Clinical trial NCT03921294
Conditions: Haemophilic Pseudotumour
Sponsor: Indiana Hemophilia &Thrombosis Center, Inc.
Start date: 2019-05-15; Completion date: 2022-03-16
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of hemophilia A patients (baseline FVIII level \<40%) with and without inhibitors with hemophilic pseudotumors; secondary outcomes will assess changes in quality of life and activity level in treated patients.

Detailed description:
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of hemophilia A patients, (baseline FVIII level \<40%), children and adults, with and without inhibitors with hemophilic pseudotumors; secondary outcomes will assess changes in quality of life and activity level in treated patients.

Hemlibra (emicizumab) will be administered as primary weekly prophylaxis after the enrollment/screening visit is complete (approximately 7-10 days after screening, if laboratory results are available and eligibility is confirmed). If an activity monitoring device is typically utilized by the patient (eg, a Fitbit) then permission will be requested from the patient at screening to access the data for 1 month prior to screening as a baseline comparator for post-treatment activity. The use of an activity-monitoring device is not required by the study.

The enrollment period is 2 years and the study will last a maximum of 4 years; subjects will receive study medication (Hemlibra, emicizumab) for a minimum of 2 years and a maximum of 4 years based upon time of enrollment. Hemlibra (emicizumab) will be administered using the FDA-approved once-weekly dosing regimen for loading dose and prophylactic dose. Breakthrough bleeding events will be recorded and treated with locally available FVIII (eg, pdFVIII or rFVIII) in non-inhibitor subjects and inhibitor subjects with low titer inhibitors (titer\<5 BU). The lowest dose of FVIII expected to achieve hemostasis will be utilized for treatment of breakthrough bleeding events in non-inhibitor and low-titer inhibitor patients. Subjects with high-titer inhibitors (titer ≥5 BU) and those with low titer inhibitors who do not respond to FVIII will be required to utilize rFVIIa as first line therapy; aPCC (\<100 U/kg/day for preferably no more than 1 day) may only be used upon approval of the Study Investigator and under the supervision of a physician.

The proposed study is seeking to address the following knowledge gaps:

Does weekly prophylactic Hemlibra (emicizumab) reduce the rate of bleeding events in subjects with hemophilia A and pseudotumor, including the rate of hospitalization, anemia and transfusion? Does weekly prophylactic Hemlibra (emicizumab) control the progression of hemophilic pseudotumor? Does weekly prophylactic Hemlibra (emicizumab) result in an increase in QoL and activity level?

Arms: arm 1: Patients with hemophilic pseudotumor will be treated with prophylactic emicizumab and assessed for improvement.
Interventions: intervention 1: Emicizumab
Intervention descriptions: intervention 1: bispecific monoclonal antibody binding to activated Factor IX and Factor X

Protocol documents:
Prot_SAP_000.pdf: 
Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 1 
Investigator Initiated Study 
 
Study Title 
Prospective, single-arm, open-label use of Hemlibra (emicizumab) 
to treat hemophilic pseudotumor 
ClinicalTrials.gov # 
NCT03921294 
Internal tracking # 
RO-IIS-2018-10581 
Study Phase 
4 
Product Name 
US-labeled Hemlibra (emicizumab-kxwh) 
Indication 
Hemophilic pseudotumor in hemophilia A patients 
Principal Investigator 
Amy D. Shapiro, M.D. 
Sponsor 
The Indiana Hemophilia and Thrombosis Center (IHTC) 
Grantor 
Genentech 
 
Protocol Version: 3.0 
Date of Original Approved Protocol (v1.1): March 28, 2019 
Date of Amendment:  June 16, 2020 
 
 
Confidentiality Statement 
Part or all the information in this protocol may be unpublished material. Accordingly, this 
protocol should be treated as confidential information and its use restricted to supplying 
information to investigators, regulatory authorities, ethics committees, and other personnel 
involved in this study who need to be aware of the content of the protocol. 
 
 
Approved by:  
      See electronic signature and date/timestamp.                     
 
 
 
              
                                     Signature                                                                                                      Date 
 
 
                         Amy D. Shapiro, MD 
                             Printed Name 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 2 
HISTORY OF PROTOCOL REVISIONS 
 
 
Version 
Date approved 
Comments 
1.1 
March 28, 2019 
Original protocol 
2.0 
February 27, 2020 
Amendment #1 
3.0 
June 16, 2020 
Amendment #2 
 
 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 3 
PROTOCOL VERSION 2.0 (AMENDMENT #1) 
RATIONALE FOR CHANGES 
 
Changes to the protocol that modify the study design or analyses, along with a rationale for each 
change are summarized below: 
 
Change 
Rationale 
Affected protocol sections 
Dose escalation from 1.5 
mg/kg QW to 3.0 mg/kg QW 
(maintenance dose) 
Subjects may continue to 
experience suboptimal 
control of breakthrough 
bleeding on Hemlibra 
(emicizumab) prophylaxis. If 
so, an increase in 
maintenance dose to 3 mg/kg 
QW may be appropriate. 
5.1.1 
5.3.2 
5.3.3 
7.3 
Visit windows row added to 
the schedule of events 
Clarify visit windows on 
visual schedule of events 
Appendix 12 
 
 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 4 
PROTOCOL VERSION 2.0 (AMENDMENT #1) 
SUMMARY OF CHANGES 
Protocol Synopsis 
The protocol synopsis has been updated to reflect the changes to the protocol, where applicable. 
Section 5.1.1 Study Drug 
The study drug is US-labeled Hemlibra (emicizumab). It will be administered using the FDA 
approved once-weekly doing regimen for loading dose (3 mg/kg) and prophylactic dose (1.5 
mg/kg, or 3 mg/kg if dose escalation is determined appropriate by the Study Investigator 
[Section 5.3.3]).  
Section 5.3.2 Prophylactic Doses of Hemlibra (emicizumab) 
Prophylactic administration of Hemlibra (emicizumab) will continue on a weekly basis (1.5 
mg/kg subcutaneous dosing, or 3 mg/kg kg if dose escalation is determined appropriate by the 
Study Investigator [Section 5.3.3]) until the subject withdraws from the study, is involuntarily 
withdrawn from the study, or the study is terminated, whichever occurs first (Section 7.3).  
5.3.3 Dose escalation of Prophylactic Hemlibra (emicizumab) 
All subjects with suboptimal control of bleeding as defined by the protocol will be offered the 
option to increase their Hemlibra (emicizumab) maintenance dose to 3 mg/kg QW, with approval 
from the Study Investigator. Suboptimal response is defined as follows: 
 Two qualifying bleeds within 24 weeks while on prophylactic Hemlibra (emicizumab) 
A qualifying bleed is defined as spontaneous, verified by an investigator (eg, by imaging or 
physical examination or reliable symptoms reported by patient including increased pain with 
swelling, decreased ability to function etc clearly related to presence/site of pseudotumor), and 
occurring while on prophylactic Hemlibra (emicizumab) at steady state (after week 5). If the 
investigator believes that a specific subject warrants dose escalation on the basis of a different 
reason, he or she may discuss the case with the Study Investigator for consideration and 
potential approval. 
If this 3 mg/kg maintenance dose does not result in increased control of breakthrough bleeding, 
the subject may return to the standard 1.5 mg/kg maintenance dose upon approval of the Study 
Investigator, assuming this 1.5 mg/kg dose had resulted in an improvement in breakthrough 
bleeding compared to their pre-study regimen. 
7.3 Prophylactic Administration of Hemlibra (emicizumab)  


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 5 
Prophylactic administration of Hemlibra (emicizumab) will continue on a weekly basis (1.5 
mg/kg subcutaneous dosing, or 3 mg/kg kg if dose escalation is determined appropriate by the 
Study Investigator [Section 5.3.3]) until subject withdrawal or study termination, whichever 
occurs first.  
 
 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 6 
PROTOCOL VERSION 3.0 (AMENDMENT #2) 
RATIONALE FOR CHANGES 
 
Changes to the protocol that modify the study design or analyses, along with a rationale for each 
change are summarized below: 
 
Change 
Rationale 
Affected protocol sections 
Update for Genentech-
required safety language for 
reporting/collecting of AEs 
and product complaints 
Genentech-required changes 
6.11.3.2j 
 
 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 7 
PROTOCOL VERSION 3.0 (AMENDMENT #2) 
SUMMARY OF CHANGES 
 
6.11.3.2j Exchange of single case reports 
The IHTC will track all protocol-defined AE and pregnancy reports IHTC will be responsible for 
collecting all protocol-defined Adverse Events (AEs)/Serious Adverse Events (SAEs), AEs of 
Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product 
Complaints (with or without an AE) originating from the Study for the Product.  
Study Investigators must report all the above-mentioned single case reports Adverse Events/ 
Serious Adverse events (SAEs), AEs of Special Interest (AESIs) pregnancy reports and special 
situation reports (if applicable) adequately to Genentech within the timelines described below. 
The completed MedWatch or CIOMS I form or Genentech approved reporting forms should be 
faxed/emailed immediately upon completion to Genentech Drug Safety at the following contacts: 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) 
and Product Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be called into: 
Product Complaint Hotline Phone Number: (800) 334-0290 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, 
AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or 
without an AE) originating from the study.  
These single case reports will be exchanged between the parties as outlined below so that 
regulatory obligations are met. Relevant follow-up information should be submitted to 
Genentech Drug Safety as soon as it becomes available and/or upon request 
Serious adverse events (SAEs), pregnancy reports, AEs of special interest (AESIs), and Special 
Situation Reports and Product Complaints (with or without an AE), where the patient has been 
exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS I form or on 
Genentech approved reporting forms to Genentech Drug Safety. Transmission of these reports 
(initial and follow-up) will be either electronically or by fax and within the timelines specified 
below: 
 SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech 
within fifteen (15) calendar days of the awareness date. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 8 
 Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date. 
 Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy where the fetus may have been exposed to the 
Product, shall be transmitted to Genentech within thirty (30) calendar days of the 
awareness date. Pregnancies will be followed up until the outcome of the pregnancy is 
known, whenever possible, based upon due diligence taken to obtain the follow-up 
information. 
 Special situation reports 
In addition to all SAEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to 
Genentech within thirty (30) calendar days: 
o Data related to the Product usage during pregnancy or breastfeeding 
o Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error (including potentially exposed in case of 
medication errors or intercepted medication errors) or occupational exposure, with 
or without association with an AE/SAE unless otherwise specified in the protocol 
o Lack of therapeutic efficacy 
o Drug interaction 
o Use of a Medicinal Product in a Pediatric and Elderly population (in addition, 
reasonable attempts should be made to obtain and submit the age or age group of 
the patient, in order to be able to identify potential safety signals specific to a 
particular population) 
 Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date. 
 
A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been 
released and distributed to the commercial market or clinical trial. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 9 
All other AEs will be reported via CTV reconciliation process (a list of all AEs) on a quarterly 
basis. 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported 
 
 
 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 10 
SYNOPSIS  
Study Title 
Prospective, Single-Arm, Open-Label use of Hemlibra (Emicizumab) to treat hemophilic 
pseudotumor 
Study Phase 
This is a phase 4 study 
Name of provided study drug 
US-labeled Hemlibra (emicizumab-kxwh) 
Study Length 
Total study length is 4 years. Enrollment period is 2 years with a minimum of 2 years on study, 
and a maximum of 4 years on study. No follow-up period is planned. 
Overview 
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess 
the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of 
hemophilia A patients (baseline FVIII level <40%) with and without inhibitors with hemophilic 
pseudotumors; secondary outcomes will assess changes in quality of life and activity level in 
treated patients. 
Study rationale 
Hemophilia A is a congenital bleeding disorder caused by deficient or dysfunctional factor VIII 
(FVIII) which leads to bleeding correlated with level of severity. Management includes 
replacement of the deficient clotting factor either in reaction to a bleeding event or administered 
prophylactically to suppress or prevent bleeding. Effective treatment is complicated by the 
ability to administer standard replacement therapy via intravenous infusion and the development 
of FVIII neutralizing antibodies, or inhibitors, in approximately ~30% of patients with severe 
hemophilia A leading to worsened morbidity and mortality and exponentially increasing the cost 
of care. Inhibitor patients often require the use of bypassing therapy to obtain hemostatic control.   
Hemophilic pseudotumor is a complication of hemophilia (1-2% of patients) that consists of a 
progressive cystic swelling of muscle and/or bone caused by recurrent hemorrhage. It is observed 
more frequently in geographic areas where hemophilia is diagnosed late, treatment is 
inconsistently available, prophylaxis is not used due to resource constraints, and in patients who 
do not recognize that a bleeding event has occurred (eg, moderate or mild deficient patients who 
experience an injury). FVIII prophylaxis has been used in patients with hemophilia A with 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 11 
pseudotumors when surgical intervention is not feasible either due to lack of local expertise or 
inability to perform the intervention due to extent or site of the pseudotumor. Pseudotumors may 
be present in patients with hemophilia either with or without an inhibitor and are more common 
in patients with inhibitors where hemostasis is less well controlled.   
It is hypothesized that an agent that confers a consistent FVIII level in the mild deficient range 
that is not associated with trough levels below 10% will confer a higher degree of hemostasis in 
patients with pseudotumors; this will result in a decreased rate of breakthrough bleeding 
requiring intermittent hemostatic therapy, and an associated decrease in uncontrolled bleeding 
resulting in anemia, transfusion, and hospitalization. If these endpoints are achieved it is also 
hypothesized that activity and quality of life may increase or improve respectively.  
The purpose of this study is to prospectively investigate the hemostatic efficacy and safety of 
weekly prophylactic Hemlibra (emizicumab) in the treatment/control of pseudotumors in 
children and adults with FVIII deficiency (baseline FVIII level <40%) either with or without an 
inhibitor; in addition, changes in quality of life and activity level in subjects with hemophilia A 
and pseudotumor will be assessed. 
Study Design 
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess 
the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of 
hemophilia A patients, (baseline FVIII level <40%), children and adults, with and without 
inhibitors with hemophilic pseudotumors; secondary outcomes will assess changes in quality of 
life and activity level in treated patients. 
Hemlibra (emicizumab) will be administered as primary weekly prophylaxis after the 
enrollment/screening visit is complete (approximately 7-10 days after screening, if laboratory 
results are available and eligibility is confirmed). If an activity monitoring device is typically 
utilized by the patient (eg, a Fitbit) then permission will be requested from the patient at 
screening to access the data for 1 month prior to screening as a baseline comparator for post-
treatment activity. The use of an activity-monitoring device is not required by the study.   
The enrollment period is 2 years and the study will last a maximum of 4 years; subjects will 
receive study medication (Hemlibra, emicizumab) for a minimum of 2 years and a maximum of 
4 years based upon time of enrollment. Hemlibra (emicizumab) will be administered using the 
FDA-approved once-weekly dosing regimen for loading dose and prophylactic dose. 
Breakthrough bleeding events will be recorded and treated with locally available FVIII (eg, 
pdFVIII or rFVIII) in non-inhibitor subjects and inhibitor subjects with low titer inhibitors (titer 
<5 BU). The lowest dose of FVIII expected to achieve hemostasis will be utilized for treatment 
of breakthrough bleeding events in non-inhibitor and low-titer inhibitor patients. Subjects with 
high-titer inhibitors (titer ≥5 BU) and those with low titer inhibitors who do not respond to FVIII 
will be required to utilize rFVIIa as first line therapy; aPCC (<100 U/kg/day for preferably no 
more than 1 day) may only be used upon approval of the Study Investigator and under the 
supervision of a physician. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 12 
The proposed study is seeking to address the following knowledge gaps: 
 Does weekly prophylactic Hemlibra (emicizumab) reduce the rate of bleeding events in 
subjects with hemophilia A and pseudotumor, including the rate of hospitalization, 
anemia and transfusion? 
 Does weekly prophylactic Hemlibra (emicizumab) control the progression of hemophilic 
pseudotumor? 
 Does weekly prophylactic Hemlibra (emicizumab) result in an increase in QoL and 
activity level? 
Primary Objective 
To determine the hemostatic efficacy* of prophylactic weekly injections of Hemlibra 
(emicizumab) in hemophilia A subjects (baseline FVIII level <40%) with pseudotumor, with or 
without FVIII inhibitors 
Secondary Objectives 
To determine the rate of breakthrough bleeding events, either related or unrelated to the 
pseudotumor, requiring alternate hemostatic therapy. 
To evaluate the control of progression, stabilization or regression of the pseudotumor. 
To determine the safety of Hemlibra (emicizumab) based on adverse events (AEs) and serious 
adverse events (SAEs) including lack of efficacy and development of anti-drug antibodies 
(ADA). Samples for ADA will be banked for analysis and performed in conjunction with 
Genentech/Roche either yearly, at the end of the study, or as determined by the Study 
Investigator based upon suspected lack of clinical efficacy. 
To evaluate the change in quality of life and activity as measured by the Haem-A-QoL and EQ-
5D-5L with Hemlibra (emicizumab) prophylaxis. If an activity monitoring device is standardly 
utilized by the patient (eg, FitBit) then data from that device will be requested from the patient to 
assist in activity monitoring as well. 
To evaluate the effect of Hemlibra prophylaxis on any surgical procedures, including the use of 
other hemostatic agents such as FVIII, aPCC or rFVIIa and overall hemostatic efficacy. 
Primary endpoints 
The number of breakthrough bleeding events over time requiring the use of alternate hemostatic 
therapy (bleed rate) related to the pseudotumor. 
                                                 
* Hemostatic efficacy is defined as the rate of breakthrough bleeding related to the pseudotumor; which is defined as 
the number of bleeding episodes while on Hemlibra that require alternative hematinic therapy. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 13 
The number of hospital admissions related to the pseudotumor. 
The number of incidences of anemia requiring transfusion or intervention related to the 
pseudotumor. 
The control of progression, stabilization or regression of the pseudotumor (ie, changes in size) as 
measured by yearly assessments including CT or MRI. 
Secondary endpoints 
The impact of weekly prophylaxis on quality of life and activity level. 
Safety including development of AEs, SAEs, and ADA. 
The dose(s) and number of infusions of alternate hemostatic therapy (FVIII, rFVIIa or aPCC) 
required to treat a breakthrough bleeding event either unrelated or related to the pseudotumor. 
The number of breakthrough bleeding events over time requiring the use of alternate hemostatic 
therapy (bleed rate) unrelated to the pseudotumor. 
The use of alternate hemostatic therapies (eg, FVIII, rFVIIa or aPCC) during surgeries and the 
hemostatic efficacy. 
Inclusion criteria 
Patients must meet the following criteria for study entry: 
 Signed informed consent form from the subject, parent or guardian 
 Diagnosis of congenital hemophilia A (baseline FVIII level <40%) with or without FVIII 
inhibitor, either high or low responding, regardless of titer 
 Diagnosis of a hemophilic pseudotumor confirmed by radiologic assessment such as CT 
or MRI 
 Any weight or BMI 
 Medical documentation of prophylactic or episodic treatment (FVIII or bypassing agent) 
and the number of bleeding episodes for at least 16 weeks, and up to 6 months if 
available, prior to entry into the study   
 Medical documentation of any need for PRBC transfusion or hospitalization for 6 months 
prior to entry into the study 
 Subjects with a history of an inhibitor should provide documentation of the inhibitor 
history including date of initial diagnosis of inhibitor, peak titer, and agent utilized for 
hemostatic control 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 14 
 Subjects with high titer inhibitors or those with low titer inhibitors who do not respond to 
FVIII must be willing to use rFVIIa as first line therapy for the treatment of breakthrough 
bleeding events  
 Medical documentation of ITI therapy for subjects with a history of a FVIII inhibitor and 
ITI, including current FVIII inhibitor titer 
 Willingness to discontinue any current prophylactic hemostatic regimen (FVIII or 
bypassing agent) and/or FVIII ITI therapy for the duration of the study 
o Subjects receiving FVIII prophylaxis must be willing to discontinue their FVIII 
prophylactic regimen immediately prior to their second loading dose of Hemlibra 
(emicizumab) 
o Subjects receiving bypassing agent prophylaxis must be willing to discontinue 
their prophylactic regimen at least 24 hours prior to their first loading dose of 
Hemlibra (emicizumab) 
o Subjects receiving FVIII ITI therapy must be willing to discontinue ITI 
immediately prior to their first loading dose of Hemlibra (emicizumab) 
 Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the health-related questionnaires, activity tracking, 
and bleed diaries, using systems provided during the study 
 Adequate hepatic function, defined as total bilirubin ≤1.5 × age-adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT ≤3 × age-adapted 
ULN at the time of screening, and no clinical signs or known laboratory/radiographic 
evidence consistent with cirrhosis  
 Subjects must be willing to be vaccinated against HAV and/or HBV if not previously 
vaccinated, exposed or immune to HAV and/or HBV 
 Adequate hematologic function, defined as a platelet count ≥100,000/μL and a PT≤1.5 
times the ULN at the time of screening  
 Adequate renal function, defined as serum creatinine ≤2.5 × age-adapted ULN and 
creatinine clearance ≥30 mL/min by Cockcroft-Gault formula  
 For women with hemophilia of childbearing potential: agreement to remain abstinent 
(refrain from heterosexual intercourse) or use highly effective contraceptive methods that 
result in a failure rate of <1% per year during the treatment period and for at least 5 
elimination half-lives (24 weeks) after the last dose of study drug   
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
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permission from Genentech. 
 
 
Page 15 
 Inherited or acquired bleeding disorder other than congenital hemophilia A  
 Baseline FVIII level ≥40% 
 Lack of a documented diagnosis of hemophilic pseudotumor 
 Patients who are at high risk for TMA (eg, have a previous medical or family history of 
TMA), in the judgement of the Study Investigator 
 History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the Study 
Investigator’s judgment 
 Previous (within the last 12 months) or current treatment for thromboembolic disease 
(with the exception of previous catheter-associated thrombosis for which anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease  
 Other conditions (eg, certain autoimmune diseases) that may currently increase the risk of 
bleeding or thrombosis  
 History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the Hemlibra (emicizumab) injection 
 Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 
 Known HIV infection with CD4 counts <200 cells/μL. HIV infection with CD4 counts 
≥200 cells/μL permitted  
 Use of systemic immunomodulators (eg, interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy 
 Concomitant disease, condition, significant abnormality on screening evaluations or 
laboratory tests, or treatment that could interfere with the conduct of the study, or that 
would, in the opinion of the Study Investigator, pose an additional unacceptable risk in 
administering study drug to the patient 
 Receipt of any of the following: 
o Hemlibra (emicizumab) in a prior investigational study 
o An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 
half-lives of last drug administration 
o A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
o Any other investigational drug currently being administered or planned to be 
administered 
 Inability to comply with the study protocol in the opinion of the Study Investigator 


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Page 16 
 Pregnancy or lactation or intention to become pregnant during the study 
 Women with a positive serum pregnancy test result within 10 days prior to initiation of 
study drug 
Randomization & Stratification 
This is a single arm prospective study without randomization. 
Hemlibra (emicizumab) will be provided at no cost to participants. The choice of FVIII 
preparation such as pdFVIII or rFVIII, to treat breakthrough-bleeding events in non-inhibitor 
subjects and subjects with low titer inhibitors (titer <5 BU) who respond to FVIII will be at the 
discretion of the local treating physician throughout the study period and the lowest expected 
dose to achieve hemostasis will be utilized. Patients with high titer inhibitors (titer ≥5 BU) or 
low titer inhibitor patients who do not respond to FVIII and require the use of bypassing agents 
for acute bleeding will be required to utilize rFVIIa as first line therapy for breakthrough 
bleeding episodes; aPCC (<100 U/kg/day for preferably no more than 1 day) may only be used 
upon approval of the Study Investigator and under the supervision of a physician. Agents other 
than Hemlibra (emicizumab) required for hemostatic control will not be supplied by the study; 
specifically, FVIII concentrate, rFVIIa and (if approved for use by the Study Investigator) aPCC. 
Reimbursement for subjects’ travel to and from the IHTC (or other medical facilities) will not be 
provided by the study. 
Schedule of assessments/events for all visits 
Initial study visit  
This visit will comprise subject consent and screening.  
Subjects will receive their initial screening and be consented by an IHTC staff member/clinician. 
Screening is expected to take up to 10 days but may be shorter depending on return of required 
laboratory testing.  
The screening visit will include obtaining informed consent; performance of a physical 
examination, vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
measurement; initiation of safety data collection; and the review/collection of clinical and 
laboratory data (adequate data in the subject’s recent medical files may negate the running of 
some of laboratory tests) including: 
 Baseline FVIII,* aPTT, PT and VWF:Ag  
 Baseline FVIII inhibitor level 
 Baseline CBC w/diff and CMP + direct bilirubin 
                                                 
* If the subject has an inhibitor, then testing for FVIII level may not be medically necessary as FVIII is usually 
undetectable in such cases. Exceptions exist, such as for a patient who has mild hemophilia with an inhibitor that 
only recognizes infused FVIII and not endogenous FVIII. 


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 Serum pregnancy test for female subjects 
 Documentation of current or past infection of Hepatitis A, B and C (tests listed below). If 
documentation is not available, then the tests will be administered as part of the screening 
process* 
o HAV:Ab 
o HBV:Ag and Ab (Core and Surface); if HBV:Ag positive, HBV viral load 
o HCV:Ab; if HCV:Ab positive, HCV viral load 
 Documentation of HIV infection (if Ab positive, viral load and CD4 count) 
 Obtain baseline Haem-A-QoL and EQ-5D-5L  
 If an activity monitoring device is standardly utilized by the patient, then permission will 
be requested to access data for the 1-month period prior to study entry and use of data 
from the device if continued during the study 
 Review of at least 16 weeks, and up to 6 months if available, of data on prior use of 
hemostatic therapy and number of breakthrough bleeding events 
 Review of 6 months of data on prior need for hospitalization or for PRBC transfusion 
 Review of therapy prior to study entry with dose and interval and trough level if available 
on prophylaxis 
 Review of history of inhibitor including date of first positive test, highest documented 
titer and date  
 Review of concomitant medications and supplements 
 Date of development or identification of pseudotumor and documentation of radiologic 
(CT or MRI) scans 
 Review of surgeries and procedures 
Second study visit (up to 10 days from screening visit) 
The study visit will comprise a 4-week period to administer the 4 loading doses of Hemlibra 
(emicizumab). This study visit will take place at the IHTC. 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 Baseline anti-drug antibody levels for Hemlibra (emicizumab) – banked plasma sample  
                                                 
* Although this testing and documentation is considered standard of care, there are important reasons to include this 
in the study and budget.  There are patients in the US who are not followed at a federally recognized hemophilia 
treatment center and this testing may be inconsistently available. In addition, there are patients who refuse entry into 
CDC studies where this testing is performed or refused vaccination to prevent Hepatitis A and/or B transmission.  
Knowing each patient’s viral exposure status and vaccination history will be important to decrease risk of 
community acquired infections that may lead to development of AEs that could be avoided.   


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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 Dispensation of a suitable quantity of Hemlibra (emicizumab) (quantity to be determined 
by the Study Investigator) 
 Baseline radiology (CT or MRI) if not performed within one month of study entry or 
provided scans are deemed inadequate to accurately assess the extent of the pseudotumor 
 Weeks 1-4 
o First 4 weekly loading doses to be administered at IHTC 
 Week 4 
o Anti-drug antibody levels for Hemlibra (emicizumab) – banked plasma sample 
o Obtain data if applicable from an activity monitoring device if standardly utilized 
by the patient 
Subsequent study visits (annual and study close-out visits at the IHTC; other study visits with 
local physician) 
Subsequent study visits will occur once a quarter, as is the standard of care for patients with 
hemophilic pseudotumor. These study visits will take place at the medical facilities of the 
subject’s local physician, except for the annual and study close-out visits, which will take place 
at the IHTC. The first subsequent study visit will be 3 months (±2 weeks) following the first 
loading dose of Hemlibra (emicizumab). 
The specific requirements of each visit are listed below. Depending on when a subject enrolls 
and when the study ends, the subject might not participate in all study visits beyond month 24. 
Study visits at months 3, 9, 15, 21, 27, 33, 39 and 45 (±2 weeks) 
The subject will follow-up with their local physician at the intervals specified above. 
During this visit: 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Review of AEs  
 Review of concomitant medications and supplements 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
Study visits at months 6, 18, 30 and 42 (±2 weeks) 
The subject will follow-up with their local physician for a more detailed clinical review at the 
intervals specified above. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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During this visit the following data will be collected and/or reviewed and transmitted to the 
IHTC: 
 CBC panel w/diff 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
Annual study visits (months 12, 24 and 36 ±2 weeks)* 
The annual study visit will take place at the IHTC.  
During this visit the following data will be collected and/or reviewed at the IHTC: 
 Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization 
or regression (ie changes in size) of the pseudotumor 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 Anti-drug antibodies (banked plasma sample) 
 Repeated Haem-A-QoL and EQ-5D-5L 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of concomitant medications and supplements 
 Review of AEs 
 Review of patient diary 
                                                 
* Subjects enrolled in the study for the maximum length of time (ie, 48 months) will also participate in an annual 
visit at approximately the 48-month time point; however, this will be the subject’s close-out visit, and the procedures 
required will be those list in Section 7.5. The primary difference between an annual visit and the close-out visit is 
the collection of used and unused vials of Hemlibra (emicizumab), rather than the dispensation of additional drug 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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Page 20 
 Patient study documentation will be collected for review of compliance and data 
collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
During this annual visit, a physical examination will be performed, used/empty vials of Hemlibra 
(emicizumab) will be collected and a suitable quantity of Hemlibra (emicizumab) will be 
dispensed. 
Unscheduled study visits 
 Any unscheduled study visits with the subject’s local hemophilia physician will be 
recorded in the CRF along with all relevant medical information (eg, reason for visit, 
diagnoses, scans, AEs, lab results, vital signs [blood pressure, pulse, temperature, and 
respiratory rate], weight, etc) 
 If a subject meets with a physician other than their local hemophilia physician, that 
information should be communicated to their hemophilia physician at the next scheduled 
quarterly study visit and appropriate medical information recorded in the CRF 
 Hospitalizations should be recorded in the CRF along with relevant medical information 
(see Section 6.11.3.2d). These should be reported to the IHTC within 7 days of their 
occurrence 
Surgeries 
 All surgeries will be recorded in the CRF, which should minimally include the following 
information (see Section 6.11.3 for additional reporting requirements): 
o Procedure type 
o Reason for procedure 
o Planned or unplanned 
o Date of procedure and length of hospitalization 
o Hemostatic therapy provided pre-procedure (type, dose and dates) 
o Hemostatic therapy provided post-procedure (type, dose and dates) 
o Hemostatic outcome immediately post-procedure 
o Hemostatic outcome at the end of hospitalization 
o Adverse events experienced (including, but not limited to clots, thromboses and 
TMA) 
o Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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Page 21 
Study close-out visit 
A study close-out visit will occur at the IHTC for all subjects during the final 2 months prior to 
the anticipated study termination date. 
During this close-out visit the following data will be collected and/or reviewed at the IHTC 
(depending on when the most recent annual visit took place and at the Study Investigator’s 
discretion, not all specified items may be necessary): 
 Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization 
or regression of pseudotumor 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
 Anti-drug antibodies (banked plasma sample) 
 Repeated Haem-A-QoL and EQ-5D-5L 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary 
 Patient study documentation will be collected for review of compliance and data 
collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
Additionally, a physical examination will be performed and all used and unused vials of 
Hemlibra (emicizumab) will be returned to the IHTC. 
Following the close-out visit, all subjects will be requested to meet with their local hemophilia 
physician to determine their ongoing treatment therapy/regimen. 
Dosing Regimen 
Genentech drug product  
Once weekly US-labeled Hemlibra (emicizumab) using FDA-approved dosing regimen 
 Four loading doses: 3 mg/kg once weekly by subcutaneous injection 
 Subsequent doses: 1.5 mg/kg once weekly by subcutaneous injection 
 Dose escalation: Should a subject have suboptimal control of breakthrough bleeding (ie, 
2 qualifying bleeds within 24 weeks) while on 1.5 mg/kg once weekly Hemlibra 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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Page 22 
(emicizumab) prophylaxis, the dose may be increased to 3 mg/kg once weekly Hemlibra 
(emicizumab) prophylaxis upon approval of the Study Investigator (Section 5.3.3). If this 
3 mg/kg maintenance dose does not result in an improvement in breakthrough bleeding, 
the subject may return to the standard 1.5 mg/kg maintenance dose upon approval of the 
Study Investigator, assuming this 1.5 mg/kg dose had resulted in an improvement in 
breakthrough bleeding compared to their pre-study regimen. 
Non-Genentech drug products 
Non-inhibitor subjects and low titer inhibitor subjects (titer <5 BU)  
 Breakthrough bleeding events should be treated with a FVIII concentrate, rFVIII or 
pdFVIII, using the local standard of care at the lowest level expected to achieve 
hemostasis 
 If the subject’s standard of care for treatment of bleeding events with low titer inhibitors 
is a bypassing product, the subject will follow treatment as outlined under high titer 
inhibitors 
High titer inhibitor subjects (titer ≥5 BU) 
 Breakthrough bleeding events should be treated with rFVIIa as first line therapy using the 
local standard of care. aPCC (<100 U/kg/day for preferably no more than 1 day) may 
only be used upon approval of the Study Investigator and under the supervision of a 
physician 
Dispensation of Hemlibra (Emicizumab) 
A suitable quantity of Hemlibra (emicizumab) (to be determined by the Study Investigator) will 
be dispensed to each subject at study visit 2 and at all annual visits. If necessary, additional 
Hemlibra (emicizumab) will be dispensed and shipped throughout the year to ensure the subject 
has a continuous supply.  
Duration of Treatment per Subject 
Minimum 2 years; maximum 4 years. No follow-up period is planned. 
Statistical Considerations 
Sample size  
Sample size of approximately 10 subjects is based on clinical feasibility and availability of 
subjects with hemophilia A and pseudotumor rather than statistical considerations. 
Statistical Analyses 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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Page 23 
Continuous variables will be summarized by descriptive statistics. Categorical variables will be 
presented with the number and percentage in each category.   
Efficacy Analyses 
The primary outcome for this study is bleeding events specifically related to the pseudotumor 
over time; total bleeding events will also be recorded and analyzed. Hemostatic efficacy is 
defined as the rate of breakthrough bleeding related to the pseudotumor (the number of bleeding 
episodes while on Hemlibra that require alternative hematinic therapy). Sample size is 
determined based on clinical feasibility rather than statistical considerations, accounting for the 
likely possibility of very few bleeding events, the limited number of available subjects with 
hemophilia A and pseudotumor, and the need to collect sufficient data to assess safety and 
efficacy. 
Safety Analyses 
Safety data collection will commence when each individual subject signs and dates the informed 
consent form and continue until the study ends or the subject withdraws from the study, 
whichever occurs first. All SAEs will be reported to and reviewed by the Study Investigator. One 
non-study physician from the IHTC will review all SAEs, deaths or other unexpected events and 
report to the Study Investigator with recommendations.  If a patient dies on study, the case will 
be evaluated in detail to determine its relatedness to the study drug and to determine if the study 
warrants stopping in the Study Investigator’s opinion. Any death or drug-related SAE will be 
reported through Genentech’s reporting system, as will all other required reportable events (see 
Section 6.11.3.2j). The study site will maintain a record of all SAE reports, interpretations and 
recommendations which will be available for Genentech to review upon request. In addition, if a 
greater than expected number of breakthrough bleeding events, or the development of 
thrombosis, thrombotic microangiopathy (TMA) or anaphylactic reaction to study medication 
occurs, the treatment of that patient will be halted. The Study Investigator may withdraw a 
patient based upon their clinical discretion and patient safety. 
Planned Interim Analyses 
Interim analyses will be conducted yearly at the discretion of the Study Investigator if sufficient 
patients are enrolled. At a minimum, an interim analysis will occur at the mid-point of the study 
(2-years following the date of informed consent of the first study subject).  
Assessments with brief summary of methods & procedures 
Data Safety Monitoring Board (DSMB) 
No DSMB will exist for the study. One designated non-study physician from the IHTC will 
review all safety data and other unexpected events and report to the Study Investigator with 
recommendations.  


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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Page 24 
Pharmacokinetics 
No pharmacokinetic studies will be performed during the study 
Pharmacodynamics 
No pharmacodynamics studies will be performed during the study 
Quality of Life (QoL) 
The change in quality of life and activity with Hemlibra (emicizumab) prophylaxis will be 
evaluated during the study. QoL and activity will be assessed using Haem-A-QoL and EQ-5D-
5L. Activity level may be assessed using a Fitbit or similar device to evaluate daily activity 
during the course of the study if such a device is standardly utilized by the subject, and the 
subject provides consent to export data from device. 
Biomarker Population 
No biomarker population analysis will be performed during the study 
Additional Details 
Due to the anticipated small study size, there will be no restrictions on BMI and the 
presence/absence of FVIII inhibitors. 
 
 
Protocol version: 3.0 
Date of Original Approved Protocol (v1.1): March 28, 2019 
Date of Most Recent Protocol Amendment (if applicable): June 16, 2020 
 
  


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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Page 25 
TABLE OF CONTENTS  
 
SYNOPSIS 
10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
31 
1 INTRODUCTION 
34 
1.1 Background Information on the Product 
34 
1.2 Hemophilia 
34 
1.3 Hemophilic Pseudotumor 
35 
1.4 Current Therapies and Unmet Medical Need 
35 
2 STUDY OBJECTIVES 
37 
2.1 Primary Objectives 
37 
2.2 Secondary Objectives 
37 
3 INVESTIGATIONAL PLAN 
38 
3.1 Overall Study Design and Plan 
38 
3.1.1 Initial Study Visit (Consent and Screening) 
38 
3.1.2 Second Study Visit [Hemlibra (emicizumab) Loading Doses] 
40 
3.1.3 Subsequent Scheduled Study Visits 
40 
3.1.3.1 Study visits at months 3, 9, 15, 21, 27, 33, 39 and 45 (±2 weeks) 
41 
3.1.3.2 Study visits at months 6, 18, 30 and 42 (±2 weeks) 
41 
3.1.3.3 Annual study visits (months 12, 24 and 36 ±2 weeks) 
42 
3.1.3.4 Study close out visit 
42 
3.1.4 Unscheduled Study Visits 
42 
3.1.5 Surgeries 
43 
3.1.6 Subject Withdrawal/Study Termination Procedures 
44 
3.1.7 Follow-up Period 
44 
3.2 Rationale for Study Design 
44 
3.3 Study Duration and Dates 
45 
4 STUDY POPULATION SELECTION 
46 
4.1 Study Population 
46 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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4.2 Inclusion Criteria 
46 
4.3 Exclusion Criteria 
47 
5 STUDY TREATMENT(S) 
49 
5.1 Description of Treatment(s) 
49 
5.1.1 Study Drug 
49 
5.1.2 Non-study Drugs 
49 
5.2 Packaging and Labeling 
49 
5.3 Treatments Administered 
49 
5.3.1 Loading Doses of Hemlibra (emicizumab) 
49 
5.3.2 Prophylactic Doses of Hemlibra (emicizumab) 
50 
5.3.3 Dose Escalation of Prophylactic Hemlibra (emicizumab) 
50 
5.4 Treatment of Breakthrough Bleeds and Concomitant Therapies 
50 
5.5 Restrictions 
51 
5.6 Treatment Compliance 
52 
5.7 Storage and Accountability 
52 
5.8 Investigational Product Retention at Study Site 
53 
5.9 Dispensation of Hemlibra (emicizumab) 
53 
6 STUDY PROCEDURES 
54 
6.1 Informed Consent 
54 
6.2 Medical History/Demographics 
54 
6.3 Physical Examination 
55 
6.4 Events of Special Interest 
55 
6.5 Quality of Life and Activity Assessments 
55 
6.5.1 Haem-A-QoL and EQ-5D-5L 
55 
6.5.2 Activity Monitoring Device 
56 
6.6 Clinical Laboratory Tests 
56 
6.6.1 Laboratory Parameters 
56 
6.6.2 Life-threatening Bleeding Due to Unreliable Standard Coagulation Tests in the 
Setting of Hemlibra (emicizumab) 
57 
6.6.3 Use & Interpretation of Coagulation Assays 
57 
6.6.3.1 aPTT assay 
58 
6.6.3.2 One-stage FVIII activity assay 
58 
6.6.3.3 FVIII chromogenic activity assay (“two-stage”) 
58 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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6.6.3.4 Bethesda assay 
58 
6.6.4 Central Laboratory Assays 
59 
6.7 Dispensation of Study Drug 
59 
6.8 Pharmacokinetic Assessments 
59 
6.9 Pharmacodynamic Assessments 
59 
6.10 Efficacy and Quality of Life Assessments 
60 
6.10.1 Primary Endpoints 
61 
6.10.2 Secondary Endpoints 
61 
6.11 Safety Reporting of Adverse Events 
62 
6.11.1 Assessment of Safety 
62 
6.11.1.1 Specification of safety variables 
62 
6.11.1.2 Adverse events 
62 
6.11.1.3 Serious adverse events 
62 
6.11.2 Methods and Timing for Assessing and Recording Safety Variables 
63 
6.11.2.1 Adverse event reporting period 
63 
6.11.2.2 Assessment of adverse events 
63 
6.11.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
64 
6.11.3.1 Eliciting adverse events 
64 
6.11.3.2 Specific instructions for recording adverse events 
64 
6.11.3.2a Diagnosis vs. signs and symptoms 
65 
6.11.3.2b Deaths 
65 
6.11.3.2c Preexisting medical conditions 
65 
6.11.3.2d Hospitalizations for medical or surgical procedures 
65 
6.11.3.2e Assessment of severity of adverse events 
66 
6.11.3.2f Pregnancy 
66 
6.11.3.2g Post-study adverse events 
66 
6.11.3.2h Case transmission verification of single case reports 
67 
6.11.3.2i AEs of special interest (AESIs) 
67 
6.11.3.2j Exchange of single case reports 
68 
6.11.3.2k Disease progression 
70 
6.11.4 Reporting Requirements for Adverse Events Originating from Patient Reported 
Outcomes 
70 
6.11.5 MedWatch 3500A Reporting Guidelines 
70 
6.11.5.1 Follow-up information 
71 
6.11.5.2 Reporting to regulatory authorities, ethics committees and investigators 
71 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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Page 28 
6.11.6 Aggregate Reports 
71 
6.11.6.1 Development safety update report 
71 
6.11.6.2 Other reports 
72 
6.11.7 Study Close-out 
72 
6.11.8 Queries 
72 
6.11.9 Safety Crisis Management 
72 
7 STUDY ACTIVITIES 
74 
7.1 Study Visit 1: Informed Consent and Screening 
74 
7.2 Study Visit 2: Loading Doses 
75 
7.2.1 Day -1 Procedures 
76 
7.2.2 Day 0 Procedures 
76 
7.2.2.1 Pre-treatment 
76 
7.2.2.2 Drug administration 
77 
7.2.2.3 Following drug administration 
77 
7.2.3 Day 7 Procedures 
77 
7.2.3.1 Pre-treatment 
77 
7.2.3.2 Drug administration 
78 
7.2.3.3 Following drug administration 
78 
7.2.4 Day 14 Procedures 
78 
7.2.4.1 Pre-treatment 
78 
7.2.4.2 Drug administration 
78 
7.2.4.3 Following drug administration 
79 
7.2.5 Day 21 Procedures 
79 
7.2.5.1 Pre-treatment 
79 
7.2.5.2 Drug administration 
79 
7.2.5.3 Following drug administration 
79 
7.3 Prophylactic Administration of Hemlibra (emicizumab) 
79 
7.4. Subsequent Study Visits 
80 
7.4.1 Study Visits at Months 3, 9, 15, 21, 27, 33, 39 and 45 (±2 Weeks) 
80 
7.4.2 Study Visits at Months 6, 18, 30 and 42 (±2 Weeks) 
81 
7.4.3 Annual Study Visits (Months 12, 24 and 36 ±2 Weeks) 
81 
7.4.4 Unscheduled Study Visits 
82 
7.4.5 Surgeries 
82 
7.5 Study Close-out Visit 
83 


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7.6 End of Study/Early Termination Procedures 
84 
8 QUALITY CONTROL AND ASSURANCE 
85 
9 PLANNED STATISTICAL METHODS 
86 
9.1 General Considerations 
86 
9.2 Determination of Sample Size 
86 
9.3 Analysis Populations 
86 
9.4 Demographics and Baseline Characteristics 
86 
9.5 Primary Endpoints 
86 
9.6 Secondary Endpoints 
87 
9.7 Safety Analyses 
87 
9.8 Interim Analysis 
88 
10 ADMINISTRATIVE CONSIDERATIONS 
89 
10.1 Investigators and Study Administrative Structure 
89 
10.2 Institutional Review Board (IRB) Approval 
89 
10.3 Ethical Conduct of the Study 
89 
10.4 Clinical Trial Safety Portal (CTSP) 
90 
10.5 Subject Information and Consent 
90 
10.6 Subject Confidentiality 
90 
10.7 Study Monitoring 
90 
10.8 Case Report Forms and Study Records 
91 
10.9 Data Monitoring 
91 
10.10 Protocol Violations/Deviations 
92 
10.11 Criteria for Terminating Study 
92 
10.12 Access to Source Documentation 
92 
10.13 Data Generation and Analysis 
92 
10.14 Retention of Data 
92 
10.15 Financial Disclosure 
93 
10.16 Publication and Disclosure Policy 
93 
11 APPENDIX 1: Safety Reporting FAX Cover Sheet 
94 
12 APPENDIX 2: Schedule of Study Visits (per Subject) 
95 


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13 REFERENCE LIST 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
 
Ab 
Antibody 
Ag 
ACT 
Antigen 
Activated clotting time 
ADA 
Anti-drug antibodies 
ADR 
Adverse drug reactions 
AE 
adverse event          
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase    
aPCC 
Activated prothrombin complex concentrate 
APC-R 
Activated protein C resistance  
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BU 
Bethesda unit 
CBC 
Complete blood count 
CD4 
Cluster of differentiation 4 glycoprotein 
CFR 
Code of federal regulations        
CHO 
Chinese hamster ovary 
CRF 
Case report form         
CRO 
Contract research organisation 
CT 
Computed tomography          
CTSP 
Clinical trial safety portal 
CTV 
Adverse event case transmission verification 
DOB 
Date of birth 
DSUR 
Development safety update report 
ELISA 
Enzyme linked immunosorbent assay 
EMA 
European medicines agency         
ePS 
ePharmaSolutions 
EQ-5D-5L 
EuroQol Group questionnaire measuring health-related quality of life 
with 5 dimensions, and responses recording five levels of severity 
EtMs 
Events to monitor of medical and scientific concern 
EU 
European Union 
EVCTM 
Eudravigilance clinical trial module 
FDA 
Food and drug administration        
FVIII 
Factor VIII          
FVIIIa 
Factor VIII activated         
FIX 
Factor IX 
FIXa 
Factor IX activated          
FX 
Factor X          


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FXa 
Factor X activated         
GCP 
Good clinical practice         
Haem-A-QoL 
Haemophilia quality of life questionnaire for adults 
HAV 
Hepatitis A virus         
HBV 
Hepatitis B virus         
HCV 
Hepatitis C virus         
HEENT 
Head, eyes, ears, nose, throat       
HIPAA 
Health information portability and accountability act 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
IB 
Investigator brochure          
IHTC 
Indiana Hemophilia and Thrombosis Center 
IMP 
Investigational medicinal product 
IND 
Investigational new drug         
IRB 
Institutional review board         
ISTH 
International Society on Thrombosis and Haemostasis  
ITI 
Immune tolerance induction 
MRI 
Magnetic resonance imaging         
NBU 
Nijmegen bethesda unit 
PD 
Pharmacodynamics 
pdFVIII 
Plasma-derived factor VIII 
PI 
Package insert 
PK 
Pharmacokinetics 
PRBC 
Packed red blood cells 
PRO 
Patient reported outcome 
PT 
Prothrombin time  
PT 
Preferred term 
QoL 
Quality of life 
rFVIIa 
Factor VII activated         
rFVIII 
Recombinant factor VIII 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event         
SD 
Standard deviation          
SOC 
System organ class 
TMA 
Thrombotic microangiopathy 
TT 
Thrombin time 
U 
Unit 
ULN 
Upper limit of normal 
US 
United States 
VWF 
Von Willebrand factor 
VWF:Ag 
Von Willebrand factor antigen 
 
 


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Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
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1 INTRODUCTION  
1.1 Background Information on the Product  
Hemlibra (also known as emicizumab, ACE910 and RO5534262) is a humanized monoclonal 
modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure produced by 
recombinant DNA technology in Chinese hamster ovary (CHO) cells. Hemlibra (emicizumab) 
bridges activated factor IX (FIXa) and factor X (FX) to restore the function of missing activated 
factor VIII (FVIIIa) that is needed for effective hemostasis.  
In patients with hemophilia A, hemostasis can be restored irrespective of the presence of factor 
VIII (FVIII) inhibitors, as emicizumab shares no sequence homology with FVIII. Due to its 
pharmacokinetic (PK) properties, emicizumab can be administered subcutaneously at a 
frequency that is less than that of other currently available therapies for hemophilia A. Therefore, 
this novel compound may have the potential to significantly change the treatment of patients 
with hemophilia A, with or without FVIII inhibitors, who are in need of prophylactic treatment 
to prevent bleeding episodes.  
Hemlibra (emicizumab) is currently indicated for prophylactic use in the US and other countries 
in patients with hemophilia A and FVIII inhibitors to prevent or reduce the incidence of bleeding 
events.  
1.2 Hemophilia 
Hemophilia A is an X-linked recessive bleeding disorder characterized by congenital 
underproduction of or dysfunction of FVIII, an essential protein in promoting clot formation. 
Hemophilia A accounts for approximately 80% of all cases of hemophilia. The incidence of 
hemophilia A is approximately 1 in 5,000 live-born male births or 1 out of every 10,000 live 
births [Franchini and Mannucci 2013, Centers for Disease Control and Prevention 2014, National 
Institutes of Health 2014]. No racial differences have been reported in the distribution of patients 
with hemophilia. The number of patients with hemophilia A registered in 2015 in various regions 
across the world, include 4,986 individuals in Japan (3.9/100,000 people), 17,285 in North 
America (4.8/100,000 people; [Canada estimate from 2014]), and 21,410 in the five major 
European nations (United Kingdom, France, Germany, Italy, and Spain; 6.7/100,000 people; 
[Spain estimate from 2011 and Italy estimate from 2014]) [World Federation of Hemophilia 
2012, World Federation of Hemophilia 2013, World Federation of Hemophilia 2016]. 
The main bleeding sites are intra-articular, intramuscular, subcutaneous, intraoral, intracranial, 
gastrointestinal, and intranasal. In particular, repeated intra-articular bleeds are a major 
contributor to decreased HRQoL in patients with hemophilia A, as the joint damage associated 
with multiple hemarthrosis may progress to hemophilic arthropathy [Gringeri, Leissinger et al. 
2013]. In advanced forms, hemophilic arthropathy is associated with significant joint pain, 
swelling, and limited range of motion, which may ultimately require surgical intervention, 
including joint replacement. Although less frequently than musculoskeletal bleeds, patients with 


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hemophilia A can also develop intracranial or severe gastrointestinal bleeding resulting in death 
[World Federation of Hemophilia 2012].  
The severity of (and bleeding risk associated with) hemophilia A is classified in  accordance 
with endogenous FVIII activity in the plasma. Those with FVIII activity less than 1% have 
severe disease; between 1% and 5%, moderate disease; and between 5% and 50%, mild disease. 
Patients with severe hemophilia A can suffer several spontaneous bleeding episodes each month 
– much more frequently than those with moderate or mild disease. In addition, such patients are 
at a greater risk for having life-threatening bleeds. Hence, the maintenance of FVIII activity 
levels about 1-3% with FVIII prophylaxis is desired, in order to effectively reduce bleeding 
episodes, morbidity (eg, arthropathy), mortality, as well as to improve HRQoL in patients with 
severe hemophilia A [Srivastava, Brewer et al. 2013]. 
1.3 Hemophilic Pseudotumor 
Hemophilic pseudotumor is a rare complication of hemophilia that occurs in 1-2% of patients 
with severe hemophilia [van Ommeren, Mooren et al. 2000]. It is observed more frequently in 
geographic areas where hemophilia is diagnosed late, treatment is inconsistently available, 
prophylaxis is not used due to resource constraints, and in patients who do not recognize that a 
bleeding event has occurred (eg, moderate or mild deficient patients who experience infrequent 
bleeds/injuries). Pseudotumors are more commonly observed in adults than pediatric patients 
[Magallon, Monteagudo et al. 1994] They may be present in patients with hemophilia either with 
or without an inhibitor and are more common in patients with inhibitors where hemostasis is less 
well controlled.  
A hemophilic pseudotumor consists of an encapsulated progressive cystic swelling of muscle 
and/or bone caused by recurrent hemorrhage which can cause a serious complication to both life 
and limb. Pseudotumors have been reported in a wide variety of bones and soft tissues [Liu, 
White et al. 1988] where repeated and unresolved hematomas lead to encapsulation, calcification 
and progressive enlargement, with subsequent erosion of adjacent bone. Most commonly the 
pseudotumor occurs in the pelvis and long bones of lower extremity; they are also observed in 
muscles, particularly the iliacus, vastus lateralis and soleus. Pseudotumors are best treated early; 
if left untreated they can result in compression pressure necrosis of adjacent structures, further 
bleeding, infection, erosion and loss of function and/or life. Complicating early diagnosis is the 
fact that patients with pseudotumors may be asymptomatic or stable for long periods of time 
(sometimes decades) before developing complications [Ahlberg 1975, Magallon, Monteagudo et 
al. 1994, van Ommeren, Mooren et al. 2000]. 
Hemophilic pseudotumors are most readily diagnosed and monitored using CT or MRI. 
1.4 Current Therapies and Unmet Medical Need 
There is no standard treatment for hemophilic pseudotumor; factor replacement therapy and 
surgical excision are the primary treatment options [van Ommeren, Mooren et al. 2000]. In 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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countries lacking significant medical resources, FVIII prophylaxis and surgical intervention are 
rarely feasible due to availability of factor replacement, lack of local expertise and/or inability to 
perform the intervention due to extent or site of the pseudotumor. Due to the limited medical 
resources, hemophilic pseudotumor has a higher incidence in these countries. 
It is hypothesized that an agent that confers a consistent FVIII-equivalent level in the mild 
deficient range that is not associated with trough levels below 10% will confer a higher degree of 
hemostasis in patients with pseudotumors. It is not practical to achieve such high trough levels 
over long periods of time using standard factor replacement therapy; instead new products, such 
as Hemlibra (emicizumab) may provide an alternative approach. If a higher degree of hemostasis 
is achieved, this is expected to result in a decreased rate of breakthrough bleeding requiring 
intermittent hemostatic therapy, and an associated decrease in uncontrolled bleeding resulting in 
anemia, transfusion, and hospitalization. If these endpoints are achieved it is also hypothesized 
that activity and quality of life may increase or improve respectively. 
 
 
  
  
 
 


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2 STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective of the study is:  
 To determine the hemostatic efficacy* of prophylactic weekly injections of Hemlibra 
(emicizumab) in hemophilia A subjects (baseline FVIII level <40%) with pseudotumor, 
with or without FVIII inhibitors.  
2.2 Secondary Objectives 
The secondary objectives of the study are:  
 To determine the rate of breakthrough bleeding events, either related or unrelated to the 
pseudotumor, requiring alternate hemostatic therapy 
 To evaluate the control of progression, stabilization or regression (ie, change in size) of 
the pseudotumor 
 To determine the safety of Hemlibra (emicizumab) based on adverse events (AEs) and 
serious adverse events (SAEs) including lack of efficacy and development of anti-drug 
antibodies (ADA). Samples for ADA will be banked for analysis and performed in 
conjunction with Genentech/Roche either yearly, at the end of the study, or as determined 
by the Study Investigator based upon any reported lack of clinical efficacy 
 To evaluate the change in quality of life and activity as measured by the Haem-A-QoL 
and EQ-5D-5L with Hemlibra (emicizumab) prophylaxis. If an activity monitoring 
device is standardly utilized by the patient (eg, Fitbit) then data from that device will be 
requested from the patient to assist in activity monitoring as well 
 To evaluate the effect of Hemlibra prophylaxis on any surgical procedures, including the 
use of other hemostatic agents such as FVIII, aPCC or rFVIIa and overall hemostatic 
efficacy 
 
                                                 
* Hemostatic efficacy is defined as the rate of breakthrough bleeding related to the pseudotumor; which is defined as 
the number of bleeding episodes while on Hemlibra that require alternative hematinic therapy. 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
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3 INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan  
This is a single arm, phase 4, prospective, open-label, US single-center study to assess the 
hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of hemophilia A 
patients (baseline FVIII level <40%), children and adults, with and without inhibitors with 
hemophilic pseudotumors. The study is not randomized. 
Subjects will be consented and screened at the IHTC and will be eligible for study participation 
if they meet all inclusion criteria. Subjects will be excluded from the study if they meet any of 
the exclusion criteria. US-labeled Hemlibra (emicizumab) will be administered using the FDA-
approved once-weekly dosing regimen for loading dose and prophylactic dose. Subjects will 
administer Hemlibra (emicizumab) for a minimum of 2 years, except in the case of subject 
withdrawal or early termination of the study, and a maximum of 4 years. Breakthrough bleeding 
episodes will be treated using the local standard of care subject to the conditions listed in 
Sections 5.1.2 and 5.4. 
The proposed study is seeking to address the following knowledge gaps: 
 Does weekly prophylactic Hemlibra (emicizumab) reduce the rate of bleeding events in 
subjects with hemophilia A and pseudotumor, including the rate of hospitalization, 
anemia and transfusion? 
 Does weekly prophylactic Hemlibra (emicizumab) control the progression, stabilization 
or regression (ie, affect the size) of the hemophilic pseudotumor? 
 Does weekly prophylactic Hemlibra (emicizumab) result in an increase in QoL and 
activity level? 
3.1.1 Initial Study Visit (Consent and Screening) 
The initial study visit will take place at the IHTC and will comprise subject consent and 
screening. The subject will be screened per the criteria listed in Section 4 of this protocol and 
will include a physical examination and the review/collection of clinical and laboratory data (if 
not included in the subject’s medical records) including: 
 Baseline FVIII,* aPTT, PT and VWF:Ag  
 Baseline FVIII inhibitor level 
 Baseline CBC w/diff and CMP + direct bilirubin 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
                                                 
* If the subject has an inhibitor, then testing for FVIII level may not be medically necessary as FVIII is usually 
undetectable in such cases. Exceptions exist, such as for a patient who has mild hemophilia with an inhibitor that 
only recognizes infused FVIII and not endogenous FVIII. 


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 Serum pregnancy test for female subjects 
 Documentation of current or past infection of Hepatitis A, B and C (tests listed below). If 
documentation is not available, then the tests will be administered as part of the screening 
process* 
o HAV:Ab 
o HBV:Ag and Ab (Core and Surface); if HBV:Ag positive, HBV viral load 
o HCV:Ab; if HCV:Ab positive, HCV viral load 
 Documentation of HIV infection (if Ab positive, viral load and CD4 count) 
 Baseline Haem-A-QoL and EQ-5D-5L  
 If an activity monitoring device is standardly utilized by the patient, then permission will 
be requested to access data for the 1-month period prior to study entry and use of data 
from the device if continued during the study 
 Review of at least 16 weeks, and up to 6 months if available, of data on prior use of 
hemostatic therapy and number of breakthrough bleeding events 
 Review of 6 months of data on prior need for hospitalization or for PRBC transfusion 
 Review of therapy prior to study entry with dose and interval and trough level if available 
on prophylaxis 
 Review of history of inhibitor including date of first positive test, highest documented 
titer and date  
 Review of concomitant medications and supplements 
 Determination of the date of development or identification of pseudotumor and 
documentation of radiologic (CT or MRI) scans 
 Review of surgeries and procedures 
If the subject is not vaccinated, previously exposed, or immune to HAV and/or HBV then they 
will receive the first dose of the HAV and/or HBV vaccine during screening. Subjects must 
follow up with their local provider to complete the recommended vaccination schedule.†   
Safety data reporting will commence at the time of subject consent and study procedures and will 
end at study discontinuation/termination or 24 weeks following the last administration of study 
treatment, whichever occurs first. Extensions to this time will be made in certain situations (eg, 
Sections 6.11.3.2.f and 6.11.3.2g). 
                                                 
* Although this testing and documentation is considered standard of care, there are important reasons to include this 
in the study and budget.  There are patients in the US who are not followed at a federally recognized hemophilia 
treatment center and this testing may be inconsistently available. In addition, there are patients who refuse entry into 
CDC studies where this testing is performed or refused vaccination to prevent Hepatitis A and/or B transmission.  
Knowing each patient’s viral exposure status and vaccination history will be important to decrease risk of 
community acquired infections that may lead to development of AEs that could be avoided.   
† Vaccinations will not be charged to the study. 


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Screening is expected to take up to 10 days but may be shorter depending on the return of 
required laboratory testing. If successfully screened, the subject may then be enrolled in the 
study and receive Hemlibra (emicizumab) loading doses during the second study visit 
3.1.2 Second Study Visit [Hemlibra (emicizumab) Loading Doses] 
The second study visit will take place at the IHTC up to 10 days after the initial screening visit. 
The purpose of the second study visit is to administer the 4 weekly loading doses of Hemlibra 
(emicizumab); acquire ADA data, vital signs (blood pressure, pulse, temperature, and respiratory 
rate) and weight; and complete baseline radiology. 
Prior to the first loading dose, a banked plasma sample will be obtained to determine baseline 
anti-drug antibody levels for Hemlibra (emicizumab). Baseline radiology (CT and/or MRI) will 
also be obtained if not previously performed within one month of study entry or if provided 
scans are deemed inadequate to accurately assess the extent of the pseudotumor. 
Subjects/caregivers will be instructed on how to inject Hemlibra (emicizumab) and how to 
recognize signs/symptoms of hypersensitivity (including anaphylaxis) and obtain emergency 
care in the event of such reactions occurring. The Study Investigator has the discretion to provide 
additional training or include additional observation (eg, after the fourth loading dose), if deemed 
appropriate, and each subject/caregiver will be able to ask any question he or she may have prior 
to being deemed capable of performing subcutaneous Hemlibra (emicizumab) injections. If, 
despite additional training, the investigator determines that the subject/caregiver is unable to 
inject Hemlibra (emicizumab), a trained and proficient caregiver or local healthcare provider 
should be identified to administer the prophylaxis injections. 
The 4 loading doses will be administered once weekly for 4 weeks using the FDA-approved 
regimen (3 mg/kg once weekly by subcutaneous injection). Following the 4th loading dose a 
second banked plasma sample will be obtained to determine anti-drug antibody levels for 
Hemlibra (emicizumab). If the subject routinely uses an activity monitoring device and has 
consented to the use of data from that device during the study, then data from the time of 
informed consent will be collected. 
During study visit 2 suitable quantities (to be determined by the Study Investigator) of Hemlibra 
(emicizumab) will be dispensed to the subject (see Section 6.7).  
3.1.3 Subsequent Scheduled Study Visits 
Subsequent study visits will occur once a quarter, as is the standard of care for patients with 
hemophilic pseudotumor. These study visits will take place at the medical facilities of the 
subject’s local physician, except for the annual and study close-out visits, which will take place 
at the IHTC. The first subsequent study visit will be 3 months (±2 weeks) following the first 
loading dose of Hemlibra (emicizumab). 


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The specific requirements of each visit are listed below. Depending on when a subject enrolls 
and when the study ends, the subject might not participate in all study visits beyond month 24. 
See Appendix 2. 
3.1.3.1 Study visits at months 3, 9, 15, 21, 27, 33, 39 and 45 (±2 weeks) 
The subject will follow-up with their local physician at the intervals specified above. 
During this visit: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Review of AEs 
 Review of concomitant medications and supplements 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
3.1.3.2 Study visits at months 6, 18, 30 and 42 (±2 weeks) 
The subject will follow-up with their local physician for a more detailed clinical review at the 
intervals specified above. 
During this visit the following data will be collected and/or reviewed and transmitted to the 
IHTC: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 


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3.1.3.3 Annual study visits (months 12, 24 and 36 ±2 weeks)* 
The annual study visit will take place at the IHTC.  
During this visit the following data will be collected and/or reviewed at the IHTC: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization 
or regression of pseudotumor 
 Anti-drug antibodies (banked plasma sample) 
 Repeated Haem-A-QoL and EQ-5D-5L 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary 
 Patient study documentation will be collected for review of compliance and data 
collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
During this annual visit, a physical examination will be performed, used/empty vials of 
emicizumab will be collected and a suitable quantity of Hemlibra (emicizumab) will be 
dispensed (see Section 6.7). 
3.1.3.4 Study close out visit 
See Section 7.5 
3.1.4 Unscheduled Study Visits 
Any unscheduled study visits with the subject’s local hemophilia physician will be recorded in 
the CRF along with all relevant medical information (eg, reason for visit, diagnoses, scans, AEs, 
lab results, vital signs [blood pressure, pulse, temperature, and respiratory rate], weight, etc).  
                                                 
* Subjects enrolled in the study for the maximum length of time (ie, 48 months) will also participate in an annual 
visit at approximately the 48-month time point; however, this will be the subject’s close-out visit, and the procedures 
required will be those list in Section 7.5. The primary difference between an annual visit and the close-out visit is 
the collection of used and unused vials of Hemlibra (emicizumab), rather than the dispensation of additional drug 


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If a subject meets with a physician other than their local hemophilia physician, that information 
should be communicated to their hemophilia physician at the next scheduled quarterly study visit 
and appropriate medical information recorded in the CRF. 
Hospitalizations should be recorded in the CRF along with relevant medical information (see 
Section 6.11.3.2d). These should be reported to the IHTC within 7 days of their occurrence. 
AEs should be reported using the instructions in Section 6.11.3. 
3.1.5 Surgeries 
All surgeries will be recorded in the CRF, which should minimally include the following 
information (see Section 6.11.3 for additional reporting requirements): 
 Procedure type 
 Reason for procedure 
 Planned or unplanned 
 Date of procedure and length of hospitalization 
 Hemostatic therapy provided pre-procedure (type, dose and dates) 
 Hemostatic therapy provided post-procedure (type, dose and dates) 
 Hemostatic outcome immediately post-procedure 
 Hemostatic outcome at the end of hospitalization 
 Adverse events experienced (including, but not limited to clots, thromboses and TMA) 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
Hemostatic outcome for surgical treatment is defined using the standard ISTH rating scale shown 
below [Blanchette, Key et al. 2014]. 
 
Excellent 
Intraoperative and postoperative blood loss similar (within 10%) to the non-
hemophilic patient with no extra (unplanned) doses of FVIII/FIX/‘bypassing 
agents’ needed and blood component transfusions are similar to the non-
hemophilic patient  
Good 
Intraoperative and/or postoperative blood loss slightly increased over 
expectation for the non-hemophilic patient (between 10 and 25% of expected), 
but the difference is judged by the involved surgeon/anesthetist/relevant 
healthcare professional to be clinically insignificant as evidenced by no extra 
(unplanned) doses of FVIII/FIX/‘bypassing agents’ needed and blood 
component transfusions are similar to the non-hemophilic patient  
Fair 
Intraoperative and/or postoperative blood loss increased over expectation (25–
50%) for the non-hemophilic patient and additional treatment is needed such as 
extra (unplanned) doses of FVIII/FIX/‘bypassing agents’ or increased blood 
component use  (within two-fold) of the anticipated transfusion requirement  


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Poor 
Significant intraoperative and/or postoperative blood loss that is substantially 
increased over expectation (> 50%) for the non-hemophilic patient, requires 
intervention, and is not explained by a surgical/medical issue other than 
hemophilia, unexpected hypotension or unexpected transfer to an Intensive Care 
Unit due to bleeding or substantially increased blood component use (>2 fold) of 
the anticipated transfusion requirement  
 
Medical details and outcome of all surgeries should be reported to the IHTC within 7 days of 
their occurrence. 
3.1.6 Subject Withdrawal/Study Termination Procedures 
See Section 7.6 
3.1.7 Follow-up Period 
No follow-up period is planned with the exception of post-study adverse events listed in Sections 
6.11.2.1 and 6.11.3.2g. 
3.2 Rationale for Study Design  
Hemophilic pseudotumor is a complication of hemophilia (1-2% of patients) that consists of a 
progressive cystic swelling of muscle and/or bone caused by recurrent hemorrhage. It is observed 
more frequently in geographic areas where hemophilia is diagnosed late, treatment is 
inconsistently available, prophylaxis is not used due to resource constraints, and in patients who 
do not recognize that a bleeding event has occurred (eg, moderate or mild deficient patients who 
experience a bleed/injury). FVIII prophylaxis has been used in patients with hemophilia A with 
pseudotumors when surgical intervention is not feasible either due to lack of local expertise or 
inability to perform the intervention due to extent or site of the pseudotumor. Pseudotumors may 
be present in patients with hemophilia either with or without an inhibitor and are more common 
in patients with inhibitors where hemostasis is less well controlled.   
It is hypothesized that an agent that confers a consistent FVIII level in the mild deficient range 
that is not associated with trough levels below 10% will confer a higher degree of hemostasis in 
patients with pseudotumors; this will result in a decreased rate of breakthrough bleeding 
requiring intermittent hemostatic therapy, and an associated decrease in uncontrolled bleeding 
resulting in anemia, transfusion, and hospitalization. If these endpoints are achieved it is also 
hypothesized that activity and quality of life may increase or improve respectively.  
The purpose of this study is to prospectively investigate the hemostatic efficacy and safety of 
weekly prophylactic Hemlibra (emizicumab) in the treatment/control of pseudotumors in 
children and adults with FVIII deficiency (baseline FVIII level <40%) either with or without an 
inhibitor; in addition, changes in quality of life and activity level in subjects with hemophilia A 
and pseudotumor will be assessed. 


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3.3 Study Duration and Dates  
The enrollment period for this study will last 2 years and is planned to start in the first quarter of 
2019. 
Each subject will receive Hemlibra (emicizumab) therapy for a minimum of 2 years unless they 
voluntarily withdraw, are involuntarily withdrawn by the Study Investigator, or the study is 
terminated early. The maximum duration of Hemlibra (emicizumab) therapy on study is 4 years. 
The maximum time on study for each subject is dependent on when they enroll. 
The study will last a maximum of 4 years from the date of the first signed consent form from the 
first subject, to the last administration of Hemlibra (emicizumab) to any subject. 


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4 STUDY POPULATION SELECTION  
4.1 Study Population  
Approximately 10 subjects will be enrolled in this study and receive study medication. There are 
no restrictions on weight or BMI. 
4.2 Inclusion Criteria  
Patients must meet the following criteria for study entry: 
 Signed informed consent form from the subject, parent or guardian 
 Diagnosis of congenital hemophilia A (baseline FVIII level <40%) with or without FVIII 
inhibitor, either high or low responding, regardless of titer 
 Diagnosis of a hemophilic pseudotumor confirmed by radiologic assessment such as CT 
or MRI 
 Any weight or BMI 
 Medical documentation of prophylactic or episodic treatment (FVIII or bypassing agent) 
and the number of bleeding episodes for at least 16 weeks, and up to 6 months if 
available, prior to entry into the study   
 Medical documentation of any need for PRBC transfusion or hospitalization for 6 months 
prior to entry into the study 
 Subjects with a history of an inhibitor should provide documentation of the inhibitor 
history including date of initial diagnosis of inhibitor, peak titer, and agent utilized for 
hemostatic control  
 Subjects with high titer inhibitors or those with low titer inhibitors who do not respond to 
FVIII must be willing to use rFVIIa as first line therapy for the treatment of breakthrough 
bleeding events  
 Medical documentation of ITI therapy for subjects with a history of a FVIII inhibitor and 
ITI, including current FVIII inhibitor titer 
 Willingness to discontinue any current prophylactic hemostatic regimen (FVIII or 
bypassing agent) and/or FVIII ITI therapy for the duration of the study 
o Subjects receiving FVIII prophylaxis must be willing to discontinue their FVIII 
prophylactic regimen immediately prior to their second loading dose of Hemlibra 
(emicizumab) 
o Subjects receiving bypassing agent prophylaxis must be willing to discontinue 
their prophylactic regimen at least 24 hours prior to their first loading dose of 
Hemlibra (emicizumab) 


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o Subjects receiving FVIII ITI therapy must be willing to discontinue ITI 
immediately prior to their first loading dose of Hemlibra (emicizumab) 
 Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures, including the health-related questionnaires, activity tracking, 
and bleed diaries, using systems provided during the study 
 Adequate hepatic function, defined as total bilirubin ≤1.5 × age-adapted upper limit of 
normal (ULN) (excluding Gilbert’s syndrome) and both AST and ALT ≤3 × age-adapted 
ULN at the time of screening, and no clinical signs or known laboratory/radiographic 
evidence consistent with cirrhosis  
 Subjects must be willing to be vaccinated against HAV and HBV if not previously 
vaccinated, exposed or immune to HAV or HBV* 
 Adequate hematologic function, defined as a platelet count ≥100,000/μL and a PT≤1.5 
times the ULN at the time of screening  
 Adequate renal function, defined as serum creatinine ≤2.5 × age-adapted ULN and 
creatinine clearance ≥30 mL/min by Cockcroft-Gault formula  
 For women with hemophilia of childbearing potential: agreement to remain abstinent 
(refrain from heterosexual intercourse) or use highly effective contraceptive methods that 
result in a failure rate of <1% per year during the treatment period and for at least 5 
elimination half-lives (24 weeks) after the last dose of study drug   
4.3 Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from study entry: 
 Inherited or acquired bleeding disorder other than congenital hemophilia A 
 Lack of a documented diagnosis of hemophilic pseudotumor 
 Patients who are at high risk for TMA (eg, have a previous medical or family history of 
TMA), in the Study Investigator’s judgment 
 History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the Study 
Investigator’s judgment 
 Previous (within the last 12 months) or current treatment for thromboembolic disease 
(with the exception of previous catheter-associated thrombosis for which anti-thrombotic 
treatment is not currently ongoing) or signs of thromboembolic disease  
 Other conditions (eg, certain autoimmune diseases) that may currently increase the risk of 
bleeding or thrombosis  
                                                 
* Vaccinations will not be charged to the study. 


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 History of clinically significant hypersensitivity associated with monoclonal antibody 
therapies or components of the Emicizumab injection 
 Planned surgery (excluding minor procedures such as tooth extraction or incision and 
drainage) during the study 
 Known HIV infection with CD4 counts <200 cells/μL.  HIV infection with CD4 counts 
≥200 cells/μL permitted  
 Use of systemic immunomodulators (eg, interferon) at enrollment or planned use during 
the study, with the exception of anti-retroviral therapy 
 Concomitant disease, condition, significant abnormality on screening evaluations or 
laboratory tests, or treatment that could interfere with the conduct of the study, or that 
would, in the opinion of the Study Investigator, pose an additional unacceptable risk in 
administering study drug to the patient 
 Receipt of any of the following: 
o Hemlibra (emicizumab) in a prior investigational study 
o An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 
half-lives of last drug administration 
o A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, 
whichever is shorter 
o Any other investigational drug currently being administered or planned to be 
administered 
 Inability to comply with the study protocol in the opinion of the Study Investigator 
 Pregnancy or lactation or intention to become pregnant during the study 
 Women with a positive serum pregnancy test result within 10 days prior to initiation of 
study drug 
 
 
 


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5 STUDY TREATMENT(S) 
5.1 Description of Treatment(s)  
5.1.1 Study Drug  
The study drug is US-labeled Hemlibra (emicizumab). It will be administered using the FDA 
approved once-weekly doing regimen for loading dose (3 mg/kg) and prophylactic dose (1.5 
mg/kg, or 3 mg/kg kg if dose escalation is determined appropriate by the Study Investigator). 
Hemlibra (emicizumab) will be provided in a clear vial as a solution. Hemlibra (emicizumab) 
will be provided by the study. 
5.1.2 Non-study Drugs 
Should a breakthrough bleed occur, then any locally approved pdFVIII or rFVIII may be used in 
subjects without a FVIII inhibitor or with a low titer inhibitor (titer <5BU) using the local 
standard of care; if the subject’s standard of care for treatment of bleeding events with low titer 
inhibitors is a bypassing product, the subject will follow treatment as outlined under high titer 
inhibitors (below).  
Should a breakthrough bleed occur in subjects with a high titer FVIII inhibitor (titer ≥5BU), then 
any locally approved rFVIIa concentrate may be used using the local standard of care. Other 
bypassing agents (eg, aPCC) may only be used with the approval of the Study Investigator. 
Agents to treat breakthrough bleeds or other sequelae (including, but not limited to pdFVIII, 
rFVIII, rFVIIa, and aPCC) will not be provided by the study. 
5.2 Packaging and Labeling  
US-labeled Hemlibra (emicizumab) will be supplied as a solution in clear glass vials at nominal 
doses of 30mg, 60mg, 105mg and 150mg. Vials will be packaged in an outer box. In addition, 
supplies for administration of Hemlibra (emicizumab) will be provided (eg, syringes, transfer 
needles, injection needles, alcohol wipes, etc).  
5.3 Treatments Administered  
5.3.1 Loading Doses of Hemlibra (emicizumab) 
After obtaining informed consent and the performance of screening procedures, patients who (at 
the discretion of the Study Investigator) meet all inclusion and exclusion will be eligible for 
study medication. 
The 4 loading doses of Hemlibra (emicizumab) will be administered as 3 mg/kg subcutaneous 
injections, dosed once-weekly over a 4-week period during study visit 2 (Section 7.2). 


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5.3.2 Prophylactic Doses of Hemlibra (emicizumab) 
Prophylactic administration of Hemlibra (emicizumab) will continue on a weekly basis (1.5 
mg/kg subcutaneous dosing, or 3 mg/kg kg if dose escalation is determined appropriate by the 
Study Investigator [Section 5.3.3]) until the subject withdraws from the study, is involuntarily 
withdrawn from the study, or the study is terminated, whichever occurs first (Section 7.3). All 
used and unused vials of Hemlibra (emicizumab) should be returned to the IHTC once a subject 
is no longer enrolled. 
5.3.3 Dose Escalation of Prophylactic Hemlibra (emicizumab) 
All subjects with suboptimal control of bleeding as defined by the protocol will be offered the 
option to increase their Hemlibra (emicizumab) maintenance dose to 3 mg/kg QW, with approval 
from the Study Investigator. Suboptimal response is defined as follows: 
 Two qualifying bleeds within 24 weeks while on prophylactic Hemlibra (emicizumab) 
A qualifying bleed is defined as spontaneous, verified by an investigator (eg, by imaging or 
physical examination or reliable symptoms reported by patient including increased pain with 
swelling, decreased ability to function etc clearly related to presence/site of pseudotumor), and 
occurring while on prophylactic Hemlibra (emicizumab) at steady state (after week 5). If the 
investigator believes that a specific subject warrants dose escalation on the basis of a different 
reason, he or she may discuss the case with the Study Investigator for consideration and 
potential approval. 
If this 3 mg/kg maintenance dose does not result in increased control of breakthrough bleeding, 
the subject may return to the standard 1.5 mg/kg maintenance dose upon approval of the Study 
Investigator, assuming this 1.5 mg/kg dose had resulted in an improvement in breakthrough 
bleeding compared to their pre-study regimen. 
5.4 Treatment of Breakthrough Bleeds and Concomitant Therapies 
No pdFVIII, rFVIII, rFVIIa or aPCC shall be administered unless required to treat a 
breakthrough bleed. The use of aPCC should be avoided and may only be administered if 
approved by the Study Investigator. The use of any bypassing agent, other than rFVIIa (eg, 
NovoSeven®), requires approval of the Study Investigator. 
Drugs intended to control or prevent bleeds, including bypassing agents, should be used at the 
lowest dose expected to achieve hemostasis according to the local standard of care. Given that 
circulating Hemlibra (emicizumab) may increase the patient’s coagulation potential, the usual 
doses of hemostatic medication (ie, bypassing agents, FVIII, antifibrinolytics, etc) required to 
achieve hemostasis may be lower than the doses used prior to starting Hemlibra (emicizumab). 
Use of aPCC in combination with Hemlibra (emicizumab) should be avoided in patients who 
have the option of using other bypassing agents to treat bleeds. In the event that aPCC is the only 
available bypassing agent, the lowest dose expected to achieve hemostasis should be prescribed, 


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with no more than 50 U/kg aPCC to be administered as an initial dose. The total dose of aPCC 
must be <100 U/kg/day for preferably less than 1 day. aPCC may only be administered if 
approved by the Study Investigator and may only be administered by a physician. 
Caution should be taken for patients who are using rFVIIa (eg, consideration of using no more 
than 90 µg/kg of rFVIIa as an initial dose). Other bypassing agents 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. Bypassing agents other than rFVIIa may 
only be administered if approved by the Study Investigator. 
The exact dose and schedule of bypassing agents should be discussed with subjects at the 
beginning and throughout the study. Repeated dosing of rFVIIa, aPCC, or other bypassing agents 
should be performed only under medical supervision, which could include laboratory monitoring 
by additional local and central laboratory assessments, and consideration should be given to 
verifying bleeds prior to repeated dosing. 
Caution should be taken if antifibrinolytics are used in conjunction with bypassing agents 
including rFVIIa and aPCC in patients receiving Hemlibra (emicizumab). Use of antifibrinolytics 
after one dose of bypassing agent (eg, as done for dental extractions) is allowed; concomitant use 
of rFVIIa and antifibrinolytics should be avoided if at all possible and concomitant use of aPCC 
and antifibrinolytics is not allowed. (see Restrictions, Section 5.5) 
Drugs and therapies to treat AEs and use of topical antiseptics, anesthetics, eye drops, etc, that 
are not considered to result in systemic exposure are permitted. 
All concomitant medications need to be registered in the subject’s medical files and the patient 
diaries and recorded in the CRF.  
5.5 Restrictions  
Use of the following therapies may be prohibited for subjects enrolled in ongoing studies and for 
at least 4 weeks prior to the initiation of study treatment.  
 Use of drugs that would affect hemostasis (eg, aspirin, non-steroidal anti-inflammatory 
drugs, or anticoagulants [other than to flush, dwell, or de-clot a central venous access 
device]) but excluding drugs intended to control bleeding episodes or used in the context 
of minor surgery (eg, tooth extraction) or injuries (eg, concussion) to prevent 
deterioration 
 Use of systemic immunomodulators (eg, rituximab, interferon) other than antiretroviral 
therapy from enrollment to last observation   
 Elective surgery (excluding minor procedures such as tooth extraction, central venous 
access device removal, or incision and drainage as well as emergency surgeries) from 
enrollment to last observation 


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 Use of aPCC for short-term or long-term prophylaxis 
 Use of antifibrinolytics concomitantly with aPCC  
 Use of other investigational drugs from enrollment to last observation 
5.6 Treatment Compliance  
All subjects will either self-administer Hemlibra (emicizumab) in an at-home setting, or have 
Hemlibra (emicizumab) administered by a trained caregiver or healthcare provider (either at 
home or at a local physician’s office) on a weekly basis.* Agents required to treat a breakthrough 
bleed may also be self-administered by the subject or a caregiver in an at-home setting, except 
aPCC, which if approved by the Study Investigator may only be administered by a physician. 
The following will be recorded by the subject in their patient diary: 
 The date and time of Hemlibra (emicizumab) administration 
 The exact dose of Hemlibra (emicizumab) administered 
 Any adverse events, duration and actions taken  
Additionally, the subject will record the following for all bleeding events 
 The date and time of onset  
 The anatomical location and severity  
 The agent(s) used to control the bleed, the exact dose(s), the number of doses and the 
time(s) of administration 
 The Study Investigator will determine whether the bleeding event was related to the 
pseudotumor based on a retrospective review of the clinical data 
Should the subject be admitted to a hospital or medical facility this should be recorded as 
described in Section 6.11.3, as should any incidences of anemia that require transfusion or 
intervention. All surgeries or deaths should also be recorded. Medical details of these events 
should be transmitted to the IHTC within 7 days of their occurrence 
The patient diary will be checked by the subject’s local physician during the quarterly study 
visits that take place at their local facilities and transmitted to the IHTC at that time. The patient 
diary will be reviewed by IHTC staff during the annual and study close-out visits at the IHTC. 
5.7 Storage and Accountability  
Hemlibra (emicizumab) must be stored in a safe and secure place at the subject’s home or local 
clinic. Hemlibra (emicizumab) should be stored between 2°C (36°F) and 8°C (46°F) in the 
                                                 
* Weekly injections of Hemlibra (emicizumab) by a nurse or qualified healthcare provider is not required by the 
study and therefore is not included in the budget. Travel by the subject to receive injections of Hemlibra 
(emicizumab) is not required by the study and therefore is not included in the budget. 


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original carton and protected from light. The product is stable at room temperature (below 30°C, 
86ºF) for up to 7 days. The product should not be frozen or shaken. 
The Study Investigator is fully responsible for all study supply of Hemlibra (emicizumab) stored 
at the IHTC. Access should be strictly limited to the Study Investigator and designated staff.  
All study supply of Hemlibra (emicizumab) received at the IHTC, dispensed to and returned 
from a subject will be documented. All empty vials will be returned to the IHTC and 
documented. This documentation must be available for review by Genentech to confirm proper 
investigational product management.  
5.8 Investigational Product Retention at Study Site  
All used and unused vials of Hemlibra (emicizumab) will be retained until accountability has 
been performed and recorded by the IHTC pharmacy. For this purpose, study staff will keep all 
used vials to perform the treatment compliance check and store them for a final accountability 
check by Genentech. 
All unused vials of Hemlibra (emicizumab) will be returned to Genentech or destroyed by the 
IHTC pharmacy.  
5.9 Dispensation of Hemlibra (emicizumab)  
See Section 6.7. 


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6 STUDY PROCEDURES  
6.1 Informed Consent  
Informed consent will be in English. The subject and/or their caregiver must be sufficiently 
proficient in English to read, understand and sign the informed consent form. 
All subjects will be informed of the aims of study, the possible adverse events, the procedures 
and possible risks to which they will be exposed, and how treatment and dose will be 
determined. They will be informed as to the strict confidentiality of their personal data, and that 
their medical records may be reviewed for study purposes by authorized individuals other than 
their treating physicians. It will be emphasized that the participation is voluntary and that the 
subject is allowed to refuse further participation in the protocol whenever they want. Once the 
subject completely understands the study and its procedures and risks they will be asked to sign 
and date the informed consent form. Study procedures may only occur after the informed consent 
form has been signed and dated. 
Any subject who provides informed consent (ie, signs and dates the informed consent form) will 
be screened, and if screening is successful they will be enrolled in the study. Screening is 
expected to take less than 10 days. Recording of safety observations will commence immediately 
with the signing and dating of the informed consent form and the initiation of study procedures. 
6.2 Medical History/Demographics  
The medical history of the subject will be obtained. Specific information will be recorded on the 
CRF relating to any prior or existing medical conditions/surgical procedures involving the 
following: Infectious Diseases (including viral infections, such as Hepatitis and HIV), Allergies, 
Metabolic/Endocrine/Nutritional, Hematopoietic, Musculoskeletal, Dermatologic, Head, Ears, 
Eyes, Nose, and Throat (HEENT), Breasts, Respiratory, Cardiovascular, 
Gastrointestinal/Hepatic, Genitourinary/Renal, Neurologic, and Psychiatric/Psychosocial.  
Specific documentation for the following should be provided to the IHTC: 
 Medical documentation of any prophylactic (FVIII or bypassing agent) therapy for at 
least 16 weeks, and up to 6 months if available, prior to entry into the study 
 Medical documentation for the number of bleeding episodes (including location, severity, 
duration and treatment) for at least 16 weeks, and up to 6 months if available, prior to 
entry into the study. If available, the hemostatic agent, number of infusions and quantity 
of drug infused for each bleeding episode will be collected 
 Medical documentation of any complications related to the pseudotumor (including any 
incidences of anemia, the need for PRBC transfusion or hospitalization) for 6 months 
prior to entry into the study 


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 Subjects with a history of an inhibitor should provide documentation of the inhibitor 
history including date of initial diagnosis of inhibitor, peak titer, and agent utilized for 
hemostatic control  
 Medical documentation of ITI therapy for subjects with a history of a FVIII inhibitor and 
ITI, including current FVIII inhibitor titer 
 Documentation of current concomitant medications and supplements 
 Date of development or identification of pseudotumor and documentation of radiologic 
(CT and/or MRI) scans 
Demographics (date of birth, race/ethnicity, gender, height, weight, etc) and vital signs (blood 
pressure, pulse, temperature, and respiratory rate) will also be collected.  
6.3 Physical Examination  
Standard physical examinations will be performed during the study. All findings from this 
examination will be recorded on source documents and entered into the CRF. The standard 
physical examination will minimally include the following observations/measurements: General 
Appearance, Skin, HEENT, Thyroid, Lymph Nodes, Heart, Lungs, Abdomen, Extremities/Joints, 
Neurological, and Mental Status.  
6.4 Events of Special Interest 
During the study the subject will be checked for the Hemlibra (emicizumab) Events of Special 
Interest (Section 6.11.3.2i), which are clinical signs of thrombotic microangiopathy, 
thromboembolic events, systemic hypersensitivity reactions and anaphylactic/anaphylactoid 
reactions. If observed, ongoing monitoring and rapid communication by the Study Investigator to 
Genentech is required. Such an event might require further investigation in order to characterize 
and understand it. If any of the above are observed, appropriate laboratory tests should be 
pursued. 
6.5 Quality of Life and Activity Assessments  
6.5.1 Haem-A-QoL and EQ-5D-5L 
Quality of life assessments will be completed by adult subjects using the Haem-A-QoL (Haem-
A-QoL Group) and EQ-5D-5L (EuroQol Group) questionnaires. They will be completed in 
English or in the subject’s native language if available and validated in that language. These 
assessments will be repeated at every annual study visit and the study close-out visit. 


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6.5.2 Activity Monitoring Device 
If the subject routinely uses an activity monitoring device (eg, Fitbit or similar) and plans to 
remain doing so during the study, then permission will be requested to access the data for the 1-
month period prior to enrollment in the study (baseline data) and continued access from 
enrollment until the end of their participation in the study (study data). These data will be 
collected and transmitted to the IHTC on at least a quarterly basis for analysis. 
6.6 Clinical Laboratory Tests  
6.6.1 Laboratory Parameters  
Subjects will be in a seated or supine position during blood collection. Clinical laboratory tests 
will include the following, and unless otherwise noted, will be carried out by the local laboratory 
of the study site. Not all of these tests will be performed at screening if there are acceptable 
results available in the subject’s medical files, or if they are considered medically unnecessary 
for a specific patient at the discretion of the Study Investigator. See Section 7 for specific details 
on when these tests might be performed. 
List of Laboratory Tests  
 FVIII level* 
 aPTT 
 PT 
 VWG:Ag 
 FVIII inhibitor level (Bethesda assay) 
 CBC w/diff 
 CMP + direct bilirubin 
 ADA for Hemlibra (emicizumab) – banked sample for analysis at central laboratory 
 HAV:Ab 
 HBV:Ag and Ab (Core and Surface); If HBV:Ag positive, then HBV viral load 
 HCV:Ab; If HCV:Ab positive, then HCV viral load 
 HIV:Ab; if HIV:Ab positive, then HIV viral load and CD4 count 
 Serum pregnancy test for female subjects 
                                                 
* If the subject has an inhibitor, then testing for FVIII level may not be medically necessary as FVIII is usually 
undetectable in such cases. Exceptions exist, such as for a patient who has mild hemophilia with an inhibitor that 
only recognizes infused FVIII and not endogenous FVIII. 


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6.6.2 Life-threatening Bleeding Due to Unreliable Standard Coagulation Tests in the Setting of 
Hemlibra (emicizumab) 
Emicizumab affects assays for non-bovine reagent aPTT and all assays based on non-bovine 
reagent aPTT, such as one-stage FVIII activity. Therefore, non-bovine aPTT-based coagulation 
laboratory test results in patients who have been treated with emicizumab prophylaxis will not be 
used to monitor either emicizumab activity or determine dosing for factor replacement, or 
measure FVIII inhibitor titers. If required for clinical care, specific specialized testing such as the 
chromogenic FVIII assay with bovine FIXa/FX to measure exogenous FVIII replacement, or a 
bovine based aPTT for inhibitor analysis will be recommended to be utilized as available; these 
analyses are not required by the study and therefore not included in the budget. 
There is a risk of life-threatening bleeding due to unreliable standard coagulation tests and 
inhibitor assays in the setting of emicizumab if a patient is treated by a practitioner other than the 
emicizumab-prescribing practitioner in settings such as an emergency room or in an acute care 
setting.  
For recommendations on the use and interpretation of coagulation assays for patients receiving 
emicizumab, see Section 6.6.3.  
6.6.3 Use & Interpretation of Coagulation Assays 
Most coagulation assays may be performed in a local laboratory for screening. Once 
administration of Hemlibra (emicizumab) has been initiated, certain coagulation assays should 
not be used due to interference; instead alternative assays at a local or central laboratory should 
be used. 
Based on its mechanism, Hemlibra (emicizumab) is expected to interfere with any laboratory 
coagulation test that is based on the intrinsic pathway. This section explains the effects of 
Hemlibra (emicizumab) on the tests most commonly used in hemophilia A.  
The following table summarizes the coagulation tests affected and unaffected by emicizumab. 
Due to the long half-life of Hemlibra (emicizumab), these effects on coagulation assays may 
persist for up to 6 months after the last dose. 
 
 
Results affected by Hemlibra (emicizumab) 
Results unaffected by Hemlibra (emicizumab) 
Activated partial thromboplastin time (aPTT)  
Activated clotting time (ACT)  
One-stage, aPTT-based, single-factor assays  
aPTT-based Activated Protein C Resistance 
(APC-R)  
Thrombin time (TT)  
One-stage, PT-based, single-factor assays  
Chromogenic-based single-factor assays other 
than FVIII* 


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Bethesda assays (clotting-based) for FVIII 
inhibitor titers  
Immuno-based assays (eg, ELISA, turbidometric 
methods)  
Bethesda assays (bovine chromogenic) for FVIII 
inhibitor titers  
Genetic tests of coagulation factor mutations (eg, 
Factor V Leiden, Prothrombin 20210)  
ACT, activated clotting time; APC-R, Activated Protein C Resistance; aPTT, activated partial thromboplastin 
time; ELISA, enzyme linked immunosorbent assay; FVIII, factor VIII; PT, prothrombin time; TT, thrombin time 
* For important considerations regarding FVIII chromogenic activity assays, please see Section 6.6.3.3  
6.6.3.1 aPTT assay 
The total clotting time as measured by aPTT is dependent on a large number of coagulation 
factors, including the feedback activation of FVIII by thrombin, which is a rate-limiting step. 
Hemlibra (emicizumab) does not require activation, resulting in a supra-physiologically short 
time to clot formation. Thus, aPTT is normalized by sub-therapeutic concentrations of 
emicizumab (as low as 5 µg/mL) and does not accurately indicate the patient’s coagulation status 
or the activity of emicizumab.  
6.6.3.2 One-stage FVIII activity assay 
This assay utilizes aPTT reagents and thus is subject to interference by Hemlibra (emicizumab). 
Very rapid clotting times result in overly high reported FVIII activity values, which do not 
correctly reflect the patient’s coagulation status or the activity of Hemlibra (emicizumab).  
6.6.3.3 FVIII chromogenic activity assay (“two-stage”) 
As an antibody, Hemlibra (emicizumab) exhibits very specific binding to its targets, human FIXa 
and FX, and it does not exhibit cofactor activity with the respective bovine proteins. Most 
commercially available chromogenic activity assays are manufactured using purified bovine 
FIXa and FX. Hemlibra (emicizumab) activity cannot be detected in these assays and can only be 
detected using a chromogenic assay composed of human proteins (Hyphen Biophen).    
6.6.3.4 Bethesda assay 
Hemlibra (emicizumab) is not inactivated by heat treatment and is not neutralized by FVIII 
inhibitors. Hemlibra (emicizumab) will cause plasma samples to clot irrespective of the presence 
FVIII inhibitors. Therefore, FVIII inhibitors cannot be detected by functional tests, such as 
Bethesda or Nijmegen-Bethesda assays, which use a one-stage clotting based readout. A 
Chromogenic Bethesda Assay using bovine FIXa and FX is required since Hemlibra 
(emicizumab) does not bind to bovine factors (Chromogenic Bethesda Assay using human FIXa 


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and FX should not be used for FVIII inhibitor detection). Immunoassays for FVIII inhibitors 
may also be used.    
6.6.4 Central Laboratory Assays 
Samples that require analysis in centralized laboratories will be appropriately processed 
according to standardized methods and stored at the IHTC based upon sample requirements until 
shipment occurs. In the case that a bovine based inhibitor titer is required, the sample will be sent 
to a laboratory with established methodology (eg, CDC) for analysis. The IHTC has experience 
with drawing, processing, storage and shipment of a wide variety of research samples. The IHTC 
has on-site equipment and SOPs for such procedures and has a -70ºC monitored freezer to store 
samples as well as an off-site secure sample storage facility agreement in place for longer term 
storage (BioStorage Technologies, Inc.) which can retrieve needed samples and/or ship per IHTC 
requirements.  
6.7 Dispensation of Study Drug  
Hemlibra (emicizumab) drug will be dispensed to the subject by the IHTC. Dispensation will 
take place at study visit 2, during annual visits to the IHTC and at other periods throughout the 
year to ensure adequate supply for the subject.  
The quantity of Hemlibra (emicizumab) dispensed will depend on the storage capacity at the 
subject’s home. It is preferred that study Hemlibra (Emicizumab) be stored in the patient’s home 
unless extenuating circumstances exist; in these circumstances a discussion with the study 
investigator will occur and a solution developed to allow local access to study medication.  
The quantity dispensed will be at the discretion of the Study Investigator and may vary from 
subject to subject. Additional quantities (ie, quantities dispensed at times other than study visit 2 
and annual visits at the IHTC) may be dispensed and shipped to the subject throughout the year 
to ensure adequate supply for the subject using standard protocols for the shipment/transport of 
medicines.  
The subject shall also receive appropriate materials for administration (eg, alcohol swabs, 
syringes, needles, etc.)  
6.8 Pharmacokinetic Assessments  
No pharmacokinetic assessments will be performed as part of the study 
6.9 Pharmacodynamic Assessments  
No pharmacodynamic assessments will be performed as part of the study 


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6.10 Efficacy and Quality of Life Assessments  
The primary outcome for this study is bleeding events specifically related to the pseudotumor 
over time; total bleeding events will also be recorded and analyzed.  
All bleeding events will be recorded in the patient diary along with the following: 
 The date and time of onset  
 The anatomical location and severity  
 The agent(s) used to control the bleed, the exact dose(s), the number of doses and the 
time(s) of administration 
 The Study Investigator will determine whether the bleeding event was related to the 
pseudotumor based on a retrospective review of the clinical data 
The efficacy of Hemlibra (emicizumab) will be determined by comparing the incidence of 
bleeding events and use of alternate hemostatic medication on study to the incidences prior to 
study enrollment and by changes over time. 
The following should also be recorded and transmitted to the IHTC within 7 days of their 
occurrence: 
 The admission of the subject to a hospital or medical facility (described in Section 6.11.3) 
 Incidences of anemia that require transfusion or intervention 
 All surgeries or deaths  
 Any other AEs or SAEs noted and recorded by a physician 
The efficacy of Hemlibra (emicizumab) will be determined by comparing the incidence of 
hospitalization and anemia that require transfusion or intervention on study to the incidences 
prior to study enrollment and by changes over time. 
The following should be acquired during study visit 2 (if they were not performed within 1 
month of study entry and if they are not considered suitable for study purposes) and at every 
annual study visit and the study close-out visit: 
 Radiology (CT and/or MRI) to observe change in the size of the pseudotumor over time 
(ie, the progression, stabilization or regression of the pseudotumor) 
The efficacy of Hemlibra (emicizumab) will be determined by the change in the size of the 
pseudotumor over time (ie, the control of progression, stabilization or regression of the 
pseudotumor). 
The following will be used to determine changes in quality of life and activity level: 
 Haem-A-QoL and EQ-5D-5L will be completed following screening and at every annual 
study visit and the study close-out visit 


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 If an activity monitoring device is standardly utilized by the patient (eg, Fitbit) and the 
subject has provided consent to use that data in the study, then data from that device will 
be transmitted to the IHTC on a quarterly basis to assist in activity monitoring 
The efficacy of Hemlibra (emicizumab) will be determined by comparing changes in activity and 
quality of life over time. 
6.10.1 Primary Endpoints  
The primary endpoints are: 
 The number of breakthrough bleeding events over time requiring the use of alternate 
hemostatic therapy (bleed rate) related to the pseudotumor  
 The number of hospital admissions related to the pseudotumor 
 The number of incidences of anemia requiring transfusion or intervention related to the 
pseudotumor 
 The change in the size of the pseudotumor over time (ie, the control of progression, 
stabilization or regression of the pseudotumor) as measured by yearly assessments 
including CT or MRI 
The study investigator will determine whether the reported event was related to the pseudotumor 
based on a retrospective review of the medical data (eg, bleed location, patient symptoms, etc).  
6.10.2 Secondary Endpoints 
The secondary endpoints are: 
 The impact of weekly prophylaxis on quality of life and activity level 
 Safety including development of AEs, SAEs, and ADA  
 The dose(s) and number of infusions of alternate hemostatic therapy (FVIII, rFVIIa or 
aPCC) required to treat a breakthrough bleeding event either unrelated or related to the 
pseudotumor 
 The number of breakthrough bleeding events over time requiring the use of alternate 
hemostatic therapy (bleed rate) unrelated to the pseudotumor 
 The use of alternate hemostatic therapies (eg, FVIII, rFVIIa or aPCC) during surgeries 
and the hemostatic efficacy 
The study investigator will determine whether the reported event was related to the pseudotumor 
based on a retrospective review of the medical data (eg, bleed location, patient symptoms, etc).  


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6.11 Safety Reporting of Adverse Events  
6.11.1 Assessment of Safety 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as adverse events. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
radiologic (CT and/or MRI) scans. In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration. However, every effort should be made to document 
progression through use of objective criteria. If there is any uncertainty as to whether an event is 
due to disease progression, it should be reported as an adverse event. 
6.11.1.1 Specification of safety variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol. This includes all events of death, and any study specific 
issue of concern. 
6.11.1.2 Adverse events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. 
This includes the following: 
 AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with hemophilia that were not 
present prior to the AE reporting period 
 Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as cardiac catheterizations) 
 If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 
 Preexisting medical conditions (other than the condition being studied) judged by the 
Study Investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period 
6.11.1.3 Serious adverse events 
An AE should be classified as an SAE if the following criteria are met: 
 It results in death (ie, the AE actually causes or leads to death) 


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 It is life threatening (ie, the AE, in the view of the Study Investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death) 
 It requires or prolongs inpatient hospitalization 
 It results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
 It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP 
 It is considered a significant medical event by the Study Investigator based on medical 
judgment (eg, may jeopardize the subject or may require medical/surgical intervention to 
prevent one of the outcomes listed above) 
6.11.2 Methods and Timing for Assessing and Recording Safety Variables 
The Study Investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
6.11.2.1 Adverse event reporting period 
The study period during which AEs and SAEs as described in Section 6.10.3.2j where the 
patient has been exposed to Genentech product must be reported. Reporting period begins after 
informed consent is obtained and initiation of any study procedures and ends 24 weeks following 
the last administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to prior study 
treatment (eg, AEs such as those described in Section 6.11.3.2g). 
6.11.2.2 Assessment of adverse events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (ie, start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the Hemlibra 
(emicizumab) (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Study Investigators should apply 
the following general guideline: 
 Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the Hemlibra (emicizumab), and the AE cannot be readily explained 
by the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the 


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AE follows a known pattern of response to the Hemlibra (emicizumab); and/or the 
AE abates or resolves upon discontinuation of the Hemlibra (emicizumab) or dose 
reduction and, if applicable, reappears upon re-challenge. 
 No 
Evidence exists that the AE has an etiology other than the Hemlibra (emicizumab) 
(eg, preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
Hemlibra (emicizumab) administration (eg, cancer diagnosed 2 days after first dose of 
study drug). 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (PI) or current Investigator Brochure (IB). 
Unexpected adverse events are those not listed in the PI or current IB or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the PI or IB. For example, under this definition, hepatic necrosis would be unexpected if the PI 
or IB only referred to elevated hepatic enzymes or hepatitis. 
Specific unexpected adverse events include, but are not limited to: 
 Fracture of a bone related to the erosion/weakening of osseous structures due to the 
pseudotumor 
 Infection of pseudotumor especially if a fistula is present 
 Requirement for emergent surgery due to expansion of pseudotumor or uncontrolled 
bleeding 
 Requirement of amputation due to expansion of pseudotumor or uncontrolled 
bleeding 
6.11.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
6.11.3.1 Eliciting adverse events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include: 
 “How have you felt since your last clinical visit?” 
 “Have you had any new or changed health problems since you were last here?” 
6.11.3.2 Specific instructions for recording adverse events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 


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6.11.3.2a Diagnosis vs. signs and symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (eg, 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, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
6.11.3.2b Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 6.11.3.2i), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
6.11.3.2c Preexisting medical conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (eg, “more frequent headaches”). 
6.11.3.2d Hospitalizations for medical or surgical procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study 
 Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 


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6.11.3.2e Assessment of severity of adverse events 
The adverse event severity grading scale for the NCI CTCAE will be used for assessing adverse 
event severity. Below Table should be used for assessing severity for adverse events that are not 
specifically listed in the NCI CTCAE. 
Adverse event severity grading scale for events not specifically listed in NCI CTCAE: 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE, which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, 
and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event" it must be reported as a serious adverse event  
d. 
Grade 4 and 5 events must be reported as serious adverse events  
6.11.3.2f Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 24 weeks after the 
last dose of study drug, a report should be completed and expeditiously submitted to Genentech, 
Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE. 
6.11.3.2g Post-study adverse events 
The Study Investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior Hemlibra (emicizumab) 
exposure. If the Study Investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject or of the female 


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partner of a male study subject who participated in the study, this should be reported as an SAE 
adequately to Genentech drug Safety during follow up period 
6.11.3.2h Case transmission verification of single case reports 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via the IHTC emailing Genentech a 
Quarterly line-listing documenting single case reports sent by the IHTC to Genentech in the 
preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon.                
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by the IHTC to Genentech within five (5) calendar days from 
request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech. 
6.11.3.2i AEs of special interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Study Investigator to the 
Sponsor is required. Such an event might require further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (eg, Regulatory Authorities) may also be warranted. 
The Hemlibra (emicizumab) Events of Special Interest are:  
 Thrombotic Microangiopathy 
 Thromboembolic Events 
 Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reactions 
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: 
o Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 


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o Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice 
 Suspected transmission of an infectious agent by the study drug, as defined below: 
o Any organism, virus, or infectious particle (eg, 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 
6.11.3.2j Exchange of single case reports 
IHTC will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious 
Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including 
pregnancy reports) and Product Complaints (with or without an AE) originating from the Study 
for the Product.  
Study Investigators must report all the above-mentioned single case reports adequately to 
Genentech within the timelines described below. The completed MedWatch or CIOMS I form or 
Genentech approved reporting forms should be faxed/emailed immediately upon completion to 
Genentech at the following contacts: 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) 
and Product Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be called into: 
Product Complaint Hotline Phone Number: (800) 334-0290 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, 
AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or 
without an AE) originating from the study.  
These single case reports will be exchanged between the parties as outlined below so that 
regulatory obligations are met. 
Serious adverse events (SAEs), pregnancy reports, AEs of special interest (AESIs), Special 
Situation Reports and Product Complaints (with or without an AE), where the patient has been 
exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS I form or on 
Genentech approved reporting forms to Genentech Drug Safety. Transmission of these reports 


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(initial and follow-up) will be either electronically or by fax and within the timelines specified 
below: 
 SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech 
within fifteen (15) calendar days of the awareness date. 
 Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date. 
 Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy where the fetus may have been exposed to the 
Product, shall be transmitted to Genentech within thirty (30) calendar days of the 
awareness date. Pregnancies will be followed up until the outcome of the pregnancy is 
known, whenever possible, based upon due diligence taken to obtain the follow-up 
information. 
 Special situation reports 
In addition to all SAEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to 
Genentech within thirty (30) calendar days: 
o Data related to the Product usage during pregnancy or breastfeeding 
o Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error (including potentially exposed in case of 
medication errors or intercepted medication errors) or occupational exposure, with 
or without association with an AE/SAE unless otherwise specified in the protocol 
o Lack of therapeutic efficacy 
o Drug interaction 
o Use of a Medicinal Product in a Pediatric and Elderly population (in addition, 
reasonable attempts should be made to obtain and submit the age or age group of 
the patient, in order to be able to identify potential safety signals specific to a 
particular population) 
 Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date. 


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A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been 
released and distributed to the commercial market or clinical trial. 
All other AEs will be reported via CTV reconciliation process (a list of all AEs) on a quarterly 
basis. 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported 
6.11.3.2k Disease progression 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as adverse events. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
radiologic (CT and/or MRI) scans. In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration. However, every effort should be made to document 
progression through use of objective criteria. If there is any uncertainty as to whether an event is 
due to disease progression, it should be reported as an adverse event. 
6.11.4 Reporting Requirements for Adverse Events Originating from Patient Reported Outcomes  
Although sites are not expected to review the PRO data, if physician/study personnel become 
aware of a potential adverse event during site review of the PRO questionnaire data, he/she will 
determine whether the criteria for an adverse event have been met and, if so, these must be 
reported using the Adverse Event and Special Situation Reporting Form or MedWatch form. 
6.11.5 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome if known 
 Supportive laboratory results and diagnostics 
 Study Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 


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6.11.5.1 Follow-up information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
 Summarizing new information and faxing it with a cover letter including patient 
identifiers (ie, DOB initial, patient number), protocol description and number, if assigned, 
brief adverse event description, and notation that additional or follow-up information is 
being submitted (the patient identifiers are important so that the new information is added 
to the correct initial report) 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
6.11.5.2 Reporting to regulatory authorities, ethics committees and investigators 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of 
individual case safety reports from the study to the regulatory authority in compliance with 
applicable regulations 
Genentech will be responsible for the expedited reporting of safety reports originating from the 
study to the EMA through Eudravigilance Clinical Trial Module (EVCTM). 
The IHTC will be responsible for the distribution of safety information to its own investigators, 
where relevant. 
The IHTC will be responsible for the distribution of safety information to the IHTC IRB: 
For questions related to safety reporting, please contact Genentech/Roche Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
6.11.6 Aggregate Reports 
6.11.6.1 Development safety update report 
The IHTC as the Sponsor of the study, will be responsible for the preparation of their own 
Development Safety Update Report (DSUR) for the study and for the submission of the report to 
the regulatory authorities and Ethics Committees of the concerned Member States, where 
applicable. The IHTC agrees to share a copy of their own DSUR with Genentech as soon as 
reasonably possible after completion.  


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Genentech agrees to forward to the IHTC an executive summary of the Genentech DSUR upon 
request. Furthermore, Genentech agrees that the IHTC may cross-reference the executive 
summary of the Genentech/Roche DSUR, as applicable. 
6.11.6.2 Other reports  
The IHTC will forward a copy of the Final Study Report to Genentech/Roche upon completion 
of the study. The IHTC will also forward a copy of any publications developed and accepted for 
publication to Genentech/Roche. 
6.11.7 Study Close-out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
Emicizumab IIS Clinical Operations 
Email: emicizumab-gsur-d@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at: 
ctvist_drugsafety@gene.com 
6.11.8 Queries 
Queries related to the study will be answered by the IHTC. However, responses to all safety 
queries from regulatory authorities or for publications will be discussed and coordinated between 
the Parties. The Parties agree that Genentech/Roche shall have the final say and control over 
safety queries relating to the Product. The IHTC agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Product independently but shall redirect 
such queries to Genentech/Roche. 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required. 
6.11.9 Safety Crisis Management 
In case of a safety crisis, eg, where safety issues have a potential impact on the indication(s), on 
the conduct of the study, may lead to labeling changes or regulatory actions that limit or restrict 
the way in which the Product is used, or where there is media involvement, the Party where the 
crisis originates will contact the other Party as soon as possible. 


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The Parties agree that Genentech/Roche shall have the final say and control over safety crisis 
management issues relating to the Product. The IHTC agrees that it shall not answer such queries 
from media and other sources relating to the Product but shall redirect such queries to 
Genentech/Roche. 
 
 


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7 STUDY ACTIVITIES 
7.1 Study Visit 1: Informed Consent and Screening 
 Informed consent signature and date  
 Determination of eligibility  
 Demographics (date of birth, race, gender, height) 
 Weight 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) 
 Medical history review, including 
o Documentation of current or past infection of Hepatitis A, B and C  
 HAV:Ab 
 HBV:Ag and Ab (Core and Surface); if HBV:Ag positive, HBV viral load 
 HCV:Ab; if HCV:Ab positive, HCV viral load 
o Documentation of HIV infection (if Ab positive, viral load and CD4 count) 
o Review of at least 16 weeks, and up to 6 months if available, of data on prior use 
of hemostatic therapy and number of breakthrough bleeding events 
o Review of 6 months of data on prior need for hospitalization or for PRBC 
transfusion 
o Review of therapy prior to study entry with dose and interval and trough level if 
available on prophylaxis 
o Review of history of inhibitor including date of first positive test, highest 
documented titer and date  
o Review of concomitant medications and supplements 
o Date of development or identification of pseudotumor and documentation of 
radiologic (CT or MRI) scans 
o Review of surgeries and procedures 
 Physical examination  
 Lab screening (if adequate results are not available in the subject’s medical records):  
o FVIII* 
o aPTT 
o PT 
o VWF:Ag 
o FVIII inhibitor level (Bethesda assay) 
                                                 
* If the subject has an inhibitor, then testing for FVIII level may not be medically necessary as FVIII is usually 
undetectable in such cases. Exceptions exist, such as for a patient who has mild hemophilia with an inhibitor that 
only recognizes infused FVIII and not endogenous FVIII. 


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o CBC w/diff 
o CMP + direct bilirubin 
o Serum pregnancy test for female subjects 
 Lab screening for hepatitis (if adequate results are not available in the subject’s medical 
records): 
o HAV:Ab 
o HBV:Ag and Ab (Core and Surface); If HBV:Ag positive, HBV viral load 
o HCV:Ab; If HCV:Ab positive, HCV viral load 
 Lab screening for HIV (if adequate results are not available in the subject’s medical 
files): 
o HIV:Ab; if HIV:Ab positive then HIV viral load and CD4 count 
 Vaccinations: If the subject is not vaccinated, previously exposed, or immune to HAV 
and/or HBV then they will receive the first dose of the HAV and/or HBV vaccine. 
Subjects must follow up with their local provider to complete the recommended 
vaccination schedule*  
 Baseline Haem-A-QoL and EQ-5D-5L surveys 
 Assessment of concomitant medication and supplements 
 If an activity monitoring device is standardly utilized by the patient, then permission will 
be requested to access data for the 1-month period prior to study entry and use of data 
from the device if continued during the study 
 Assessment of adverse events 
7.2 Study Visit 2: Loading Doses  
Study visit 2 will comprise 4 weeks during which the 4 loading doses of Hemlibra (emicizumab) 
will be administered. During study visit 2, baseline radiology (CT and/or MRI scan) will be 
acquired if they were not performed within 1 month of study entry and if they are not considered 
suitable for study purposes. The subject and/or caregiver will also be trained for self-infusion of 
Hemlibra (emicizumab) and trained to look for signs of adverse events.  
Subjects/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. The 
Study Investigator has the discretion to provide additional training or include additional 
observation (eg, after the fourth loading dose), if deemed appropriate, and each subject/caregiver 
will be able to ask any question he or she may have prior to being deemed capable of performing 
subcutaneous Hemlibra (emicizumab) injections. If, despite additional training, the investigator 
                                                 
* Vaccinations will not be charged to the study 


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determines that the subject/caregiver is unable to inject Hemlibra (emicizumab), a trained and 
proficient caregiver or local healthcare provider should be identified to administer the injections. 
Subjects will be observed for a minimum of 30 minutes after the first three loading doses of 
Hemlibra (emicizumab).  
Following each of the first 3 loading doses of Hemlibra (emicizumab), the site will call a subject 
who has a previous history of a clinically significant hypersensitivity reaction 24 hours after each 
dose to assess the status of the subject.  
Additional precautions following each of these doses may also be considered, including having 
an extended observation period or IV access prior to dosing, etc. The Study Investigator may 
include these or other precautions, as deemed appropriate. 
A subject utilizing a prophylactic FVIII regimen, a prophylactic bypassing agent regimen or ITI 
therapy must discontinue those regimens according to the schedule below and for the duration of 
the study. 
 Subjects receiving FVIII prophylaxis must discontinue their FVIII prophylactic regimen 
immediately prior to their second loading dose of Hemlibra (emicizumab) 
 Subjects receiving bypassing agent prophylaxis must discontinue their prophylactic 
regimen at least 24 hours prior to their first loading dose of Hemlibra (emicizumab) 
 Subjects who are receiving FVIII ITI therapy must discontinue ITI immediately prior to 
their first loading dose of Hemlibra (emicizumab) 
During study visit 2, a suitable quantity (at the discretion of the Study Investigator) of Hemlibra 
(emicizumab) will be dispensed (see Section 6.7). 
7.2.1 Day -1 Procedures 
If the subject is on a bypassing agent prophylactic regimen, that regimen must be discontinued at 
least 24 hours prior to the administration of the first loading dose of Hemlibra (emicizumab). 
Bypassing agent prophylaxis must remain discontinued for the duration of the study. 
7.2.2 Day 0 Procedures 
7.2.2.1 Pre-treatment 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Confirmation of eligibility 
o Subject should not have received aPCC or rFVIIa within 24 hours prior to study 
drug administration 
o Subject should not have an active bleeding event 


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o Subject should not have any other temporary or permanent exclusionary event (at 
the discretion of the Study Investigator) 
 Subjects who are receiving FVIII ITI therapy must discontinue ITI at this time and ITI 
must remain discontinued for the duration of the study 
 Assessment of concomitant medication and supplements 
 Assessment of adverse events 
 Banked plasma sample [baseline antidrug antibody levels for Hemlibra (emicizumab)] for 
testing at the central laboratory 
 Other diagnostic procedures as needed and ordered by the Study Investigator and 
recommended by the standard of care 
7.2.2.2 Drug administration 
 The loading dose for Hemlibra (emizicumab) is 3 mg/kg 
 The vial(s) of Hemlibra (emicizumab) should be removed from the refrigerator and 
warmed to room temperature at least 15 minutes prior to administration 
 Hemlibra (emicizumab) should be administered subcutaneously to the thigh, abdomen or 
upper arm 
7.2.2.3 Following drug administration 
 Observation at the IHTC for 30 minutes and assessment of adverse events 
 For subjects with a history of hypersensitivity, the IHTC should follow up with the 
subject 24 hours after administration of Hemlibra (emicizumab) for assessment of 
adverse events 
7.2.3 Day 7 Procedures 
7.2.3.1 Pre-treatment 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Assessment of concomitant medication and supplements 
 Assessment of adverse events 
 Subjects who are receiving FVIII prophylaxis must discontinue their FVIII prophylactic 
regimen at this time and FVIII prophylaxis must remain discontinued for the duration of 
the study 


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 Other diagnostic procedures as needed and ordered by the Study Investigator and 
recommended by the standard of care 
7.2.3.2 Drug administration 
 The loading dose for Hemlibra (emizicumab) is 3 mg/kg 
 The vial(s) of Hemlibra (emicizumab) should be removed from the refrigerator and 
warmed to room temperature at least 15 minutes prior to administration 
 Hemlibra (emicizumab) should be administered subcutaneously to the thigh, abdomen or 
upper arm at least 1-inch away from the previous site of administration 
7.2.3.3 Following drug administration 
 Observation at the IHTC for 30 minutes and assessment of adverse events 
 For subjects with a history of hypersensitivity, the IHTC should follow up with the 
subject 24 hours after administration of Hemlibra (emicizumab) for assessment of 
adverse events 
7.2.4 Day 14 Procedures 
7.2.4.1 Pre-treatment 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Assessment of concomitant medication and supplements 
 Assessment of adverse events 
 Other diagnostic procedures as needed and ordered by the Study Investigator and 
recommended by the standard of care 
7.2.4.2 Drug administration 
 The loading dose for Hemlibra (emizicumab) is 3 mg/kg 
 The vial(s) of Hemlibra (emicizumab) should be removed from the refrigerator and 
warmed to room temperature at least 15 minutes prior to administration 
 Hemlibra (emicizumab) should be administered subcutaneously to the thigh, abdomen or 
upper arm at least 1-inch away from the previous site of administration 


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7.2.4.3 Following drug administration 
 Observation at the IHTC for 30 minutes and assessment of adverse events 
 For subjects with a history of hypersensitivity, the IHTC should follow up with the 
subject 24 hours after administration of Hemlibra (emicizumab) for assessment of 
adverse events 
7.2.5 Day 21 Procedures 
7.2.5.1 Pre-treatment 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Assessment of concomitant medication and supplements 
 Assessment of adverse events 
 Other diagnostic procedures as needed and ordered by the Study Investigator and 
recommended by the standard of care 
7.2.5.2 Drug administration 
 The loading dose for Hemlibra (emizicumab) is 3 mg/kg 
 The vial(s) of Hemlibra (emicizumab) should be removed from the refrigerator and 
warmed to room temperature at least 15 minutes prior to administration 
 Hemlibra (emicizumab) should be administered subcutaneously to the thigh, abdomen or 
upper arm at least 1-inch away from the previous site of administration 
 Assessment of adverse events 
7.2.5.3 Following drug administration 
 Assessment of adverse events 
 Banked plasma sample [antidrug antibody levels for Hemlibra (emicizumab)] for testing 
at the central laboratory 
 Obtain data from an activity monitoring device (for the period from informed consent to 
Day 21) if standardly utilized by the patient and prior consent has been provided 
7.3 Prophylactic Administration of Hemlibra (emicizumab)  
Prophylactic administration of Hemlibra (emicizumab) will continue on a weekly basis (1.5 
mg/kg subcutaneous dosing, or 3 mg/kg kg if dose escalation is determined appropriate by the 


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Study Investigator [Section 5.3.3]) until subject withdrawal or study termination, whichever 
occurs first. The weekly injections will be administered by the subject, a trained caregiver, or a 
local healthcare provider, depending on the needs of the subject. Each subject will receive 
Hemlibra (emicizumab) for a minimum of 2 years and a maximum of 4 years based upon time of 
enrollment. 
The subject will record the following in the patient diary at the time of each Hemlibra 
(emicizumab) infusion 
 Adverse event assessment  
 Any concomitant medication or supplement 
 Date, time and quantity of Hemlibra (emicizumab) infused  
7.4. Subsequent Study Visits 
Subsequent study visits will be scheduled once a quarter, as is the standard of care for patients 
with hemophilic pseudotumor. These study visits will take place at the medical facilities of the 
subject’s local physician, except for the annual and study close-out visits, which will take place 
at the IHTC. The first subsequent study visit will be 3 months (±2 weeks) following the first 
loading dose of Hemlibra (emicizumab). 
The specific requirements of each visit are listed below. Depending on when a subject enrolls 
and when the study ends, the subject might not participate in all study visits beyond month 24. 
See Appendix 2. 
7.4.1 Study Visits at Months 3, 9, 15, 21, 27, 33, 39 and 45 (±2 Weeks) 
The subject will follow-up with their local physician at the intervals specified above. 
During this visit: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Review of AEs 
 Review of concomitant medications and supplements 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 


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7.4.2 Study Visits at Months 6, 18, 30 and 42 (±2 Weeks) 
The subject will follow-up with their local physician for a more detailed clinical review at the 
intervals specified above. 
During this visit the following data will be collected and/or reviewed and transmitted to the 
IHTC: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary for completeness 
 Patient study documentation will be submitted to the IHTC for review of compliance and 
data collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
7.4.3 Annual Study Visits (Months 12, 24 and 36 ±2 Weeks)  
The annual study visit will take place at the IHTC.  
During this visit the following data will be collected and/or reviewed at the IHTC: 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization 
or regression of pseudotumor 
 Anti-drug antibodies (banked plasma sample) 
 Repeated Haem-A-QoL and EQ-5D-5L 
 CBC panel w/diff 
 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 


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 Patient diary will be collected for review 
 Patient study documentation will be collected for review of compliance and data 
collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
During this annual visit, a physical exam will be performed, used/empty vials of Hemlibra 
(emicizumab) will be collected, and a suitable quantity of Hemlibra (emicizumab) will be 
dispensed (see Section 6.7). 
7.4.4 Unscheduled Study Visits 
Any unscheduled study visits with the subject’s local hemophilia physician will be recorded in 
the CRF along with all relevant medical information (eg, reason for visit, diagnoses, scans, AEs, 
lab results, vital signs [blood pressure, pulse, temperature, and respiratory rate], weight, etc).  
If a subject meets with a physician other than their local hemophilia physician, that information 
should be communicated to their hemophilia physician at the next scheduled quarterly study visit 
and appropriate medical information recorded in the CRF. 
Hospitalizations should be recorded in the CRF along with relevant medical information (see 
Section 6.11.3.2d). These should be reported to the IHTC within 7 days of their occurrence. 
AEs should be reported using the instructions in Section 6.11.3. 
7.4.5 Surgeries 
All surgeries will be recorded in the CRF, which should minimally include the following 
information (see Section 6.11.3 for additional reporting requirements): 
 Procedure type 
 Reason for procedure 
 Planned or unplanned 
 Date of procedure and length of hospitalization 
 Hemostatic therapy provided pre-procedure (type, dose and dates) 
 Hemostatic therapy provided post-procedure (type, dose and dates) 
 Hemostatic outcome immediately post-procedure 
 Hemostatic outcome at the end of hospitalization 
 Adverse events experienced (including, but not limited to clots, thromboses and TMA) 
 Vital signs (blood pressure, pulse, temperature, and respiratory rate) and weight 
Hemostatic outcome for surgical treatment is defined using the standard ISTH rating scale shown 
below [Blanchette, Key et al. 2014]. 


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Excellent 
Intraoperative and postoperative blood loss similar (within 10%) to the non-
hemophilic patient with no extra (unplanned) doses of FVIII/FIX/‘bypassing 
agents’ needed and blood component transfusions are similar to the non-
hemophilic patient  
Good 
Intraoperative and/or postoperative blood loss slightly increased over 
expectation for the non-hemophilic patient (between 10 and 25% of expected), 
but the difference is judged by the involved surgeon/anesthetist/relevant 
healthcare professional to be clinically insignificant as evidenced by no extra 
(unplanned) doses of FVIII/FIX/‘bypassing agents’ needed and blood 
component transfusions are similar to the non-hemophilic patient  
Fair 
Intraoperative and/or postoperative blood loss increased over expectation (25–
50%) for the non-hemophilic patient and additional treatment is needed such as 
extra (unplanned) doses of FVIII/FIX/‘bypassing agents’ or increased blood 
component use  (within two-fold) of the anticipated transfusion requirement  
Poor 
Significant intraoperative and/or postoperative blood loss that is substantially 
increased over expectation (> 50%) for the non-hemophilic patient, requires 
intervention, and is not explained by a surgical/medical issue other than 
hemophilia, unexpected hypotension or unexpected transfer to an Intensive Care 
Unit due to bleeding or substantially increased blood component use (>2 fold) of 
the anticipated transfusion requirement  
 
Medical details and outcome of all surgeries should be reported to the IHTC within 7 days of 
their occurrence. 
7.5 Study Close-out Visit  
All subjects will participate in a study close-out visit at the IHTC within 2 months of the planned 
study termination date. 
During this close-out visit the following data will be collected and/or reviewed at the IHTC 
(depending on when the most recent annual visit took place and at the Study Investigator’s 
discretion, not all specified items may be necessary): 
 Measurement of vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight 
 Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization 
or regression of pseudotumor 
 Anti-drug antibodies (banked plasma sample) 
 Repeated Haem-A-QoL and EQ-5D-5L 
 CBC panel w/diff 


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 Review of breakthrough bleeding events requiring alternate hemostatic therapy 
 Review of the number of hospital admissions 
 Review of the development of anemia requiring transfusion or intervention 
 Review of AEs 
 Review of concomitant medications and supplements 
 Review of patient diary 
 Final Haem-A-QoL and EQ-5D-5L 
 Patient study documentation will be collected for review of compliance and data 
collection 
 Data will be obtained from an activity monitoring device if standardly utilized by the 
patient (if applicable) 
Additionally, a physical exam will be performed and all used and unused vials of Hemlibra 
(emicizumab) will be returned to the IHTC. 
Following the close-out visit, all subjects will be requested to meet with their local hemophilia 
physician to determine their ongoing treatment therapy/regimen. 
7.6 End of Study/Early Termination Procedures  
The subject has the right to withdraw consent and exclude him/herself from the study at any 
time. The Study Investigator has the right to involuntarily withdraw a subject from the study at 
any time for any reason (eg, lack of compliance, unwillingness to complete study visits, SAEs, 
etc). The study may also be terminated early by Genentech as detailed in Section 10.11. 
If the study is not terminated early, then the study will end 4 years following the date on the 
informed consent form of the first subject. 
At subject withdrawal or study end/termination: 
 All unused vials of Hemlibra (emicizumab) will be returned to the IHTC 
 All empty vials of Hemlibra (emicizumab) will be returned to the IHTC 
 The patient diary, study medical files and any activity data covering the final partial 
quarter of the study will be transmitted to the IHTC 
Following subject withdrawal, the subject will be requested to meet with their local hemophilia 
physician to determine their ongoing treatment therapy/regimen. 
 


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8 QUALITY CONTROL AND ASSURANCE  
This study will be sponsored by the IHTC. The IHTC research personnel undergo comprehensive 
clinical research training per Standard Operating Procedure (SOP) “Personnel Training, 
Competency and Qualifications” and comply with Food and Drug Administration (FDA), GCP 
and Institutional Review Board (IRB) regulations. All study staff will be CITI Trained  
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol should not be made without agreement of the Investigator, the Sponsor, and Genentech. 
Changes to the protocol will require written IRB approval prior to implementation, except when 
the modification is needed to eliminate an immediate hazard(s) to subjects. The Sponsor will 
ensure the study is conducted in compliance with the protocol through various quality processes, 
including:  
 Creating, implementing, and upholding SOPs for trial execution  
 A quality scientific and medical design of the protocol  
 Clinical investigator and site pre-assessment and selection  
 Regulatory agency and ethics committee approval  
 Developing and providing appropriate informed consent (language, transparency of 
benefits and risks) and obtaining IRB approval of the informed consent process  
 Investigator meetings and training  
 Adequate recording and reporting of data  
 Periodic monitoring  
 Audits  
Regulatory authorities, the IRB, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, database, and any other applicable study 
documentation for an on-site audit or inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities. All 
study sites may be audited by Genentech. Study sites will receive written notice in advance of 
any audit.  
Additional standards and resources for Quality Assurance and Quality Control will be employed 
by the Sponsor during this study as appropriate. 
 
 


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9 PLANNED STATISTICAL METHODS  
9.1 General Considerations  
All data collected in this study will be documented using summary tables and subject data 
listings. Continuous variables will be summarized using descriptive statistics, specifically the 
sample size (n), mean, median, standard deviation, minimum and maximum. Categorical 
variables will be summarized by frequencies and percentages.  
9.2 Determination of Sample Size  
Sample size is based on clinical feasibility rather than statistical considerations, accounting for 
the likely possibility of very few bleeding events, the limited number of available subjects with 
hemophilia A and pseudotumor, and the need to collect sufficient data to assess safety and 
efficacy. Approximately 10 subjects will receive study medication (the Treated Population). 
9.3 Analysis Populations  
The Study population is defined as all subjects who provide informed consent. The Treated 
Population is defined as all subjects who receive study medication. All analyses of efficacy, 
quality of life and safety will be performed based on the Treated Population.  
9.4 Demographics and Baseline Characteristics  
Demographic and baseline characteristics for all subjects will be summarized using descriptive 
statistics for continuous variables and frequencies and percentages for categorical variables.  
9.5 Primary Endpoints  
The primary endpoints are: 
 The number of breakthrough bleeding events over time requiring the use of alternate 
hemostatic therapy (bleed rate) related to the pseudotumor  
 The number of hospital admissions related to the pseudotumor 
 The number of incidences of anemia requiring transfusion or intervention related to the 
pseudotumor 
 The control of progression, stabilization or regression of the pseudotumor (ie, changes in 
size) as measured by yearly assessments including CT and/or MRI 
The study investigator will determine whether the reported event was related to the pseudotumor 
based on a retrospective review of the medical data (eg, bleed location, patient symptoms, etc).  
Efficacy analyses will be performed based on the parameters listed above. As there is no control 
group or placebo in the study, the on-study data will be compared to that listed in the subject’s 


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Page 87 
medical files prior to study enrollment. The efficacy analyses will exclude data acquired during 
the 4 loading doses (study visit 2). Analyses will be performed on a per-subject basis and in 
aggregate. Sub-analyses will be considered based upon the included study population. 
Demographic and baseline characteristics for all subjects will be summarized using descriptive 
statistics for continuous variables and frequencies and percentages for categorical variables.  
9.6 Secondary Endpoints  
The secondary endpoints are: 
 The impact of weekly prophylaxis on quality of life and activity level 
 Safety including development of AEs, SAEs, and ADA  
 The number of infusions of alternate hemostatic therapy required (FVIII preparation, 
rFVIIa or aPCC) to treat a breakthrough bleeding event either unrelated or related to the 
pseudotumor 
 The number of breakthrough bleeding events over time requiring the use of alternate 
hemostatic therapy (bleed rate) unrelated to the pseudotumor. 
 The use of alternate hemostatic therapies (eg, FVIII, rFVIIa or aPCC) during surgeries 
and the hemostatic efficacy. 
The study investigator will determine whether the reported event was related to the pseudotumor 
based on a retrospective review of the medical data (eg, bleed location, patient symptoms, etc).  
Efficacy analyses will be performed based on the parameters listed above. As there is no control 
group or placebo in the study, the on-study data will be compared to that listed in the subject’s 
medical files prior to study enrollment. The efficacy analyses will exclude data acquired during 
the 4 loading doses (study visit 2). Analyses will be performed on a per-subject basis and in 
aggregate. Sub-analyses will be considered based upon the included study population. 
Changes in quality of life will be determined using the Haem-A-QoL and EQ-5D-5L 
assessments. The Haem-A-QoL scales range from 0 to 100, with lower scores reflecting better 
health-related quality of life. Clinically meaningful differences are 10 points for the score on the 
physical health subscale and 7 points for the total score. Scores on the EQ-5D-5L visual-
analogue scale range from 0 to 100, and index utility scores range from -0.4 to 1.0; higher scores 
indicate better health status. Clinically meaningful differences are 7 and 0.07 points, 
respectively.  
9.7 Safety Analyses  
The number and percentage of subjects with any AEs, any serious AEs (SAEs), and any 
treatment related AEs/SAEs will be presented for all subjects. AEs will be summarized at the 
subject level by MedDRA system organ class (SOC) and preferred term (PT) using frequencies 


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and percentages. AEs will also be tabulated at the event level by SOC, PT and severity and by 
SOC, PT and relationship to study treatment.  
9.8 Interim Analysis  
Interim analyses will be conducted yearly at the discretion of the study investigator if sufficient 
patients are enrolled. At a minimum, an interim analysis will occur at the mid-point of the study 
(2-years following the date of informed consent of the first study subject). This will include a 
detailed review of safety data. Depending on the number of subjects enrolled, an interim review 
of additional data may also be considered. 
 
 
 


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10 ADMINISTRATIVE CONSIDERATIONS  
10.1 Investigators and Study Administrative Structure  
Genentech may contract a CRO to perform specific study related tasks. The division of 
responsibilities will be documented in mutually agreed documents. Written procedures will be 
used to assure that the study is conducted according to all applicable rules and regulations.  
The Study Investigator will ensure that this study is conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with Good 
Clinical Practice and any other local regulations and guidelines.  
The Study Investigator will review all study related documents including the protocol and the 
current version of the Investigator’s Brochure. It is obligatory that the Study Investigator be 
familiar with the protocol and all sections of the Investigator’s Brochure prior to initiation of the 
study.  
10.2 Institutional Review Board (IRB) Approval  
A copy of the protocol, Investigator’s Brochure, proposed Informed Consent Form and any other 
written subject information must be submitted to the IHTC IRB for written approval. A copy of 
the written IRB approval of the protocol and Informed Consent Form must be received by 
Genentech before recruitment of subjects into the study and shipment of investigational drug.  
The Study Investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent form. The Study 
Investigator should notify the IRB of deviations from the protocol or SAEs/reportable safety 
events at the site or reports of such events received from Genentech in accordance with local 
procedures.  
The Study Investigator will be responsible for obtaining annual IRB approval and renewal 
throughout the duration of the study.  
The Study Investigator will promptly report to the IRB all changes in research activity and all 
unanticipated problems involving risks to human subjects and will not make any changes in the 
research without prior approval from Genentech and the IRB, except where necessary to 
eliminate immediate hazards to human subjects.  
10.3 Ethical Conduct of the Study  
This study will be conducted in compliance with Good Clinical Practice (GCP) as described in 
the International Conference on Harmonisation (ICH) document Guidance for Industry-E6 Good 
Clinical Practice: Consolidated Guidance dated April 1996. These practices are consistent with 
the principles stated in the Declaration of Helsinki (October 2000 revised version). All other 
applicable regulations will be adhered to.  


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10.4 Clinical Trial Safety Portal (CTSP) 
The Study Investigator is required to complete CTSP training to access the safety documents 
required for the study. It is the sponsor’s responsibility to ensure that all safety documents are 
obtained from CTSP and submitted to the appropriate authorities such as your institution’s IRB. 
The Sponsor will receive an email from ePharmaSolutions (ePS) with details of training sessions. 
This training should be completed as quickly as possible. 
10.5 Subject Information and Consent  
Written informed consent must be obtained for all subjects who are potential study candidates 
before any study-specific tests or procedures are performed. Subjects who meet general entry 
criteria will be asked to sign and date the study specific, IRB-approved Informed Consent form 
before any study-specific test or procedures are performed. The written informed consent should 
be obtained after the context of the study has been fully explained to the subject/legal guardian in 
a language that is easily understood by the subject/legal guardian. There must also be adequate 
opportunity to ask questions and have those questions answered to their satisfaction. Study 
personnel should explain that even if a subject agrees to participate in the study and signs an 
Informed Consent form, the study specific test or procedures may demonstrate that the subject is 
not a candidate for the study.  
The written informed consent will be in English and will be administered according to national 
requirements. All subjects and/or caregivers must be proficient in English and able to read and 
understand the informed consent for participation in the study. 
10.6 Subject Confidentiality  
Subject participation is voluntary; subjects may refuse to participate or withdraw from the study 
at any time and for any reason. Subjects who participate in the study will be informed that 
information about them is being entered into a study database and their consent will be obtained 
and recorded. Subjects will be identified only by a subject number and date of birth. They will be 
informed as to the strict confidentiality of their subject data, and that their medical records may 
be reviewed for study purposes by authorized individuals other than their treating physician.  
10.7 Study Monitoring  
The IHTC is responsible for study monitoring which will be conducted periodically to ensure 
that all aspects of the current, approved protocol are being followed. The study monitor will be a 
non-study physician from the IHTC. 
The study monitor should be given direct access to original source documents and the Case 
Report Form (CRF). For this study, source documents include but are not limited to the Informed 
Consent Form, subject’s medical records, patient diaries, laboratory results, reports of AEs, and 
drug accountability logs.  


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10.8 Case Report Forms and Study Records  
Subject data will be collected electronically and/or on paper. The Study Investigator must ensure 
the accuracy and completeness of the recorded data and provide his/her signature on the 
appropriate CRFs and/or in the electronic system. The Study Investigator’s signature for specific 
CRFs will be documented in compliance with ICH/GCP guidelines. Visual and/or computer data 
review will be performed to identify possible data discrepancies. Data cleaning will be 
performed on all data in the CRF. Queries will be created in the data management system and 
will be issued for appropriate response.  
10.9 Data Monitoring 
The IHTC is responsible for the oversight of subject safety.  
Safety data collection will commence when each individual subject signs and dates the informed 
consent form and initiates study procedures and will continue until the study ends or the subject 
withdraws from the study, whichever occurs first. All SAEs will be reported to and reviewed by 
the Study Investigator. One non-study physician from the study site will review all SAEs, deaths 
or other unexpected events and report to the Study Investigator with recommendations. If a 
patient dies on study, the case will be evaluated in detail to determine its relatedness to the study 
drug and to determine if the study warrants stopping in the opinion of the Study Investigator.  
Any drug-related SAE (SADR) will be reported through Genentech’s reporting system, as will 
all AEs stipulated in Section 6.11.3.2j. The study site will maintain a record of all SAE reports, 
interpretations and recommendations which will be available for Genentech to review upon 
request. In addition, if a greater than expected number of breakthrough bleeding events, or the 
development of thrombosis or thrombotic microangiopathy (TMA) outside of the established 
associations occurs, treatment of the subject with Hemlibra (emicizumab) may be halted. If an 
anaphylactic reaction to Hemlibra (emicizumab) occurs, then treatment of that patient may be 
halted. The Study Investigator may withdraw a patient based upon their clinical discretion and 
patient safety. 
During the course of the trial, the IHTC will review safety data at least at the following time 
points:  
 
On the occasion of every SAE, death or other unexpected event. The event will be 
assessed by a non-study physician from the IHTC who will report their findings to the 
Study Investigator. Any drug-related SAE (SADR) will also be reported through 
Genentech’s reporting system 
 
Every 3 months on a subject-by-subject basis by a non-study physician from the IHTC 
 
Comprehensively by a non-study physician from the IHTC during every interim analysis 
(minimally at the 2-year midpoint of the study). 
A non-study physician from the study site and the Study Investigator will make 
recommendations, if necessary, for study modification or termination because of concerns over 


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subject safety or issues relating to data monitoring or quality control. This will be submitted in 
writing to Genentech for consideration and final decision. However, if the Study Investigator at 
any time determines that a potential serious risk exists to subjects in the trial, the Study 
Investigator will immediately notify Genentech. 
10.10 Protocol Violations/Deviations  
Deviations from clinical protocol requirements will be reviewed and evaluated on an ongoing 
basis and, as necessary, appropriate corrective actions put into place.  
10.11 Criteria for Terminating Study  
Genentech reserves the right to terminate the study but only intends to exercise this right for 
valid scientific or administrative reasons and reasons related to subject safety and protection. 
Investigators and the associated IRB will be notified in the event of termination.  
Possible reasons for study termination include:  
 
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled 
in the study 
 
A decision on the part of the Genentech to suspend or discontinue development of the 
investigational product  
10.12 Access to Source Documentation  
The non-study IHTC physician monitoring the study will check the CRF form entries against the 
original source documents. The consent form will include a statement by which the subjects 
allow the non-study physician access to source data (eg, original laboratory reports, etc) which 
substantiate information in the CRF. These personnel, bound by professional confidentiality, will 
not disclose any personal information.  
10.13 Data Generation and Analysis  
See the Statistical section of this protocol (Section 9).  
10.14 Retention of Data  
The IHTC should maintain the trial documents as specified in ICH E6 Good Clinical Practice 
Consolidated Guidance and as required by the applicable regulatory requirement(s). The Study 
Investigator and the IHTC should take measures to prevent accidental or premature destruction 
of these documents. If for any reason the Study Investigator withdraws responsibility for 
maintaining the trial documents, custody must be transferred to an individual who will assume 
responsibility. Genentech must receive written notification of this custodial change.  


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Essential documents should be retained for as long as necessary to meet applicable regulatory 
requirements or as required by agreement with Genentech.  
10.15 Financial Disclosure  
All rules and regulations on the documentation and disclosure of any potential financial conflicts 
will be adhered to.  
10.16 Publication and Disclosure Policy  
The study will be listed in the public database on clinical studies www.clinicaltrials.gov. A 
summary report of the study will be made available after the conclusion of the study. It is the 
intention of the IHTC to publish the results of this study in a peer reviewed journal.  
 
 
 


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11 APPENDIX 1: Safety Reporting FAX Cover Sheet 
Genentech Supported Research 
AE / SAE FAX No: (650) 238-6067 
 
 
Genentech Study Number 
Principal Investigator 
Amy D. Shapiro, MD 
Site Name 
The Indiana Hemophilia & Thrombosis Center 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
Initial Report Date 
 
[DD] / [MON] / [YY] 
Follow-up Report Date 
 
[DD] / [MON] / [YY] 
 
 
 


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12 APPENDIX 2: Schedule of Study Visits (per Subject) 
 
Evaluation 
 
Visit Window: 
Study Visit 1 
Study Visit 2* 
Day -10 
Day -1† 
Day 0 
Day 7 
n/a 
n/a 
n/a 
±2 days 
±2 we
Screening 
Pretreatment 
Treatment 
Post-treatment 
Pretreatment 
Treatment 
Post-treatment 
Informed consent 
X 
 
 
 
 
 
 
 
I/E criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
Vital signs  
X 
 
X 
 
 
X 
 
 
Weight 
X 
 
X 
 
 
X 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
Haem-A-QoL & EQ-5D-5L 
X 
 
 
 
 
 
 
 
Clinical lab tests (6.6.1) 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
X 
 
 
X 
 
 
AE assessment 
X 
 
X 
X 
X 
X 
X 
X 
Eligibility 
X 
 
X 
 
 
 
 
 
ADA Hemlibra (emicizumab) 
 
 
X 
 
 
 
 
 
Drug administration (loading 
dose) 
 
 
 
X 
 
 
X 
 
Cease BPA prophylaxis 
 
X 
 
 
 
 
 
 
Cease ITI 
 
 
X 
 
 
 
 
 
Cease FVIII prophylaxis 
 
 
 
 
 
X 
 
 
Activity monitoring device 
(data acquisition) 
X 
 
 
 
 
 
 
 
 
 
                                                 
* An adequate quantity of Hemlibra (emicizumab) will be dispensed during study visit 2 for the loading and maintenance doses. The quantity will be at the 
discretion of the Study Investigator and will depend on the storage capacity at the subject’s home 
† A minimum of 24 hours prior to first loading dose of Hemlibra (emicizumab) 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written permission from Genentech. 
 
 
Page 96 
Evaluation 
 
Visit Window: 
Study Visit 2* 
Day 14 
Day 21 
±2 days 
±2 days 
Pretreatment 
Treatment 
Post-treatment 
Pretreatment 
Treatment 
Post-treatment 
Informed consent 
 
 
 
 
 
 
I/E criteria 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
Medical history review 
 
 
 
 
 
 
Vital signs 
X 
 
 
X 
 
 
Weight 
X 
 
 
X 
 
 
Physical examination 
 
 
 
 
 
 
Haem-A-QoL & EQ-5D-5L 
 
 
 
 
 
 
Clinical lab tests (6.6.1) 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
X 
 
 
AE assessment 
X 
X 
X 
X 
X 
X 
Eligibility 
 
 
 
 
 
 
ADA Hemlibra 
(emicizumab) 
 
 
 
 
 
X 
Drug administration 
(loading dose) 
 
X 
 
 
X 
 
Activity monitoring device 
(data acquisition) 
 
 
 
 
 
X 
 
 
 
 
                                                 
* An adequate quantity of Hemlibra (emicizumab) will be dispensed during study visit 2 for the loading and maintenance doses. The quantity will be at the 
discretion of the Study Investigator and will depend on the storage capacity at the subject’s home 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written permission from Genentech. 
 
 
Page 97 
 
Month 3 
Month 6 
Month 9 
Month 12 
Month 15 
Month 18 
Month 21 
Month 24 
Visit Window: 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
Visit @ local provider 
X 
X 
X 
 
X 
X 
X 
 
Visit @ IHTC 
 
 
 
X 
 
 
 
X 
Activity monitoring device 
(data acquisition) 
X 
X 
X 
X 
X 
X 
X 
X 
Subject study documentation 
(transfer to IHTC) 
X 
X 
X 
X 
X 
X 
X 
X 
CBC panel w/diff 
 
X 
 
X 
 
X 
 
X 
Review of breakthrough BEs 
 
X 
 
X 
 
X 
 
X 
Review of hospitalizations 
 
X 
 
X 
 
X 
 
X 
Review of incidences of 
anemia 
 
X 
 
X 
 
X 
 
X 
Haem-A-QoL & EQ-5D-5L 
 
 
 
X 
 
 
 
X 
CT and/or MRI 
 
 
 
X 
 
 
 
X 
ADA Hemlibra (emicizumab) 
 
 
 
X 
 
 
 
X 
Hemlibra (emicizumab) 
dispensation* 
 
 
 
X 
 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
 
 
X 
 
 
 
X 
Review of patient diary 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of used/empty vials 
 
 
 
X 
 
 
 
X 
 
 
                                                 
* Hemlibra (emicizumab) will be dispensed and shipped to the subject at various times of the year to ensure the subject has a continuous supply 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written permission from Genentech. 
 
 
Page 98 
 
Month 27* 
Month 30* 
Month 33* 
Month 36* 
Month 39* 
Month 42* 
Month 45* 
Visit Window: 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
±2 weeks 
Visit @ local provider 
X 
X 
X 
 
X 
X 
X 
Visit @ IHTC 
 
 
 
X 
 
 
 
Activity monitoring device (data 
acquisition) 
X 
X 
X 
X 
X 
X 
X 
Subject study documentation 
(transfer to IHTC) 
X 
X 
X 
X 
X 
X 
X 
CBC panel w/diff 
 
X 
 
X 
 
X 
 
Review of breakthrough BEs 
 
X 
 
X 
 
X 
 
Review of hospitalizations 
 
X 
 
X 
 
X 
 
Review of incidences of anemia 
 
X 
 
X 
 
X 
 
Haem-A-QoL & EQ-5D-5L 
 
 
 
X 
 
 
 
CT and/or MRI 
 
 
 
X 
 
 
 
ADA Hemlibra (emicizumab) 
 
 
 
X 
 
 
 
Hemlibra (emicizumab) 
dispensation† 
 
 
 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Review of AEs 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
 
 
X 
 
 
 
Review of patient diary 
X 
X 
X 
X 
X 
X 
X 
Collection of used/empty vials 
 
 
 
X 
 
 
 
 
 
 
                                                 
* Depending on when a subject enrolls and when the study ends, the subject might not participate in all study visits beyond month 24. Although the study is 48 
months, a month 48 visit is not specified in the protocol as the study close-out visit will occur at approximately the same time and will comprise largely the same 
labs and procedures 
† Hemlibra (emicizumab) will be dispensed and shipped to the subject at various times of the year to ensure the subject has a continuous supply 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written permission from Genentech. 
 
 
Page 99 
 
Study close-out visit* 
Visit @ local provider† 
 
Visit @ IHTC 
X 
Activity monitoring device (data acquisition) 
X 
Subject study documentation (transfer to IHTC) 
X 
CBC panel w/diff 
X 
Review of breakthrough BEs 
X 
Review of hospitalizations 
X 
Review of incidences of anemia 
X 
Haem-A-QoL & EQ-5D-5L 
X 
CT and/or MRI 
X 
ADA Hemlibra (emicizumab) 
X 
Hemlibra (emicizumab) collection‡ 
X 
Concomitant medications 
X 
 
 
 
 
 
 
 
Review of AEs 
X 
Vital signs 
X 
Weight 
X 
Physical examination 
X 
Review of patient diary 
X 
 
 
 
                                                 
* Depending on the date of the most recent annual visit, the Study Investigator may decide that not all specified items are necessary at the close-out visit 
† Following the close-out visit, the subject will be requested to meet with their local hemophilia physician to determine ongoing care 
‡ Unused vials and empty vials of Hemlibra (emicizumab) will be returned to the IHTC 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 100 
13 REFERENCE LIST  
 
Ahlberg, A. K. (1975) On the natural history of hemophilic pseudotumor. J Bone Joint Surg Am 
57:1133-1136. 
Blanchette, V. S., N. S. Key, L. R. Ljung, M. J. Manco-Johnson, H. M. van den Berg, A. 
Srivastava, F. I. X. Subcommittee on Factor Viii, S. Rare Coagulation Disorders of the, T. 
Standardization Committee of the International Society on and Hemostasis (2014) Definitions in 
hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 12:1935-1939. 
Centers for Disease Control and Prevention (2014). Hemophilia Data & Statistics   Retrieved 
April 22, 2014, from http://www.cdc.gov/ncbddd/hemophilia/data.html 
Franchini, M. and P. Mannucci (2013) Hemophilia A in the third millennium. Blood Rev:179-
184. 
Gringeri, A., C. Leissinger, P. Cortesi, H. Jo, F. Fusco, S. Riva, B. Antmen, E. Berntorp, C. 
Biasoli and S. Carpenter (2013) Health‐related quality of life in patients with haemophilia and 
inhibitors on prophylaxis with anti‐inhibitor complex concentrate: results from the Pro‐FEIBA 
study. Haemophilia 19:736-743. 
Liu, S. S., W. L. White, P. C. Johnson and C. Gauntt (1988) Hemophilic pseudotumor of the 
spinal canal. Case report. J Neurosurg 69:624-627. 
Magallon, M., J. Monteagudo, C. Altisent, A. Ibanez, A. Rodriguez-Perez, J. Riba, J. Tusell and 
J. Martin-Villar (1994) Hemophilic pseudotumor: multicenter experience over a 25-year period. 
Am J Hematol 45:103-108. 
National Institutes of Health (2014). What Is Hemophilia? Retrieved April 22, 2014, from 
https://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/ 
Srivastava, A., A. K. Brewer, E. P. Mauser-Bunschoten, N. S. Key, S. Kitchen, A. Llinas, C. A. 
Ludlam, J. N. Mahlangu, K. Mulder, M. C. Poon, A. Street and H. Treatment Guidelines 
Working Group on Behalf of The World Federation Of (2013) Guidelines for the management of 
hemophilia. Haemophilia 19:e1-47. 
van Ommeren, J. W., D. W. Mooren, R. P. Veth, I. R. Novakova and C. A. van de Kaa (2000) 
Pseudotumor occurring in hemophilia. Arch Orthop Trauma Surg 120:476-478. 
World Federation of Hemophilia (2012). Guidelines for the management of hemophilia   
Retrieved February 16, 2015, from http://www1.wfh.org/publication/files/pdf-1472.pdf 


Prospective, single-arm, open-label use of Hemlibra (emicizumab) to treat hemophilic pseudotumor (RO-IIS-2018-10581) 
The Indiana Hemophilia & Thrombosis Center (IHTC) 
 
APPROVED FOR USE. Protocol Version: 3.0 
 
CONFIDENTIAL. None of the information supplied in this document may be disclosed to the public without prior written 
permission from Genentech. 
 
 
Page 101 
World Federation of Hemophilia (2012). World Federation of Hemophilia report on the annual 
global survey 2011   Retrieved December 20, 2016, from 
http://www1.wfh.org/publication/files/pdf-1488.pdf 
World Federation of Hemophilia (2013). World Federation of Hemophilia report on the annual 
global survey 2013   Retrieved February 5, 2015, from 
http://www1.wfh.org/publications/files/pdf-1591.pdf 
World Federation of Hemophilia (2016). World Federation of Hemophilia report on the annual 
global survey 2015   Retrieved December 20, 2016, from 
http://www1.wfh.org/publication/files/pdf-1669.pdf.