A Phase III Study on the Safety, Pharmacokinetics, and Efficacy of Coagulation Factor VIIa (Recombinant) in Congenital Hemophilia A or B Pediatric Patients From Birth to <12 Years Old With Inhibitors to Factor VIII or IX: PerSept 2
Phase: PHASE3
Conditions: Hemophilia A With Inhibitors, Hemophilia B With Inhibitors
Sponsor: Laboratoire français de Fractionnement et de Biotechnologies

Official Title:  A Phase III Study on the Safety, Pharmacokinetics, and Efficacy of Coagulation Factor VIIa 
(Recombinant) in Congenital Hemophilia A or B Pediatric Patients from birth to <12 years old with 
Inhibitors to Factor VIII or IX: PerSept 2 
 
NCT Number:  NCT02448680 
 
Document: Protocol Amendment 4 
 
Date of the Document:  29 June 2016 

 
 
Clinical Trial Protocol: LFB-FVIIa-007-14 
Study Title: 
A Phase III Study on the Safety, Pharmacokinetics, and Efficacy of 
Coagulation Factor VIIa (Recombinant) in Congenital Hemophilia A or 
B Pediatric Patients from birth to <12 years old with Inhibitors to 
Factor VIII or IX: PerSept 2 
Study Number: 
LFB-FVIIa-007-14 
Study Phase: 
Phase 3 
Product Name: 
Coagulation Factor VIIa (Recombinant), LR769 
EudraCT #: 
2015-000958-38 
IND #: 
15183 
Indication: 
LR769 is intended to be used for the treatment of bleeding episodes 
and for the prevention of bleeding in those undergoing surgery or 
invasive procedures in patients with congenital hemophilia A or B with 
inhibitors to coagulation factors VIII (FVIII) or IX (FIX) 
Investigators: 
Multicenter, multinational study 
Principal 
Investigator: 
 
 
 
Sponsor: 
LFB USA Inc. 
Sponsor Contact: 
 
Sr. Director Clinical Operations 
 
 
Sponsor’s Legal 
Representative: 
 
Sr. Vice President Regulatory Affairs and Pharmacovigilance 
 
 
 
Medical Monitor: 
 
Vice President Clinical Development 
 
 
Original Protocol: 
30 April 2015 
Amendment 1 
04 August 2015 
 
Amendment 2 
26 August 2015 
Amendment 3 
09 October 2015 
Amendment 4 
29 June 2016 
Confidentiality Statement 
Part or all of the information in this protocol may be unpublished material.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.  

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
1 
INTRODUCTION ...........................................................................................................21 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objectives.................................................................................................24 
2.2 
Secondary Objective ..............................................................................................24 
2.3 
Other Objective ......................................................................................................24 
3 
INVESTIGATIONAL PLAN ..........................................................................................25 
3.1 
Overall Study Design and Plan ..............................................................................25 
3.1.1 
Phase A (Initial Safety and PK Phase) .........................................................27 
3.1.2 
Phase B (Treatment Phase) ..........................................................................27 
3.1.2.1 
Classification of Severity of Bleeding Episodes ................................27 
3.1.2.2 
Treatment of Mild/Moderate Bleeding Episodes ...............................28 
3.1.2.3 
Treatment of Severe Bleeding Episodes ............................................29 
3.1.2.4 
Rescue Treatment...............................................................................30 
3.1.2.5 
Prevention of Bleeding for Surgical Procedures ................................30 
3.1.3 
Follow-Up Visits ..........................................................................................31 
3.2 
Rationale for Study Design and Control Group .....................................................31 
3.3 
Study Duration and Dates ......................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................33 
4.1 
Study Population ....................................................................................................33 
4.2 
Inclusion Criteria ...................................................................................................33 
4.3 
Exclusion Criteria ..................................................................................................33 
5 
STUDY TREATMENT(S) ..............................................................................................35 
5.1 
Description of Treatment(s) ...................................................................................35 
5.1.1 
Study Drug ...................................................................................................35 
5.1.2 
Placebo .........................................................................................................35 
5.2 
Treatments Administered .......................................................................................35 
5.2.1 
Phase A (Initial Safety and PK Phase) .........................................................35 
5.2.2 
Phase B (Treatment Phase) ..........................................................................35 
5.3 
Selection and Timing of Dose for Each Patient .....................................................35 
5.4 
Method of Assigning Patients to Treatment Groups..............................................36 
5.5 
Blinding..................................................................................................................36 
5.6 
Concomitant Therapy.............................................................................................36 
5.7 
Restrictions ............................................................................................................36 
5.7.1 
Prior Therapy ...............................................................................................36 

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5.7.2 
Fluid and Food Intake ..................................................................................37 
5.7.3 
Patient Activity Restrictions ........................................................................37 
5.8 
Treatment Compliance ...........................................................................................37 
5.9 
Packaging and Labeling .........................................................................................37 
5.10 
Storage and Accountability ....................................................................................37 
5.11 
Investigational Product Retention at Study Site ....................................................37 
6 
STUDY PROCEDURES .................................................................................................39 
6.1 
Informed Consent...................................................................................................39 
6.2 
Medical History .....................................................................................................39 
6.3 
Physical Examination.............................................................................................40 
6.4 
Vital Signs ..............................................................................................................40 
6.5 
Clinical Laboratory Tests .......................................................................................40 
6.5.1 
Laboratory Parameters .................................................................................41 
6.5.1.1 
Safety Laboratory Tests .....................................................................41 
6.5.1.2 
Coagulation Tests...............................................................................42 
6.5.1.3 
Drug Concentration Tests ..................................................................42 
6.5.1.4 
Immunogenicity Testing ....................................................................42 
6.5.1.5 
Sample Storage ..................................................................................42 
6.5.2 
Sample Collection, Storage, and Shipping ..................................................42 
6.6 
Dispensing Study Drug ..........................................................................................42 
6.7 
Pharmacokinetic Assessments ...............................................................................43 
6.8 
Efficacy Assessments.............................................................................................43 
6.8.1 
Efficacy Endpoint: .......................................................................................45 
6.9 
Adverse Events Assessments .................................................................................46 
6.9.1 
Performing Adverse Events Assessments ....................................................46 
6.9.2 
Timing ..........................................................................................................47 
6.9.3 
Severity ........................................................................................................47 
6.9.4 
Relationship .................................................................................................48 
6.9.5 
Expectedness ................................................................................................48 
6.9.6 
Clinical Significance ....................................................................................48 
6.9.7 
Clinical Laboratory Adverse Events ............................................................48 
6.9.8 
Serious Adverse Events ...............................................................................49 
6.9.8.1 
Definition ...........................................................................................49 
6.9.8.2 
Reporting Serious Adverse Events ....................................................49 
6.9.9 
Treatment-Emergent Adverse Events ..........................................................50 
6.10 
Concomitant Medication Assessments ..................................................................51 
6.11 
Study Stopping Rules .............................................................................................51 
6.12 
Removal of Patients from the Trial or Study Drug ................................................52 
6.13 
Replacement of Patients .........................................................................................52 

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6.14 
Other Study Procedures .........................................................................................52 
6.15 
Appropriateness of Measurements .........................................................................52 
7 
STUDY ACTIVITIES .....................................................................................................53 
7.1 
Phase A: Initial Safety and PK Phase ....................................................................53 
7.1.1 
Screening (Days -21 to -1) ...........................................................................53 
7.1.2 
Visit 1 (Day 0) Procedures ...........................................................................53 
7.1.2.1 
Predose ...............................................................................................53 
7.1.2.2 
Drug Administration (0 min) .............................................................53 
7.1.2.3 
10±2 min after start of infusion .........................................................54 
7.1.2.4 
30±5 min after start of infusion .........................................................54 
7.1.2.5 
1 hour ±10 minutes after start of infusion ..........................................54 
7.1.2.6 
2 hours ±10 minutes after start of infusion ........................................54 
7.1.2.7 
4 hours ±10 minutes after start of infusion ........................................54 
7.1.2.8 
8 hours ±10 minutes after start of infusion ........................................54 
7.2 
Phase B: Treatment of a Bleeding Episode ............................................................54 
7.2.1 
Mild/Moderate Bleeding Episode Procedures .............................................55 
7.2.1.1 
Pre treatment ......................................................................................55 
7.2.1.2 
Treatment (Time 0 hrs) ......................................................................55 
7.2.1.3 
3, 6, 9, 12, 15, 18, 21 hours after first administration ........................55 
7.2.2 
Severe Bleeding Episode Procedures ...........................................................56 
7.2.2.1 
Pre Treatment .....................................................................................56 
7.2.2.2 
Treatment (Time 0 hrs) ......................................................................57 
7.2.2.3 
After first administration until improvement of the bleeding 
episode ...............................................................................................57 
7.2.2.4 
During Continued Treatment .............................................................58 
7.2.3 
Rescue Treatment.........................................................................................58 
7.3 
Procedures at Follow-Up Visits in Phase B ...........................................................59 
7.3.1 3 Weeks (±2 days) visit ..........................................................................................59 
7.3.2 6 Weeks (±5 days) visit ..........................................................................................59 
7.3.3 12 Weeks (±5 days) visit ........................................................................................60 
7.3.4 18 Weeks (±5 days) visit ........................................................................................60 
7.3.5 24 Weeks (±5 days) visit ........................................................................................60 
7.3.6 All Subsequent Visits 6 and 12 Weeks after Week 24 visit ..................................61 
7.3.6.1 6 Weekly (±5 days) ................................................................................................61 
7.3.6.2 12 Weekly (±5 days) ..............................................................................................61 
7.3.7 End of Study Visit/Early Termination Procedures ................................................61 
8 
QUALITY CONTROL AND ASSURANCE .................................................................63 
9 
PLANNED STATISTICAL METHODS ........................................................................64 
9.1 
General Considerations ..........................................................................................64 
9.2 
Determination of Sample Size ...............................................................................64 
9.3 
Analysis Populations ..............................................................................................64 

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9.4 
Demographics and Baseline Characteristics ..........................................................65 
9.5 
Primary Endpoint ...................................................................................................65 
9.5.1 
Primary Efficacy Endpoint ..........................................................................65 
9.6 
Secondary Endpoints .............................................................................................66 
9.7 
Tertiary Efficacy Endpoints ...................................................................................67 
9.8 
Safety Analyses ......................................................................................................68 
9.9 
Pharmacokinetic Analyses .....................................................................................68 
9.10 
Other Analyses .......................................................................................................69 
9.11 
Interim Analysis .....................................................................................................69 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................70 
10.1 
Investigators and Study Administrative Structure .................................................70 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................70 
10.3 
Ethical Conduct of the Study .................................................................................70 
10.4 
Patient Information and Consent ...........................................................................71 
10.5 
Patient Confidentiality ...........................................................................................71 
10.6 
Study Monitoring ...................................................................................................71 
10.7 
Case Report Forms and Study Records .................................................................72 
10.8 
Data Monitoring Committee ..................................................................................72 
10.9 
Protocol Deviations ................................................................................................72 
10.10 Criteria for Terminating Study ...............................................................................73 
10.11 Criteria for Suspending/Terminating a Study Center ............................................73 
10.12 Access to Source Documentation ..........................................................................73 
10.13 Data Generation and Analysis ...............................................................................73 
10.14 Retention of Data ...................................................................................................74 
10.15 Financial Disclosure...............................................................................................74 
10.16 Publication and Disclosure Policy .........................................................................74 
11 REFERENCE LIST .........................................................................................................75 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Classification of severity of bleeding episodes ............................................28 
Table 2. 
Total Amounts of Blood Taken During the Study .......................................40 
Table 3. 
List of Laboratory Tests ...............................................................................41 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design Flowchart ...............................................................................26 
 

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LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................77 
Appendix 2 
Sponsor Signatures.............................................................................81 
 
 

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SYNOPSIS 
Sponsor: 
LFB USA Inc. 
Name of Finished Product: 
Coagulation Factor VIIa (Recombinant), LR769  
Name of Active Ingredient: 
Coagulation Factor VIIa (Recombinant), LR769 
Study Title: 
A Phase III Study on the Safety, Pharmacokinetics, and Efficacy of Coagulation Factor VIIa 
(Recombinant) in Congenital Hemophilia A or B Pediatric Patients from birth to <12 years 
old with Inhibitors to Factor VIII or IX: PerSept 2  
Study Number: 
LFB-FVIIa-007-14 
Study Phase: Phase 3 
Primary Objective(s):  
 To assess the efficacy of 2 separate dose regimens (75 µg/kg and 225 µg/kg) of LR769 
for the treatment of bleeding episodes in hemophilia A or B pediatric patients, from birth 
to <12 years old, with inhibitors to factor VIII or IX 
 To assess the safety of LR769, including the immunogenic potential of the drug product 
 
Secondary Objective: 
• To assess the pharmacokinetics (PK) of LR769 in hemophilia A or B pediatric patients, 
from birth to <12 years old, with inhibitors to factor VIII or IX, without a current 
bleeding episode 
  
Other Objective: 
• To assess the healthcare resource utilization of hemophilia A or B pediatric patients, from 
birth to <12 years old, with inhibitors treated with LR769 
 
Study Design: 
This is a global, multicenter, Phase III, Prospective, Open-Label, Randomized, Crossover 
Study.  
After obtaining informed consent and performance of screening procedures, patients from 
birth to <12 years old who meet all inclusion and exclusion criteria will be randomized to 
start with one of two treatment regimens: 
1. 75 µg/kg treatment regimen 
2. 225 µg/kg treatment regimen 
 
The assigned treatment regimen is the dose administered for initial assessment of safety and 
PK in Phase A and the starting dose in the treatment phase, Phase B. In addition, the 

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sampling regimen (sampling schedule 1: at 10±2 minutes and 1 and 4 hours (±10 minutes), 
and sampling schedule 2: at 30±5 minutes and 2 and 8 hours (±10 minutes) relative to the 
start of infusion of study drug) for the PK sampling is assigned. The study consists of two 
phases. 
Phase A (Initial safety and PK phase): Depending on the treatment regimen to which 
patients are randomized, they will receive a single intravenous (IV) administration of either 
75 µg/kg or 225 µg/kg of LR769 as a bolus injection administered in ≤2 minutes in a hospital 
setting or hemophilia treatment center. Patients must not be experiencing an active bleeding 
episode at that time and may not have received treatment with any factor VII(a) [FVII(a)] 
product within 24 hours prior to this administration. This administration is for the assessment 
of the safety of LR769. The patient will remain in the hospital or hemophilia treatment center 
and will be observed for any potential acute adverse event (AE) for at least 2 hours after 
dosing.  
Pharmacokinetics: 
During Phase A, approximately 12 patients from birth to <6 years old and 12 patients ≥6 
years old to <12 years old, not currently experiencing a bleeding episode will, in addition to 
the safety assessments, have blood samples drawn for PK analysis during the initial 
administration of study drug. This is expected to result in at least 10 evaluable patients in 
each age group. PK sampling will be done according to the International Society of 
Thrombosis and Haemostasis (ISTH) guidance on PK studies (Lee et al., 2001). Samples will 
be taken pre-dose in all patients. To reduce the number of blood draws, subsequent sampling 
will be done in approximately half of the patients (sampling schedule 1) at 10±2 minutes 
followed by 1 and 4 hours (±10 minutes); the other half (sampling schedule 2) will be done at 
30±5 minutes followed by 2 and 8 hours (±10 minutes) relative to the start of infusion of 
study drug. 
Phase B (treatment phase): Patients who complete Phase A without any safety concerns will 
begin Phase B on a treatment schedule that consists of 12-week periods of treatment with the 
dose to which they were randomized. Depending on randomization, the treatment phase will 
begin with either 75 µg/kg or 225 µg/kg and each patient will subsequently “cross over” to 
the alternate treatment regimen every 12 weeks until the end of study (EOS). From 24 hours 
after the administration of LR769 in Phase A, patients are eligible to be treated with LR769 
in the event of a bleeding episode.  
Treatment of Mild/Moderate Bleeding Episodes: 
Treatment of a mild/moderate bleeding episode will be initiated as soon as possible, but 
certainly within 4 hours of first symptoms of the onset of the bleeding episode. Treatment 
will consist of IV administration of either 75 µg/kg or 225 µg/kg (depending on 
randomization) of LR769 as a bolus injection administered in ≤2 minutes.  
During the 75 µg/kg treatment regimen, the initial 75 µg/kg dose may be followed 3 hours 
± 15 minutes later with 75 µg/kg every 3 hours ± 15 minutes  until the bleed is successfully 
treated. A maximum of 8 administrations in total over a 21-hour period are allowed in this 

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Study Population:  
Enrollment will continue until approximately 24 patients (12 patients from birth to <6 years 
old, and 12 patients ≥6 years old to <12 years old) have passed all screening procedures in 
the study and begun treatment. Patients in these age categories with congenital hemophilia A 
or B complicated by high-responding inhibitors (peak Bethesda Units [BU] ≥5) or lower-titer 
inhibitor refractory to increased dosing with factor concentrates may be enrolled. All grades 
of severity of hemophilia are allowed, as long as they have regular bleeding episodes and 
inhibitors, as evidenced by a BU ≥5. Some patients may have lower detectable levels of 
inhibitors in the Bethesda assay, i.e., BU<5 but still cannot be treated with factor VIII or IX 
concentrates since they are known to have a strong memory (anamnestic) response after re-
exposure to factor concentrates or, despite low titers of inhibitors, are still refractory to 
increased dosing with factor concentrates. These patients can therefore not be treated with 
these concentrates and may be included in this study. Only patients with at least 3 bleeding 
episodes of any severity in the 6 months prior to entry in the study will be enrolled; and 
patients <6 months of age with at least 3 bleeding episodes since birth will be enrolled.  
Patients receiving immune tolerance induction (ITI) therapy are allowed to be treated in the 
study as well if they have breakthrough bleeding episodes at a rate of at least 3 bleeding 
episodes in any severity within the last 6 months; if < 6 months old; at least 3 bleeding 
episodes in any severity since birth. 
The study will continue until at least 352 mild/moderate bleeding episodes have been treated 
and at least 6 months have passed since first administration of LR769 in at least 22 patients 
(approximately 11 from each age group).  
Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria 
To be eligible for enrollment into this study, patients must: 
1. be male with a diagnosis of congenital hemophilia A or B of any severity 
2. have one of the following: 
a. a positive inhibitor test BU ≥5, OR  
b. a BU <5 but expected to have a high anamnestic response to FVIII or FIX, as 
demonstrated from the patient’s medical history, precluding the use of factor 
VIII or IX products to treat bleeding episodes, OR 
c. a BU <5 but expected to be refractory to increased dosing of FVIII or FIX, as 
demonstrated from the patient’s medical history, precluding the use of factor 
VIII or IX products to treat bleeding episodes 
3. be aged from birth to <12 years old 
4. have experienced at least 3 bleeding episodes of any severity in the past 6 months; if 
< 6 months old, have experienced at least 3 bleeding episodes since birth 
5. parents or legal guardians must be capable of understanding and be willing to comply 
with the conditions of the protocol 
6. parents or legal guardians must have read, understood, and provided written informed 
consent 

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Exclusion Criteria 
Patients will be excluded from participation in the study if any of the following criteria 
apply: 
1. have any coagulation disorder other than hemophilia A or B 
2. be immunosuppressed (i.e., the patient may not be receiving systemic 
immunosuppressive medication; CD4 counts at screening must be >200/µL) 
3. have a known allergy or hypersensitivity to rabbits  
4. have platelet count <100,000/µL 
5. have had a major surgical procedure (e.g. orthopedic, abdominal) within 1 month 
prior to first administration of study drug  
6. have received an investigational drug within 30 days of first study drug 
administration, or be expected to receive such drug during participation in this study 
7. have a clinically relevant hepatic (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT] >3 times the upper limit of normal [ULN]) and/or renal 
impairment (creatinine >2 times the ULN) 
8. have an active malignancy (those with non-melanoma skin cancer are allowed) 
9. have any life-threatening disease or other disease or condition which, in the 
investigator’s judgment, could pose a potential hazard to the patient or interfere with 
the trial participation or trial outcome (e.g., a history of non-responsiveness to 
bypassing products or thromboembolic disease) 
10. known or suspected hypersensitivity to the active substance or to any of its excipients 
 
Test Product, Dose, and Mode of Administration:  
Coagulation Factor VIIa (Recombinant), LR769. 
LR769 will be administered IV at a dose of either 75 µg/kg or 225 µg/kg as a crossover 
treatment every 12 weeks, as multiple bolus doses, each administered in ≤2 minutes to treat 
mild/moderate bleeding episodes and severe bleeding episodes. 
Reference Therapy; Dose; and Mode of Administration: 
No reference therapy will be used. 
Duration of Treatment:  
In Phase A, patients will receive a single administration of study drug in a non-bleeding state. 
Patients are eligible for treatment of a bleeding episode 24 hours after the initial 
administration of LR769 in Phase A. Treatment for such bleeding episodes will continue 
until satisfactory resolution of the bleeding episode has occurred, but with a last 
administration of study drug no later than 21 hours after first treatment (with an efficacy 
assessment at 24 hours after initiation of treatment). Severe bleeding episodes may need to be 
treated for several days until the investigator determines the bleeding has stopped and the risk 
of recurrence of the bleeding is minimal. 
Patients will be followed initially at 3 weeks ±2 days, and 6 weeks ±5 days following the first 

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administration in Phase A and subsequently every 6 weeks ± 5 days. Patients may be treated 
for multiple bleeding episodes during the course of the study. All patients will be followed 
for at least 6 months after the first LR769 administration, or, in case the study ends, for 14 
days (±2 days) after the last administration of study drug. 
The study will continue until at least 352 mild/moderate bleeding episodes have been treated 
and at least 6 months have passed since first administration of LR769 in at least 22 patients 
(approximately 11 from each age group).  
The overall duration of the study is approximately 16 months from First Patient First Visit 
until Last Patient Last Visit. The enrollment period is expected to last approximately 9 
months.  
The duration of an individual patient’s participation in this part of the study (from signing the 
informed consent form until the last study visit in Phase B) may vary from approximately 7 
months to approximately16 months depending on when the patient is enrolled, unless 
discontinued prematurely. 
Pharmacokinetic Variables: 
PK blood draws will occur for all patients while receiving treatment in Phase A in a non-
bleeding state. FVIIa concentrations will be determined using a validated modified activity 
assay (Staclot® VIIa-rTF, Diagnostica Stago)  at Good Biomarker Sciences (Leiden, The 
Netherlands). 
PK data analysis will be performed using non-linear mixed effects modeling. The following 
parameters will be determined: clearance (Cl); volume of distribution (Vd); terminal half-life 
(t1/2); area under the plasma concentration--time curve from time 0 to infinity (AUC0-∞); and 
maximum plasma concentration (Cmax). 
Efficacy Assessments: 
Efficacy of the treatment of each bleeding episode will be assessed by the patient/parent 
(“parent” includes guardian and/or caregiver in the context of this protocol, with the 
understanding that “patient” participation depends on the patient’s age and maturity). 
Efficacy categories (see Section 6.8) will be reviewed with the patient/parent at the first 
study visit. In case of treatment in the hospital, the physician will also assess the efficacy. 
Response to treatment will be rated as “none,” “moderate,” “good,” or “excellent.” None or 
moderate are usually followed by continued treatment with the study drug, good or excellent 
means that no further treatment is needed or, in case of a severe bleeding episode, the dosing 
interval can be increased. Additionally, the patient diary contains a Visual Analogue Scale 
(VAS) to rate the pain experienced by the patient will be completed by the same assessors as 
described above, to evaluate the response to treatment on pain.  
Efficacy assessment of LR769 to treat a mild/moderate bleeding episode will occur within 15 
minutes prior to each administration of study drug.  
 Mandatory efficacy assessment timepoints for 75 µg/kg – 3, 12, and 24 hours after 

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initial dose.  
 Mandatory efficacy assessment timpoints for 225 µg/kg – 9, 12, and 24  hours after 
initial dose. 
If additional adminstrations are needed after the initial injection then assessements are to be 
completed within 15 minutes prior to each subsequent injection. 
Efficacy assessment of  LR769 to treat severe bleeding episodes will be assessed within 15 
minutes prior to each administration of study drug. 
 Mandatory efficacy assessment timepoints for 75 µg/kg – 2, 12, and 24 hours after 
initial dose.  
 Mandatory efficacy assessment timpoints for 225 µg/kg – 6, 12, and 24  hours after 
initial dose. 
If additional adminstrations are needed after the initial injection then assessements are to be 
completed within 15 minutes prior to each subsequent injection.  
The timepoint for the primary evaluation of efficacy will be 12 hours after first 
administration of study drug.  
Efficacy Endpoint:  
The primary efficacy endpoint for this study is defined as successful treatment of a bleeding 
episode at 12 hours after first administration of the study drug.  The following are 
clarification definitions to satisfy regulatory requirements in multiple regions (i.e., the FDA 
and the EMA). 
Definition of  the primary efficacy endpoint for the FDA: the successful treatment of a 
bleeding episode at 12 hours after first administration of the study drug. For primary efficacy 
endpoint for the FDA, only treatment of mild/moderate bleeding episodes is taken into 
account. Severe bleeding episodes will be a minority of the bleeding episodes treated in the 
study, and will require treatment even if the bleeding has improved. Efficacy in severe 
bleeding episodes will be described separately. For primary efficacy endpoint for the FDA, 
successful treatment of a bleeding episode is defined as a combination of the following:  
• Good or Excellent response noted by patient/parent/guardian,depending on patient’s age 
and maturity 
• Study drug treatment: No further treatment with study drug beyond timepoint where a 
Good or Excellent response for this bleeding episode was noted 
• No other hemostatic treatment needed for this bleeding episode 
• No administration of blood products indicating continuation of bleeding beyond 
timepoint where a Good or Excellent response for this bleeding episode was noted 
• No increase of pain beyond timepoint where a Good or Excellent response for this 

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bleeding episode was noted that cannot  be explained other than as continuation of 
bleeding   
 
Definition of the primary efficacy endpoint for EMA:  the proportion of bleeding episodes 
(mild/moderate and severe combined) with a “good” or “excellent” patient (for 
mild/moderate bleeding episodes) and physician (for severe bleeding episodes) reported 
assessment of efficacy at 12 hours after the first administration of study drug. 
Secondary efficacy endpoints include: 
• Proportion of mild/moderate bleeding episodes successfully treated, according to the 
same criteria as the primary endpoint of efficacy, at all other timepoints  
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” patient (and/or physician when available) reported 
assessment of the efficacy at all timepoints 
• Time to assessment of a “good” or “excellent” response of the bleeding episodes 
(mild/moderate and severe, separately and combined) by the patient/parent (and/or 
physician when available) 
• The number of administrations and total amount of drug administered per bleeding 
episode 
 
Tertiary efficacy endpoints include: 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” physician-reported assessment of the efficacy at 12 hours (if 
available) 
• Proportion of recurrences (defined as a bleeding episode in the same joint/anatomical 
location within 24 hours after an initial successful response) 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
requiring alternative treatment 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with successful pain relief 
 
All assessments described as done by the patient may be done by the parent depending on the 
age of the patient. 
Where applicable, analyses will be done for all patients and by age group (from birth to 
<6 years and ≥6 years to <12 years). 
Safety Assessments: 
Safety assessments on all patients will include physical examination, vital signs, clinical 
laboratory tests (serum chemistry, hematology/coagulation), immunology tests (including 
storage for potential future use). Safety assessments will be done at screening, at clinic visits 
3 weeks (±2 days), and subsequently every 6 weeks (±5 days) following first administration 

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of study drug in this study in Phase A. Monitoring of AEs will occur continuously throughout 
the entire study.  
Other Assessments: 
As part of the healthcare resource utilization, data will be collected on use of product, 
number of visits to hospital, days of inpatient hospitalization, use of concomitant medication, 
and days away from school or work (if applicable) for patient/parent, due to bleeding. 
Statistical Methods:  
All data collected in this study will be documented using summary tables and patient 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.  
Analysis Populations: 
The Enrolled Population will be defined as all patients who signed informed consent. 
Analyses of non-treatment emergent AEs (non TEAEs) will be done on the Enrolled 
Population. 
The Safety Population will be defined as all patients who received treatment (either in Phase 
A and/or Phase B). All analyses of safety will be performed based on the Safety Population. 
The Treated Population will be defined as all patients who received treatment for at least one 
bleeding episode, and each such bleeding episode will be analyzed as treated. All analyses of 
efficacy will be performed based on the Treated Population. 
Pharmacokinetic analyses will be performed on the Evaluable PK Population, defined as all 
treated patients who have a post-injection  Factor VIIa activity measurement. 
Sample Size Determination:  
The proportion ( pˆ ) of mild/moderate bleeding episodes treated with each dose of LR769 that 
are classified as being successfully treated will be compared with an objective performance 
criterion (OPC) of 0.55. A one-sided, one-sample normal approximation test, with an alpha = 
0.0125 (adjusted from 0.025 to 0.0125 to account for multiplicity of testing), will be used to 
test the null hypothesis that p≤0.55 versus the alternative hypothesis that p>0.55, where p is 
the true proportion of mild/moderate bleeding episodes that are classified as successes. This 
will be done for each treatment regimen. 
With a true proportion of success of 0.70, a correlation among bleeding episodes for a given 
patient of 0.1, and an OPC of 0.55, a sample size of 22 patients with a total of 352 
mild/moderate bleeding episodes (assuming 8 bleeding episodes per treatment regimen per 
patient) will provide statistical power ≥80%. The study will enroll at least 24 patients, to 
account for dropouts and potential unevaluable bleeding episodes. 
Efficacy Evaluation: 
The primary efficacy endpoint for this study is defined as successful treatment of a bleeding 

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episode at 12 hours after first administration of the study drug.  The following are 
clarification definitions to satisfy regulatory requirements for the FDA and the EMA. 
The definition of the primary endpoint for the FDA was established to satisfy the design 
requirements of the United States Food and Drug Administration (US FDA). For the primary 
efficacy endpoint for the FDA, only mild/moderate bleeding episodes are considered. The 
primary efficacy endpoint for the FDA is defined as successful treatment of a mild/moderate 
bleeding episode by 12 hours from initiation of treatment defined as meeting all of the 
following criteria:  
• Good or Excellent response noted by patient/parent/guardian,depending on patient’s age 
and maturity 
• Study drug treatment: No further treatment with study drug beyond timepoint where a 
Good or Excellent response for this bleeding episode was noted 
• No other hemostatic treatment needed for this bleeding episode 
• No administration of blood products indicating continuation of bleeding beyond 
timepoint where a Good or Excellent response for this bleeding episode was noted 
• No increase of pain beyond timepoint where a Good or Excellent response for this 
bleeding episode was noted that cannot  be explained other than as continuation of 
bleeding   
 
For each LR769 treatment, the proportion ( pˆ ) of mild/moderate bleeding episodes rated as 
successfully treated at 12 hours will be summarized using the count and percentage. A 95% 
normal approximation CI for the true percentage will be calculated taking into account the 
correlation between bleeding episodes for a given patient in calculating the standard error of 
the estimate pˆ .  
The null and alternative hypotheses for the primary efficacy endpoint are as follows: 
        H0: p≤0.55 
        H1: p>0.55 
The null hypothesis will be tested using a one-sided, one-sample, normal approximation test 
and a test statistic obtained by dividing ( pˆ -0.55) by its estimated standard error, taking into 
account the correlation between bleeding episodes for a given patient. The test will be 
conducted at the 0.0125 level (adjusted from 0.025 to 0.0125 to account for multiplicity of 
testing). Treatment of mild/moderate bleeding episodes in the study with LR769 of a given 
dose will be regarded as successful if it is concluded that the true percentage of successfully 
treated bleeding episodes with that dose is greater than 0.55. The primary endpoint for the 
FDA was established to satisfy the requirements of the US FDA for the evaluation of 
success. 
For primary efficacy endpoint for the EMA, the proportion of bleeding episodes 
(mild/moderate and severe combined) evaluated with a “good” or “excellent” response at 12 
hours after first administration of the study drug will be calculated. This proportion of 

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success will be evaluated by the European Medicines Agency (EMA) as part of the 
assessment of the benefit:risk ratio for each dosing regimen.  
In addition, the proportions of successfully treated mild/moderate bleeding episodes 
(according to the primary efficacy endpoint definition) will be compared between the two 
LR769 treatment dose regimens at a 2-sided alpha of 0.05. 
The time to assessment of a “good” or “excellent” response of the bleeding episodes 
(mild/moderate and severe, separately and combined) by the patient/parent will be analyzed 
at the bleeding episode level using the Kaplan-Meier (K-M) method to estimate the survival 
distribution for this endpoint for each treatment regimen separately and combined. Patients 
who receive rescue medication will be considered failures and will be assigned a censored 
value of the final timepoint. Patients who do not achieve a “good” or “excellent” response 
will be censored at the time of last response. 
For each treatment, the patient-level mean number of administrations and patient-level mean 
total amount of drug required per bleeding episode (mild/moderate and severe, separately and 
combined) will be summarized using descriptive statistics, and a 95% CI for the true mean 
(across patients) will be calculated based on normal approximation. 
Safety evaluations: 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The number and percentage of patients with any AEs, any serious AEs (SAEs), and any 
TEAEs will be presented for all patients and for the different dose regimens and for the Phase 
A and B separately. AEs will be summarized at the patient level by MedDRA system organ 
class (SOC) and preferred term (PT) using frequencies 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. 
PK evaluations: 
The Evaluable PK Population will be defined to be all treated patients who have a post- 
injection Factor VIIa activity measurement. Descriptive statistics for plasma concentrations 
at each timepoint and for PK parameters will be tabulated and plasma concentrations (FVIIa 
activity levels) over time will be graphically presented.  A separate pharmacokinetic analysis 
plan (PKAP) will be written and signed off prior to performing the analyses. 
Date of Original Approved Protocol: 30 April 2015 
Date of Amendment 1: 04 August 2015 
 
Date of Amendment 2: 26 August 2015 
Date of Amendment 3: 09 October 2015 
Date of Amendment 4: 29 June 2016 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AA 
amino acid 
AE 
adverse event 
ALB 
albumen 
ALT 
alanine aminotransferase (SGPT) 
aPCC 
activated prothrombin complex concentrate 
AST 
aspartate aminotransferase (SGOT) 
AUC0-∞ 
area-under-the-concentration-versus-time curve from time 0 to ∞ 
BU 
Bethesda units 
CI 
confidence interval 
Cl 
clearance 
Cmax 
maximum concentration achieved 
CNS 
central nervous system 
CRO 
contract research organization 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
EOS 
end of study 
DMC 
Data Monitoring Committee 
DVT 
deep vein/venous thrombosis 
EGF 
epidermal growth factor 
EMA 
European Medicines Agency 
EU 
European Union 
EudraCT 
European clinical trials database 
FDA 
Food and Drug Administration 
FEIBA 
FVIII Inhibitor Bypassing Activity 
FVII 
factor VII 
FVIIa 
factor VII activated 
FVIII 
factor VIII 
FVIIIa 
factor VIII activated 
FIX 
factor IX 
FX 
factor X 
FXa 
factor X activated 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
Hct 
hematocrit 
HEENT 
Head, Eyes, Ears, Nose, Throat 

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Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HTRS 
Hemophilia and Thrombosis Research Society 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISTH 
International Society of Thrombosis and Haemostasis 
ITI 
immune tolerance induction 
IV 
intravenous 
K-M 
Kaplan-Meier 
LDH 
lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
OPC 
Objective Performance Criterion 
PKAP 
pharmacokinetic analysis plan 
PD 
pharmacodynamics 
pd 
plasma derived 
PE 
pulmonary Embolism 
PK 
pharmacokinetics 
PT 
preferred term 
rhFVIIa 
activated recombinant human Factor VII 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SOC 
system organ class 
t1/2 
terminal half life 
tmax 
time at which maximum concentration is achieved 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
USA 
United States of America 
VAS 
visual analogue scale 
Vd 
volumes of distribution 
WBC 
white blood cell (count) 
 

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1 
INTRODUCTION 
LFB is developing an activated recombinant human factor VII ( LR769) protein produced in 
and purified from the milk of 
, selected for the production of this complex 
human glycoprotein. 
The investigational product is produced by recombinant DNA technology employing site-
directed expression of the human factor VII (FVII) gene in the mammary gland of 
 
. The transgene containing the human factor VII has been stably integrated 
into the genome of the 
. The rhFVII gene is exclusively expressed by the mammary 
gland under the control of a beta-casein specific promoter. Milk from these 
 
is collected and the FVII protein expressed is subsequently purified and activated during the 
purification process. The production of recombinant human factor VII in 
 
offers certain economic advantages over production of the protein in other genetically 
engineered cells, such as Baby Hamster Kidney and/or Chinese Hamster Ovary cells. 
Congenital Hemophilia 
Hemophilia is an inherited coagulation disorder due to deficiency of either factor VIII 
(hemophilia A) (Patek and Taylor, 1937) or IX (hemophilia B) (Biggs et al., 1952). Reported 
prevalence of hemophilia is approximately 2 in 10,000 males globally, prevalence in 
developed countries has been reported as around 1 in 10,000 males (Stonebraker et al., 2010). 
Hemophilia A is the most common form, with the prevalence of hemophilia B being one-
fifth that of hemophilia A. Virtually only males are affected with the congenital form of 
hemophilia as both the FVIII and FIX genes are located on the X chromosome.  
Severe hemophilia can cause serious bleeding problems in babies. Therefore, children who 
have severe hemophilia are usually diagnosed early in life. People who have milder forms of 
hemophilia may not be diagnosed until they are adults.  
Treatment of Hemophilia A and B patients is usually with anti-hemophilic factor products 
that replace the deficient factor. However, the development of inhibiting antibodies to factors 
VIII and IX is an ongoing concern. Individuals with severe Hemophilia A develop inhibitors 
more often (20 to 30%) than those with Hemophilia B (<5%) (Astermark, 2006), though the 
reasons why are unclear. People who have more severe hemophilia, have a family history of 
inhibitors, patients with certain genetic mutations, and minorities with hemophilia are at a 
higher risk of developing inhibitors. In patients who have developed inhibitors these may 
disappear again over time. This is due to the spontaneous disappearance of low-titer 
inhibitors and the eradication of inhibitors with ITI therapy (Astermark, 2006). The 
prevalence of inhibitors to factor VIII or IX is therefore much lower than the lifetime risk for 
inhibitors, and is in the range of 5% to 8%. Inhibitors may occur at any time in a patient’s 
life, but the majority of patients develop inhibitors early in life after a median of 10 exposure 
days. It is rare to develop inhibitors after >150 exposure days (Hay et al, 2006). The inhibitor 
titers are usually given in Bethesda Units (BU), where one BU is defined as the amount of 
antibody that neutralizes 50% of FVIII or FIX in normal plasma (Astermark, 2006).  

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Inhibitors are also classified as high or low responding based on the titers found. Low 
responders are those who have a persistently low inhibitor titer of <5 BU despite repeated 
challenge with substitution factor concentrate, i.e., no anamnestic response. High responders 
are those who reportedly have a consistently high titer of ≥5 BU or had this in the past after 
re-exposure (high anamnestic response) resulting in an inability to treat hemorrhage with 
factor concentrates (White et al., 2001). A small group of patients also exist who have a 
constantly low inhibitor titer (<5 BU), but who still do not respond sufficiently to (increasing 
doses of) factor VIII or IX treatment. 
Since replacement therapy with the missing coagulation factor is ineffective in patients with 
inhibitors, bypassing agents are commonly used to stop a bleeding episode in inhibitor 
patients. Treatment with the activated form of factor VII (FVIIa) provides a way to bypass 
the need for FVIII or FIX and initiates clotting at a site of bleeding. Thrombin (factor IIa) 
generation under normal circumstances is initiated by the formation of FXa from FX by the 
complex of FVIIIa and FIX (via the intrinsic pathway).  
FVIIa can either be provided by administration of plasma-derived activated prothrombin 
complex concentrate (aPCC, or factor eight inhibitor bypassing agent, FEIBA®) or by 
administration of factor VIIa concentrate, either plasma-derived or recombinant (currently 
available as NovoSeven®). 
Results from the Hemophilia and Thrombosis Research Society (HTRS) registry indicate that 
FVIIa was effective in approximately 90% of joint bleeding episodes (Valentino LA, 2009). 
A study looking at home treatment with 90 µg/kg of NovoSeven® every 3 hours up to three 
times showed 92% of bleeding episodes (including joints, muscle and mucocutaneous 
bleeding episodes) responded well (Key et al., 1998). The dosing regimen for treatment of 
bleeding is dependent on the type and severity of the bleeding episode, but usually 90 µg/kg 
administered every 2-3 hours is effective (NovoSeven® SmPC). Higher doses (e.g., 
270 µg/kg) may also be utilized for treatment of mild–to-moderate bleeding episodes.  
Short-term prophylactic treatment is given to hemophilia patients with inhibitors before they 
undergo surgical procedures or, for example, tooth extractions or insertion of venous access 
devices. Arthropathy is very prevalent in hemophilia patients and orthopedic surgery, 
including joint replacements is relatively frequent. Recombinant FVIIa has been used 
successfully in these major surgical procedures (Obergfell et al., 2008; Takedani et al., 2010).  
Factor VIIa is also used for other bleeding disorders such as acquired hemophilia and 
congenital factor VII deficiency. 
Background Information on the Product 
LR769 is a recombinant human coagulation factor VIIa of the vitamin K dependent family of 
coagulation factors. In the presence of both calcium and phospholipids, factor VII/VIIa in a 
complex with Tissue Factor (TF) can activate factor X to factor Xa directly bypassing factor 
IX or factor VIII. Activation of factor X to factor Xa initiates the common pathway of the 
coagulation cascade in which prothrombin is activated to thrombin and then converts 
fibrinogen to fibrin.  

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FVIIa is a 406 amino acid (AA) glycoprotein (~50 kDa) with 12 disulfide bridges. The 
protein contains four distinct structural domains: the N-terminal γ-carboxylic-domain (GLA-
domain), two epidermal growth factor (EGF) like domains and one serine protease domain. 
Activation of FVII into FVIIa results in the cleavage of the peptide bond Arg152-Ile153 
generating an N-terminal Light Chain (LC) of 152 AA and a C-terminal Heavy Chain (HC) 
of 254 AA held together by a single disulfide bridge (Cys135-Cys262). 
The clinical development plan has been designed to support registration of LR769, initially, 
for the treatment of bleeding episodes and for the prevention of bleeding in surgical 
interventions or invasive procedures in congenital hemophilia A or B patients with inhibitors. 
The population foreseen is both adults and children. 
At this time, there are no European Union (EU) or FDA guidelines for the development of 
factor VIIa products. However, in Europe, there are guidelines for the development of FVIII 
and FIX products, including the most recently released Guideline for the development of 
factor IX products (EMA/CHMP/BPWP/144552/2009). This guideline has been updated to 
include pediatric studies in conformance with the pediatric regulations. For this reason, a 
stepwise approach following the basic principles of the FIX Guideline has been adopted for 
purposes of preparing our clinical development plan (including studies in the pediatric 
population). Indeed, the epidemiology of patients with hemophilia with inhibitors to FVIII 
and FIX is similar to that of all patients with hemophilia B. 
This study will evaluate two separate dose regimens of LR769: 75 µg/kg and 225 µg/kg for 
both mild/moderate and severe bleeding episodes in congenital hemophilia A or B patients 
with inhibitors (BU ≥5) or with a known high anamnestic response or refractory to increased 
dosing of either FVIII or FIX, aged less than 12 years. Administration of LR769 will be 
repeated depending on the type and severity of the event.  
Preliminary efficacy and safety results of a similar, ongoing, study in the same but older 
population (12 years and older) provide the basis for the current study. The available results 
of this other study and of the Phase 1b study completed earlier are more extensively 
described in the current LR769 Investigator’s Brochure.  

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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives  
The primary objectives of this study are: 
• To assess the efficacy of 2 separate dose regimens (75 µg/kg and 225 µg/kg) of LR769 
for the treatment of bleeding episodes in hemophilia A or B pediatric patients, from birth 
to <12 years old, with inhibitors to factor VIII or IX  
• To assess the safety of LR769. This includes the immunogenic potential of the drug 
product 
 
2.2 
Secondary Objective  
The secondary objective of this study is: 
• To assess the PK of LR769 in hemophilia A or B pediatric patients, from birth to <12 
years old, with inhibitors to factor VIII or IX, without a current bleeding episode 
 
2.3 
Other Objective 
• To assess the healthcare resource utilization of hemophilia A or B pediatric patients, from 
birth to <12 years old, with inhibitors treated with LR769 
 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a global, multicenter, Phase III, prospective, open-label, randomized, crossover study. 
There are two patient age ranges (birth to < 6 years and ≥ 6 years to < 12 years); 12 patients 
will be enrolled within each age range. 
After obtaining informed consent (from parents/guardians and assent of the patient if 
applicable) and performance of screening procedures, patients who meet all inclusion and 
exclusion criteria will be randomized to start with one of the two treatment regimens: 
• 75 µg/kg treatment regimen 
• 225 µg/kg treatment regimen 
 
The assigned treatment regimen is the dose administered in the safety phase, Phase A, for the 
initial assessment of safety and PK, and the dose to be used when starting the treatment 
phase, Phase B, before crossover to the other treatment regimen (Figure 1). 
 
 

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3.1.1 
Phase A (Initial Safety and PK Phase) 
Depending on randomization, patients will receive a single intravenous administration of 
either 75 µg/kg or 225 µg/kg of LR769 as a bolus injection administered in ≤2 minutes in a 
hospital setting or hemophilia treatment center. Patients must not have an active bleeding 
episode at that time and have not received treatment with any FVII(a) product within 24 
hours prior to this administration. This administration is for the initial assessment of safety 
and PK of LR769. Patients will remain in the hospital or hemophilia treatment center and 
will be observed for any potential acute AE for at least 2 hours after dosing.  
If the patient has a bleeding episode on the day of randomization  prior to receiving study 
drug and therefore is unable to receive a first dose of LR769, but is otherwise eligible to 
receive the Phase A dose of LR769, he may receive this dose if the bleeding episode is 
resolved and after 24 hours have passed since his last hemostatic treatment. 
Patients are eligible to be rescreened for a screening failure only if the patient was unable to 
be randomized during the 21 day screening period due to scheduling issues or due to 
bleeding. 
Pharmacokinetics: 
During Phase A, all patients will, in addition to the safety assessments, have samples drawn 
for PK analysis during the initial administration of the study drug (see the PK Analyses 
Section 9.9 for details). This is expected to result in at least 10 evaluable patients in each age 
group. PK sampling will be done according to the ISTH guidance on PK studies (Lee et al., 
2001). Samples will be taken pre-dose in all patients. To reduce the amount of blood draws, 
subsequent sampling will be done in approximately half of the patients (sampling schedule 1) 
at 10±2 minutes, 1 and 4 hours (±10 minutes), and the other half of the patients (sampling 
schedule 2) at 30±5 minutes and 2 and 8 hours (±10 minutes) relative to the start of infusion 
of study drug. Population PK modeling will be used to analyze pharmacokinetics of LR769 
in this pediatric population with this sparse sampling. 
3.1.2 
Phase B (Treatment Phase) 
Patients who complete Phase A will start with a treatment regimen that consists of 12-week 
periods of treatment with a certain dose. Depending on randomization, the treatment regimen 
will start with either 75 µg/kg or 225µg/kg and patients will then cross over to the alternate 
treatment regimen every 12 weeks until the end of the study. From 24 hours after the 
administration of LR769 in Phase A, patients are eligible to be treated with LR769 in case 
they have a mild, moderate, or severe bleeding episode.  
3.1.2.1 
Classification of Severity of Bleeding Episodes 
All levels of severity of bleeding episodes are allowed to be treated in this study. For the 
purposes of this study, mild, moderate and severe bleeding episodes are descriptively defined 
as presented in Table 1. 

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3.1.3 
Follow-Up Visits 
Patients will be followed initially at 3 weeks (±2 days) and 6 weeks (±5 days) following the 
first administration in Phase A and subsequently every 6 weeks (±5 days). Patients may be 
treated for multiple bleeding episodes during the course of the study. All patients will be 
followed for at least 6 months after the first LR769 administration or, if the study ends, for 
14 (±2 days) after the last administration of study drug.  
3.2 
Rationale for Study Design and Control Group 
At this time, there are no EU or FDA guidelines for the development of factor VIIa products. 
However, in Europe, there are guidelines for the development of FVIII and FIX products, 
including the most recently released guideline for the development of factor IX products 
(EMEA/CHMP/BPWP/144552/2009). This Guideline has been updated to include pediatric 
studies in conformance with the pediatric regulations. In view of this, a stepwise approach 
following the basic principles of the draft FIX Guideline has been adopted for purposes of 
preparing our clinical development plan (including studies in the pediatric population). 
Indeed, the epidemiology of patients with hemophilia with inhibitors to FVIII and FIX is 
similar to that of all patients with hemophilia B. This study is the second in a series of three 
planned studies of rhFVIIa. 
This is not an active or placebo-controlled study, as a control arm is not feasible. A placebo 
cannot be used, as that would result in insufficient treatment of a bleed, leading to potentially 
irreversible damage to the patient (mostly arthropathy), or could even be life-threatening 
depending on the location of the bleed. A comparison with current standard of care would 
then be the next best option, which, in this case, could be either aPCC (FEIBA®), plasma-
derived FVIIa (pdFVIIa), or NovoSeven®. Such studies would need to be designed as a non-
inferiority study, and the most obvious comparator would be NovoSeven® as it is most used 
in the developed world for this indication. However, if powered sufficiently, the size of such 
a study would not be feasible.  
For the primary efficacy endpoint for the FDA, efficacy will be evaluated by comparing the 
percentage of mild/moderate bleeding episodes that are evaluated as being successfully 
treated to an objective performance criterion (OPC). LR769 will be regarded as effective 
when the success percentage is statistically significantly higher than the OPC. This OPC was 
determined by reviewing the literature on what the reported success is of the treatment with 
bypassing agents. However, due to the use of a different endpoint in this study vs. several 
different other ones in literature, an estimate of what the OPC should be is difficult. Several 
publications provide a wide range of bleeding treatment success at different timepoints 
depending on the type of efficacy assessment used. An OPC of 55% was chosen, taking into 
account the stringent criteria for success (including elements to more objectively judge 
treatment success) in this study.  
In addition, as the primary efficacy endpoint for the EMA, the proportion of bleeding 
episodes (mild, moderate and severe combined) evaluated with a “good” or “excellent” 
response as assessed by the patient/parent (mild/moderate bleeding episodes) and the 

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physician (severe bleeding episodes) at 12 hours after first administration of the study drug 
will be calculated. 
3.3 
Study Duration and Dates 
The study will continue until at least 352 mild/moderate bleeding episodes have been treated 
and at least 6 months have passed for 22 patients since first administration of LR769, 
approximately 11 in each age group (birth to < 6 years and ≥ 6 years to < 12 years). First 
patient enrolled in the study is planned for the second half of 2015. The overall duration of 
the study up to and including Phase B is approximately 16 months from First Subject First 
Visit until Last Subject Last Visit. The enrollment period is expected to be approximately 9 
months.  
The duration of a patient’s participation in the study (from signing the informed consent form 
until the last study visit in Phase B) may vary from approximately 7 months to approximately 
16 months depending on when the patient was enrolled, unless discontinued prematurely. 

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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study will enroll male congenital hemophilia A and hemophilia B pediatric patients from 
birth to <12 years old. All grades of severity of hemophilia are allowed, as long as they have 
regular bleeding episodes and inhibitors, as evidenced by a BU≥5. Some patients may have 
low levels of inhibitors i.e., a BU<5 but still cannot be treated with factor concentrates since 
they are known to have a strong memory (anamnestic) response after re-exposure to factor 
concentrates. In other cases, patients with inhibitor levels <5 BU, even after re-exposure to 
factor concentrates, may still be refractory to increased dosing with these factor concentrates. 
All of these patients therefore cannot be treated with these concentrates and need a bypassing 
agent, and are also allowed in the study. Patients on ITI therapy are allowed to be treated in 
the study as well, i.e., patients under this regimen are not excluded from the study, as long as 
they fulfill the criteria for inhibitors as described above and have regular bleeding episodes. 
4.2 
Inclusion Criteria 
To be eligible for enrollment into this study, patients must: 
1. be male with a diagnosis of congenital hemophilia A or B of any severity 
2. have one of the following: 
a. a positive inhibitor test BU ≥5, OR  
b. a BU<5 but expected to have a high anamnestic response to FVIII or FIX, as 
demonstrated from the patient’s medical history, precluding the use of factor VIII or 
IX products to treat bleeding episodes, OR 
c. a BU<5 but expected to be refractory to increased dosing of FVIII or FIX, as 
demonstrated from the patient’s medical history, precluding the use of factor VIII or 
IX products to treat bleeding episodes 
3. be aged from birth to <12 years old 
4. have experienced at least 3 bleeding episodes of any severity in the past 6 months; if <6 
months old, have experienced at least 3 bleeding episodes since birth 
5. parents or legal guardians must be capable of understanding and willing to comply with 
the conditions of the protocol 
6. parents or legal guardians must have read, understood and provided written informed 
consent 
 
4.3 
Exclusion Criteria 
Patients will be excluded from participation in the study if any of the following criteria 
apply:  
1. have any coagulation disorder other than hemophilia A or B 
2. be immunosuppressed (i.e., the patient should not be receiving systemic 
immunosuppressive medication, CD4 counts at screening should be >200/µl) 
3. have a known allergy or hypersensitivity to rabbits  

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4. have platelet count <100,000/µL 
5. have had a major surgical procedure (e.g. orthopedic, abdominal) within 1 month prior to 
first administration of the study drug in this study 
6. have received an investigational drug within 30 days of the first study drug 
administration, or is expected to receive such drug during participation in this study 
7. have a clinically relevant hepatic (AST and/or ALT >3 times ULN) and/or renal 
impairment (creatinine >2 times ULN) 
8. have an active malignancy (those with non-melanoma skin cancer are allowed) 
9. have any life-threatening disease or other disease or condition which, in the investigator’s 
judgment, could imply a potential hazard to the patient, or interfere with the trial 
participation or trial outcome (e.g., a history of non-responsiveness to bypassing products 
or thromboembolic disease) 
10. known or suspected hypersensitivity to the active substance or to any of its excipients 
 
Exclusion Criteria for PK portion: 
Patients will not be included in the pharmacokinetic samplings process if they have had 
active bleeding and therefore received any hemostatically-active drugs within 24h prior to the 
administration of LR769. If so, their participation to the PK portion of the study will be 
delayed to a later date. 

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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Study Drug 
Coagulation Factor VIIa (Recombinant), LR769, is a pure FVIIa product produced using 
recombinant technology. It will be provided in a vial as a lyophilized powder to be 
reconstituted with water for injection. 
5.1.2 
Placebo 
Not applicable. 
5.2 
Treatments Administered 
After obtaining informed consent of the parents/guardians and assent of the patient, if 
applicable, screening procedures are performed. Patients who meet all inclusion and 
exclusion criteria will be randomized to start with one of two treatment regimens: 
1. 75 µg/kg treatment regimen 
2. 225 µg/kg treatment regimen 
 
The assigned treatment regimen is the dose administered in the safety phase, Phase A, for the 
initial assessment of safety and PK, and is the dose to be used when starting the treatment 
phase, Phase B, before crossover to the other treatment regimen. 
5.2.1 
Phase A (Initial Safety and PK Phase) 
Depending on their randomization, patients will receive a single intravenous administration 
of either 75 µg/kg or 225 µg/kg of LR769 as a bolus injection in ≤2 minutes in a hospital 
setting or hemophilia treatment center in a non-bleeding situation. During Phase A, the initial 
administration of the study drug, patients will have samples drawn for PK analysis in 
addition to the safety assessments.  
5.2.2 
Phase B (Treatment Phase)  
Patients who completed Phase A will start with a treatment regimen that consists of 12 week 
periods of treatment with a either dose of LR769. Depending on their randomization, the 
treatment schedule will start with either 75 µg/kg or 225µg/kg and they will cross over to the 
alternate treatment regimen every 12 weeks until the end of the study.  
5.3 
Selection and Timing of Dose for Each Patient 
The treatment regimens used in this study are selected based on a Phase 1b study assessing 
the PK and pharmacodynamic (PD) effects of 3 doses of LR769 (25, 75, and 225 µg/kg) in 
hemophilia A or B patients. Safety and efficacy results of a study (RB-FVIIa-006-13, 

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5.7.2 
Fluid and Food Intake  
No restrictions on fluid or food intake apply. 
5.7.3 
Patient Activity Restrictions 
No restrictions on patient activity apply beyond any the patient may already be following. 
5.8 
Treatment Compliance 
All patients will be treated in a hospital or hemophilia treatment center in Phase A of the 
study in a non-bleeding state. Compliance is then managed by the site staff who will record 
the exact dose and time of infusion. Compliance of treatment of bleeding episodes at home 
will be recorded by the patient/parent in a patient diary where the exact time of onset of a 
bleeding episode will be noted as well as the number of vials used and the amount 
administered at what time points to treat that bleeding episode. These data will be checked by 
the study staff at the next visit to the study center, and compared to the number of vials 
remaining at the patient’s home. 
5.9 
Packaging and Labeling 
The investigational product, LR769, will be supplied in clear glass vials as lyophilized 
powder of 1 mg and 5 mg. The vials will be labeled using multilingual labels, which will 
comply with local regulations and requirements. Vials will be packaged in an outer box. In 
addition, prefilled syringes with Water for Injection, as well as supplies for reconstitution and 
administration of the study drug will be provided. 
5.10 Storage and Accountability 
The investigational product, LR769, must be stored in a safe and secure place at the study 
center. The investigational product is to be stored at room temperature, is not to be frozen 
and should be protected from light. The Investigator is fully responsible for investigational 
product stored at the study center. Access should be strictly limited to the Investigator and 
designated staff. Neither the Investigator nor designated staff may provide investigational 
product to any patient not in the study. Dispensing of investigational product may be 
delegated, e.g., to a hospital pharmacy as locally applicable. 
All investigational products received at the investigational site, dispensed to and returned 
from a patient will be documented on investigational product accountability forms. This 
documentation must be available for review by the monitor at the monitoring visit to confirm 
proper investigational product management. 
5.11 Investigational Product Retention at Study Site 
All used and unused vials of LR769 (Coagulation Factor VIIa [Recombinant]) will be 
retained until accountability has been performed by the monitor. For this purpose, patients 
will keep all used vials and bring them to the study center at each visit, where the study staff 

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will perform the treatment compliance check and store the vials for the accountability check 
by the monitor (unless local regulation does not allow this, in which case the containers 
should be stored as a ‘surrogate’).  
All unused vials will be returned or destroyed according to the instructions of the Sponsor at 
the end of the study. Please refer to the pharmacy manual. 

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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All patients/parents will be informed of the aims of study, the possible AEs, 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 the patients’ personal 
data, and that the patients’ medical records may be reviewed for study purposes by 
authorized individuals other than their treating physician. It will be emphasized that the 
participation is voluntary and that the parent patient is allowed to refuse further participation 
in the protocol whenever he wants. Once the patient/parent completely understands the study 
and its procedures and risks he/she will be asked to sign and date the informed consent. No 
study procedures may begin prior to signing of the informed consent/assent document(s). 
The patient may, depending on his age, receive age-appropriate information and be asked to 
sign and date an assent form. Age of providing information and assent form may differ 
between institutions and will be determined by local law and Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) requirements. 
Once the informed consent has been signed and dated by the parents/guardians (and assent 
form by the patient, if applicable), the patient is considered enrolled in the study. 
6.2 
Medical History 
The medical history of the patient will be obtained. Specific information will be recorded on 
the eCRF relating to any prior or existing medical conditions/surgical procedures involving 
the following: Infectious Diseases (including viral infections, like Hepatitis B and C and 
human immunodeficiency virus (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. 
In addition, specific detailed information regarding the clinical symptoms and treatment of 
the hemophilia will be collected. This will include the following: type of hemophilia (A or 
B), severity (including factor VIII or IX level), number of bleeding episodes during the past 6 
months (if <6 months old, number of bleeding episodes since birth), existence of a target 
joint/bleeding site (i.e., a joint in which recurrent bleeding has occurred on four or more 
occasions during the previous 6 months or one in which 20 lifetime bleeding episodes have 
occurred), date of first detection of inhibitors, treatment for bleeding episodes (product and 
dose for each bleeding episode) in past month (or in case there were no bleeding episodes in 
the prior month, details from the last 2 bleeding episodes of the patient), ITI (current or in the 
past, including product, dose and dates of treatment). 
 
Demographics (date of birth, race/ethnicity, sex) will also be collected.  

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6.3 
Physical Examination 
A standard physical examination will be performed at set timepoints during the study. All 
findings from this examination will be recorded on source documents and entered into the 
eCRF. The standard physical examination will include the following 
observations/measurements: Height/Weight, General Appearance, Skin, HEENT, Lymph 
Nodes, Heart, Lungs, Abdomen, Extremities/Joints, Neurological, and Mental Status.  
The patient will be weighed every 6 weeks and dose adjustment made if necessary. 
When the standard physical exam is performed and at some additional timepoints, the patient 
will be checked for any signs of thromboembolic events such as pulmonary embolism (e.g., 
shortness of breath, chest pain, cyanosis), or deep venous thrombosis (e.g., calf pain, 
swelling/edema, redness, venous distension, pain on dorsiflexion). 
6.4 
Vital Signs 
Vital signs will be obtained at set timepoints during the study. The assessments of vital signs 
include systolic and diastolic blood pressures (mmHg), heart rate (beats/minute), respiratory 
rate (breaths/minute), and body temperature (°C or °F, sublingual or tympanic). 
6.5 
Clinical Laboratory Tests 
Investigator will contact the Medical Monitor regarding any patient who weighs <12 kg for 
adaptation of the blood sample schedule to the patient’s body weight in consideration of ICH 
Harmonised Tripartite Guideline “Clinical Investigations of Medicinal Products in the 
Paediatric Population, ICH Topic E 11,” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002926.pdf). Blood volume drawn cannot exceed 3% of the total blood volume of the 
patient during a period of 4 weeks and cannot exceed 1% of the total blood volume at any 
single time.  
For subjects < 12 kg, the minimum weight requirement is 10.5 kg ,when blood will be 
collected by peripheral venipuncture. The investigator must contact the Medical Monitor to 
discuss enrollment of any subject weighing < 12 kg with an indwelling catheter, Port-a-cath 
or PICC line.The following total amounts of blood will be taken at each visit as described in 
Table 2. 
Table 2. 
Total Amounts of Blood Taken During the Study 
Visit 
Child 
weighs 
<12 kg at 
screening 
Child weighs 
≥12 kg to<19 kg 
at screening 
Child weighs 
≥19 kg at 
screening 
Screening 
7.5 mL 
9.6 mL 
15.2 mL 
Visit 1 
7.8 mL 
9.6 mL 
15.1 mL 

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Visit 
Child 
weighs 
<12 kg at 
screening 
Child weighs 
≥12 kg to<19 kg 
at screening 
Child weighs 
≥19 kg at 
screening 
Week 3 
2.5 mL 
2.5 mL 
3 mL 
Week 6 
2.5 mL 
2.5 mL 
3 mL 
Week 12 
6.5 mL 
7 mL 
10 mL 
Week 18 
2.5 mL 
2.5 mL 
3 mL 
Week 24 
8 mL 
9.7 mL 
14 mL 
Every 6 weeks 
after Week 24 
2.5 mL 
2.5 mL 
3 mL 
End of 
Study/Early 
Termination 
8 mL 
9.2 mL 
15 mL 
 
6.5.1 
Laboratory Parameters 
6.5.1.1 
Safety Laboratory Tests 
Clinical safety laboratory tests will include the following and will be carried out by the 
central laboratory for the study as presented in Table 3:  
Table 3. 
List of Laboratory Tests 
Hematology: 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Platelet count 
- 
White blood cell (WBC) count with 
differential (automated) 
- 
CD4 count1 
Coagulation 
- 
FVIII2 or FIX3 
- 
FVIII2 or FIX3 inhibitors 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Creatinine 
- 
Gamma-glutamyl transferase 
(GGT) 
- 
Lactate dehydrogenase (LDH) 
- 
Total protein 
1 
Only at Screening 
2 
In hemophilia A patients only  
3 
In hemophilia B patients only 
 

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6.5.1.2 
Coagulation Tests 
Factor VIII (in hemophilia A patients) and factor IX (in hemophilia B patients) concentration 
will be assessed at Screening. The titer of inhibitors to factor VIII (in hemophilia A patients) 
or factor IX (in hemophilia B patients) will be assessed at Screening, 24 weeks, and EOT at 
the central laboratory. The Bethesda assay will be used for inhibitor testing.  
6.5.1.3 
Drug Concentration Tests 
FVIIa concentration will be determined in all patients who have PK assessments done after 
receiving study drug in Phase A. The concentration will be determined by using a validated 
modified activity assay (Staclot® VIIa-rTF from Diagnostica Stago) in a single central 
laboratory. 
6.5.1.4 
Immunogenicity Testing 
Serum samples to test for antibodies against LR769 and any host related impurities will be 
taken at set timepoints during the study. Testing for antibodies against LR769 will be done 
by a screening assay (electrochemiluminescent method) that is able to detect all antibody 
isotypes. If the sample is screen positive (which is expected in about 5% of samples), the 
sample will be tested in a confirmatory assay using binding inhibition as a way to confirm the 
specificity of the signal seen in the screening assay. If confirmed positive, the sample will be 
tested in an assay that has been set up to determine if antibodies in patient plasma that are 
known to bind LR769 (as suggested by the screening and confirmatory assay) will also 
neutralize FVIIa clotting activity. A dot blot assay has been developed to screen the patient 
samples for reactivity to rabbit’s milk proteins. This will allow identifying patients that are 
generating an immune response to milk proteins as a result of study drug treatment. 
6.5.1.5 
Sample Storage  
Serum samples (if available) will be stored (for a maximum of 5 years after the end of the 
study) for purposes of any safety evaluations deemed necessary in the future (e.g., infectious 
disease evaluations). These samples will be stored by the Sponsor (or designee) in a central 
location. 
6.5.2 
Sample Collection, Storage, and Shipping 
A separate laboratory manual will be prepared that describes the appropriate sample 
collection, storage, and shipping procedures. 
6.6 
Dispensing Study Drug 
When treatment is taking place in the hospital or hemophilia treatment center in Phase A, or 
for severe bleeding episodes in Phase B, drug will be prepared by and dispensed to the study 
staff according to the local study center’s procedures. After the patient completes Phase A 
without any safety concerns, the patient/parent, after due training by the study staff, will 
receive study medication as well as materials for reconstitution and administration (e.g., 

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alcohol swabs, syringes, butterfly needles, etc.) to store at home, in order to be able to treat 
subsequent mild/moderate bleeding episodes at home. 
6.7 
Pharmacokinetic Assessments 
In Phase A, blood draws will occur at baseline (prior to LR769 administration) in all patients. 
To reduce the amount of blood draws, subsequent sampling will be done in approximately 
half of the patients (sampling schedule 1) at 10±2 minutes, 1 and 4 hours (±10 minutes), and 
the other half of the patients (sampling schedule 2) at 30±5 minutes and 2 and 8 hours (±10 
minutes) relative to the start of infusion of study drug. FVIIa concentrations will be 
determined using a validated modified activity assay (Staclot® VIIa-rTF, Diagnostica Stago) 
at Good Biomarker Sciences (Leiden, The Netherlands). 
6.8 
Efficacy Assessments 
Efficacy of the treatment of each bleeding episode will be assessed by the parent(s)/guardian 
or other caregiver in conjunction with the patient where possible (e.g., depending on age) and 
noted in the patient diary. In case of treatment the efficacy assessment in the hospital is also 
done by the physician and recorded in the patient’s records. Response to treatment will be 
rated as “none,” “moderate,” “good,” or “excellent,”  
These are defined as follows: 
• None: no noticeable effect of the treatment on the bleeding or worsening of patient’s 
condition. Continuation of treatment with the study drug is needed. 
• Moderate (fair): some effect of the treatment on the bleeding is noticed, e.g., pain 
decrease or bleeding signs improvement, but bleeding continues and requires continued 
treatment with the study drug. 
• Good: symptoms of bleeding (e.g., swelling, tenderness, and decreased range of motion 
in the case of musculoskeletal hemorrhage) have largely been reduced by the treatment, 
but have not completely disappeared. Symptoms have improved enough to not require 
more infusions of the study drug. 
• Excellent: full relief of pain and cessation of objective signs of bleeding (e.g., swelling, 
tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage). 
No additional infusion of study drug is required. 
Source: (Amby et al., 2009)  
A response of none or moderate is usually followed by continued treatment with the study 
drug; a response of good or excellent means that no further treatment is needed or, in the case 
of a severe bleeding episode, the dosing interval can be increased. This four point scale is a 
frequently used tool in hemophilia to assess efficacy of treatment (Amby et al., 2009). If a 
bleeding episode is treated in the hospital, the physician will be asked to assess efficacy using 
the same scoring system at the same timepoints.  

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Additionally, as part of the patient diary, a VAS to rate pain will be completed by the 
parent/guardian/ caregiver in conjunction with the patient where possible (e.g., depending on 
age) to assess the response of pain to treatment.  
Efficacy assessment of LR769 to treat a mild/moderate bleeding episode will occur within 15 
minutes prior to each administration of study drug.  
 Mandatory efficacy assessment timepoints for 75 µg/kg – 3, 12, and 24 hours after 
initial dose.  
 Mandatory efficacy assessment timpoints for 225 µg/kg – 9, 12, and 24  hours after 
initial dose. 
If additional adminstrations are needed after the initial injection then assessements are to be 
completed within 15 minutes prior to each subsequent injection.  
Efficacy assessment of  LR769 to treat severe bleeding episodes will be assessed within 15 
minutes prior to each administration of study drug.  
 Mandatory efficacy assessment timepoints for 75 µg/kg – 2, 12, and 24 hours after 
initial dose.  
 Mandatory efficacy assessment timpoints for 225 µg/kg – 6, 12, and 24  hours after 
initial dose. 
If additional adminstrations are needed after the initial injection then assessements are to be 
completed within 15 minutes prior to each subsequent injection.  
The timepoint for the primary evaluation of efficacy will be 12 hours after first 
administration of study drug.  
Patient diaries will be used for the collection of information on the efficacy of treatment, as 
assessed by the parent/guardian/caregiver in conjunction with the patient where possible 
(e.g., depending on age). Efficacy of treatment assessed by the physician during severe 
bleeding treatment in clinic will be documented in patient’s source records.  
In addition to the above score the following information will be collected for each bleeding 
episode (by patient for mild/moderate bleeding episodes and by physician for severe bleeding 
episodes treated onsite): 
• Date and start time (first symptoms) of bleeding episode 
• Cause of bleeding episode 
• Severity of bleeding episode (according to Table 1) 
• Type and anatomical site of bleeding episode 
• In case of joint: target joint or not; specify joint 

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• Did any recurrence of bleeding episode (defined as bleeding in the same joint/anatomical 
location within 24 hours after an initial “good” or “excellent” response) occur 
• Did the bleeding episode require any alternative treatment (including information on the 
nature of the alternative treatment, start date/time and stop date/time of alternative 
treatment, if applicable) 
• Did the bleeding episode require visit to the hospital 
• Occurrence of pain (prior to the 1st infusion of study drug to treat this bleeding episode) 
and progression/resolution of pain assessed at each efficacy assessment timepoint. Pain 
caused by a bleeding episode will be measured on a VAS in millimeters from 0 (no pain) 
to 100 (worst possible pain).  
• Time to cessation of bleeding episode 
• Date, dose and total volume, time of administration of each dose, lot numbers, and 
number of vials used. 
 
All assessments described as done by the patient may be done by the parent/legal guardian or 
other caregiver depending on the age of the patient. 
 
6.8.1 
Efficacy Endpoint:  
The primary efficacy endpoint for this study is defined as successful treatment of a bleeding 
episode at 12 hours after first administration of the study drug.  The following are 
clarification definitions to satisfy regulatory requirements in multiple regions (i.e., the FDA 
and the EMA). 
The primary efficacy endpoint for the FDA is defined as the successful treatment of a 
mild/moderate bleeding episode at 12 hours after start of treatment. Successful treatment of a 
mild/moderate bleeding episode is defined as a combination of the following:  
• Good or Excellent response noted by patient/parent/guardian,depending on patient’s age 
and maturity 
• Study drug treatment: No further treatment with study drug beyond timepoint where a 
Good or Excellent response for this bleeding episode was noted 
• No other hemostatic treatment needed for this bleeding episode 
• No administration of blood products indicating continuation of bleeding beyond 
timepoint where a Good or Excellent response for this bleeding episode was noted 
• No increase of pain beyond timepoint where a Good or Excellent response for this 
bleeding episode was noted that cannot  be explained other than as continuation of 
bleeding   
 
The primary efficacy endpoint for the EMA is defined as the proportion of bleeding episodes 
(mild/moderate and severe combined) with a “good” or “excellent” patient (for 
mild/moderate bleeding episodes) and physician (for severe bleeding episodes) reported 
assessment of efficacy at 12 hours after the first administration of study drug. 

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Secondary efficacy endpoints include: 
• Proportion of mild/moderate bleeding episodes successfully treated according to the same 
criteria as the primary endpoint of efficacy, at all other timepoints  
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” patient (and/or physician when available) reported 
assessment of efficacy at all timepoints 
• Time to assessment of a “good” or “excellent” response of the bleeding episodes 
(mild/moderate and severe, separately and combined) by the patient/parent (and/or 
physician when available) 
• The number of administrations and mean total amount of drug administered per bleeding 
episode  
 
Tertiary efficacy endpoints include: 
 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” physician reported assessment of the efficacy at 12 hours (if 
available) 
• Proportion of recurrences (defined as a bleeding episode in the same joint/anatomical 
location within 24 hours after an initial successful response 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
requiring alternative treatment 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with successful pain relief 
 
Where applicable, analyses will be done for all patients and by age group aged from birth to 
<6 years and ≥6 years to <12 years). 
6.9 
Adverse Events Assessments 
6.9.1 
Performing Adverse Events Assessments 
An Adverse Event (AE) is defined as any undesirable physical, psychological or behavioral 
effect experienced by a patient during their participation in an investigational study, in 
conjunction with the use of a drug or biologic, whether or not product-related. Events that 
match this description but occur between the time of informed consent and the first 
administration of the study drug are also regarded AEs, but will be listed as nonTEAEs. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to informed 
consent are not considered AEs, unless they reoccur after the patient has recovered from the 
pre-existing condition or they represent an exacerbation in severity, duration or frequency. 
Bleeding episodes such as in the case of Hemophilia, which are the subject of this study are 
not regarded AEs. If a bleeding episode was caused by an injury, the injury should not be 
reported as an AE, unless it resulted in a medical finding other than a bleeding episode (e.g., 

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scratch of skin). Therefore, any hemophilia-related events (e.g., hemarthrosis [presenting as 
swelling, pain, and limited motion], bruising, hemorrhages, or pain at bleeding site) will not 
be reported as AEs. However, the event may be regarded as an AE if it had occurred in a 
hemostatically normal patient under the same circumstances. 
Hospitalization for the treatment of a bleeding episode regardless of severity, should not be 
reported as an AE.  
All AEs will be recorded in the eCRFs. A description of the event (preferably medical 
diagnosis, or if no diagnosis is made symptom or sign) including start date/time, resolution 
date/time, seriousness, severity, relationship to the investigational product, action taken, and 
outcome should be provided. 
All AEs will be followed up until resolution or 30 days after EOS/Termination visit, 
whichever comes first. 
6.9.2 
Timing 
Adverse events will be collected from the time of signing of the informed consent until 
completion of the study. At each study visit the patient/parent will be asked to report any and 
all changes in health status or condition (AEs) experienced since the previous visit. 
Additionally, the patient/parent will be asked specifically whether the patient experienced 
any signs and symptoms that may indicate a thromboembolic event occurred. These may 
include, among others, headache, shortness of breath, chest pain, cyanosis, calf pain, 
swelling/edema, redness, venous distension or pain on dorsiflexion of the foot. 
6.9.3 
Severity 
Adverse events will be graded by the investigator according to severity: 
 Mild: Symptom(s) barely noticeable to the patient and/or does not make the patient 
uncomfortable. The AE does not influence daily performance or functioning. Medical 
intervention is not ordinarily needed for relief of symptom(s). 
 Moderate: Symptom(s) of a sufficient severity to make the patient uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) may be 
needed. 
 Severe: Symptom(s) of a sufficient severity to cause the patient severe discomfort, 
and/or result in a marked impairment of function or may be even life-threatening. 
Severity may cause cessation of treatment with the study drug. Treatment for 
symptom(s) is given. The AE produces sequelae, which may also require (prolonged) 
treatment.  
Note: Severe is not equivalent to serious. 

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6.9.4 
Relationship 
For all AEs, the Investigator will be asked to record the drug relatedness of the event in the 
source documents and enter the data in the eCRF. For this assessment the investigator will 
need to take into account the time relationship between drug administration and the 
occurrence of the event, the expected pharmacology of the study drug, the potential 
contribution of the underlying disease under investigation and/or any other concomitant 
diseases/medical history, evolution of the event when the drug was withdrawn and whether 
the event re-occurred after a re-challenge. 
The relationship criteria include: 
• unrelated (event with a time to drug intake that makes a relationship unlikely and disease 
or other drugs provide a clear explanation, negative re-challenge) 
• remote/unlikely (event with a time to drug that makes a relationship improbable (but not 
impossible) and disease or other drugs provide plausible explanations) 
• possibly (event with reasonable time relationship to drug intake that could also be 
explained by disease or other drugs and information on drug withdrawal/re-challenge 
lacking or unclear) 
• probably (event occurred within reasonable time relationship to drug intake, is unlikely to 
be attributed to disease or other drugs and response to withdrawal) 
• definitely (event with plausible time relationship to drug intake which cannot be 
explained by disease or other drugs and/or plausible response to withdrawal and/or 
definitively pharmacologically plausible and/or positive re-challenge). 
 
6.9.5 
Expectedness 
An AE is expected if the nature, severity and outcome of the event are consistent with the 
reference safety information, i.e., the Investigator’s Brochure. 
6.9.6 
Clinical Significance 
Clinical significance is defined as any variation in physical/laboratory findings that has 
medical consequences that result in an alteration in the patient’s medical care. 
6.9.7 
Clinical Laboratory Adverse Events 
Any change in laboratory value outside the normal range will be regarded an AE if the 
investigator assesses the value as clinically significant. Changes in coagulation parameters 
expected in hemophilia patients are not regarded as AEs, unless they lead to clinical 
measures to prevent or treat any untoward events associated with the deviation of the 
parameter. 

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6.9.8 
Serious Adverse Events 
6.9.8.1 
Definition 
A serious adverse event (SAE) is defined as any AE occurring at any dose that results in 
death, is life-threatening, requires in-patient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect. 
Important medical events that may not result in one of the above may be considered SAEs 
when, based upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in patient hospitalization, or the development of drug dependency or drug abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered 
an SAE. 
6.9.8.2 
Reporting Serious Adverse Events 
The necessity and time requirements for reporting of SAEs to the Sponsor or designee and 
regulatory agencies are as follows: 
 All SAEs will be reported via the eCRF system within 24 hours of the Investigator’s first 
knowledge of the event, even if the event does not appear to be related to the study drug. 
If reporting via the eCRF is not available, the SAE may be recorded on the SAE form and 
reported via fax in order to meet the reporting requirements.  
 
In case of failure of the eCRF reporting, SAE forms 
are to be directed to:  
Fax:  +1 877-329-8717 (country-specific fax 
instructions will be provided where applicable) 
 For all SAEs, a detailed written description that includes copies of available relevant 
patient records, autopsy reports, and other documents will be sent within 24 hours of the 
Investigator’s first knowledge of the SAE.  
 SAEs that are life threatening or result in death, and are unexpected and related to study 
drug will be reported to regulatory authorities within 7 days of receipt of the event. Any 
follow up to the initial SAE report will be submitted to regulatory authorities within 8 
days of the initial report (ie, 15 days of receipt of the initial report).  
 Any SAE that is unexpected and related to study drug, results in hospitalization or 
prolongs an existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly/birth defect will be reported to regulatory 
authorities within 15 days of receipt of the report. Some regulatory authorities may have 

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alternative timelines for submission of suspected unexpected serious adverse reactions. In 
those cases, specific local requirements for submission of SAE reports will be applied. 
 All SAEs will be followed until resolution or stabilization. Follow-up reports for SAEs 
reported as 7- or 15-day reports will be submitted within the same time frame as the 
initial report. 
 
Additionally, the Institutional Review Board (IRB) and/or Ethics Committee (EC) must be 
notified in writing of any unexpected, related SAEs or as required by the local IRB/EC. It is 
the responsibility of the Investigator to notify the IRB/EC. 
If applicable, SAEs will be reported to the appropriate regulatory agencies by the Sponsor. In 
case the local regulations require notification through the investigator, the Sponsor will 
facilitate this process. 
Any SAEs ongoing at the time of study termination will be followed until resolution or 
stabilization, with a maximum of 30 days after last study drug administration. Any SAE 
occurring within 30 days of the last dose of study drug will be reported even if the SAE 
occurs after the study has ended.  
6.9.9 
Treatment-Emergent Adverse Events 
All AEs that occur after the first administration of the study drug will be regarded as 
treatment emergent. All AEs occurring from signing informed consent up to the first 
administration of the study drug will also be collected and will be referred to as non TEAEs. 
A potential risk associated with the administration of Coagulation Factor VIIa (Recombinant) 
is the occurrence of an allergic type reaction to either the recombinant molecule or any of the 
potentially present host related impurities. Specific emphasis will be put on the observation 
of the patient after administration of the study drug to detect the occurrence of any potential 
allergic reaction. Symptoms of such reaction may consist of, but are not limited to:  
• Skin redness, rash, hives 
• Mucosal and/or skin swelling 
• Difficulty breathing 
• Hypotension 
• Headache 
• Dizziness 
• Nausea 
 
If any one or more of these symptoms occur, the responsible physician at the site should 
assess the patient and determine whether the symptoms are consistent with an acute allergic 
reaction and treat the symptoms accordingly.  

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Although reported to be rare in hemophilia patients, a potential risk associated with the 
administration of LR769, Coagulation Factor VIIa (Recombinant) is an exaggerated PD 
action, leading to a thromboembolic event. Specific emphasis will be put on the observation 
of the patient directly after administration of the study drug as well as during the follow-up 
visits to detect the occurrence of any thromboembolic events. Events that may occur are 
myocardial infarction, ischemic cerebrovascular accident, arterial thrombosis (e.g., aorta, 
intestinal), deep venous thrombosis (DVT), and pulmonary embolism (PE). In case signs and 
symptoms of any of these occur in the patients during the study, the responsible physician at 
the site will need to assess the symptoms and order and review diagnostic procedures (ECG, 
ultrasound, CT, MRI, Doppler, D-dimer, etc.) as appropriate to confirm or refute the 
diagnosis. In case of symptoms suggestive of a DVT or PE, the guidelines for diagnosis as 
published by the American College of Physicians (Qaseem et al., 2007) is suggested as 
guidance for determining the need for additional diagnostic tools.  
In case an acute allergic reaction or a confirmed thrombotic event occurs in association with 
the administration of the study drug, such event should be reported in the same manner and 
timelines as a Serious Adverse Event (see Section 6.9.8.2), even when it does not meet the 
criteria for seriousness as listed in Section 6.9.8.1. 
6.10 Concomitant Medication Assessments 
All concomitant medication that was used by the patient during participation in the study will 
be recorded in the patients’ files and/or patients’ diaries and subsequently recorded in the 
eCRF. Specific emphasis will be put on the recording of concomitant medication for the 
treatment of bleeding episodes as well as for the treatment of pain. Patients who receive 
factor VIII or factor IX concentrates as part of either treatment of a bleeding episode or ITI 
therapy will maintain a detailed record of the actual treatment dates, times and doses. 
6.11 Study Stopping Rules 
The study will be stopped (i.e., cease enrollment as well as treatment of already enrolled 
patients) in the following cases: 
• The Data Monitoring Committee (DMC) recommends after their scheduled review, or 
after an ad-hoc meeting in case of an SAE, that the study should be (temporarily) stopped 
• A confirmed thrombotic event has been reported in any of the patients treated in the study 
• An acute allergic reaction, or signs and symptoms strongly indicative of such reaction, 
has occurred in association with the administration of LR769 
• A patient develops a neutralizing antibody to LR769 
 
If one of these events occurs, participating sites, competent authorities as well as all involved 
ECs/IRBs will be informed of the (temporary) stop of the study. Investigations into the 
case(s) will need to be done and the results will then be reported to the competent authorities 
and ECs/IRBs, together with a recommendation on whether and how to proceed with the 

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study. Only after approval of the competent authorities and ECs/IRBs may the study 
continue. 
6.12 Removal of Patients from the Trial or Study Drug 
The investigator may withdraw a patient from the study for any of the following reasons: 
• The investigator believes it is in the best interest of the patient to discontinue the study, or 
• A protocol deviation occurs that makes the interpretation of the data not feasible, or 
• A clinically significant change in a laboratory parameter occurs that does not allow safe 
administration of the study drug and/or interferes with the interpretation of the study 
results, or 
• Lack of compliance with study requirements, or 
• The sponsor or investigator terminates the study, or 
• The patient requests to be discontinued from the study. 
In case of early withdrawal of the patient, he will be asked to perform the end of study visit 
assessments, unless he has withdrawn informed consent. 
6.13 Replacement of Patients 
Patients who are withdrawn will only be replaced if the minimum number of 
patients/bleeding episodes needed for Phase A or Phase B will not be met. 
6.14 Other Study Procedures 
For the healthcare resource utilization assessments, the direct healthcare costs will be 
determined by collecting data on use of product, number of visits to hospital/hemophilia 
treatment center, days of inpatient hospitalization and use of concomitant treatments. 
Secondary economic effects will be assessed by collecting data on days away from school or 
work. 
6.15 Appropriateness of Measurements 
Efficacy assessments are done according to existing guidelines and published literature. The 
patient/parent is the best person to assess the effect of the treatment on the bleed, as it most 
often is an internal bleeding episode in a joint or soft tissue. 
Occurrence of pain and progression/resolution of pain is assessed at each efficacy assessment 
timepoint. Pain caused by a bleeding episode will be measured in the patient diary on a VAS 
in millimeters from 0 (no pain) to 100 (worst possible pain).  
Analysis of concomitant medications will be performed in the trial with a focus on clotting 
factors (FVIII, FIX, FVIIa), blood products, analgesics, anti-inflammatory agents, and other 
drugs that may impair platelet and/or coagulation function. 

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7 
STUDY ACTIVITIES 
7.1 
Phase A: Initial Safety and PK Phase 
7.1.1 
Screening (Days -21 to -1) 
• Informed consent signature 
• Determine eligibility 
• Demographics (Date of birth, race/ethnicity, sex) 
• Medical history 
• Physical examination, including height and weight 
• Safety labs (hematology, coagulation, chemistry), by central lab 
• Vital signs 
• Assessment of concomitant medication 
• Assessment of AEs 
 
7.1.2 
Visit 1 (Day 0) Procedures 
At randomization, patients will also be assigned to a specific PK sampling schedule. Half of 
the patients will be assigned to sampling schedule 1: at 10±2 minutes, 1 and 4 hours (±10 
minutes). The other half will be assigned to sampling schedule 2: at 30±5 minutes and 2 and 
8 hours (±10 minutes) relative to the start of infusion of study drug. 
7.1.2.1 
Predose 
• Confirmation of eligibility (patient should not have received any FVIIa product within 24 
hours prior to study drug administration) 
• Physical examination 
• Vital signs 
• Randomization 
• Blood sample for Pharmacokinetic Assessment 
• Assessment of concomitant medication 
• Assessment of AEs 
• Immunogenicity sample  
 
7.1.2.2 
Drug Administration (0 min) 
• A ≤2 minute IV push of 75 µg/kg or 225 µg/kg of LR769, depending on dosing 
randomization of the patient 
• Assessment of AEs  
 

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7.1.2.3 
10±2 min after start of infusion 
• Blood sample for PK Assessment (when assigned to sampling schedule 1) 
• Assessment of AEs  
 
7.1.2.4 
30±5 min after start of infusion 
• Vital signs 
• Blood sample for PK Assessment (when assigned sampling schedule 2) 
• Assessment of AEs  
 
7.1.2.5 
1 hour ±10 minutes after start of infusion 
• Vital signs 
• Blood sample for PK Assessment (when assigned to sampling schedule 1) 
• Assessment of AEs 
 
7.1.2.6 
2 hours ±10 minutes after start of infusion 
• Vital signs 
• Blood sample for PK Assessment (when assigned to sampling schedule 2) 
• Assessment of AEs 
 
7.1.2.7 
4 hours ±10 minutes after start of infusion 
• Vital signs 
• Blood sample for PK Assessment (when assigned to sampling schedule 1) 
• Assessment of AEs  
 
7.1.2.8 
8 hours ±10 minutes after start of infusion 
• Vital signs 
• Blood sample for PK Assessment (when assigned to sampling schedule 2) 
• Assessment of AEs 
 
7.2 
Phase B: Treatment of a Bleeding Episode 
Treatment of any bleeding episode will be initiated as soon as possible, but certainly within 4 
hours of first symptoms of the onset of the bleeding episode. 

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7.2.1 
Mild/Moderate Bleeding Episode Procedures 
7.2.1.1 
Pre treatment 
• AE assessment 
• Assessment of concomitant medication 
• Bleeding Episode Characteristics  
– Location 
– Date/Time of start of bleeding episode 
– Severity 
– Spontaneous/traumatic 
• Patient Diary 
 
7.2.1.2 
Treatment (Time 0 hrs) 
• A ≤2 min IV push of 75 or 225 µg/kg of LR769, depending on the dosing randomization 
of the patient and the 12 weeks treatment regimen he is in at the time of bleeding episode 
• Record date, time and total dose of study drug as well as number and lot of vials used for 
preparation in patient diary (patient/parent); if in hospital or hemophilia treatment center 
in patient records by study staff 
• AE assessment 
• Assessment of concomitant medication 
 
7.2.1.3 
3, 6, 9, 12, 15, 18, 21 hours after first administration 
• AE assessment (assessed over a period of 21 hours after first study drug administration, 
reported by the patient/parent in the patient diary if home treatment and in addition by 
study staff if in hospital or hemophilia treatment center)  
• Efficacy assessments (within 15 minutes before each new administration of the study 
drug) to be done by the patient/parent if home treatment and by study staff if in hospital 
or hemophilia treatment center in addition to patient assessments 
• Record date, time and outcome of the assessments in patient diary (patient/parent); if in 
hospital or hemophilia treatment center in patient records by study staff in addition to 
patient’s assessment 
• Assessment of concomitant medication 
 
ADMINISTRATION OF STUDY DRUG: 
When in 75 µg/kg dose treatment regimen: 
– If response to treatment 3 hours after last administration is unsatisfactory (i.e., 
efficacy assessment is not rated as good or excellent): a ≤2 min IV push of 75 

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µg/kg of LR769 may be administered. This may be repeated, if needed every 3 
hours up to and including 21 hours after first administration. 
– If response to treatment 3 hours after the first or any of the subsequent 
administrations is satisfactory (i.e., efficacy assessment is rated as good or 
excellent): no study drug administration. Perform the 3 hourly efficacy assessments 
until 3 hours after the last administration as well as the 12 hours efficacy 
assessments (if not already done). 
 
When in 225 µg/kg dose treatment regimen: 
– If response to treatment 9 hours after first administration is unsatisfactory (i.e., 
efficacy assessment is not rated as good or excellent): a ≤2 min IV push of 75 
µg/kg of LR769 may be administered. This may be repeated, if needed every 3 
hours up to and including 21 hours after first administration. 
– If response to treatment 9 hours after first administration, or 3 hours after any 
subsequent administrations, is satisfactory (i.e., efficacy assessment is rated as good 
or excellent): no study drug administration. Perform the 12 hours efficacy 
assessments (if not already done). 
• Record date, time and total dose of study drug as well as number and lot of vials used for 
preparation in patient diary (by the patient/parent); if in hospital or hemophilia treatment 
center in patient records by study staff. 
• If, because of an initial sufficient response at 9 hours post initial dose of study drug, no 
additional study drug is administered, it may re-started before the 24-hour cut off in case 
of a recurrence of a bleeding episode. This should be noted in the patent’s diary. 
 
24 HOURS AFTER FIRST ADMINISTRATION 
• AE assessment 
• Efficacy assessments. If the response to treatment is still unsatisfactory (i.e., efficacy 
assessment is not rated as good or excellent): do not administer any more study drug. 
Alternative treatment should be initiated in consultation with the study staff. 
• Record date, time and outcome of the assessments in patient diary (by the patient/parent); 
if in hospital or hemophilia treatment center in patient records by study staff in addition 
to patient’s assessment 
• Assessment of concomitant medication 
 
7.2.2 
Severe Bleeding Episode Procedures 
Severe bleeding episodes always need to be treated in a hospital or hemophilia treatment 
center. Exception may be the first administration for the treatment of a bleeding episode, 
which can be done at home if the patient qualifies for that (see Section 3.1.2.3). 
7.2.2.1 
Pre Treatment 
• AE assessment 

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• Assessment of concomitant medication 
• Bleeding Episode Characteristics  
– Location 
– Date/time of start of bleeding episode 
– Severity 
– Spontaneous/traumatic 
• Patient Diary 
 
7.2.2.2 
Treatment (Time 0 hrs) 
• A ≤2 min IV push of 75 or 225 µg/kg of LR769, depending on the dosing randomization 
of the patient and the 12 weeks treatment regimen he is in at the time of the bleeding 
episode 
• Record date, time and total dose of study drug as well as number and lot of vials used for 
preparation in patient diary (by the patient/parent); if in hospital or hemophilia treatment 
center in patient records by study staff 
• AE assessment 
• Assessment of concomitant medication 
 
7.2.2.3 
After first administration until improvement of the bleeding episode 
• AE assessment (reported by the patient/parent) in the patient diary and by study staff in 
the patient records in hospital or hemophilia treatment center)  
• Assessment of concomitant medication 
• Efficacy assessments (before each new administration of the study drug to be done by the 
patient/parent) if home treatment and by study staff if in hospital or hemophilia treatment 
center in addition to patient’s assessments. 
• Record date, time and outcome of the assessments in patient diary (by the patient/parent); 
if in hospital or hemophilia treatment center in patient records by study staff in addition 
to patient’s assessment 
 
ADMINISTRATION OF STUDY DRUG: 
When in 75 µg/kg dose treatment regimen: 
– If response to treatment 2 hours after first or any subsequent administration is 
unsatisfactory (i.e., efficacy assessment is not rated as good or excellent): a ≤2 min 
IV push of 75 µg/kg of LR769 may be administered.  
– If 2 hours after last administration the bleeding episode has improved (i.e., efficacy 
assessment is rated at least as moderate): change to treatment at 3-hour intervals for 
1-2 days until good or excellent result is reached  
– After 1-2 days, the interval may be increased to 4-12 hours depending on the type of 
bleeding episode for as long as needed 
 

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When in 225 µg/kg dose treatment regimen: 
– If response to treatment 6 hours after first administration is unsatisfactory (i.e., 
efficacy assessment is not rated as good or excellent): a ≤2 min IV push of 
75 µg/kg of LR769 may be administered. This will be repeated every 2 hours until 
improvement in bleeding symptoms is observed 
– If response to treatment after the first or any subsequent administration is satisfactory 
(i.e., efficacy assessment is rated as good or excellent): change to 3 hour intervals 
of treatment for 1-2 days 
– After 1-2 days, the interval may be increased to 4-12 hours depending on the type of 
bleeding episode for as long as needed  
• Record date, time and total dose of study drug as well as number and lot of vials used for 
preparation in patient diary (by the patient/parent); if in hospital or hemophilia treatment 
center in patient records by study staff. 
 
7.2.2.4 
During Continued Treatment 
• AE assessment 
• Assessment of concomitant medication 
• Efficacy assessments:  
• before each new administration of study drug 
• at 12 and 24 hours after start of study drug treatment (if not done as part of pre 
administration assessment) 
• 12 hours after last study drug administration 
• Record date, time and outcome of the assessments in patient diary (by the patient/parent); 
if in hospital or hemophilia treatment center in patient records by study staff in addition 
to patient’s assessment 
• Administration of study drug: continue with every 3 hours administration of a ≤2 min IV 
push of 75 µg/kg of rhFVIIa as long as indicated by the treating physician for 1-2 days, 
depending on the severity and location of the bleeding episode. The duration and 
treatment interval may be extended (up to every 4-12 hours) based on the judgment of the 
treating physician. 
• Record date, time and total dose of study drug as well as number and lot of vials used for 
preparation in patient diary (by the patient/parent) if treatment is continued at home); if 
still in hospital or hemophilia treatment center in patient records by study staff 
 
7.2.3 
Rescue Treatment 
In case of an insufficient effect of LR769 (e.g., insufficient effect after 24 hours for a 
mild/moderate bleeding episode, or continued excessive bleeding in a severe bleeding 
episode), the treating physician should stop treatment with LR769 and treat the patient with 
another therapy, such as the treatment they used prior to enrollment in this study. This may 

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7.3.3 
12 Weeks (±5 days) visit  
• Check for physical signs of thromboembolic events 
• Safety labs (hematology, chemistry) 
• Immunogenicity sample 
• Weight and dose adjustment if necessary 
• Crossover to alternative treatment regimen 
• Vital signs 
• AE assessment 
• Assessment of concomitant medication 
• Drug accountability 
• Healthcare utilization assessments 
• Patient diary check and collection 
• Issue new diary 
 
7.3.4 
18 Weeks (±5 days) visit  
• Immunogenicity sample 
• AE assessment 
• Assessment of concomitant medication  
• Check for physical signs of thromboembolic events 
• Weight and dose adjustment if necessary 
• Drug accountability  
• Patient diary check and collection 
• Issue new diary 
 
7.3.5 
24 Weeks (±5 days) visit 
• Immunogenicity sample  
• Safety labs (hematology, chemistry) 
• FVIII or FIX inhibitor sample for central lab 
• Physical examination, including check for physical signs of thromboembolic events 
• Weight and dose adjustment if necessary 
• Vital signs 
• AE assessment 
• Healthcare utilization assessments 
• Assessment of concomitant medication 
• Drug accountability  

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• Patient diary check and collection 
• Issue new diary 
 
7.3.6 
All Subsequent Visits 6 and 12 Weeks after Week 24 visit 
7.3.6.1 
6 Weekly (±5 days)  
• Immunogenicity sample 
• AE assessment 
• Assessment of concomitant medication 
• Weight and dose adjustment if necessary 
• Check for physical signs of thromboembolic events 
• Drug accountability  
• Patient diary check and collection 
• Issue new diary 
 
7.3.6.2 
12 Weekly (±5 days)  
• Immunogenicity sample 
• Check for physical signs of thromboembolic events 
• Weight and dose adjustment if necessary 
• Crossover to alternative treatment regimen 
• Vital signs 
• AE assessment 
• Healthcare utilization assessments 
• Assessment of concomitant medication 
• Drug accountability  
• Patient diary check and collection 
• Issue new diary 
 
7.3.7 
End of Study Visit/Early Termination Procedures 
• Immunogenicity sample 
• Safety labs (hematology, chemistry) 
• FVIII or FIX inhibitor sample for central lab 
• Vital signs 
• Physical examination, including check for physical signs of thromboembolic events 
• AE assessment 

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• Healthcare utilization assessments 
• Assessment of concomitant medication 
• Drug accountability and patient diary collection 
 

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8 
QUALITY CONTROL AND ASSURANCE 
This study will be sponsored by LFB USA Inc. The sponsor will delegate specific tasks 
regarding the conduct of this study to a contract research organization (CRO).  
Quality Control Procedures as described in LFB USA’s Quality System as well as those of 
the CRO will be applied. A document describing which procedures will be used for which 
study activities at each stage of the clinical study will be part of the arrangements between 
the Sponsor and the CRO. This will ensure patient safety and reliability of the data. 
Monitoring visits to the study sites will be conducted periodically during the study according 
a study specific monitoring plan to ensure that all aspects of the protocol are being followed. 
The study site may be audited by LFB USA’s Clinical Quality Assurance auditor (or 
designee). The study sites will receive written notice in advance of any audit. 

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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
This section outlines the key components of the planned statistical analyses. Detailed 
methodology for the statistical analyses will be documented in a Statistical Analysis Plan 
(SAP). The SAP may modify the plan outlined in the protocol; however, any major 
modifications will also be reflected in a protocol amendment. If after database lock changes 
are made to the SAP, these deviations will be documented in the Clinical Study Report 
(CSR). 
All data collected in this study will be documented using summary tables and patient 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. 
Where applicable, analyses will be done for all patients and by age group (aged from birth to 
<6 years and ≥6 years to <12 years). 
9.2 
Determination of Sample Size 
The proportion ( pˆ ) of mild/moderate bleeding episodes treated with each dose of LR769 that 
are classified as being successfully treated will be compared with an objective performance 
criterion (OPC) of 0.55. A one-sided, one-sample normal approximation test, with an alpha = 
0.0125 (adjusted from 0.025 to 0.0125 to account for multiplicity of testing), will be used to 
test the null hypothesis that p ≤ 0.55 versus the alternative hypothesis that p > 0.55, where p 
is the true proportion of mild/moderate bleeding episodes that are classified as successes. 
(Note: The standard error used in the denominator of the test statistic will account for the 
correlation among bleeding episodes for a given patient.) This will be done for each 
treatment regimen. 
With the assumptions of a true proportion of success of 0.70, a correlation among bleeding 
episodes for a given patient of 0.1, and an OPC of 0.55, a sample size of 22 patients with a 
total of 352 mild/moderate bleeding episodes (assuming 8 bleeding episodes per treatment 
regimen per patient) will provide statistical power ≥ 80%. The study will enroll at least 24 
patients, in order to account for dropouts and potential unevaluable bleeding episodes. 
9.3 
Analysis Populations  
The Enrolled Population will be defined as all patients who signed informed consent. 
Analyses of non TEAEs will be done on the Enrolled Population. 
The Safety Population will be defined as all patients who received treatment (either in Phase 
A and/or Phase B). All analyses of safety will be performed based on the Safety Population. 

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The Treated Population will be defined as all patients who received treatment for at least one 
bleeding episode, and each such bleeding episode will be analyzed as treated. All analyses of 
efficacy will be performed based on the Treated Population. 
The Evaluable PK Population will be defined as all treated patients who have a post-study 
drug administration factor VIIa activity level. All PK analyses will be based on the Evaluable 
PK Population. 
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics for all patients, patients in the PK group and for 
patients in each dose group will be summarized using descriptive statistics for continuous 
variables and frequencies and percentages for categorical variables. 
9.5 
Primary Endpoint 
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is defined as successful treatment of a bleeding 
episode at 12 hours after first administration of the study drug.  The following are 
clarification definitions to satisfy regulatory requirements in multiple regions (i.e., the FDA 
and the EMA). 
For primary efficacy endpoint for the FDA, only mild/moderate bleeding episodes are taken 
into account. Severe bleeding episodes will be a minority of the bleeding episodes treated in 
the study, and require further treatment even if the bleeding has improved. Efficacy in severe 
bleeding episodes will be analyzed separately, using descriptive statistics only.  
The primary efficacy endpoint for the FDA is defined as the successful treatment of a 
bleeding episode at 12 hours (bleeding episode level), where a success is defined as meeting 
all of the following criteria:  
• Good or Excellent response noted by patient/parent/guardian,depending on patient’s age 
and maturity 
• Study drug treatment: No further treatment with study drug beyond timepoint where a 
Good or Excellent response for this bleeding episode was noted 
• No other hemostatic treatment needed for this bleeding episode 
• No administration of blood products indicating continuation of bleeding beyond 
timepoint where a Good or Excellent response for this bleeding episode was noted 
• No increase of pain beyond timepoint where a Good or Excellent response for this 
bleeding episode was noted that cannot  be explained other than as continuation of 
bleeding   
  
For each LR769 treatment, the proportion ( pˆ ) of mild/moderate bleeding episodes rated as 
successfully treated at 12 hours will be summarized using the count and percentage. A 95% 

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normal approximation CI for the true percentage will be calculated taking into account the 
correlation between bleeding episodes for a given patient in calculating the standard error of 
the estimate pˆ .  
The null and alternative hypotheses for the primary efficacy endpoint are as follows: 
        H0: p ≤0.55 
        H1: p >0.55. 
The null hypothesis will be tested using a one-sided, one-sample, normal approximation test 
and a test statistic obtained by dividing ( pˆ -0.55) by its estimated standard error, taking into 
account the correlation between bleeding episodes for a given patient. The test will be 
conducted at the 0.0125 level (adjusted from 0.025 to 0.0125 to account for multiplicity of 
testing). Treatment of mild/moderate bleeding episodes in the study with LR769 of a given 
dose will be regarded as successful if it is concluded that the true percentage of successfully 
treated bleeding episodes with that dose is greater than 0.55. The primary endpoint for the 
FDA is to satisfy the requirements of the US FDA for the evaluation of success. 
No imputation of missing data will be performed for the primary analysis of the primary 
efficacy endpoint. However, two sensitivity analyses will be performed in order to examine 
the effect of missing data, if any, on the results of the primary analysis. In the first sensitivity 
analysis, all bleeding episodes for which the value of the primary efficacy endpoint is 
missing will be assigned as failures. In the second sensitivity analysis, all such bleeding 
episodes will be assigned as successes. 
In addition, the proportions of successfully treated mild/moderate bleeding episodes will be 
compared between the two LR769 treatment doses at a 2-sided alpha of 0.05. 
Two sensitivity analyses based on Generalized estimating equations (GEE) logistic 
regression analyses and Generalized linear mixed effects models (GLMM) will be used to 
assess the robustness of the result by accounting for the within-subjects correlation.  
The primary efficacy endpoint for the EMA is defined as the proportion of bleeding episodes 
(mild/moderate and severe combined) with a “good” or “excellent” patient (for 
mild/moderate bleeding episodes) and physician (for severe bleeding episodes) reported 
assessment of efficacy at 12 hours after the first administration of study drug. This proportion 
of success will be evaluated by the EMA as part of the assessment of the benefit risk ratio for 
each dosing regimen. 
9.6 
Secondary Endpoints 
The secondary efficacy endpoints consist of the following: 
• Proportion of mild/moderate bleeding episodes successfully treated according to the same 
criteria as the primary endpoint of efficacy, at all other timepoints  

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• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” patient (and/or physician when available) reported 
assessment of efficacy at all timepoints 
• Time to assessment of a “good” or “excellent” response of the bleeding episodes 
(mild/moderate and severe, separately and combined) by the patient (and/or physician 
when available) 
• Descriptive analysis of the number of administrations and mean total amount of drug 
administered per bleeding episode  
 
For each treatment regimen and both treatment regimens together, the proportions of 
bleeding episodes successfully treated, according to the same criteria as the primary endpoint 
of efficacy at all timepoints will be summarized using descriptive statistics, and a 95% CI for 
the true mean patient level proportion will be calculated based on normal approximation. 
For each treatment regimen and both treatment regimens together, the proportions of 
bleeding episodes with a “good” or “excellent” patient reported assessment of the efficacy at 
all timepoints will be summarized using descriptive statistics, and a 95% CI for the true 
proportion will be calculated based on normal approximation. 
 
The time to assessment of a “good” or “excellent” response of the bleeding episodes 
(mild/moderate and severe, separately and combined) by the patient/parent will be analyzed 
at the bleeding episode level using the K-M method to estimate the survival distribution for 
this endpoint for each treatment regimen separately and combined. Patients who receive 
rescue treatment at any time will be considered failures and will be assigned a censored value 
at the final timepoint. Patients who do not achieve a “good” or “excellent” response will be 
censored at the time of last response. 
 
9.7 
Tertiary Efficacy Endpoints 
The tertiary efficacy endpoints consist of the following: 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with a “good” or “excellent” physician reported assessment of the efficacy at 12 hours (if 
available) 
• Proportion of recurrences (defined as a bleeding in the same joint/anatomical location 
within 24 hours after an initial successful response 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
requiring alternative treatment 
• Proportion of bleeding episodes (mild/moderate and severe, separately and combined) 
with successful pain relief 
 
For each treatment, the mean number of administrations and mean total amount of drug 
administered per bleeding episode (mild/moderate and severe, separately and combined) will 

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be summarized using descriptive statistics. Also a 95% CI for the true mean will be 
calculated based on normal approximation. 
9.8 
Safety Analyses 
All AEs will be coded using MedDRA. The number and percentage of patients with any 
AEs, any SAEs, and any TEAEs will be presented for all patients and for the different dose 
regimens and Phases A and B separately. An AE will be considered treatment related if it has 
a definite, probable, or possible relationship to the study treatment or if the relationship to the 
study treatment is missing. AEs will be summarized at the patient level by MedDRA SOC 
and PT using frequencies 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. 
Descriptive statistics for the actual value at each timepoint and the change from baseline to 
each post-baseline timepoint in systolic and diastolic BP, heart rate, respiratory rate, and 
body temperature will be tabulated for each treatment. Two-sided paired t-tests will be used 
to test whether the mean changes from baseline equal 0. Baseline is defined as the last 
measurement prior to study treatment.  
For continuous laboratory parameters, descriptive statistics for the actual value at each 
timepoint and the change from baseline (screening) to each post baseline timepoint will be 
tabulated for each treatment. Two-sided paired t-tests will be used to test whether the mean 
changes from baseline equal 0. Shift tables for laboratory parameters will be prepared. 
9.9 
Pharmacokinetic Analyses 
A separate PKAP will be written and signed off prior to performing the analyses. 
Descriptive statistics for plasma concentrations at each timepoint and for PK parameters will 
be tabulated and FVIIa concentration data (as measured by activity assay) over time will be 
graphically presented.  
Pharmacokinetic data analysis will be performed using non-linear mixed effects modeling, 
which considers the repeated PK observations as a function of time using all available PK 
data collected in hemophilia patients who have received LR769 to date. Estimates and 
summary statistics of PK parameters (clearance, Cl; volume of distribution, Vd; terminal 
half-life, t1/2; area under the plasma concentration-time curve from time 0 to infinity, AUC0-
inf; and maximum  plasma concentration, Cmax. will be presented by dose group. The analyses 
will closely follow the guidelines of the US FDA and EMA for performing and reporting 
population PK analyses (FDA, 1999; EMA, 2007).  
Analyses of the PK of LR769 in pediatric patients will be based on the evaluable PK 
population. It is expected that at least 10 of the 12 PK patients in each age group will be 
evaluable (for both PK assessments).  

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9.10 Other Analyses 
A descriptive analysis of the healthcare utilization by patients treated with LR769 will be 
performed. For this purpose, data will be collected on use of product, number of visits to 
hospital, days of inpatient hospitalization, use of concomitant medication, and patient’s days 
away from school or work (if applicable) for patient and parent/legal guardian due to 
bleeding episodes. 
9.11 Interim Analysis 
One interim analysis will be performed: 
• Upon availability of FVIIa plasma activity data for at least 6 patients in each age group, 
PK profiles along with all safety and efficacy data available at that time will be reviewed 
by the DMC. Data will be used to identify any unexpected results that may impact safety 
or efficacy. 
• At the time at least 80 bleeding episodes have been treated, data collected will be 
reviewed to identify any safety or efficacy issues. 
 
The DMC will review these data and make recommendations to continue the study unaltered, 
or to make any modifications to the study. 
 

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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The Sponsor will 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 in order to assure that the study is conducted according to all applicable rules and 
regulations. 
The Principal 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 (GCP) and any other local regulations and guidelines. 
The Principal Investigator will review all study related documents including the protocol and 
the current version of the Investigator’s Brochure. It is essential that the Principal 
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) or Independent Ethics Committee 
(IEC) Approval 
A copy of the protocol, Investigator’s Brochure, proposed Informed Consent/Assent Form 
and any other written patient information must be submitted to the IRB/IEC for written 
approval. A copy of the written IRB/IEC approval of the protocol and Informed 
Consent/Assent Form must be received by the Sponsor before recruitment of patients into the 
study and shipment of investigational drug.  
The Principal Investigator must submit and, where necessary, obtain approval from the 
IRB/IEC for all subsequent protocol amendments and changes to the informed consent form. 
The Principal Investigator should notify the IRB/IEC of deviations from the protocol or 
SAEs/reportable safety events at the site or reports of such events received from the sponsor 
in accordance with local procedures.  
The Principal Investigator will be responsible for obtaining annual IRB/IEC approval and 
renewal throughout the duration of the study. 
The Principal Investigator will promptly report to the IRB/IEC all changes in research 
activity and all unanticipated problems involving risks to human patients and will not make 
any changes in the research without prior Sponsor and IRB/IEC approval, except where 
necessary to eliminate immediate hazards to human patients. 
10.3 Ethical Conduct of the Study 
This study will be conducted in compliance with 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 

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principles stated in the Declaration of Helsinki (October 2013 revised version). All other 
applicable regulations will be adhered to. 
10.4 Patient Information and Consent 
Written informed consent must be obtained for all patients who are potential study candidates 
before any study-specific tests or procedures are performed. Parent/legal guardian of the 
patients who meet general entry criteria will be asked to sign the study-specific, IRB/IEC 
approved Informed Consent form before any study-specific test or procedures are performed. 
The written informed consent will be obtained after the context of the study has been fully 
explained to the patient’s parent/legal guardian in a language that is easily understood by the 
parent/legal guardian. There must also be adequate opportunity to ask questions and have 
those questions answered to their satisfaction. Study personnel will explain that even if a 
patient/parent(s)/legal guardians agree to participate in the study and signs an Informed 
Consent form, the study-specific test or procedures may demonstrate that the patient is not a 
candidate for the study.  
The written informed consent will be prepared in the language(s) of the potential study 
population and will be administered according to national requirements.  
The patient may, depending on his age, receive age-appropriate information as well as asked 
to sign and date an assent form. Age of providing information and assent form may differ 
between institutions and will be determined by local law and IRB or IEC requirements. 
10.5 Patient Confidentiality 
Patient participation is voluntary and patients or his parents/guardians may refuse to 
participate or withdraw from the study at any time and for any reason. Patients and/or their 
parents/guardians 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. 
Patients will be identified only by a patient number and date of birth. They will be informed 
as to the strict confidentiality of their patient data, and that their medical records may be 
reviewed for study purposes by authorized individuals other than their treating physician. 
10.6 Study Monitoring 
Monitoring visits to the Study Sites will be conducted periodically during the study 
according to the study monitoring plan to ensure that all aspects of the current, approved 
protocol are being followed. Monitors will be given direct access to original source 
documents, which will be reviewed for 100% data verification captured in the eCRF. For this 
study, source documents include but are not limited to the Informed Consent Form, patient’s 
medical records, patient diaries, laboratory results, reports of SAEs, and drug accountability 
logs. It is important that the investigator and relevant study personnel are available during 
monitoring visits and audits and that sufficient time is devoted to the process. 

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10.7 Case Report Forms and Study Records 
Patient data will be collected both electronically and on paper. The Principal Investigator 
must ensure the accuracy and completeness of the recorded data and provide his/her 
signature on the appropriate eCRFs and/or in the electronic system. The Investigator’s 
electronic signature for specific eCRFs 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 eCRF. Queries will be 
created in the data management system and will be issued for appropriate response. 
10.8 Data Monitoring Committee 
The DMC is responsible for the oversight of patient safety. The DMC will consist of three 
specialists in the care of hemophilia patients. DMC members will be independent of the 
study and sponsor. During the course of the trial, the DMC will review efficacy, PK, and/or 
safety data at a minimum of the following timepoints: 
• Each serious adverse drug reaction (i.e., an SAE for which at least a possible, probable, 
or definite causal relationship is assessed by the investigator and/or the sponsor) 
• Quarterly: a concise cumulative listing of all SAEs (regardless of relationship to study 
drug) that occurred in the study 
• After interim analysis specified in Section 9.11 
 
The DMC will make recommendations, as appropriate, for study modification or termination 
because of concerns over patient safety or issues relating to data monitoring or quality 
control. This will be submitted in writing to the sponsor’s Medical Monitor for consideration 
and final decision. However, if the DMC at any time determines that a potential serious risk 
exists to patients in the trial, the DMC Chairperson will immediately notify the Sponsor’s 
Medical Monitor per the DMC Charter. 
10.9 Protocol Deviations 
Deviations from clinical protocol requirements will be reviewed and evaluated on an ongoing 
basis and, as necessary, appropriate corrective actions put into place. 
An important subset of protocol deviations is “important protocol deviations,” which are 
defined by ICH E3 as “protocol deviations that may significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a patient’s rights, 
safety, or well being. For example, important protocol deviations may include enrolling 
patients in deviation of key eligibility criteria designed to ensure a specific patient population 
or failing to collect data necessary to interpret the primary endpoint, as this may compromise 
the scientific value of the trial.” An example of an important protocol deviation provided in 
the guideline is “deviations related to entry criteria, conduct of the trial, patient management, 
or assessment.” An analysis of important protocol deviations will be presented in the CSR. 

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10.10 Criteria for Terminating Study 
The sponsor reserves the right to terminate the study at any time, but intends only to exercise 
this right for valid scientific or administrative reasons and reasons related to patient safety 
and protection. Investigators and the associated IRB/IEC will be notified in the event of 
unplanned termination.  
Possible reasons for unplanned study termination include but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study. 
• A decision on the part of the sponsor to suspend or discontinue development of the 
investigational product 
 
10.11 Criteria for Suspending/Terminating a Study Center 
The sponsor reserves the right to terminate enrollment of patients at a study site at any time 
after study initiation. Reasons for site termination or suspension include, but are not limited 
to: 
• Non-enrollment of patients 
• Significantly slower-than-expected enrollment 
• The study site has multiple and/or critical protocol deviations without justification or fails 
to follow corrective actions 
• Failure to obtain/maintain IRB/IEC approval 
• Failure to obtain written informed consent 
• Failure to report SAE within 24 hours of knowledge 
• Failure to enter data in the eCRF in a timely manner 
• Loss of, or unaccounted for, investigational product inventory 
 
10.12 Access to Source Documentation 
The monitor (or auditors, regulatory inspectors) will check the eCRF form entries against the 
original source documents. The consent form will include a statement by which the patients 
allow the monitor/auditor/inspector access to source data (e.g., original laboratory reports 
etc.) which substantiate information in the eCRF. 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). 

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10.14 Retention of Data 
The investigator/institution will maintain the trial documents as specified in ICH E6 Good 
Clinical Practice Consolidated Guidance and as required by the applicable regulatory 
requirement(s). The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents. If for any reason the Principal Investigator 
withdraws responsibility for maintaining the trial documents, custody must be transferred to 
an individual who will assume responsibility. The sponsor must receive written notification 
of this custodial change. 
Essential documents will be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. 
10.15 Financial Disclosure 
All rules and regulation 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 public databases on clinical studies www.clinicaltrials.gov and 
www.clinicaltrialsregister.eu. A summary report of the study will be made available after the 
conclusion of the study. The final report may be submitted to relevant regulatory authorities 
to support a request for product registration. It is the intention of the sponsor to publish the 
results of this study in a peer-reviewed journal. 

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11 REFERENCE LIST 
Amby LK, Seremetis S, Obergfell A, Bjerre J (2009) Challenges of defining reliable clinical 
surrogate end points in haemophilia trials: a critical review. Blood Coagul Fibrinolysis 
20:488-493 
Astermark J (2006) Overview of inhibitors. Semin Hematol 43:S3-S7 
Biggs R, Douglas AS, MacFarlane RG, Dacie JV, Pitney WR, Merskey (1952) Christmas 
disease: a condition previously mistaken for haemophilia. Br Med J 2:1378-1382 
Hay CR, Brown S, Collins PW, Keeling DM, Liesner R (2006) The diagnosis and 
management of factor VIII and IX inhibitors: a guideline from the United Kingdom 
Haemophilia Centre Doctors Organisation. Br J Haematol 133:591-605 
Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, Gilchrist GS, 
Gill JC, Glader B, Hoots WK, Kisker CT, Lusher JM, Rosenfield CG, Shapiro AD, Smith H, 
Taft E (1998) Home treatment of mild to moderate bleeding episodes using recombinant 
factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 80:912-918 
Lee M, Morfini M, Schulman S, Ingerslev J (2001) Scientific and Standardization Committee 
Communication The Design and Analysis of Pharmacokinetic Studies of Coagulation 
Factors. ISTH org 
Obergfell A, Auvinen MK, Mathew P (2008) Recombinant activated factor VII for 
haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the 
literature. Haemophilia 14:233-241 
Patek AJ, Taylor FH (1937) Hemophilia. II. Some properties of a substance obtained from 
normal human plasma effective in accelerating the coagulation of hemophilic blood. J Clin 
Invest 16:113-124 
Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, 
Bass EB, Weiss KB, Green L, Owens DK (2007) Current diagnosis of venous 
thromboembolism in primary care: a clinical practice guideline from the American Academy 
of Family Physicians and the American College of Physicians. Ann Intern Med 20;146:454-
458 
Stonebraker JS, Bolton-Maggs PH, Soucie JM, Walker I, Brooker M (2010) A study of 
variations in the reported haemophilia A prevalence around the world. Haemophilia 16:20-32 
Takedani H, Kawahara H, Kajiwara M (2010) Major orthopaedic surgeries for haemophilia 
with inhibitors using rFVIIa. Haemophilia 16:290-295 

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White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J (2001) 
Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII 
and factor IX of the scientific and standardization committee of the International Society on 
Thrombosis and Haemostasis. Thromb Haemost 85:560 
 

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Appendix 1 
Schedule of Events 
Phase A - Initial Safety and PK Phase 
Evaluation 
Screening 
Days -21 to-1 
Pre-
dose 
0 min 
10 ± 2  
min. 
30 ± 5 
min. 
1 hour   
± 10 min. 
2 hours 
± 10 min. 
4 hours 
± 10 min. 
8 hours 
± 10 min. 
Informed Consent 
X 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
Physical Examination1 
X 
X 
 
 
 
 
 
 
 
Clinical Laboratory Tests2,5 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
X3 
X3 
X3 
X3 
X3 
Randomization 
 
X 
 
 
 
 
 
 
 
Drug Administration 
 
 
X 
 
 
 
 
 
 
Concomitant Medication Assessment 
X 
X 
 
 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
X 
 
X4 
X4 
X4 
X4 
X4 
X4 
Immunogenicity Sample5 
 
X 
 
 
 
 
 
 
 
 
1 
See Section 6.3 for physical examination assessments 
2 
See Section 6.5 for clinical laboratory tests; CD4 will only be tested at Screening 
3 
For all patients, regardless whether PK sample is taken 
4 
Depending on assigned sampling schedule (half of the patients sampling schedule 1: at 10±2 minutes, 1 and 4 hours (±10 minutes), and the other half of the 
patients sampling schedule 2: at 30±5 minutes and 2 and 8 hours (±10 minutes) relative to the start of infusion of study drug) 
5 
Investigator will contact the Medical Monitor regarding any patient who weighs <12 kg for adaptation of the blood sample schedule to the patient’s body 
weight 
 

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Phase B - Treatment of Mild/Moderate Bleeding Episodes 
 
Evaluation 
Mild/Moderate Bleeding Episode 
Pre- 
treatment 
0  
hrs 
3  
hrs 
6  
hrs 
9 
hrs 
12 
hrs 
15 
hrs 
18 
hrs 
21 
hrs 
24 
hrs 
Bleeding Characteristics1 
X 
 
 
 
 
 
 
 
 
 
Drug Administration2 
 
X 
X3 
X3 
X 
X 
X 
X 
X 
 
Efficacy Assessment4 
 
 
X 
X 
X 
X5 
X 
X 
X 
X5 
Patient Diary6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
Throughout Study 
Conmed Assessment 
Throughout Study 
 
1 
Includes location, date, time of start of bleeding, severity, spontaneous or traumatic 
2 
Exact date, time and dose administered to be noted for each administration 
3 
No study drug administration when in the 225 µg/kg treatment regimen  
4 
Before each (planned) study drug administration and 3 hours after last 
5 
Always to be done, regardless of study drug administration 
6 
By the parent(s)/guardian or other caregiver in conjunction with the patient where possible (e.g., depending on age). Additionally, the site staff will collect 
their assessment in the patient’s records (if applicable). 
 
 

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Phase B - Treatment of Severe Bleeding Episodes 
 
Evaluation 
Severe Bleeding Episode 
Pre- 
treatment 
0  
hrs 
q 2  
hrs 
q 3  
hrs 
q 4-12 
hrs 
Bleeding Characteristics1 
X 
 
 
 
 
Drug Administration2 
 
X 
X5 
X 
X 
Efficacy assessment3 
 
 
X 
X 
X 
Patient Diary4 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
Concomitant Medication Assessment 
X 
X 
X 
X 
X 
 
1 
Includes location, date, time of start of bleeding, severity, spontaneous or traumatic 
2 
Exact date, time and dose administered to be noted for each administration. Duration and interval of treatment upon judgment of the 
treating physician, depending on the type of bleeding 
3 
Prior to each (planned) study drug administration (initially every 2 hours when treated with 75 µg/kg, and at 6 hours after the initial 225 
µg/kg administration). In case the treatment is continued beyond 24 hours, efficacy is assessed every 12 hours during the administration 
of study drug and 12 hours after last study drug administration. 
4 
By patient/caregiver at each study drug administration and efficacy assessment timepoint. Additionally the site staff will collect their 
assessment in the patient’s records (as applicable). 
5 
No study drug administration and efficacy assessment at 2 and 4 hours if assigned to the 225 µg/kg treatment regimen 
 
 

Coagulation Factor VIIa (Recombinant), LR769 
 
LFB USA Inc. 
Clinical Trial Protocol: LFB-FVIIa-007-14 
 
29 June 2016  
 
 
 
 
Confidential 
Page 80 of 81 
 
Schedule of Events (Phase B Follow-Up Visits) 
 
Following treatment in Phase A 
Following 24 weeks visit 
 
Evaluation 
3 wks  
± 2 days 
6 wks  
± 5 days 
12 wks 
± 5 days 
18 wks 
± 5 days 
24 wks 
± 5 days 
Every 6 wks 
± 5 days 
Every 12 wks 
± 5 days 
End of 
Study/Early 
Termination Visit 
Physical Examination1 
X3 
X3 
X3 
X3 
X 
X3 
X3 
X 
Safety Labs (Hematology, chemistry)5,6 
 
 
X 
 
X 
 
 
X 
Coagulation5,6  
 
 
 
 
X2 
 
 
X2 
Adverse Event Assessment 
Throughout Study 
Weight 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
 
 
X 
 
X 
 
X 
X 
Health Care Resource Utilization 
 
 
X 
 
X 
 
X 
X 
Conmed Assessment 
Throughout Study 
Check drug accountability and patient 
diary 
X4 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity sample6 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 
See Section 6.3 for physical examinations 
2 
Inhibitor testing only 
3 
Only check for physical signs of thromboembolic events 
4 
Only check patient diary, no drug accountability 
5 
See Section 6.5.1 for clinical laboratory tests and coagulation tests; CD4 will only be tested at Screening 
6 
Investigator will contact the Medical Monitor regarding any patient who weighs <12 kg for adaptation of the blood sample schedule to the patient’s body 
weight