and summary tables. 
In addition, the number of patients who received dose up-titration will also be described. 
Enrollment, major protocol deviations and reasons for early discontinuation will be listed 
and evaluated for their potential effects on the interpretation of study results. The type of 


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major protocol deviations and the number of patients with at least one major protocol 
deviation will be summarized in terms of both the safety and ITT populations. Major 
protocol deviations related to COVID-19 will be summarized and listed. 
Patient disposition table describes the flow of patients through the study up to the cutoff. 
Patients will be tabulated with: 
• 
Number of patients enrolled  
• 
Number of patients who discontinued prematurely prior to Study day 1 
• 
Number of patients with duration of efficacy period <2 years 
• 
Number of patients who completed 24 months in the study (efficacy period) 
• 
Number of patients with at least one dose up-titration (up-titrated population) 
• 
Number of patients who started safety follow-up (for interim analyses only) 
• 
Number of patients who completed safety follow-up 
• 
Number of patients who discontinued treatment  
• 
Number of patients who discontinued from the study 
• 
Number of patients who completed the study 
 
Number of patients included and excluded from each analysis population is listed and 
summarized. All analysis populations defined for the study are included.  
Major protocol deviations are listed and summarized by category and type of deviation.  
A listing of investigators is produced with a column indicating the number of patients 
enrolled. Also enrollment will be summarized by country and investigator number. 
Observation time, duration of efficacy period and duration of follow-up (as defined in 
section 4.1) are summarized descriptively (unit weeks) and categorically (cumulative): >0 
week, ≥4 weeks, ≥12 weeks, ≥24 weeks, ≥36 weeks, ≥48 weeks, ≥72 weeks, ≥96 weeks. 
 
4.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
The following baseline and demographic characteristics will be presented using 
appropriate descriptive statistics: 
For each variable (continuous or categorical), the number of available observations will be 
reported. 
Demographics: demographic information collected at baseline (including age, sex, and 
self-reported race, ethnicity, height, weight, BSA and BMI). The age will be presented as 
continuous and categorical (≥12-<18 years, ≥18- <65 and ≥ 65 years) variable. Medical 
history and Baseline conditions assessment: number and percentage of patients with at 
least one medical condition and number and percentage of patients by system organ class 
and preferred term will be presented. Separate summaries will be presented for active and 
past medical history, where active is defined as ticked on eCRF as ongoing (with or without 
treatment) and past is defined as ticked as resolved. A listing of all previous and concurrent 
medical history will also be provided. 
 


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Hemophilia history: The following characteristics of the hemophilia history will be 
presented using appropriate descriptive statistics: 
- Hemophilia severity at baseline  
- Time from Factor VIII inhibitor diagnosis date (months)  
 
= (Date of Day 1 - Date of FVIII inhibitor diagnosis)/month  
 
(continuous and categorical: <24 months, 24-<48 months, 4-<72 months, 
>=72 
months) 
- Highest historical inhibitor titer (continuous and categorical: <5 BU, >=5 BU, Unknown) 
- Number of patients who already had treatment with ITI 
- Time from start of most recent ITI date (years) 
 
= (Date of Day 1 - Date of Start date of most recent ITI treatment)/year 
 
(continuous and categorical (< 2 years, 2 – 5 years, >5 years, Unknown)) 
- Prior episodic treatment in the last 24 weeks  
 
- Prior prophylactic treatment in the last 24 weeks  
 
- Reason for not being on prophylactic treatment regimen  
- Number of bleeds in last 24 weeks  
- Number of target joints prior to study   
 
In addition, the baseline and demographic characteristics will also be summarized on the 
subset of patients with at least one surgical procedure during study conduct. 
Surgery and procedures: 
All surgeries and procedures collected on the eCRF page for Surgery and Procedure 
History Assessment will be listed. In case surgeries are coded, previous surgeries and 
procedures will in addition be summarized in a frequency table. 
4.5 
PREVIOUS AND CONCOMITANT MEDICATIONS 
Use of prior and concomitant medication will be presented by medication class and 
standardized medication name. Number and percentage of patients and number of 
medications will be presented. Summary tables on concomitant medications will include 
all dates (before and after up-titration). 
A medication is considered concomitant if the start date/time is on or after the date/time 
of Original Study Day 1. Otherwise, a medication is considered prior if the end date/time 
is not missing and is before the date/time of Original Study Day 1. Otherwise a medication 
is considered prior-concomitant.  
All hemophilia medication (collected on the electronic handheld device or the site data 
entry system) will be reported separately. The number of doses and the cumulative doses 
will be summarized by category of hemophilia medication. Summary tables for hemophilia 
medications will include data up to the up-titration (if any) only. If at least 10 patients are 
up-titrated then the frequency table will also be produced on the period after up-titration. 
Also all prior episodic and prophylactic hemophilia medication collected on the hemophilia 
history page will be summarized separately. 
 
 


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4.6 
EFFICACY ANALYSIS 
This is a single arm study and, consequently, no formal treatment group comparisons will 
be conducted.  
The efficacy analyses will be based on the ITT population. Efficacy analyses will be 
restricted to the period before up-titration, if any, except if stated otherwise. 
4.6.1 
Efficacy endpoints 
The analysis of efficacy endpoints will be based on the efficacy period defined in Section 
4.1. 
4.6.1.1 
Bleeds 
The primary analysis will be based on treated bleeds (see definition 2.2.2.2).The number 
of bleeds over time will be estimated using a negative binomial (NB) regression model, 
which accounts for different follow-up times. The time that each patient stays in the study 
(efficacy period) will be included as an offset in the model. 
An additional model which adjusts for number of bleeds (< 9 or ≥ 9, according to eCRF) 
in the last 24 weeks prior to study entry will be used to support the primary analysis.  
In the rare case that the negative binomial model does not converge or no bleeds were 
observed for a given endpoint, the primary analysis will be based on “calculated” 
annualized bleed rate (ABR). 
The ABR is calculated using the following formula (called Calculated ABR on all outputs): 
Number of bleeds during the efficacy period 
Number of days during efficacy period
× 365.25 
The efficacy analyses will include the following endpoints defined in section 2.2.2: treated 
bleeds, all bleeds, treated joint bleeds, treated target joint bleeds and treated spontaneous 
bleeds. For each endpoint, the model based ABR will be estimated along with its 
corresponding 95% CI. In addition, the mean, 95% CI based on Exact Poisson, median, 
IQR, min and max will be provided for the calculated ABR.  
A corresponding listing will be provided which will include for each patient the duration of 
efficacy period, number of bleeds together with calculated ABR for treated bleeds, all 
bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds 
(based on data before up-titration only). A separate listing will also be provided for the up-
titrated population, based on data on or after the up-titration. 
4.6.1.2 
Number of Bleeds/ABR categories 
Number of patients with 0, 1-3, 4-10, >10 bleeds as well as number of patients with 
calculated ABR <1, 1-3.4, 3.5-10, >10 will be summarized. Figures including 95% CI will 
also be provided. All summaries and figures will be produced for treated bleeds, all 
bleeds and treated spontaneous bleeds. 
 
 


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4.6.1.3 
Cause, type and location of bleed 
Cause of bleed (spontaneous, traumatic, procedure/surgery) and location of bleed by 
bleed type (Joint, Muscle, other) will be summarized. The analysis will be performed 
separately for treated bleeds (with 72-hour rule) and all bleeds without applying the 72-
Hour rule and including bleeds due to surgeries/procedures. 
4.6.1.4 
Type of trauma 
Type of trauma will be summarized according to the categories on the eCRF. The traumas 
are analyzed separately for bleed related trauma and non-bleed related trauma including 
all trauma. Non-bleed related trauma are identified through bleed number=ND on the 
trauma form. 
4.6.1.5 
Time of bleed 
Time of bleed will be summarized by calculating the difference between start time of bleed 
and start of efficacy period. The time of bleed will be presented as continuous and 
categorical (1-4 weeks, >4-12 weeks, >12-24 weeks, >24-36 weeks, >36-52 weeks, >52-
88 weeks, >88-104 weeks, > 104 weeks). 
The analysis will be conducted separately for treated bleeds and all bleeds without 
applying the 72-Hour rule and including bleeds due to surgeries/procedures. 
4.6.1.6 
Use of non-emicizumab hemophilia treatments 
The number of treatments to treat a bleed will be summarized. The number of infusions is 
counted per bleed corresponding to the definition of the primary endpoint, i.e. all 
treatments that are linked to the same bleed per the 72h rule are considered to belong to 
the same bleed. If the same treatment/s are associated with multiple bleeds, these are 
counted multiple times, i.e. linked to both bleeds.  
The cumulative dose per kg administered will be summarized by product, e.g.  
RECOMBINANT FACTOR VIIA [E.G. NOVOSEVEN] or PROTHROMBIN COMPLEX 
CONCENTRATE [E.G. FEIBA].  The following formulas will be used to annualize the dose 
and the number of infusions: 
 
Number of Infusions 
Efficacy Period
× 365.25 
 
Cumulative dose/kg
Efficacy Period
× 365.25 
4.6.1.7 
Bleed and Medication Questionnaire Compliance 
Patient compliance to the Bleed and Medication Questionnaire (BMQ) will be analyzed. 
The compliance will be analyzed separately for entries done via the electronic handheld 
device only, and for all entries (via electronic handheld device or Site data entry system). 
A patient will be considered to be compliant if he completes the BMQ at least every 8 days 
(a filled out BMQ makes the patient compliant for the preceding 7 days, i.e. 8 days in total). 
The compliance rate will be defined as the number of days covered by a BMQ 
questionnaire divided by the duration in days of the efficacy period. The BMQ compliance 
will be summarized in a table and listed. The mean of the compliance rate will also be 
plotted overtime. 
 


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4.6.2 
HRQoL (Haem-A-QoL and Haemo-QoL-SF) 
As different HRQoL measures (Haem-A-QoL and the Haemo-QoL-SF) will be used for 
adult and adolescent patients, all calculations and analyses will be conducted separately 
for each patient population.  
The number and percentage of patients who complete the Haem–A–Qol or Haemo-Qol-
SF will be summarized at each scheduled time point. The compliance rate will be plotted 
over time. The compliance rate is based on the total number of patients expected to 
complete the questionnaire at a particular time point – i.e., those patients who had the 
opportunity to complete the scale. The number of expected questionnaires is calculated 
using the time windows of scheduled visits defined in the protocol. The analysis period 
used will overlap with the corresponding efficacy period, as the start will be the start of the 
efficacy period and the end will be either then end of the efficacy period or will be extended 
to the last entry on the device, for the last efficacy period of a subject, if it occurred later. 
Total score and domain sub-scales at each visit for the Haem-A-QoL and Haemo-QoL-SF 
will be calculated and summarized descriptively. The corresponding mean along with its 
95%CI plots will be provided. 
The change from baseline to 6 months as well as for each of the post-baseline time points 
in the total score for each questionnaire will be analyzed by the paired t-test. 
The proportion of patients who report changes that exceed clinically meaningful thresholds 
will be reported. A clinically meaningful threshold is defined as a decrease of 7 points in 
the Haem-A-QoL total score (Wyrwich et al., 2015), 5 points in the Haemo-QoL-SF total 
score (Santagostino et al., 2014) and 10 points for physical health. 
A descriptive summary of each of the scale will be produced, in which the domain score 
at each visit and the associated change from baseline will be summarized. Paired t-tests 
will be performed on the change from baseline to 6months for the scales.  
Note: before calculation the scale and total score, several items need to be reverse scored. 
The reverse scoring for those items is as follows: (1=5), (2=4), (3=3), (4=2), and (5=1). 
Any (0) will be recoded as missing data for the purposes of scale scoring. For details see 
Appendix 3: HRQoL QUESTIONNAIRES 
 
4.6.3 
EQ-5D-5L 
The EQ-5D-5L Questionnaire is a health utility measure to assess patients’ health status 
using 5 dimensions. All five dimensions can be combined in a five-digit number which then 
describes the patient’s health state. This descriptive number is converted to a single 
summary index utility score by using published weights; in this study we use the UK 
crosswalk value set (as published by the EuroQol Research Foundation at 
http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d). 
Additionally, in the second part of the questionnaire, the current health status is measured 
by the visual analog scale VAS with values ranging from 0 to 100. 
The number and percentage of patients who complete the EQ-5D-5L will be summarized 
at each scheduled time point. The compliance rate (see section 4.6.2) will be plotted over 
time. For each of the EQ-5D-5L assessments over time, the number and percentage of 
patients in each of the five categories for each question will be evaluated. A summary of 
the EQ-5D-5L index utility score at each visit and the associated change from baseline will 


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also be provided. The summary statistics presented will include the mean, standard 
deviation, median, minimum, maximum and interquartile range. Corresponding mean (+95% 
CI) plots are provided. 
In addition, summary statistics including mean, standard deviation, median, minimum, and 
maximum will be calculated according to the patients’ health state using the EuroQoL 
visual analogue scale (EQ-VAS).  
The change from baseline to Post-baseline will be analyzed using the paired t-test. The 
same outputs will be produced for the EQ-5D-5L VAS score.  
The proportion of patients who report changes that exceed the clinically meaningful 
threshold on the EQ-5D-5L index and the EQ-VAS scores will be reported. A clinically 
meaningful improvement threshold is defined as a change of +0.07 points in the index 
utility score and +7 points in the VAS score. 
For all completed assessments the five dimensions, the index utility score and VAS score 
is displayed in a separate listing.  
4.6.4 
Patient preference 
Summary statistics on patient preference for the emicizumab regimen compared with the 
previous regimen used will be presented. 
Preference survey, which is administered to patients at Month 3, consists in main 
questions:  
• 
the first question is related to the treatment preference with 3 possible responses: 
(a) older hemophilia IV treatment prior to enrollment in the study; (b) new study 
drug SC emicizumab treatment; (c) no treatment preference. 
• 
the second question, only asked to patients with a preference (responses a or b at 
first question), is related to factors influencing treatment preference (14 possible 
factors). For each factor, the patient should tick whether the factor is important and, 
if yes, provide an importance rank for the top 3 factors (“1” being the most important, 
“2” the second most important and “3” the third most important) 
The number and percentage of patients who complete the Preference survey will be 
summarized. 
Proportion of patients preferring the older hemophilia treatment, emicizumab, or without 
treatment preference will be computed along with 95% CIs (using the Pearson−Clopper 
one sample binomial method). 
This defines two sub-populations of the “All patient population”: 
• 
The PREFSC population, which includes all the patients that responded: “Prefer 
the new study treatment (SC)” 
• 
The PREFIV population, which includes all the patients that responded: “Prefer my 
old hemophilia treatment (IV)” 
For patients who have a preference to either emicizumab or the old IV hemophilia 
treatment, the factors influencing the preference can be treated like ordered categorical 
variables as follow: 


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• 
Category 1 = “Most important”, when factor was ranked first among top factors 
• 
Category 2 = “2nd most important”, when factor was ranked second among top 
factors 
• 
Category 3 = “3rd most important”, when factor was ranked third among top factors 
• 
Category 4 = “Influenced preference but not most important”, when factor was 
ticked but not ranked among top factors 
• 
Category 5 = “Did not influence preference”, when factor was not ticked as 
important 
Summaries of these categories will be produced by factor for the PREFSC and the 
PREFIV populations. Bar charts showing proportions of patient within each preference 
factors will also be produced for the PREFSC and the PREFIV populations: 
4.6.5 
Exploratory Efficacy Endpoints 
Analysis on 12- and 24-week interval: 
Additional analysis of the calculated ABR and the number of patients with zero bleeds will 
be performed for 12- and 24-week intervals on treated bleeds, all bleeds, treated 
spontaneous bleed, treated joint bleeds and treated target joint bleeds. The 12/24-week 
intervals are based on the start and end of the Efficacy Period. A patient has only as many 
12/24-week intervals as fully fit into this period. E.g. if the duration of Efficacy Period is 98 
days (=14 weeks) he has one full 12-week interval and no full 24-week interval. A bleed is 
assigned to a certain 12/24-week interval based on the distance between bleed date and 
start of efficacy period. If a bleed is after the end of the last full interval it is not taken into 
account.  
The calculated ABR for a 12/24-week interval will be derived using the following formula 
which is based on the general formula: 
Number of bleeds during the 12 or 24 −week interval
84 or 168 days
× 365.25 
The calculated ABRs will be summarized and a graph for the 12- and 24-week intervals 
for all subjects will be provided. The table will include the mean with the 95% CI based on 
Exact Poisson, the median with the IQR and the minimum and maximum. 
The number of subjects with zero bleeds within a 12- or 24-week interval will be 
summarized separately and a graph for all subjects will be provided. The table will include 
the number and percentage of the subjects with zero bleeds and the 95% CI using the 
Clopper-Pearson method. 
The same analysis as described above may also be performed on 36-, 48-, 60- and 72- 
and 98-week interval if sufficient number of patients available. 
 
4.6.6 
Sensitivity Analyses 
The sensitivity analyses will include different methods to define bleeds or eligible bleed 
data and different statistical models and will be applied to all efficacy endpoints defined 
in section 4.6.1.1.  


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Different ways to define bleeds or eligible bleed data: 
• 
Include all bleeds recorded: without the 72-hour rule and “treated bleeds” but 
excluding bleed due to surgery and procedure  
• 
Include only patients who received at least 12 weeks of emicizumab treatment, i.e. 
efficacy period ≥12 weeks 
• 
Include only the first 24 weeks of efficacy period in the analysis. The calculated 
ABR is based on Bleeds that occurred before or on day 168 from efficacy period 
start. Withdrawals are included for the time they were followed for. The 24 weeks 
Efficacy Period ends 168 days after efficacy period start, the Cut-off date, the date 
of withdrawal or the end date of efficacy period 1, whichever comes first. 
4.6.7 
Subgroup Analyses 
Descriptive summaries of both treated bleeds and all bleeds will be produced on the 
subgroups presented below. The summaries will include subgroup model based ABR (95% 
CI) and calculated mean ABR (95% CI).  
The pre-specified subgroups are:  
• 
Age at baseline:  18,  18  
• 
Age at baseline:  65,  65 
• 
Race: Asian, Black or African American, White, Other 
• 
Number of bleeds during 24 weeks prior to study entry: 9, ≥ 9 
• 
Number of target joints at baseline: no target joint, any target joint 
• 
Hemophilia severity: mild, moderate, severe 
• 
Previous treatment regimen: prior episodic, prior prophylactic (in case a subject have 
history of both prior episodic and prior prophylactic treatments, he will be considered 
as prophylactic) 
 
Additional region- and/or country-specific analyses may be performed to support 
regulatory submission as needed. 
4.6.8 
Number of Days Hospitalized 
The number of days of hospitalization, during the efficacy period, will be summarized. 
4.7 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
PK analyses will be provided by clinical pharmacology. 
For all patients, pre-dose (concentration at the end of the dosage interval [Ctrough]) plasma 
concentrations of emicizumab will be presented descriptively for each timepoint. Data 
presented will include arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation. 


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4.8 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one pre-dose and one 
post-dose anti-emicizumab antibody assessment. 
Immunogenicity summary tables will be restricted to the period before up-titration, if any, 
except if stated otherwise. 
 
Patients treated with emicizumab may develop anti-therapeutic antibodies (ATA).  
 
The proportion of all ATA positive patients will be summarized by visit and overall. The by 
visit summary includes positive/negative status directly from the data. For the overall 
summary the status is derived as described below.  
 
Overall ATA positivity/negativity to be reported in 4 categories: 
• 
NEGATIVE 
✓ patient negative at baseline and negative after treatment start 
 
• 
NEGATIVE (TREATMENT UNAFFECTED) 
✓ patient positive at baseline and negative after treatment start 
✓ treatment unaffected (negativity after baseline) defined as a maximum post-
baseline titer lower than patient’s baseline titer multiplied by 4 
 
• 
POSITIVE (TREATMENT BOOSTED) 
✓ patient positive at baseline and positive after treatment start 
✓ treatment boosting (positivity after baseline) defined as a maximum post-
baseline titer increase greater or equal to patient’s baseline titer multiplied by 
4 
 
• 
POSITIVE (TREATMENT INDUCED) 
✓ patient negative at baseline and positive after treatment start 
 
A patient is considered positive if a titer value > 0 is reported. As soon as a patient fulfils 
the criteria of positivity at one post baseline time point, the patient is counted as positive, 
i.e., a negative patient has a negative result at all timepoints. 
 
The relationship between ATA (anti-emicizumab antibodies) and safety, efficacy, and/or 
PK may be analyzed and reported descriptively via subgroup analyses.  
Note: The summaries will be provided separately for up-titrated patients and the overall 
status is defined separately by dose. The baseline is the original baseline and not the 
baseline just before up-titration.  
 
4.9 
SAFETY ANALYSES 
Safety will be assessed through descriptive summaries of adverse events, antibodies to 
emicizumab, laboratory test results (serum chemistry and hematology, including complete 
blood count with differential) and vital signs. 
For all safety analyses, the summary tables will include data up to the up-titration (if any) 
only, except if specified otherwise. 


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4.9.1 
 Exposure of Study Medication 
In addition, as part of the safety evaluation, additional assessments will be summarized 
descriptively as follows: 
• 
Cumulative study medication doses, dose modifications (delays and interruptions), 
and duration of exposure (continuous and categorized) 
• 
Administration injection site (listed only) 
• 
Patients with up-titrated dose. 
• 
Dose intensity (compliance with respect to emicizumab intake: planned vs. received), 
for initial and maintenance phases separately 
A dose is considered to be missed if there is an interval of >10 days between two doses. 
A patient who received < 90% or >110% of the planned dose is considered to have 
received a lower or higher dose than the planned dose, respectively. The planned dose is 
calculated using the last patient’s weight before or at the day of the emicizumab injection 
and the dose per kilogram according to protocol. 
 
The emicizumab dose is reported by the patient in ml. In order to convert the ml entered 
by the patient to mg, the following formula should be applied: 
𝑥 𝑚𝑙 × 150 𝑚𝑔
𝑚𝑙= 𝑦 𝑚𝑔 𝑜𝑓 𝑒𝑚𝑖𝑐𝑖𝑧𝑢𝑚𝑎𝑏 
4.9.1.1 
Administration problems 
The number and proportion of patients experiencing problems with emicizumab 
administration at Week 1 will be provided. Details of problems will also be summarized. 
 
4.9.1.2 
Exposure to Anti-coagulant factors by bleed 
The number of infusions is counted per bleed corresponding to the definition of treated 
bleed, i.e. all treatments that are linked to the same bleed per the 72h rule are considered 
to belong to the same bleed. If the same treatment/s are associated with multiple bleeds, 
these are counted multiple times, i.e. linked to both bleeds.  
The treatments are summarized separately for bleeds which were treated with an 
individual coagulation factors or combinations. In addition the outputs will include a total 
column which includes all the data for the Prothrombin Complex Concentrate or 
Recombinant Factor VIIa (only and both combined). That is, the n in this analysis is the 
number of treated bleeds and not the number of patients. The exposure (dose/kg) by bleed 
is summarized by using descriptive statistics and categorically: Prothrombin Complex 
Concentrate (U/kg/bleed: <50, 50-100, 101-150, >150) and Recombinant Factor VIIa 
(ug/kg/bleed: <90, 90-180, 181-270, >270).The duration of treatment per bleed is 
summarized: 1, 2, 3, 4, >4. Duration of treatment per bleed is defined as time from the first 
to the last dose per bleed. 
4.9.2 
Adverse Events 
Definitions of adverse events can be found in the CSP in section 5.2. 
The primary objective of this study is to evaluate the overall safety and tolerability of 
prophylactic administration of emicizumab in patients with congenital hemophilia A who 


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have persistent inhibitors against FVIII at enrollment. Of primary interest in this study are 
the incidence and severity of all adverse events, including thromboembolic events, 
microangiopathic hemolytic anemia or TMA, systemic hypersensitivity, anaphylaxis, and 
anaphylactoid events.  
Overall summaries of adverse events, serious adverse events and local injection site 
reactions will be presented by the number and percentage of patients having any event, 
having a related event, having an event leading to modification/interruption of study 
treatment, having an event leading to discontinuation from study, having an event leading 
to study treatment withdrawal, having an AESI, having a fatal AE, having grade 3 and 
above event. The overall number of events will also be presented.  
The incidence of AEs, SAEs, AEs grade 3 and above, AEs related to study treatment, 
SAEs related to study treatment, AEs leading to modification/interruption of study 
treatment, AEs leading to discontinuation of study, AESIs, local ISRs by injection and by 
highest grade, fatal AEs, AEs occurring immediately after injection and AEs occurring 
within 24 hours after injection will be summarized. The incidence of AEs will also be 
summarized by highest grade. 
A patient with more than one occurrence of the same adverse event in a particular System-
Organ Class (SOC) or adverse event category will be counted only once in the total of 
those experiencing adverse events in that particular SOC or adverse event category. Any 
missing severity, causality, or outcome will not be imputed and classed as unknown. 
Patients who died will be listed together with the cause of death. 
All other information collected (e.g. action taken) will be listed as appropriate.  
Only treatment emergent adverse events (starting on or after exposure to study treatment) 
starting on or before the end of the reporting period will be included in summaries. To 
define if an AE is treatment-emergent, only the date of the AE will be used (not the time). 
The end of the reporting period is defined as the end of the 2-year treatment period, for 
patients who completed the treatment, and as 24 weeks after the last dose of study 
treatment or 2 years after the first dose of study treatment, whichever occurs first, for 
patients who early discontinued from treatment. Non-treatment emergent events and AEs 
starting after the reporting period will be included in the patient listings and flagged but not 
included in the above summaries. Where an AE start date is partially or fully missing, and 
it is unclear as to whether the AE is treatment emergent, it will be assumed that it is. 
In addition, AEs which start during follow up will be summarized in a separate single table. 
Confirmed and suspected COVID-19 AEs will be listed, as well as AEs associated with 
COVID-19 (i.e. confirmed/suspected COVID-19 AEs and AEs with onset from -7 days to 
+30 days from the start of a confirmed COVID-19 AE).  
Notes: 
Tables presented will contain both counts of patients and events (at SOC level only). 
Patients who have multiple events in the same system organ class and preferred term will 
be counted only once in the patient counts.  
AEs will be coded using MedDRA. The version of the dictionary used will be updated 
throughout the study.   
In addition, a summary of non-serious AEs occurring in 5% or more of patients will be 
provided (for Disclosure purposes). 
 
 
 


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Adverse event rate per 100 patient-years 
Adverse events per patient years will be calculated for all grade AEs, SAEs, grade ≥3 AEs, 
TMA, thromboembolic events (TE) and TMA+TE combined. For each category of events, 
multiple occurrences of the same event (Preferred term) in the same patient will be 
counted multiple times.  
The adverse event rate per 100 patient-years is computed as follows: 
AE Rate = (Number of AEs observed/ Total patient-years at risk) * 100 
 
Total patient years is computed as follows: 
 
Total patient-years at risk is the sum over patients of the time intervals (in years) between 
start of study therapy (study day 1) and the end of follow up or up to the cutoff whichever 
is earlier. This approach assumes that during an adverse event, patients remain at risk for 
additional events.  
The 95% confidence interval for the event rate is calculated using the following method.  
Assume that we observe Y events over a total of T person-years at risk. 
Exact confidence interval:   
If chisq(p,df) is the quantile of the upper tail probability of the 2 distribution on df degrees 
of freedom, then the lower and upper bounds (LB, UB) of the exact (1 − /2) level interval 
are given by: 
LB = chisq(p = /2, df = 2 Y)/(2T) 
UB = chisq[p = 1 − /2, df = 2(Y + 1)]/(2T) 
 
Details on AE reporting 
 
A flag will indicate to which study phase an AE belongs to: before therapy, treatment period 
(initial treatment 3 mg/kg/week SC for 4 weeks, followed by 1.5 mg/kg/week SC) up-
titration period, or follow up (general section 4.1).  
 
All treated patients will be analyzed by descriptive summaries of the AEs by SOC mapped 
term (by descending frequency) and by Preferred Term (PT) (by descending frequency).  
 
 Multiple occurrences of the same AE (by PT) per subject are counted only once unless 
defined otherwise, this also applies for Bleeds which are reported as SAE. For Total 
number of Events multiple occurrences of the same AE on an individual are counted 
separately. Symptoms of Injection Site Reactions are summarized separately.  For some 
specific adverse event types, an additional table will display instances where multiple 
occurrences of the same AE in the same patient are all counted (for Disclosure purposes). 
 
A listing of AEs will be generated for patients with at least one up-titration. If at least 10 
patients are up-titrated then a summary table will be produced on the period after up-
titration. 
 
A standard summary table is produced for AEs falling into SMQ-hemorrhage (wide). 
 
 


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4.9.2.1 
Adverse events of special interest 
Adverse Events of Special Interest (AESI) are defined as cases of: 
 
1. Potential drug-induced liver injuries 
2. Suspected transmission of an infectious agent by the study drug 
3. Systemic hypersensitivity or anaphylactic or anaphylactoid reactions, 
4. Thromboembolic events search. 
5. TMA events 
Notes: 
The AESI categories and preferred terms to be summarised will be identified from the 
project level list which covers the categories defined for this study, if applicable; or based 
on the investigator’s judgement as collected in the eCRF otherwise.  
In addition, potential drug-induced liver injuries will have to meet the Hy’s Law criteria, 
based on laboratory results: 
o ALT or AST > 3 × baseline 
and 
o Total bilirubin > 2 × ULN (of which ≥35% is direct bilirubin) 
4.9.3 
Deaths 
 
Deaths are AEs with fatal outcomes and will be presented separately as described in 
section 4.9.2. 
4.9.4 
Surgeries 
Surgeries and procedures during study conduct, collected on the eCRF page for “On-
study Surgery and Related Hemophilia Medication Log”, will be summarized in a 
frequency table, for the safety population. 
 
In addition, the following analyses will be conducted on the Surgery population, for minor 
and major surgeries separately, and by surgery category (arthroplasty / CVADs / dental / 
joint / other). 
 
Surgeries and procedures during study conduct will be summarized by PT. 
 
Surgeries and procedures during study conduct, as well as hemophilia medications related 
to these surgeries (as collected on the BMQ) and occurrence of post-operative bleeds 
(treated and untreated), i.e. bleeds caused by a surgery or procedure, will be summarized. 
The surgery leading to a post-operative bleed will be identified as the last on-study surgery 
on or prior the start of the post-operative bleed. 
 
The duration of exposure to emicizumab (in days) prior to the start of the surgery will be 
summarized. 
The cumulative dose (dose/kg) of prophylactic hemophilia medications received by 
surgery, as well as the number of injections by surgery, will be summarized for each 
hemophilia medication separately. In the same manner, the number of infusions per post-
operative bleed, the cumulative dose (dose/kg) by bleed and the duration of treatment (in 
days) will be summarized, for each hemophilia medication separately. 
 


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All on-study surgeries and prophylactic hemophilia medications as collected in the BMQ 
will be listed together. In addition, all on-study surgeries and prophylactic hemophilia 
medications as collected on the eCRF page for “Related Hemophilia Medications” will also 
be listed together. 
An additional listing on post-operative bleeds and corresponding treatment for bleed will 
also be provided. 
 
4.9.5 
Laboratory Data 
A detailed list of the laboratory parameters can be found in the CSP in section 4.5.6. 
Laboratory parameters (hematology and chemistry) will be presented in shift tables of 
WHO toxicity grade at baseline versus worst grade post-baseline. Low/normal/high 
categories derived from investigator normal ranges will be listed. The reporting unit of 
laboratory values are SI units. 
Selected laboratory parameters will be summarized in terms of mean, standard deviation, 
minimum, and maximum. 
In calculating change from baseline at any scheduled Visit, only patients with non-missing 
values at both baseline and that Visit are included. All available data (i.e., scheduled and 
unscheduled assessments) are, however, used in identifying abnormalities in shift tables. 
 
The laboratory data will be summarized in the following ways: 
1) Summary statistics over time  
2) Shift tables – this method requires the following; 
a) type of categorization: WHO  
b) time intervals of the shift defined – “shift from baseline” and “shift to worst value 
during treatment” intervals; 
c) the worst assessment per laboratory parameter is selected per time interval, 
separately for hypo and hyper. Note, the worst assessment does not have to be 
unique as the table includes only the grade of the worst assessment. 
3) Plots:    
a) Mean Plots of Laboratory Parameters including 95% CI (Hematology and 
Biochemistry) 
CI interval should be calculated only for time points where there is data for at least 10 
patients 
 
 
Derived parameters 
1) Creatinine Clearance 
The creatinine clearance will be derived based on the Cockcroft-Gault formula unadjusted 
and adjusted for body surface area (BSA). Both formulas are given below. 
 
Unadjusted Cockcroft-Gault formula: 
 
𝐶𝐶𝑅 [𝑚𝑙𝑚𝑖𝑛
⁄
] = (140 −𝐴𝑔𝑒 [𝑦𝑒𝑎𝑟𝑠]) × 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]𝑥𝐹
0.8143 × 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑢𝑚𝑜𝑙𝑙
⁄ ] 
 
 
 
 
 
where F=1 for male subjects and F=0.85 for female subjects 
 
BSA-adjusted Cockcroft-Gault formula: 
 


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𝐶𝐶𝑅−𝑎𝑑𝑗 [𝑚𝑙𝑚𝑖𝑛
⁄
] = 𝐶𝐶𝑅[𝑚𝑙𝑚𝑖𝑛
⁄
] × 1.73 [𝑚2]
𝐵𝑆𝐴 [𝑚2] 
 
2) Total Neutrophils 
Total Neutrophils are derived as the sum of segmented and band Neutrophils. If one of 
the parameters is missing, it is assumed to be zero. Following this derivation, if there is 
more than one result per timepoint, the earliest record will be kept. If more than one result 
is at the same time, the smallest result is kept. In case the total neutrophils are reported 
together with the segmented and the bands, no calculation will be done and the total 
neutrophils are used. 
 
3) Corrected Calcium 
Corrected Calcium is derived using the following formula: 
 
𝐶𝐴𝑐𝑜𝑟𝑟 [𝑚𝑚𝑜𝑙𝑙
⁄ ] = 𝑆𝑒𝑟𝑢𝑚 𝐶𝑎𝑙𝑐𝑖𝑢𝑚 [𝑚𝑚𝑜𝑙𝑙
⁄ ] + 0.02 × (40 [𝑔𝑙
⁄ ] −𝐴𝑙𝑏𝑢𝑚𝑖𝑛 [𝑔𝑙
⁄ ]) 
 
4.9.6 
Vital Signs 
Vital signs will include measurement of body temperature (oral, rectal, axillary, or 
tympanic), heart and respiratory rates, blood pressure and weight. Height will be only 
measured at selected visits. Vital signs data together with their change from baseline will 
be summarized descriptively over time.  
4.10 
BIOMARKER 
Data from pharmacodynamics (PD), safety biomarker, safety coagulation system 
biomarker will be analyzed descriptively with summaries over time. Summary statistics, 
will include arithmetic and geometric means (if appropriate), median, range, and standard 
deviations. 
 
At least the following safety biomarkers, safety coagulation system biomarkers, and PD 
biomarker will be analyzed:  
 
Table 2: List of analyzed biomarkers 
Factor VIII Inhibitor, chromogenic 
CBU 
Factor VIII Activity, chromogenic 
U/dL 
Activated Partial Thromboplastin Time 
sec 
D-Dimer  
ug/mL (FEU) 
Factor IX,concentration 
ug/mL 
Factor X,concentration 
ug/mL 
Prothrombin fragment 1+2 
ng/mL 
Prothrombin INR 
Fraction of 1 
Fibrinogen 
g/L 
All parameters are quantitative 
 
Outputs to be produced for selected biomarkers and FVIII inhibitor titer are as follows 
(Table 3: List of outputs to be generated for biomarkers and FVIII inhibitor titers). Additional 
detail for each lab parameter is provided below. 
 


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Table 3: List of outputs to be generated for biomarkers and FVIII inhibitor titers 
Output 
FIX 
Antigen 
FX 
Antigen 
FVIII 
Inhibi- 
tor 
titer 
Pro-
thrombi
n 
INR 
D-
dimer 
aPTT 
(not 
diluted) 
Reporte
d FVIII 
Activity 
Pro-
thrombi
n 
fragment 
Fibri-
nogen 
Biomarker Test 
Results and 
Change from 
Baseline by Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plot of Mean and 
Individual 
<Biomarker> 
over Time by 
Treatment Group 
X 
X 
 
X 
 
X 
X 
 
 
Plot of Median 
and Individual 
<Biomarker> 
over Time by 
Treatment Group 
 
 
X 
 
X 
 
 
X 
X 
Categorical 
summary over 
time 
 
 
 
X 
 
 
 
 
 
Listing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
The following specific data handling rules are used in plots and descriptive summaries. 
Listings will include the original values. 
 
• 
FVIII activity: for any value reported as <1% use 0.5 (LLOQ/2)  
• 
D-dimer: for any value reported as <0.36 use 0.18 (LLOQ/2)  
• 
aPTT: for any value reported as >255 exclude from analysis and add footnote "If 
clotting not detected, the sample is excluded from the analysis" 
 
The bone and joint biomarkers may be analyzed later and presented in a separate report.  
 
4.11 
MISSING DATA 
The following rules will be used to impute missing data: 
• 
In order to implement the 72-hour rule, it is assumed that the bleeds and treatments 
with missing time occurred at 12:00 (noon).   
• 
If, on a given day, the treatment time is partial and the bleed time complete, the 
partial time is assumed to be the same as the complete time. In case of multiple 
events per day, the last complete time is used. 
• 
All bleeds with an anatomical location in a joint are considered joint bleeds 
• 
All bleeds with missing cause are included as spontaneous bleeds 
• 
If a bleed which was entered through the hand held device was edited through a 
Data Clarification Process (bleed type changed from other/muscle to joint), it is 
possible to leave the symptoms unanswered. In this case, the bleed should count 
as a joint bleed. 
See also endpoint definitions for specific data handling rules. 
 


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4.12 
INTERIM ANALYSES 
Owing to the long-term nature of this study, two interim analyses will be conducted in order 
to obtain accurate information on the safety, efficacy, immunogenicity, and PK of 
prophylactic emicizumab at specific points throughout the study.  The first analysis will be 
performed once approximately 100 patients have received treatment with emicizumab for 
at least 24 weeks. A second analysis will be performed when approximately 100 patients 
have received treatment with emicizumab for at least 52 weeks. The data from these 
analyses will subsequently be presented to the iDMC in order to enable them to effectively 
monitor the study. 
  


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5. 
REFERENCES 
Acharya SS. Rare bleeding disorders in children: identification and primary care 
management. Pediatrics 2013;132:882–92.  
Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. 
Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 
2014;12:1935–9.  
Bullinger M, Von Mackensen S, Fischer K, et al. Pilot testing of the “Haemo-QoL” quality 
of life questionnaire for haemophiliac children in six European countries. Haemophilia 
2002;8 (suppl 2):47–54.  
CDC. Centers for Disease Control and Prevention: Hemophilia Data & Statistics. Available 
from: https://www.cdc.gov/ncbddd/hemophilia/data.html. Last accessed: 17 August 2016  
Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013;27:179–
84.  
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-
level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727–36.  
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life 
Res 2013;22:1717–27.  
Mackensen SV, Gringeri A. Quality of life in hemophilia. In: Preedy VR, Watson RR, 
editors. Handbook of disease burdens and quality of life measures. New York: Springer, 
2010:1895–920.  
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion 
protein in severe hemophilia A. Blood 2014;123:317–25.  
NIH. National Institutes of Health: National Heart, Lung, and Blood Institute. What Is 
Hemophilia? 
Available 
from: 
http://www.nhlbi.nih.gov/health/health-
topics/topics/hemophilia. Last accessed: 17 August 2016  
Pollak E, Mühlan H, Von Mackensen S, Bullinger M. The Haemo-QoL Index: developing 
a short measure for health-related quality of life assessment in children and adolescents 
with haemophilia. Haemophilia 2006;12:384–92.  
Santagostino E, Morfini M, Auerswald GK-H, et al. Paediatric haemophilia with inhibitors: 
existing management options, treatment gaps and unmet needs. Haemophilia  
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management 
of hemophilia. Haemophilia 2013;19:e1–47.  
Von Mackensen S, Bullinger M. Development and testing of an instrument to assess the 
quality of life of children with haemophilia in europe (haemo-qol). Haemophilia 2004;10 
(suppl 1):17–25.  
Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. 
Ther Adv Hematol 2013;4:59–72. 
World Federation of Hemophilia. Annual Global Survey Data 2014. Available from: 
http://www1.wfh.org/GlobalSurvey/Public_AGS/AGS_Patients_Severity_EN.aspx. 
Last 
accessed: 16 August 2016  
Wyrwich KW, Krishnan S, Poon JL, et al. Interpreting important health-related quality of 
life change using the Haem-A-QoL. Haemophilia 2015;21:578–84. 


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APPENDIX 1: PROTOCOL SYNOPSIS 
TITLE:  
A SINGLE-ARM, MULTICENTER PHASE 
IIIB CLINICAL TRIAL TO EVALUATE THE 
SAFETY AND TOLERABILITY OF 
PROPHYLACTIC EMICIZUMAB IN 
HEMOPHILIA A PATIENTS WITH 
INHIBITORS  
PROTOCOL NUMBER:  
MO39129  
VERSION NUMBER:  
3  
EUDRACT NUMBER:  
2016-004366-25  
TEST PRODUCT:  
Emicizumab (RO5534262)  
PHASE:  
IIIb  
INDICATION:  
Hemophilia A  
SPONSOR:  
F. Hoffmann-La Roche Ltd  
 
Objectives and Endpoints  
This study will evaluate the safety and tolerability of emicizumab in patients with hemophilia A 
who have persistent inhibitors against Factor VIII (FVIII) at enrolment. Specific objectives and 
corresponding endpoints for the study are outlined below (Table 1). 
 
Table 1 Objectives and Corresponding Endpoints 
Objectives  
Corresponding Endpoints  
Primary Objective:  
 
 To evaluate the overall safety and 
tolerability of prophylactic administration of 
emicizumab  
 
 
 Incidence and severity of adverse events, 
including thromboembolic, thrombotic events, 
microangiopathic hemolytic anemia or 
microangiopathy (TMA), systemic 
hypersensitivity, anaphylaxis, and 
anaphylactoid events  
 Changes in physical examination findings, 
vital signs, and laboratory parameters  
 
Secondary Objective:  
 
 To evaluate the efficacy of prophylactic 
administration of emicizumab  
 
 
 To evaluate the efficacy of prophylactic 
administration of emicizumab on the basis of 
the number of bleeds over time  
 To evaluate the HRQoL of patients 
according to Haem-A-QoL (≥18 y) or Haemo-
QoL-SF (ages 12−17) scores over time  
 To evaluate the health status of patients 
according to EQ-5D-5L scores over time  
 To assess patient preference for the 
emicizumab regimen compared with the 
previous regimen used  
 
Immunogenicity Objective:  
 
 To evaluate the immuno-genicity of 
emicizumab  
 
 
 To assess the incidence and clinical 
significance of anti-emicizumab antibodies  
 
PK Objective:  
 
 


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 To obtain emicizumab PK data  
 
 To obtain PK data for emicizumab at 
defined timepoints  
 
 
EQ-5D-5L=EuroQoL Five-Dimension-Five Levels Questionnaire; Haem-A-QoL=Hemophilia Adult 
Quality of Life Questionnaire; Haemo-QoL-SF=Hemophilia Quality of Life Short Form; 
HRQoL=Health-Related Quality of Life; PK=pharmacokinetic; TMA=thrombotic microangiopathy  
 
Study Design  
Description of Study  
This single-arm, multicenter, open label, Phase IIIb clinical study will enroll patients aged 12 
years or older with congenital hemophilia A who have persistent inhibitors against FVIII at 
enrollment. Approximately 200 patients with inhibitors will be enrolled globally. Patients will 
receive prophylactic emicizumab at 3 mg/kg/week subcutaneously for 4 weeks, followed by 1.5 
mg/kg/week subcutaneously for the remainder of the 2-year treatment period.  
 
The primary objective of this study is to evaluate the overall safety and tolerability of prophylactic 
administration of emicizumab in patients with congenital hemophilia A who have persistent 
inhibitors against FVIII at enrollment. In order to achieve this objective, all adverse events, 
including adverse events of special interest, will be captured on an ongoing basis, as they occur 
during the study. Physical examinations, vital signs, and laboratory values will be assessed as 
per the schedule of activities (Protocol Appendix 1).  
 
The secondary objective of this study is to evaluate the efficacy of prophylactic administration of 
emicizumab. As part of this objective, the number of bleeds over time will be recorded for all of 
the enrolled patients.  
 
The final analysis will be conducted when all patients have completed 2 years of treatment or 
have withdrawn, whichever occurs sooner. Patients, or their legally authorized representative, will 
be asked to report bleed information on an electronic patient-reported outcome (ePRO) device 
where possible, including site of bleed, type of bleed, time of each individual bleed (day, start and 
stop time), and treatment for bleed. Health-Related Quality of Life (HRQoL) will be assessed and 
the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) will be completed prior to 
the first emicizumab administration (Week 1), at the Month 3, 6, 12, and 18 assessments, and at 
study completion as outlined in the schedule of activities (Protocol Appendix 1). Additional 
secondary endpoints include assessing patient preference for the emicizumab regimen compared 
with the previous regimen using a questionnaire (EmiPref). 
 
Immunogenicity will be monitored by incidence and clinical significance of antibodies to 
emicizumab. In addition, pharmacokinetic (PK) data for emicizumab will be obtained at defined 
timepoints as per the schedule of activities (Protocol Appendix 1).  
 
Drugs intended to control breakthrough bleeds (e.g. rFVII, FVIII, activated prothrombin complex 
concentrate [aPCC]) or bleeds during surgeries should be used at the lowest dose expected to 
achieve hemostasis. Given that circulating emicizumab may increase the patient’s coagulation 
potential, the doses required to achieve hemostasis may be lower than doses used prior to 
starting emicizumab. Investigators shall discuss at the start of the study with patients 
recommended doses of any additional coagulation factors used, following the guidance below. 
 
The use of aPCC for breakthrough bleed treatment for patients on emicizumab should be avoided 
if possible, and recombinant activated human Factor VII (rFVIIa) should be the first option used to 
treat, starting with no more than 90 μg/kg as an initial dose. If aPCC needs to be used, no more 
than 50 IU/kg should be administered as an initial dose and doses of > 100 U/kg/24 hours or 
more should be avoided, as cases of TMA and thrombotic events were reported when on average 
a cumulative amount of > 100 U/kg/24 hours aPCC was administered for 24 hours or more. 


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Investigators should provide or remind patients of the exact dose and schedule of bypassing 
agents or FVIII required to treat any bleed. 
 
When a bleed has occurred, patients (or their legally authorized representative) will be required to 
report bleed information on an ePRO device where possible, including site of bleed, type of bleed, 
time of each individual bleed (day, start and stop time), and treatment for bleed (e.g., other than 
emicizumab in case of breakthrough bleeds). The reason for the use of rFVIIa will be documented 
(e.g., bleeding, preventative dose before activity). Thorough documentation of the treatments for 
bleeds and/or surgeries will be requested, including agent, start time, dose, route of 
administration, and number of infusions needed to treat the bleed. Local and central laboratory 
assessments are required to monitor the risk for thromboembolic events or microangiopathic 
hemolytic anemia or TMA, as per the schedule of activities (Protocol Appendix 1), if bypassing 
agents are used to treat a breakthrough bleed. 
  
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 a potential increase in emicizumab dose to 3 
mg/kg/week and additional laboratory evaluations (e.g., coagulation tests), as well as to re-
evaluate the patient’s individual benefit-risk for continuing treatment.  
 
An independent Data Monitoring Committee (iDMC) will be responsible for monitoring safety 
throughout the duration of the study. 
 
Number of Patients  
This global study will enroll approximately 200 patients with congenital hemophilia A who have 
persistent inhibitors against FVIII at enrollment. The patients are expected to be enrolled at 
approximately 85 sites globally.  
 
Target Population  
Inclusion Criteria  
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form  
2. As per the investigator’s judgement, a willingness and ability to comply with scheduled 
visits, treatment plans, laboratory tests, and other study procedures, including the patient-
reported outcome (PRO) questionnaires and bleed diaries through the use of an 
electronic device or paper 
3. Aged 12 years or older at the time of informed consent 
4. Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII 
5. Documented treatment with bypassing agents or FVIII concentrates in the last 6 months 
(on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day 
before starting emicizumab 
6. Adequate hematologic function, defined as platelet count ≥100,000/μL and hemoglobin 
≥8 g/dL (≥4.97 mmol/L) at the time of screening 
7. Adequate hepatic function, defined as total bilirubin ≤1.5 × the upper limit of normal 
(ULN) (excluding Gilbert’s syndrome) and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤3 ×ULN at the time of screening; no clinical signs or known 
laboratory/radiographic evidence consistent with cirrhosis 
8. Adequate renal function, defined as serum creatinine ≤2.5 × ULN and creatinine 
clearance by Cockcroft-Gault formula ≥30 mL/min 
9. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a highly effective contraceptive method with a failure 
rate of <1% per year during the treatment period and for at least five elimination half-lives 
(24 weeks) after the last dose of emicizumab: 
• 
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (≥12 


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continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus) 
• 
Examples of highly effective contraceptive methods with a failure rate of 
<1% per year include proper use of combined oral or injected hormonal 
contraceptives, bilateral tubal ligation, male sterilization, hormone-
releasing intrauterine devices, and copper intrauterine devices. 
Alternatively, two methods (e.g., two barrier methods such as a condom 
and a cervical cap) may be combined to achieve a failure rate of <1% per 
year. Barrier methods must always be supplemented with the use of a 
non-lipid-based spermicide 
• 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.  
 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry:  
1. Inherited or acquired bleeding disorder other than hemophilia A 
2. Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy 
(prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to 
enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-
hour washout period prior to the first emicizumab administration  
3. History of illicit drug or alcohol abuse within 12 months prior to screening, as per the 
investigator’s judgment  
4. High risk for TMA (e.g., have a previous medical or family history of TMA), as per the 
investigator’s judgment  
5. Previous (in the past 12 months) or current treatment for thromboembolic disease (with 
the exception of previous catheter-associated thrombosis for which antithrombotic 
treatment is not currently ongoing) or current signs of thromboembolic disease  
6. Other conditions (e.g., certain autoimmune diseases) that may increase the risk of 
bleeding or thrombosis  
7. History of a clinically significant hypersensitivity reaction associated with monoclonal 
antibody therapies or components of the emicizumab injection  
8. Known human immunodeficiency virus (HIV) infection with CD4 count <200 cells/μL 
within 6 months prior to screening  
9. Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or 
planned use during the study, with the exception of antiretroviral therapy  
10. 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  
11. Receipt of: 
• 
Emicizumab in a prior investigational study  
• 
An investigational drug to treat or reduce the risk of hemophilic bleeds 
within five half-lives of last drug administration  
• 
A non-hemophilia-related investigational drug within last 30 days or five 
half-lives, whichever is shorter  
• 
Any concurrent investigational drug.  
12. Pregnancy or lactation, or intent to become pregnant during the study  


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13. Positive serum pregnancy test result within 7 days prior to initiation of emicizumab 
(females only)  
 
End of Study and Length of Study  
The approximate length of the entire study from the first patient enrolled to the last patient, last 
visit (LPLV; see below) is approximately 3 years. For each individual patient, the study is 
expected to last approximately 2 years (patients will receive 3 mg/kg/week emicizumab for the 
first 4 weeks followed by 1.5 mg/kg/week emicizumab for the remainder of the 2-year treatment 
period). Patients who discontinue emicizumab prior to the completion of the 2-year treatment 
period will undergo a Safety Follow-up Visit 24 weeks after the patient’s last emicizumab dose or 
at 2 years after emicizumab treatment start, whichever occurs first. 
The end of this study is defined as the date when the last remaining patient has completed the 
last visit (i.e., LPLV). The study will end when all patients have been treated with emicizumab for 
2 years, or earlier, if one of the following is documented: 
 
Withdrawal of consent  
OR  
Completed the Safety Follow-up Visit 24 weeks after discontinuing emicizumab  
OR  
Lost to follow-up  
OR  
Death.  
 
Investigational Medicinal Products  
Test Product (Investigational Drug)  
Emicizumab will be administered at a dose of 3 mg/kg/week subcutaneously for 4 weeks when 
initiating treatment, followed by 1.5 mg/kg/week subcutaneously for the remainder of the 2-year 
treatment period. There will be an option to increase the dose to 3 mg/kg/week in cases of 
insufficient control of bleeds on the 1.5 mg/kg/week emicizumab dose. If the investigator believes 
that a specific patient warrants dose up-titration following the occurrence of, for example, at least 
two spontaneous bleeds, significant bleeds, or a traumatic bleed out of proportion to the degree 
of injury, they must discuss the case with the Medical Monitor for consideration and potential 
approval. 
 
To support home administration of the drug, patients/caregivers will be required to complete in-
person, instructional training on how to administer emicizumab as a subcutaneous (SC) injection. 
Patients/caregivers will be taught to perform the injections utilizing the Instructions for Use 
document. In addition, the healthcare provider (HCP) is to inform the patient/caregiver of the 
volumetric dose to be administered and the dosing frequency. The patients/caregivers will 
observe at least one SC injection performed by a HCP and will need to successfully administer at 
least one SC injection under an HCP’s supervision prior to starting home administration. The 
patient/caregiver will also have the opportunity to ask any questions to the HCP before starting 
home administration. The first three weekly treatments will be administered in a monitored 
setting, such as an infusion center, clinic, or hospital, in conjunction with emicizumab PK and 
pharmacodynamic (PD) assessments. Patients will be observed for a minimum of 60 minutes 
after the first three doses. Patients/caregivers will be instructed on how to recognize 
signs/symptoms of hypersensitivity (including anaphylaxis) and obtain emergency care in the 
event of such reactions occurring. Each site will have the discretion to provide additional training 
or include additional observation (e.g., after the third or fifth doses), if deemed appropriate. If, 
despite additional training, the investigator determines that the patient/caregiver is unable to inject 
emicizumab, a trained and proficient caregiver or HCP should be identified to administer the SC 
injections. Patients/caregivers will be provided with contact information for the clinic in case they 
have questions related to self-administration between visits. 
 


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Compliance in the home setting is to be monitored at each site by reviewing reported hemophilia 
medication use and recording collected used and unused vials. 
 
Statistical Methods  
Primary Safety Analyses  
 
The primary objective of this study is to evaluate the overall safety and tolerability of prophylactic 
administration of emicizumab in patients with congenital hemophilia A who have persistent 
inhibitors against FVIII at enrollment. Of primary interest in this study are the incidence and 
severity of all adverse events, including thromboembolic events, microangiopathic hemolytic 
anemia or TMA, systemic hypersensitivity, anaphylaxis, and anaphylactoid events. 
 
All adverse events will be assessed according to the World Health Organization (WHO) toxicity 
grading scale. The incidence, type, and grade of adverse events will be summarized according to 
the primary system-organ class (SOC) and, within each SOC, by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. For each adverse event, data will be provided on 
the timing (start and stop date, time of onset in comparison with last dose of emicizumab 
received, and doses of emicizumab received), severity, relationship to emicizumab, outcome, and 
effect on therapy. The data may be presented together with two-sided 95% Clopper-Pearson 
confidence intervals (CIs) if appropriate. 
 
In addition, as part of the safety evaluation, additional assessments will be summarized 
descriptively as follows:  
1. Cumulative emicizumab doses, dose modifications (delays and interruptions), and 
duration of exposure  
2. Compliance with respect to emicizumab intake (planned vs. received)  
3. Changes from baseline in physical examination findings  
4. Vital signs over time:  
• 
Vital signs will be analyzed using descriptive statistics for continuous variables 
and presented graphically over time with associated 95% CIs.  
5. Laboratory parameters (hematology and chemistry):  
• 
These parameters will be presented in shift tables of WHO toxicity grade at 
baseline versus worst grade during the treatment period. Selected laboratory 
parameters will be summarized in terms of mean, standard deviation, minimum, 
and maximum. Laboratory parameters will also be presented graphically over 
time.  
 
All safety variables will be analyzed for the safety population. For each variable, the number of 
available observations will be reported. The safety population includes all patients who have 
received at least one dose of emicizumab. 
 
The primary safety analysis will occur at the end of the study. 
 
The iDMC will evaluate the study data, including the emerging safety results, at periodic reviews 
and recommend to the Sponsor whether the study should be stopped early. All summaries and 
analyses will be prepared by the SMT statistician and presented for iDMC review. Members of the 
iDMC will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities. 
  
A detailed description of the statistical methods that will be used for the primary and secondary 
analyses will be provided in the Statistical Analysis Plan (SAP). 
 
Determination of Sample Size  


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A sample size of approximately 200 patients is planned for this study.  
For the purpose of the sample size calculation, the incidence of adverse events was chosen as 
the safety endpoint of primary interest. 
 
If the observed incidence of adverse events is between 2.5% and 15%, the precision for the 
estimated incidence rate is presented below according to the 95% Clopper-Pearson CIs (Table 
2).  
 
Table 2 Clopper-Pearson 95% CIs for the Incidence of AEs (Based on N=200) 
Number of AE Events (Observed 
AE Incidence) 
95% Clopper-Pearson CIs 
5 (2.5%) 
0.8%–5.7% 
10 (5.0%) 
2.4%–9.0% 
20 (10.0%) 
6.2%–15.0% 
30 (15.0%) 
10.4%–20.7% 
 
Interim Analyses  
The first analysis will be performed once approximately 100 patients have received treatment with 
emicizumab for at least 24 weeks. A second analysis will be performed when 100 patients have 
received treatment with emicizumab for at least 52 weeks. The data from these analyses will 
subsequently be presented to an iDMC in order to enable them to effectively monitor the study. 
Details regarding the planned interim analyses will be provided in the SAP and iDMC charter. 








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d. Medical history and demographics data will be collected from patient medical records and documented in the eCRF. Medical history includes 
hemophilia-related history, clinically significant diseases, procedures (including prior surgeries), use of alcohol and drugs of abuse within the 
past year, and medication allergies. In particular, sites should record whether the patient has any history of prior ITI, anaphylaxis, or known 
thrombophilia. It should also include all medication taken in the 4 weeks prior to screening (including prescription drugs, over-the-counter drugs, 
and herbal/homeopathic remedies and therapies). Any hemostatic medications (e.g. bypassing agents) and other medications used to treat or 
prevent bleeds in the 6-month period prior to starting emicizumab treatment will also be collected. Demographic data will include age, sex, and 
self-reported race and ethnicity.  
e. A complete physical examination will be performed during Screening and should include, but not necessarily be limited to, an evaluation of 
the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological 
systems. Any abnormality identified during screening should be recorded on the General Medical History and Baseline Conditions eCRF. 
Targeted physical examinations (i.e., joints for bleeds, evidence of arthropathy; skin for bruises, hematomas, and ISRs; ), other organ systems 
as clinically indicated, should be conducted at subsequent visits or as clinically indicated. New or worsened clinically significant abnormalities 
from screening should be recorded as adverse events, if appropriate, on the Adverse Event eCRF.  
f. 
Vital signs include measurement of body temperature (oral, rectal, axillary, or tympanic), heart and respiratory rates, blood pressure and 
weight. On treatment days, measurement should occur prior to micizumab administration, if applicable. Height will be measured and recorded 
only during at Screening and 6 and 12 months after starting emicizumab. Additional vital signs assessments may also be taken anytime as 
unscheduled assessments as judged by the investigator. In addition, vital signs may be taken to help monitor for hypersensitivity reactions 
during or after injections at the investigator's discretion, although these data but they should not be entered into the eCRF.  
g. The definition of concomitant medications, as well as permitted and prohibited medications is described in Section 4.4. Concomitant 
medications used by a patient from 4 weeks prior to initiation of emicizumab to the Study Completion/Early Termination Visit (or to the Safety 
Follow-up Visit, if applicable) should be reported to the investigator and recorded on the Concomitant Medications eCRF. Treatments for bleeds 
(i.e., bypassing agents and other medications to treat bleeds), will be collected in the bleed records.  
h. Hematology and blood chemistry assessments will include a complete blood count with differential and serum chemistries (see Section 
4.5.6.1). Safety Laboratory assessments completed at during Screening do not have to be repeated at Week 1, if the period between Screening 
and Week 1 is ≤ 5 days and there has been no change in the patient’s health status as assessed by the investigator. Samples will be sent to 
the central laboratory for analysis.  
i. 
Pregnancy tests: Female patients of childbearing potential (including those who have had a tubal ligation) will be required to have a negative 
serum pregnancy test result during Screening and again within 7 days prior to the first dose of emicizumab. Urine pregnancy tests will be 
performed throughout the study treatment period. Pregnancy testing will be conducted at the local laboratory.  
j. 
The specific tests utilized for hepatitis and HIV serology testing are per local standard of care. As this patient population is at high risk for HIV, 
hepatitis A, B and C, sites should consider testing for these. While the specific serological tests used is at the discretion of the Investigator, this 
is with the understanding that the status of that participants’ hepatitis or HIV is confidently known at time at enrollment. HIV and hepatitis 
serology tests will be conducted at the local laboratory.  
k. For the assessment of anti-FVIII antibodies (inhibitors), functional assays that utilize a clotting readout (classic Bethesda or Nijmegen assay) 
cannot be used for patients on emicizumab therapy as emicizumab drives clotting even in the presence of FVIII inhibitors, causing a false-


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negative test result (see Section 5.1.3). After the first dose, local measurement of FVIII inhibitors, if indicated, requires use of an ELISA-based 
test or a chromogenic Bethesda assay. At the discretion of the local investigator, any additional urgent request to assess FVIII inhibitors will 
need to be sent to the central laboratory (see Protocol Appendix 2 for additional information). Plasma samples for anti-FVIII antibodies will be 
analysed at the central laboratory  
l. 
Plasma samples are required for immunogenicity assessments to detect anti-emicizumab antibodies. Additional samples to detect anti-
emicizumab antibodies may also be drawn at the time of hypersensitivity events or following suspected loss of efficacy.  
m. ePRO bleed / medication recording: At the Week 1 visit, patients will be trained on how to record their bleeds and hemophilia medication use 
on the ePRO device where possible. Data that need to be recorded will include the site of bleed, type of bleed, time of each individual bleed 
(day, start and stop time), and treatment for bleed. At least once a week, patients will need to record any hemophilia medication use (including 
emicizumab) and information regarding any bleeding events. Investigator review of patient-reported bleed/medication records with the 
patient/caregiver will occur for completeness and accuracy at all of the visits during the treatment period, at study completion, at any 
unscheduled visits (if required), and at the Early Termination Visit (if required).  
n. Thorough documentation on surgical events will be requested, including type of surgery or procedures, treatments, outcomes, etc.  
o. Adverse events: After informed consent has been obtained but prior to initiation of emicizumab, only serious adverse events caused by a 
protocol-mandated intervention should be reported. Injection-site reaction adverse events will be collected on a the injection site reaction form.  
p. Management of emicizumab: Drug dispensation will not occur at the Study Completion Visit or the Early Termination Visit (if required). 
Patients will only receive emicizumab during an unscheduled visit if drug dispensation is required at this time.  
q. HRQoL and EQ-5D-5L: Patients will be requested to complete Haem-A-QoL (adults age: ≥ 18 years) or the Haemo-QoL-SF (adolescents 
ages: 12−17 years) questionnaire and the EQ-5D-5L questionnaire. Questionnaires will be self-administered electronically before the 
patient/caregiver receives any information on disease status, prior to the performance of non-PRO assessments, and prior to emicizumab 
administration (if on a treatment day). Paper versions of the questionnaires are also available in case of ePRO outage or if an ePRO device is 
otherwise unavailable.  
r. 
EmiPref: At the 3-month assessment, patients will be prompted to complete a paper version of the EmiPref questionnaire (Protocol Appendix 
3). The questionnaire will be self-administered before the patient/caregiver receives any information on disease status, prior to the performance 
of non-PRO assessments, and prior to emicizumab administration (if on a treatment day).  
s. On treatment days, blood collection should occur within 2 hours prior to emicizumab administration unless otherwise specified. Unless 
otherwise specified, additional analysis will be performed at a local laboratory, as per the investigator’s discretion. Any additional laboratory 
results which are required as part of the patient’s safety assessment should be recorded in the unscheduled visit eCRFs. Central labs are part 
of the non-eCRF data which will be sent to the Sponsor directly by the central lab vendor.  
t. 
Plasma samples are required for PK assessments. On days where samples are to be collected, the emicizumab injection will be performed in 
the clinical unit. One single pre-dose sample is required on the applicable visits. Samples will be analysed by the central laboratory.  
u. Plasma samples for safety biomarkers must be citrate plasma. Tests may include, but are not limited to, D-dimer. Samples will be analysed by 
the central laboratory. See Protocol Appendix 2.  


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v. Plasma samples for safety coagulation system biomarker assessments must be citrate plasma. Tests include FVIII:Ag, FIX:Ag and FX:Ag 
Samples will be analysed by the central laboratory. See Protocol Appendix 2.  
w. Plasma samples for PD biomarker assessments must be citrate plasma. Tests will include, but are not limited to, FVIII activity and modified 
aPTT (one stage). will beTime windows for sample collection are specified in Protocol Appendix 2. Additional plasma samples will be collected 
for future exploratory research, which may include tests such as clot waveform analysis (CWA) and others (see Protocol Appendix 2). Samples 
will be analysed by the central laboratory.  
x. Serum and plasma EDTA samples for bone and joint biomarkers must be collected after fasting (no food or drink other than water for at least 
8 hours prior to the blood draw). Ideally these samples should be collected in the morning (before noon), in order to control for diurnal variation. 
Please consult the Central Laboratory Services Manual for details. The selection of exploratory bone and joint biomarkers to be tested will build 
on findings from biomarker analyses in other emicizumab trials and may include CTX-1, OPG, P1NP, and soluble RANK-L (see Protocol 
Appendix 2). Samples will be analysed by the central laboratory.  
y. Additional laboratory assessments: In the event of a breakthrough bleed that is treated with bypassing agents, it is recommended that the 
following laboratory tests will be performed within 24−48 hours of initial bypassing agent use (these tests will be conducted so that the 
investigator can monitor the patient for potential thromboembolic events and microangiopathic hemolytic anemia or TMA). These tests include 
platelet count, serum creatinine, LDH and schistocytes. A plasma sample should also be provided for central laboratory monitoring of 
prothrombin fragment F1+2, fibrinogen and D-dimer. Samples for these tests should ideally be analysed at the central laboratory. Exceptionally 
in urgent situations where results are required quickly, local laboratory testing can be used, with results recorded in the eCRF. For patients who 
require multiple doses of bypassing agents, laboratory monitoring should be performed every 24−48 hours until 24−48 hours after the last dose 
of bypassing agents is administered to treat a specific bleed. If applicable, laboratory results should be recorded in the unscheduled visit 
eCRFs.  
 


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APPENDIX 3: HRQOL QUESTIONNAIRES 
Recoding and Scales 
Before calculating the scale and total scores several items need to be reverse scored 
(Table_App3.01, Table_App3.02). The reverse scoring for those items is as follows: (1=5), 
(2=4), (3=3), (4=2), and (5=1). Any (0) will be recoded as missing data for the purposes of 
scale scoring. In listings of frequencies, the number of patients reporting ‘Not applicable’ can 
also be displayed.  
After the recoding the 3 scores can be calculated as follows: 
1. Raw Scale Score: Derived as the sum of all items in a scale. , e.g. the raw score for 
physical health is the sum of the 5 items from this scale. A Total score is calculated 
by summing up all of the raw and reverse coded items in the available scales. 
2. Standardized Scale Score: The raw scale score is divided by the number of items in 
the scale. That way a comparison of scores across scales per patient is possible. 
3. Transformed Scale Score: The scores for each scale can be standardized onto a 
100 point scale. This is done with the following formula:  
𝑇𝑆𝐶= 100 × (𝑟𝑎𝑤 𝑠𝑐𝑎𝑙𝑒 𝑠𝑐𝑜𝑟𝑒−𝑚𝑖𝑛𝑖𝑚𝑎𝑙 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒)
𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑛𝑔𝑒 𝑜𝑓 𝑟𝑎𝑤 𝑠𝑐𝑎𝑙𝑒 𝑠𝑐𝑜𝑟𝑒𝑠 
 
 
= 100 × (𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑𝑖𝑧𝑒𝑑 𝑠𝑐𝑎𝑙𝑒 𝑠𝑐𝑜𝑟𝑒−1) 
4 
 
The transformed Scale Score will be used for all analyses and referred as domain score or 
total score on the outputs. 
Table_App3.01: The questions from Haem-A-QoL whose items need recoding are: 
Category 
Question 
View of yourself 
I felt comfortable with my body 
 
I was able not to think all the time about my 
hemophilia 
Dealing with hemophilia 
I tried to recognize early on when a bleed developed 
 
I was able to tell whether or not I was bleeding 
 
I was able to control my bleeds 
Treatment 
I was satisfied with the hemophilia center 
Future 
I have been expecting that things will get better in 
the future 
Sports and leisure 
I played sports just as much as others 


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Work and school 
I was able to go to work/school regularly in spite of 
my hemophilia 
 
I was able to work/study like healthy colleagues 
 
Table_App3.02: The questions from Haemo-QoL-SF whose items need recoding are: 
Category 
Question 
View of yourself 
I felt as well as other boys my age 
I felt contented about my body 
Friends 
My best friend cared about how I was feeling 
There was a best friend that I felt very close to 
My friends took care of me when I felt bad 
Sports and school 
I did as much sports as any other kid 
Dealing with hemophilia 
I was in control of my complaints due to 
haemophilia 
Haemophilia was a normal part of my life 
I felt healthy in spite of my haemophilia 
I accepted having haemophilia 
Treatment 
The treatment I got was okay 
 
Missing items 
Scales can be calculated if > 50% of the items have been answered. As the questionnaire is 
being administered electronically and patients are not able to skip items, there should not be 
any missing items. However, as patients can answer “Not applicable” to questions in the 
sports and leisure, work and school, and family planning scales, items could be treated as 
missing. In this case, the minimum number of items that needs to be completed and not 
responded to as “Not applicable” is: 
• 
Sports and leisure: 3 
• 
Work and school: 2 
• 
Family planning: 2