Phase 3 Study of Safety and Efficacy of Coagulation Factor VIIa (Recombinant) for Prevention of Excessive Bleeding in Congenital Hemophilia A/B Patients With Inhibitors to Factor VIII/IX Undergoing Elective Surgery/Other Invasive Procedures
Phase: PHASE3
Conditions: Hemophilia
Sponsor: Laboratoire français de Fractionnement et de Biotechnologies

Clinical Trial Protocol: LFB-FVIIa-008-14 
Study Title: 
A Phase 3 Study of the Safety and Efficacy of Coagulation Factor VIIa 
(Recombinant) for the Prevention of Excessive Bleeding in Congenital 
Hemophilia A or B Patients with Inhibitors to Factor VIII or IX 
Undergoing Elective Surgery or Other Invasive Procedures (PERSEPT 
3) 
Study Number: 
LFB-FVIIa-008-14 
Study Phase: 
Phase 3 
Product Name: 
LR769 
Indication: 
LR769 is intended to be used for the on-demand treatment of bleeding 
episodes and for the prevention of excessive blood loss and 
achievement of hemostasis in surgery or other invasive procedures in 
patients with congenital hemophilia A or B with inhibitors to 
coagulation factors VIII or IX 
Investigators: 
Multicenter, multinational study 
Principal 
Investigator: 
Miguel A. Escobar, MD 
University of Texas Health Science Center 
Houston, TX 
EudraCT #: 
2015-000957-19 
IND # 
15183 
Sponsor: 
LFB USA Inc. 
Sponsor Contact: 
Meg Carini, LPN, BS, CCRA 
Senior Clinical Project Manager 
Tel: +1 508 370 5100 
margaret.carini@lfb-usa.com 
Sponsor’s Legal 
Representative: 
Richard A Scotland 
Senior Vice President, Regulatory Affairs 
175 Crossing Blvd 
Framingham, MA 01702, USA 
dick.scotland@lfb-usa.com 
Medical Monitor: Jeffry B Lawrence, MD 
Vice President, Clinical Development 
jeffry.lawrence@lfb-usa.com 
Original Protocol: 
02 September 2015 
Amendment 1 
14 December 2015 
Amendment 2 
18 February 2016 
Amendment 3 
03 August 2016 
Amendment 4 
20 December 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Part or all of the information in this protocol may be unpublished material.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 that need to be aware of the content of the protocol.  

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SYNOPSIS 
Sponsor: 
LFB USA Inc.  
Name of Finished Product: 
LR769  
Name of Active Ingredient: 
Coagulation Factor VIIa (Recombinant) 
Study Title: 
A Phase 3 Study of the Safety and Efficacy of Coagulation Factor VIIa (Recombinant) for 
the Prevention of Excessive Bleeding in Congenital Hemophilia A or B Patients with 
Inhibitors to Factor VIII or IX Undergoing Elective Surgery or Other Invasive Procedures 
(PERSEPT 3)  
Study Number: 
LFB-FVIIa-008-14 (Protocol Amendment 4) 
Study Phase: Phase 3 
Primary Objective(s): 
• To assess the efficacy of LR769 to prevent excessive bleeding and to achieve hemostasis 
in hemophilia A or B patients with inhibitors to factor VIII (FVIII) or factor IX (FIX) 
undergoing elective surgical or other invasive procedures.  
 
Secondary Objective: 
• To assess the safety of LR769 including the immunogenic potential of the drug product.  
 
Study Design: 
This is an international, multicenter, single-arm, Phase 3 study. Patients aged 6 months to 
75 years, inclusive, who have congenital hemophilia A or B with inhibitors and who are 
scheduled for an elective surgical or other invasive procedure will be enrolled. Different age 
restrictions may apply per local regulation and ethical considerations; enrollment of children 
<12 years of age will not begin until after review of data from the PERSEPT 2 study by the 
DMC. 
After obtaining Informed Consent from the patient and/or the patient’s parent(s)/legal 
guardian(s), patients who are scheduled for an elective surgical or other invasive procedure 
will have screening assessments performed to determine eligibility.  
Patients who are or were participating in another LR769 study (eg, PERSEPT 2) and who meet 
all eligibility criteria will be allowed in this study if the study is open for enrollment in that 
age group.  
Safety follow up will continue until 28 (±3) days after the last dose of LR769. 

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Intraoperative Efficacy Assessments 
Immediately after completion of the procedure, the surgeon or practitioner performing the 
procedure will assess the intraoperative efficacy of LR769. The patient’s intraoperative 
response to treatment with LR769 will be assessed by the surgeon/practitioner and recorded 
as “excellent,” “good,” “moderate,” or “poor.”  
Postoperative Efficacy Assessments 
Efficacy assessments will be completed every 24 (±2) hours and at last administration of 
LR769. The patient’s postoperative response to treatment with LR769 will be assessed by the 
investigator or designee and recorded as “excellent,” “good,” “moderate,” or “poor.” If the 
patient is discharged while on treatment, these assessments will be done via telephone. The 
final assessment (which represents the primary efficacy outcome) will be performed by the 
investigator at the study center 48 (±4) hours after last dose of LR769 and will be based upon 
the totality of assessments performed on the patient at each timepoint.  
Safety Assessments 
Patients will be assessed for safety throughout the study via physical examinations, 
assessments for thromboembolic events, postoperative assessments, clinical safety laboratory 
tests, vital signs, immunogenicity tests, and the recording of adverse events (AEs).  
Study Population:  
Patients, aged 6 months to 75 years, inclusive, who have congenital hemophilia A or B 
complicated by high titer inhibitors (peak Bethesda Units [BU] ≥5). Some patients may have 
low levels of inhibitors (i.e., BU<5) but still cannot be treated with factor VIII or factor IX 
concentrates since these patients are known to have high-responding inhibitors, manifested 
by an anamnestic response (defined as a peak titer >5 BU after re-exposure to factor 
concentrates); or, if not demonstrating an anamnestic response, remain refractory to 
increased dosing with factor concentrates. Therefore, these patients cannot be treated with 
these products but may be included in this study if they are scheduled for an elective surgical 
or other invasive procedure. Detailed medical history will be obtained for these patients to 
document the high-responding features of their inhibitors.  Both major and minor surgical or 
other invasive procedures are allowed in the study.  

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Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study: 
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 (as confirmed at screening by the institutional lab, 
with the exception being for patients <12 kg where samples will only be collected 
centrally), OR  
b. an inhibitor test BU <5 (as confirmed at screening by the institutional lab, with 
the exception being for patients <12 kg where samples will only be collected 
centrally) but expected to have an anamnestic response to FVIII or FIX, as 
demonstrated by a history of a high-responding inhibitor manifested by a previous 
anamnestic response (defined as a peak inhibitor titer >5 after re-exposure to 
factor concentrates), precluding the use of FVIII or FIX products to treat or 
prevent bleeding, OR 
c. an inhibitor test BU <5 (as confirmed at screening by the institutional lab, with 
the exception being for patients <12 kg where samples will only be collected 
centrally) but expected to be refractory to FVIII or FIX, as demonstrated by the 
patient’s history of previous failure to respond to FVIII or FIX concentrates, even 
in the absence of a documented anamnestic response, precluding the use of FVIII 
or FIX products to treat or prevent bleeding episodes 
3. be ≥6 months to ≤75 years of age; different age restrictions may apply per local 
regulation and ethical considerations (enrollment of children <12 years of age will not 
begin until after review of data from the PERSEPT 2 study by the DMC) 
4. be scheduled for an elective surgical or other invasive procedure 
5. be capable of understanding and willing to comply with the conditions of the protocol 
OR in the case of a patient <18 years of age, parent(s)/legal guardian(s) must be 
capable of understanding and willing to comply with the conditions of the protocol  
6. have read, understood, and provided written Informed Consent (patient and/or 
parent(s)/legal guardian(s) if the patient is <18 years of age) or Assent, if applicable 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
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. known intolerance to LR769 or any of its excipients 
4. currently receiving immune tolerance induction (ITI) therapy 
5. have a known allergy or hypersensitivity to rabbits  
6. have a platelet count <100,000/µL 
7. have received an investigational drug within 30 days of the planned first LR769 
administration , or is expected to receive such drug during participation in this study 
(with the exception of patients who are or were participating in another LR769 study, 

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e.g., a study assessing the treatment of bleeding episodes with LR769) 
8. 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) 
9. have a history of arterial and/or venous thromboembolic events (such as myocardial 
infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis 
[DVT] or pulmonary embolism [PE]) within 2 years prior to the planned first dose of 
LR769, uncontrolled arrhythmia, or current New York Heart Association (NYHA) 
functional classification score of stages II – IV 
10. have an active malignancy (those with non-melanoma skin cancer are allowed) 
11. have any life-threatening disease or other disease or condition which, according to the 
investigator’s judgment, could imply a potential hazard to the patient, or interfere 
with the trial participation or trial outcome (eg, a history of non-responsiveness to 
bypassing products) 
12. be using aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), herbs, natural 
medications, or other drugs with platelet inhibitory properties within one week prior 
to surgery and for the duration of treatment with LR769 
13. have active gastric or duodenal ulcer disease  
 

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Test Product, Dose, and Mode of Administration:  
LR769 (Coagulation Factor VIIa (Recombinant).  
Initial Treatment: For a minor elective surgery or other minor invasive procedure, a dose of 
75 µg/kg of LR769 administered within ≤2 minutes will be used as the initial dose; for a 
major elective surgery or other major invasive procedure, a dose of 200 µg/kg of LR769 
administered within ≤2 minutes will be used as the initial dose before the surgical incision or 
start of an invasive procedure. For both minor and major procedures, administration will be 
repeated no more frequently than every 2 hours (±5 minutes) at a dose of 75 µg/kg during 
and after surgery or invasive procedure.  
If the patient requires further treatment with LR769 after hospital discharge, the patient will 
administer LR769 at home according to the investigator’s judgment and the dosing 
guidelines specified below; however, the efficacy assessment will be completed by the 
investigator or designee every 24 (±2) hours and at last administration of LR769 via 
telephone. The assessment at 48 (±4) hours after the last dose of LR769 will be performed by 
the investigator at the study center. The patient will be provided with LR769 and directions 
for its storage, reconstitution and administration along with a patient diary in which to record 
LR769 administration.  
If physical therapy is planned, an IV bolus dose of 75 µg/kg of LR769 administered within 
≤2 minutes is recommended each time before the therapy begins. Similarly, before drain or 
suture removal, an IV bolus dose of 75 µg/kg of LR769 administered within ≤2 minutes is 
recommended.   
Major Surgical Procedures 
Major surgical procedures are those that usually require ≥5 days of factor replacement in 
hemophilia patients with inhibitors and typically involve entry into a body cavity and/or 
organ removal or similarly complex procedures. These include, but are not limited to, the 
following: abdominal (eg, cholecystectomy, bowel resection, appendectomy), thoracic (eg, 
lobectomy, mediastinal procedures), orthopedic (eg, spinal, hip and knee surgery, joint 
replacements, synovectomy), genitourinary (eg, prostate resection, non-endoscopic bladder 
surgery), neurological, and cosmetic/reconstructive surgery (eg, facelift, burn scar surgery).  
Placement of a central venous access device may qualify as a major surgical procedure if the 
complexity of the procedure and patient, based on the investigator’s judgement, require ≥5 
days of coagulation factor replacement.  
Treatment for Major Surgical Procedures: The initial dose of LR769 (200 µg/kg) will be 
followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the 
first 48 hours after completion of the procedure. The minimum duration of LR769 treatment 
for major procedures will be 5 days, according to the frequency listed in the table below. 
 
  

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Dose(s) and Dosing Schedule(s) for Major Surgical Procedures 
Day 
Dose 
Recommended Frequency 
Day 0 (within 2 minutes of 
surgical incision or 
invasive procedure) 
200 µg/kg  
 
Initial dose 
Day 0 (post first dose) – 48 
hours 
75 µg/kg 
Every 2 hours (±5 minutes) 
Days 3-4 
75 µg/kg 
Intervals of up to every 4 
hours but not more 
frequently than every 2 
hours  
Days 5-6 
75 µg/kg 
Intervals of up to every 6 
hours but not more 
frequently than every 2 
hours  
Days 7-10 
75 µg/kg 
Intervals of up to every 8 
hours but not more 
frequently than every 2 
hours 
Day 11 to Last 
Administration of LR769 
75 µg/kg 
Intervals of up to every 12 
hours but not more 
frequently than every 2 
hours  
 
The patient will be followed postoperatively according to the site’s standard of care. 
NOTE: If clinically indicated because of oozing or similar findings suggesting the need for 
more frequent LR769 infusions, the treatment interval may be shortened in consecutive doses 
within the guidelines above. 

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Minor Surgical or Other Invasive Procedures 
Minor surgical or other invasive procedures typically require <5 days of factor replacement 
and usually involve the skin, mucous membranes, or superficial connective tissue and 
include, but are not limited to, the following: placement of a PICC or other central venous 
access device, isotopic synovectomies, tooth extractions, and skin biopsies. Patients who are 
about to undergo invasive procedures, including lumbar puncture, arterial blood gas 
determination, bronchoscopy with brushings or biopsy, and gastrointestinal endoscopy with 
biopsy are allowed in the study as well; these are also regarded as minor procedures.  
Treatment for Minor Surgical or Other Invasive Procedures: The initial dose of LR769 
(75 µg/kg) will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours 
(±5 minutes) for the first 48 hours. The minimum duration of LR769 infusion for minor 
procedures will be 2 days, according to the frequency listed in the table below, except for 
certain procedures that may not require this duration of treatment to achieve hemostasis as 
noted below.  
Dose(s) and Dosing Schedule(s) for Minor Surgical or Other Invasive Procedures 
Day 
Dose 
Recommended Frequency 
Day 0 (within 2 minutes of 
surgical incision or invasive 
procedure) 
75  µg/kg  
Initial dose 
Day 0 (post first dose) – 48 
hours 
75 µg/kg 
Every 2 hours (±5 minutes) 
initially. Interval may be 
increased upon the 
investigator’s judgment  
Day 3 to Last Administration of 
LR769 
75 µg/kg 
Intervals of up to every 24 
hours but not more 
frequently than every 2 
hours 
For less invasive procedures, such as PICC or Port-a-Cath placement and for procedures such 
as dental extractions, the patient may be treated for ≤48 hours if the investigator or designee 
determines this shorter duration of treatment is sufficient to achieve hemostasis.  
NOTE: If clinically indicated because of oozing or similar findings suggesting the need for 
more frequent LR769 infusions, the treatment interval may be shortened in consecutive doses 
within the guidelines above. 
For all procedures: Discharge and Follow up 
If the patient requires further treatment with LR769 after the outpatient procedure or hospital 
discharge, the patient will administer LR769 at home according to the investigator’s 
judgment and the dosing guidelines specified for both major and minor surgical or other 
invasive procedures. The patient will be provided with LR769 and directions for its storage, 
reconstitution and administration along with a patient diary in which to record LR769 

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administration. 
Reference Therapy; Dose; and Mode of Administration: 
No reference therapy will be used.  
Duration of Treatment:  
For major surgeries, treatment with LR769 will be for ≥5 days; for minor surgeries, treatment 
will typically be for ≥2 days, though for some less invasive procedures (eg, dental 
procedures), ≤48 hours treatment may be appropriate based on the investigator’s judgment. 
The duration of treatment will be the time required to achieve and maintain adequate 
hemostasis based on the investigator’s judgment.  
Duration of Study: 
The study will continue until at least 12 surgical procedures (including a minimum of 
6 major surgeries, of which at least 5 must be procedures other than central venous access 
device placement) have been performed in at least 6 patients. 
Efficacy Assessments: 
Intraoperative Assessment of Efficacy by Surgeon or Practitioner Performing the Procedure 
Efficacy of treatment with LR769 intraoperatively will be assessed by the surgeon/ 
practitioner immediately after completion of the procedure and recorded based on the 
following parameters:  
• Estimated blood loss in the surgical patient as compared to the maximum expected 
volume of blood loss in a patient without a bleeding disorder;  
• Prior to surgery, the surgeon/practitioner will note if the procedure is major or minor 
and the type of anesthesia that is planned, and estimate the maximum expected 
volume of blood loss based upon the type of surgery and the surgeon/practitioner’s 
previous experience in a patient who does not have a bleeding disorder. After the 
procedure, the surgeon/practitioner will determine the actual characteristics of the 
procedure and estimate the volume of blood lost during the procedure using the 
following factors as a guide: volume of drainage fluid, volume of fluid on sponges 
and towels, etc. The maximum expected volume of blood loss and the estimated 
volume of blood loss during the procedure will be recorded.  
• The surgeon/practitioner will assess the intraoperative hemostasis by comparing the 
estimated intraoperative blood loss with the maximum expected blood loss estimated 
prior to the procedure as well as the amount of fluid replacement given, transfusion 
requirements, hemodynamic stability, etc.  
• Comments from the surgeon/practitioner may be necessary if extenuating circumstances 
occurred (eg, an artery was briefly severed and required additional time for surgical 
control of the bleeding creating a larger than expected blood loss)  
 
Taking into account the above parameters, intraoperative response to treatment will be rated 
as follows: 
• Excellent: intraoperative blood loss similar to or less than expected for this type of 
procedure in a patient who does not have a bleeding disorder and who is undergoing the 
same surgical or other invasive procedure; no blood component transfusion is required 

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• Good: intraoperative blood loss that is greater than expected (but not more than 50% 
greater) for this type of procedure in a patient who does not have a bleeding disorder and 
who is undergoing the same surgical or other invasive procedure; no unexpected 
increased blood component transfusion requirement  
• Moderate: intraoperative blood loss that is substantially greater than expected (more than 
50% greater) for this type of procedure in a patient who does not have a bleeding disorder 
and who is undergoing the same surgical or other invasive procedure, not explained by a 
surgical/medical issue other than hemophilia; additional blood component (within 2-fold 
greater than expected) transfusion is necessary  
• Poor: uncontrolled intraoperative blood loss, not explained by a surgical/medical issue 
other than hemophilia, that requires intervention (rescue therapy requirement [bypass 
agent or porcine FVIII], and/or increased blood component [>2-fold greater than 
expected] transfusion, and/or leads to hypotension or unexpected transfer to Intensive 
Care Unit [ICU]) 
 
Investigator or Designee Assessment of Hemostasis on Postoperative Days 
The investigator or designee will make postoperative efficacy assessments at 24 (±2) hours 
after procedure completion, at 24 (±2) hour intervals while treatment with LR769 is ongoing, 
after the last dose of LR769, and during follow-up visits. The final assessment (which 
represents the primary efficacy outcome) will be performed by the investigator at the study 
center 48 (±4) hours after the last dose of LR769 and will be based upon the totality of the 
assessments performed on the patient at each timepoint also taking into consideration the 
surgeon/practitioner’s intraoperative hemostatic assessment, the number of (interventions 
for) bleeding episodes, oozing, blood transfusions, and the amount of LR769 used. All 
assessments will be recorded in the patient’s record.  
Postoperative response to treatment will be rated as follows: 
• Excellent: postoperative blood loss similar to or less than expected following this type of 
procedure in a patient who does not have a bleeding disorder and who is undergoing the 
same surgical or other invasive procedure; no blood component transfusion is required 
• Good: postoperative blood loss greater than expected following this type of procedure in 
a patient who does not have a bleeding disorder and who is undergoing the same surgical 
or other invasive procedure, not explained by a surgical/medical issue other than 
hemophilia; no unexpected need for blood component transfusion 
• Moderate: postoperative blood loss that is substantially greater than expected following 
this type of procedure in a patient who does not have a bleeding disorder and who is 
undergoing the same surgical or other invasive procedure, not explained by a 
surgical/medical issue other than hemophilia; additional blood component [within 2-fold 
greater than expected] transfusion is necessary 
• Poor: uncontrolled postoperative blood loss, not explained by a surgical/medical issue 
other than hemophilia that requires intervention (rescue therapy requirement [bypass 
agent or porcine FVIII], and/or increased blood component [>2-fold greater than 
expected] transfusion, and/or leads to hypotension or unexpected transfer to Intensive 

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Care Unit [ICU]) 
 
Safety Assessments 
Safety of treatment with LR769 will be assessed by the following: 
• Physical examinations at screening, pre-procedure and 48 (±4) hours after last dose of 
LR769  
• Assessment for signs and symptoms of thromboembolic events every 24 (±2) hours 
from completion of the procedure until 48 (±4) hours and 28 ( ± 3) days after last dose 
of LR769, to include checking for any signs or symptoms of thromboembolic events, 
such as pulmonary embolism (PE) (e.g., shortness of breath, chest pain, cyanosis) or 
deep vein thrombosis (e.g., calf pain, swelling/edema, redness, venous distension, pain 
on dorsiflexion) 
• Postoperative assessment performed on all patients while hospitalized every 24 (±2) 
hours from completion of the procedure until 48 (±4) hours after last dose of LR769 
(unless discharged from the hospital sooner) to include checking patient’s incision or 
procedure site for inflammation, bleeding, infection, oozing, discoloration 
• Clinical safety laboratory tests (chemistry, hematology and urinalysis) at screening, 
24 (±2) hours after completion of the procedure, and during follow up 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) at 
screening, just prior to the surgical or other invasive procedure, 24 (±2) hours after 
completion of the procedure, and follow up at 48 (±4) hours after last dose of LR769 
• Electrocardiogram (ECG) at screening 
• AEs recorded throughout the study 
• Immunogenicity of LR769 at pre-procedure and during follow-up visits 
 
Statistical Methods:  
All data collected in this study will be displayed using summary tables and patient data 
listings. Continuous variables will be summarized using descriptive statistics, specifically 
the mean, median, standard deviation, minimum, and maximum. Categorical variables will 
be summarized by frequencies and percentages.  
Analysis Populations: 
The Efficacy Population is defined as all patients who receive LR769 treatment, undergo a 
surgical or invasive procedure, and have at least 1 efficacy assessment. The Safety 
Population is defined as all patients who receive at least 1 dose of LR769. All efficacy 
analyses will be performed on the Efficacy Population and all safety analyses will be 
performed on the Safety Population.  
Sample Size Determination: 
The sample size was determined based on adaptations of international guidelines for 
coagulation factors and after US and EU health authority consultations.  

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Efficacy Evaluations: 
Primary efficacy endpoint: 
• Percentage of surgical or other invasive procedures with a “good” or “excellent” 
response to LR769 treatment 48 (±4) hours after the last administration of LR769 as 
assessed by the investigator.  
 
A point estimate of this endpoint will be calculated together with a Clopper-Pearson exact 
95% confidence interval.  
Secondary efficacy endpoints: 
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the investigator or designee for all efficacy timepoints other than the 
primary  
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the 
investigator or designee for all efficacy timepoints  
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the surgeon/practitioner 
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the 
surgeon/practitioner for the intraoperative period 
• Intraoperative blood loss determined by the surgeon/practitioner as compared to the 
surgeon/practitioner’s maximum predicted blood loss 
• Number of events requiring transfusion between start of procedure and 48 (±4) hours 
after last administration of LR769 
• Changes in hemoglobin between start of procedure and 48 (±4) hours after last 
administration of LR769 
• Amount of LR769 used. Total, and separated by use in hospital, at home, or for 
specific reasons (eg, physical therapy, or other reasons like drain or suture removal) 
• Number and type of bleeding episodes at the surgical site between start of procedure 
and 48 (±4) hours after last administration of LR769 
• Number of surgical interventions/re-explorations for bleeding episodes between start of 
procedure and 48 (±4) hours after last administration of LR769 
 
Point estimates will be computed together with 95% confidence intervals for the 
proportion of successes, mean difference between intraoperative blood loss and 
surgeon/practitioner’s maximum predicted blood loss, proportion of events requiring 
transfusion, mean hemoglobin level at each time point, mean number of bleeding episodes, 
mean amount of LR769 used, and mean number of surgical interventions/re-explorations 
for bleeding episodes. Clopper-Pearson exact confidence intervals will be used for 
dichotomous endpoints; confidence intervals for continuous variables will be based on the 
normal approximation. 

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Safety Evaluations 
Safety endpoints include the following: 
• Analysis (including relationship to LR769, severity, and outcome) of AEs/SAEs 
between first LR769 administration and 28 (±3) days after last administration of 
LR769 
• Analysis of treatment-emergent thromboembolic events between start of procedure and 
28 (±3) days after last administration of LR769 
• Analysis of allergic and anaphylactic reactions between start of procedure and 28 (±3) 
days after last administration of LR769 
• Analysis of treatment-emergent antibodies against LR769 or host-related impurities 
between start of procedure and 28 (±3) days after last administration of LR769 
 
All AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). 
The number and percentage of patients with any treatment-emergent AEs (TEAEs) and 
any treatment-emergent serious AEs (SAEs) will be presented for all patients. The number 
and percentage of patients with any treatment-emergent thromboembolic event and/or 
allergic and anaphylactic reactions will be presented for all patients.  
For vital signs and clinical laboratory test results, descriptive statistics for the actual value 
at each timepoint and the change from baseline to each post baseline timepoint will be 
tabulated. Descriptive statistics for immunogenicity data will also be produced for the 
specified timepoints. 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. 
Data Monitoring Committee 
The Data Monitoring Committee (DMC) is responsible for the oversight of patient safety. 
The DMC will consist of 3 specialists in the care of hemophilia patients. DMC members will 
be independent of the study and Sponsor. During the course of the study, the DMC will 
review immediate serious adverse drug reactions and quarterly review of SAE listings. In 
addition the DMC will review the data and recommendation from the DMC in the PERSEPT 2 
pediatric study to determine when enrollment of patients <12 years of age is appropriate for 
this study. 
Date of Original Approved Protocol: 02 September 2015 
Date of Protocol Amendment 2: 18 February 2016 
Date of Protocol Amendment 3: 03 August 2016 
Date of Protocol Amendment 4: 20 December 2016 
Date of Most Recent Protocol Amendment (if applicable): Not applicable 
Prepared in: Microsoft Word 2010 

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................17 
LIST OF APPENDICES ..........................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
1 
INTRODUCTION ...........................................................................................................21 
1.1 
Congenital Hemophilia ..........................................................................................21 
1.2 
Background Information on LR769 .......................................................................23 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objective ..................................................................................................24 
2.2 
Secondary Objective ..............................................................................................24 
3 
INVESTIGATIONAL PLAN ..........................................................................................25 
3.1 
Overall Study Design and Plan ..............................................................................25 
3.2 
Rationale for Study Design and Control Group .....................................................26 
3.3 
Study Duration and Dates ......................................................................................27 
4 
STUDY POPULATION SELECTION ...........................................................................28 
4.1 
Study Population ....................................................................................................28 
4.2 
Inclusion Criteria ...................................................................................................29 
4.3 
Exclusion Criteria ..................................................................................................29 
5 
STUDY TREATMENT(S) ..............................................................................................31 
5.1 
Description of Treatment(s) ...................................................................................31 
5.1.1 
Study Drug ...................................................................................................31 
5.1.2 
Placebo .........................................................................................................31 
5.2 
Treatments Administered .......................................................................................31 
5.2.1 
Selection and Timing of Dose for Each Patient ...........................................31 
5.2.2 
Treatment for Major Surgical Procedures....................................................31 
5.2.3 
Treatment for Minor Surgical or Other Invasive Procedures ......................32 
5.2.4 
All Procedures ..............................................................................................33 
5.3 
Method of Assigning Patients to Treatment Groups..............................................33 
5.4 
Blinding..................................................................................................................33 
5.5 
Concomitant Therapy.............................................................................................34 
5.6 
Restrictions ............................................................................................................34 
5.6.1 
Prohibited Medications ................................................................................34 
5.6.2 
Prior Therapy ...............................................................................................34 
5.6.3 
Prior Gastrointestinal Distress/Ulcers ..........................................................34 
5.6.4 
Fluid and Food Intake ..................................................................................34 

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5.6.5 
Patient Activity Restrictions ........................................................................34 
5.7 
Treatment Compliance ...........................................................................................35 
5.8 
Packaging and Labeling .........................................................................................35 
5.9 
Storage and Accountability ....................................................................................35 
5.10 
Investigational Product Retention at Study Site ....................................................35 
6 
STUDY PROCEDURES .................................................................................................36 
6.1 
Informed Consent...................................................................................................36 
6.2 
Medical History .....................................................................................................36 
6.3 
Physical Examination.............................................................................................37 
6.3.1 
All findings from physical examinations 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. 
Postoperative Assessments ..........................................................................37 
6.4 
Vital Signs ..............................................................................................................37 
6.5 
Electrocardiography ...............................................................................................37 
6.5.1 
12-Lead Electrocardiograms ........................................................................37 
6.6 
Clinical Laboratory Tests .......................................................................................37 
6.6.1 
Laboratory Parameters .................................................................................40 
6.6.1.1 
Clinical Safety Laboratory Tests .......................................................40 
6.6.1.2 
Factor and Inhibitor Tests ..................................................................41 
6.6.1.3 
Immunogenicity Testing ....................................................................42 
6.6.1.4 
Storage Samples .................................................................................42 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................42 
6.7 
Dispensing Study Drug ..........................................................................................42 
6.8 
Efficacy Assessments.............................................................................................42 
6.8.1 
Efficacy Endpoints .......................................................................................44 
6.9 
Adverse Events Assessments .................................................................................45 
6.9.1 
Performing Adverse Events Assessments ....................................................45 
6.9.2 
Timing ..........................................................................................................45 
6.9.3 
Severity ........................................................................................................46 
6.9.4 
Relationship .................................................................................................46 
6.9.5 
Expectedness ................................................................................................47 
6.9.6 
Clinical Significance ....................................................................................47 
6.9.7 
Clinical Laboratory Adverse Events ............................................................47 
6.9.8 
Serious Adverse Events ...............................................................................47 
6.9.8.1 
Definition ...........................................................................................47 
6.9.8.2 
Reporting Serious Adverse Events ....................................................47 
6.9.9 
Treatment-Emergent Adverse Events ..........................................................48 

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6.10 
Surgical or Invasive Procedure Characteristics .....................................................49 
6.11 
Concomitant Medication Assessments ..................................................................50 
6.11.1 
Excluded Medications ..................................................................................50 
6.12 
Study Stopping Rules .............................................................................................50 
6.13 
Removal of Patients from the Trial or Treatment ..................................................51 
6.14 
Replacement of Patients .........................................................................................51 
6.15 
Other Study Procedures .........................................................................................51 
6.16 
Appropriateness of Measurements .........................................................................51 
7 
STUDY ACTIVITIES .....................................................................................................52 
7.1 
Screening (Days -21 to -1) .....................................................................................52 
7.2 
Surgery/Invasive Procedure and LR769 Treatment ...............................................52 
7.2.1 
Before Surgery/Invasive Procedure .............................................................52 
7.2.2 
During Surgery/Invasive Procedure .............................................................53 
7.2.3 
Surgeon/Practitioner’s Assessment ..............................................................53 
7.3 
After Surgery/Invasive Procedure..........................................................................53 
7.3.1 
24 Hours ± 2 Hours After Completion of Procedure ...................................53 
7.3.2 
Every 24 Hours ± 2 Hours After Completion of Procedure ........................54 
7.3.3 
7-14 Days After Start of Treatment with LR769 .........................................54 
7.4 
Last Dose of LR769 ...............................................................................................54 
7.5 
Early Termination Procedures ...............................................................................54 
7.6 
Follow-Up Visits ....................................................................................................54 
7.6.1 
48 Hours ± 4 Hours After the Last Dose of LR769 .....................................54 
7.6.2 
28 Days ± 3 Days After the Last Dose of LR769 ........................................55 
8 
QUALITY CONTROL AND ASSURANCE .................................................................56 
9 
PLANNED STATISTICAL METHODS ........................................................................57 
9.1 
General Considerations ..........................................................................................57 
9.2 
Determination of Sample Size ...............................................................................57 
9.3 
Analysis Populations ..............................................................................................57 
9.4 
Demographics and Baseline Characteristics ..........................................................57 
9.5 
Efficacy Endpoints .................................................................................................57 
9.5.1 
Primary Efficacy Endpoint ..........................................................................57 
9.5.2 
Secondary Efficacy Endpoints .....................................................................58 
9.6 
Safety Endpoints and Analysis ..............................................................................58 
9.7 
Interim Analysis .....................................................................................................59 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................60 
10.1 
Investigators and Study Administrative Structure .................................................60 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................60 

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10.3 
Ethical Conduct of the Study .................................................................................60 
10.4 
Patient Information and Consent ...........................................................................61 
10.5 
Patient Confidentiality ...........................................................................................61 
10.6 
Study Monitoring ...................................................................................................61 
10.7 
Case Report Forms and Study Records .................................................................62 
10.8 
Data Monitoring Committee ..................................................................................62 
10.9 
Protocol Deviations ................................................................................................62 
10.10 Criteria for Terminating Study ...............................................................................62 
10.11 Criteria for Suspending/Terminating a Study Center ............................................63 
10.12 Access to Source Documentation ..........................................................................63 
10.13 Data Generation and Analysis ...............................................................................63 
10.14 Retention of Data ...................................................................................................63 
10.15 Financial Disclosure...............................................................................................64 
10.16 Publication and Disclosure Policy .........................................................................64 
11 REFERENCE LIST .........................................................................................................69 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Dose(s) and Dosing Schedule(s) for Major Surgical Procedures ................32 
Table 2. 
Dose(s) and Dosing Schedule(s) for Minor Surgical or Other Invasive 
Procedures ....................................................................................................................33 
Table 3. 
Total Amounts (mL) of Blood Taken During the Study for Patients <12 
kg 
38 
Table 4. 
Total Amounts (mL) of Blood Taken During the Study for Pediatric 
Patients ≥12 kg and <27 kg ..........................................................................................39 
Table 5. 
Total Amounts (mL) of Blood Taken During the Study for Pediatric 
Patients ≥27 kg .............................................................................................................39 
Table 6. 
Total Amounts (mL) of Blood Taken During the Study for Adult 
Patients (≥18 Years) .....................................................................................................40 
Table 7. 
List of Laboratory Tests ...............................................................................41 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .............................................................................65 
Appendix 2 
Sponsor Signatures.............................................................................68 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AA 
amino acid 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPCC 
activated prothrombin complex concentrate 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase (SGOT) 
BU 
Bethesda Units 
BUN 
blood urea nitrogen 
Ca 
calcium 
CRO 
contract research organization 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
DVT 
deep venous thrombosis 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EGF 
epidermal growth factor 
EMA 
European Medicines Agency 
EOT 
last administration of LR769 
FDA 
Food and Drug Administration 
FEIBA® 
factor eight inhibitor bypassing agent 
FIX 
factor IX 
FVII 
factor VII  
FVIIa 
activated factor VII 
FVIII 
factor VIII 
FVIIIa 
activated factor VIII 
FX 
factor X 

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FXa 
activated factor X 
GCP 
Good Clinical Practice 
HC 
heavy chain 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head, ears, eyes, nose, throat 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
hr 
hour 
HTRS 
Hemophilia and Thrombosis Research Society 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
ICU 
intensive care unit 
IRB 
Institutional Review Board 
ITI 
immune tolerance induction 
K 
potassium 
LC 
light chain 
LDH 
lactic acid dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
Na 
sodium 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
Pd 
plasma-derived 
PD 
pharmacodynamic(s) 
PE 
pulmonary embolism 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 

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PT 
preferred term 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SOC 
system organ class 
TF 
tissue factor 
US 
United States 
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 transgenic rabbits, selected for the production of this complex 
human glycoprotein.  
1.1 
Congenital Hemophilia 
LR769 is produced by recombinant DNA technology employing site-directed expression of 
the human factor VII (FVII) gene in the mammary gland of genetically engineered rabbits. 
The transgene containing the human factor VII has been stably integrated into the genome of 
the rabbits. The rhFVII gene is exclusively expressed by the mammary gland under the 
control of a beta-casein specific promoter. Milk from these transgenic rabbits is collected and 
the FVII protein expressed is subsequently purified and activated during the purification 
process. The production of recombinant human factor VII in transgenic rabbits 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.  
Hemophilia is an inherited coagulation disorder due to deficiency of either factor VIII 
(FVIII; hemophilia A) (Patek and Taylor, 1937) or factor IX (FIX; hemophilia B) (Biggs, 
1952). Reported prevalence of hemophilia is approximately 2 in 10,000 males globally, and 
prevalence in developed countries has been reported as approximately 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 usually are 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 FVIII or FIX 
products, replacing the deficient factor. However, the development of inhibiting antibodies to 
FVIII and FIX 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, a family 
history of inhibitors, 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 immune tolerance induction (ITI) therapy (Astermark, 2006). 
The prevalence of inhibitors to FVIII or FIX 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 (BUs), where one BU is defined as the 

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amount of antibody that neutralizes 50% of FVIII or FIX in normal plasma (Astermark, 
2006).  
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) with consequently 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 still do not respond sufficiently to (increasing 
doses of) FVIII or FIX 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 patients with inhibitors. 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 
bleeding site. Thrombin (factor IIa) generation under normal circumstances is driven 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 et al., 2009). 
A study looking at home treatment with 90 µg/kg of NovoSeven® every 3 hours up to 3 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 
episodes is dependent on the type and severity of the bleeding, but usually 90 µg/kg 
administered every 2 to 3 hours is effective (NovoSeven® SmPC). Higher doses (eg, 
270 µg/kg) may also be utilized for treatment of mild/moderate bleeding episodes.  
Surgery in patients with hemophilia and high-titer inhibitors is challenging as bypassing 
products are required and there is no direct measure, such as a factor level, to monitor 
hemostasis (Shapiro and Cooper, 2012). Treatment varies in patients with hemophilia based 
on inhibitor status and surgical procedure (Shapiro, 2014). This makes management of 
bleeding episodes difficult and poses a particular therapeutic challenge for elective or 
emergency surgical procedures (Shapiro et al., 1998). For these reasons this study is focusing 
on planned elective procedures and using assessments of hemostasis at completion of 
procedure and at multiple postoperative timepoints.  
For patients with inhibitors, only 2 randomized trials have been performed to investigate 
postoperative hemostasis: one compared 2 doses of rFVIIa and the other compared bolus and 
continuous infusion of rFVIIa. These studies documented that elective surgery, including 
orthopedic interventions, was feasible in patients with inhibitors (Shapiro, 2014). In addition, 
consensus panels have published guidelines for surgical procedures in patients with 
inhibitors, though these guidelines largely focus on maximizing short-term hemostatic 

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outcomes and minimizing the potential for complications immediately after surgery (Escobar 
et al., 2012;Giangrande et al., 2009;Teitel et al., 2009). 
Short-term prophylactic treatment is typically 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). FVIIa is also used for other bleeding disorders such as acquired hemophilia and 
congenital FVII deficiency.  
1.2 
Background Information on LR769 
LR769 is a recombinant human coagulation FVIIa of the vitamin K dependent family of 
coagulation factors. In the presence of both calcium and phospholipids, FVII/FVIIa in a 
complex with Tissue Factor (TF) can activate factor X to factor Xa directly bypassing FIX or 
FVIII. 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.  
FVIIa is a 406 amino acid (AA) glycoprotein (~50 kDa) with 12 disulfide bridges. The 
protein contains 4 distinct structural domains: the N-terminal γ-carboxylic-domain 
(GLA-domain), 2 epidermal growth factor (EGF)-like domains, and 1 serine protease 
domain. Activation of FVII to 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 for the on-
demand treatment of bleeding episodes and for the prevention of excessive bleeding and 
achievement of hemostasis in surgical interventions or other invasive procedures in 
congenital hemophilia A or B patients with inhibitors. The population foreseen is both adults 
and children (≥6 months of age to ≤75 years of age).  
This study, PERSEPT 3, will evaluate LR769 for the prevention of excessive bleeding and 
achievement of hemostasis in congenital hemophilia A or B patients who have inhibitors (BU 
≥5) or a known high anamnestic response or refractory to increased dosing of either FVIII or 
FIX (detailed history for these patients will be obtained to document the high-responding 
characteristics of their inhibitors); are aged 6 months to 75 years, inclusive; and who are 
undergoing elective surgical or other invasive procedures. Administration of LR769 will be 
performed just prior to surgery/procedure and will be repeated during and after the 
surgery/procedure to achieve and maintain adequate hemostasis as determined by the 
investigator’s judgment.  
Interim efficacy and safety results from a study (RB-FVIIa-006-13, PERSEPT 1) in patients 12 
years and older provide the basis for the current study. The available results of this 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 Objective 
The primary objective of this study is: 
• To assess the efficacy of LR769 to prevent excessive bleeding and achieve hemostasis in 
hemophilia A or B patients with inhibitors to FVIII or FIX undergoing elective surgical 
or other invasive procedures.  
 
2.2 
Secondary Objective 
The secondary objective of this study is: 
• To assess the safety of LR769 including the immunogenic potential of the drug product.  

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is an international, multicenter, single-arm, Phase 3 study. Patients aged 6 months to 
75 years, inclusive, who have congenital hemophilia A or B with inhibitors and who are 
scheduled for an elective surgical or other invasive procedure will be enrolled. Different age 
restrictions may apply per local regulation and ethical considerations; enrollment of children 
<12 years of age will not begin until after review of data from the PERSEPT 2 study by the 
DMC. 
After obtaining Informed Consent from the patient and/or the patient’s parent(s)/legal 
guardian(s), patients who are scheduled for an elective surgical or other invasive procedure 
will undergo screening assessments to determine eligibility.  
Patients who are or were participating in another LR769 study (eg, PERSEPT 2) and who meet 
all eligibility criteria will be allowed in this study if the study is open for enrollment in that 
age group.  
Safety follow up will continue until 28 (±3) days after the last dose of LR769. 
Initial Treatment: For a minor elective surgery or other minor invasive procedure, a dose of 
75 µg/kg of LR769 administered within ≤2 minutes will be used as the initial dose; for a 
major elective surgery or other major invasive procedure, a dose of 200 µg/kg of LR769 
administered within ≤2 minutes will be used as the initial dose before the surgical incision or 
start of the invasive procedure.  For both minor and major procedures, administration will be 
repeated no more frequently than every 2 hours (±5 minutes) at a dose of 75 µg/kg during 
and after surgery or invasive procedure. 
Treatment for Major Surgical Procedures: The initial dose (200 µg/kg) will be followed by 
repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 
hours after completion of procedure. The minimum duration of LR769 treatment for major 
procedures will be 5 days, according to the frequency listed in Table 1. The patient will be 
followed postoperatively according to the site’s standard of care. 
Discharge and Follow up: If the patient requires further treatment with LR769 after hospital 
discharge, the patient will administer LR769 at home according to the investigator’s 
judgment and the dosing guidelines specified in Table 1. The efficacy assessment will be 
completed by the investigator or designee every 24 (±2) hours and at last administration of 
LR769 via telephone. The assessment 48 (±4) hours after the last dose of LR769 will be 
performed by the investigator at the study center. The patient will be provided with LR769 
and directions for its storage, reconstitution and administration along with a patient diary in 
which to record LR769 administration.  
If physical therapy is planned, an IV bolus dose of 75 µg/kg of LR769 administered within 
≤2 minutes is recommended each time before physical therapy begins. Similarly, before drain 

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or suture removal, an IV bolus dose of 75 µg/kg of LR769 administered within ≤2 minutes is 
recommended.  
Treatment for Minor Surgical or Invasive Procedures: The initial dose (75µg/kg) will be 
followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the 
first 48 hours, although, depending on the investigator’s judgment, the interval may be 
extended in the first 48 hours. The minimum duration of LR769 infusion for minor 
procedures will be 2 days, according to the frequency listed in Table 2. For less invasive 
procedures, such as peripherally inserted central catheter (PICC) or Port-a-Cath placement 
and for procedures such as dental extractions, the patient may be treated for ≤48 hours if the 
investigator determines this shorter duration of treatment is sufficient to achieve hemostasis.  
Discharge and Follow up: If the patient requires further treatment with LR769 after the 
outpatient procedure or hospital discharge, the patient will administer LR769 at home 
according to the investigator’s judgment and the dosing guidelines in Table 2; however, the 
efficacy assessment will be completed by the investigator or designee every 24 (±2) hours 
from completion of the procedure and at last administration of LR769 via telephone, and by 
the investigator at 48 (±4) hours after the last dose of LR769 at the study center. The patient 
will be provided with LR769 and directions for its storage, reconstitution and administration 
along with a patient diary in which to record LR769 administration.  
Efficacy Assessments: Immediately after completion of the procedure, the 
surgeon/practitioner will assess the intraoperative efficacy of LR769. The patient’s 
intraoperative response to treatment with LR769 will be assessed by the surgeon/practitioner 
and recorded as “excellent,” “good,” “moderate,” or “poor.” Subsequent assessments will be 
performed by the investigator or designee at all other timepoints. The final assessment 
(which represents the primary efficacy outcome) will be performed by the investigator at the 
study center 48 (±4) hours after last dose of LR769 and will be based upon the totality of 
assessments performed on the patient at each timepoint.  
Patients will be assessed for safety throughout the study until 28 (±3) days after the last dose 
of LR769 via physical examinations, clinical safety laboratory tests, assessments for 
thromboembolic events and postoperative assessments, vital signs, immunogenicity tests, and 
the recording of adverse events (AEs). The Schedule of Events is presented in Appendix 1.  
3.2 
Rationale for Study Design and Control Group 
At this time, there are no European Medicines Agency (EMA) or United States (US) Food 
and Drug Administration (FDA) guidelines for the development of FVIIa 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 FIX products 
(EMEA/CHMP/BPWP/144552/2009 rev 1). 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 FIX guideline has been adopted for the 
purposes of preparing LFB USA’s clinical development plan (including studies in the 
pediatric population). Indeed, the epidemiology of patients with hemophilia with inhibitors to 

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FVIII and FIX is similar to that of all patients with hemophilia B. This study is the third in a 
series of three for full development of LR769.  
This is a single-arm, non-comparative study, ie, 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 
prevention of bleeding associated with the procedure, leading to potentially irreversible 
damage to the patient, or could even be life threatening. A comparison with current standard 
of care would then be the next best option, which in this case could either be 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. Therefore, the sample size was 
selected based on FIX guidance in agreement with US and EU health authorities. 
3.3 
Study Duration and Dates 
The study will continue until at least 12 surgical procedures (including a minimum of 6 
major surgeries, of which at least 5 must be procedures other than central venous access 
device placement) have been performed in at least 6 patients.  
The duration of the patient’s participation in the study (from signing the Informed Consent 
form until the last follow-up visit) may vary. In patients undergoing a major procedure the 
duration of participation will be approximately 6 to 9 weeks (or longer if treatment with 
LR769 is extended). In patients undergoing a minor procedure the duration of participation 
will be approximately 5 to 8 weeks (or longer if treatment with LR769 is extended).  

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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The population for this study is patients, aged 6 months to 75 years, inclusive, who have 
congenital hemophilia A or B complicated by high titer inhibitors (peak BU ≥5). Some 
patients may have low levels of inhibitors i.e, BU<5 but still cannot be treated with FVIII or 
FIX concentrates since they are known to have a strong memory (anamnestic) response after 
re-exposure to factor concentrates. This should be evident from the patient records where it is 
documented that administration of Factor VIII or IX has led to a sharp increase in inhibitor 
levels (BU>5), preventing further use of the factor concentrate (ie, need for bypassing agent).  
A small group of patients may, despite titers of inhibitors <5 BU, be refractory or intolerant 
to increased dosing with factor concentrates. This may be the case when there is an allergic 
response to factor concentrates (with Factor IX). Refractory patients may fail to exhibit a 
documented anamnestic response due to variability in the Bethesda inhibitor assay or due to 
diminished titers after long periods without exposure to factor concentrate.  It would not be 
considered ethical to expose such patients to factor when their medical history indicates a 
high likelihood of a rapid and/or significant increase in their inhibitor titers.  The allergic 
response or ineffective treatment with factor concentrates despite low inhibitor titer (BU<5) 
should be evident from the patient records with detailed description of the insufficient effect 
of Factor VIII or IX concentrate, thus confirming the need for a bypassing agent.  Since 
patients with an anamnestic response and those refractory or intolerant to factor concentrates 
cannot be treated with these products, they represent candidates for inclusion in this study if 
they are scheduled for an elective surgical or other invasive procedure.  Details for these 
potential anamnestic or refractory patients will be obtained for patients lacking an inhibitor 
titer of ≥5 BU to document the high-responding features of their inhibitors (including 
documentation through their medical history of pre- and post-factor infusion levels of Factor 
VIII or IX, and the corresponding BU titer levels). 
 
Different age restrictions may apply per local regulation and ethical considerations; 
enrollment of children <12 years of age will not begin until after review of data from the 
PERSEPT 2 study by the DMC. 
 
Patients who are or were participating in another LR769 study (eg, PERSEPT 2) are allowed in 
this study, if the study is open for enrollment in that age group. 
Both major and minor surgical or other invasive procedures are allowed in the study.  
Major Surgical Procedures: Major surgical procedures are those that usually require ≥5 days 
of factor replacement in hemophilia patients with inhibitors and typically involve entry into a 
body cavity and/or organ removal or similarly complex procedures. These include, but are 
not limited to, the following: abdominal (e.g., cholecystectomy, bowel resection, 
appendectomy), thoracic (e.g., lobectomy, mediastinal procedures), orthopedic (eg, spinal, 
hip and knee surgery, joint replacements, synovectomy), genitourinary (eg, prostate 
resection, non-endoscopic bladder surgery), neurological, and cosmetic/reconstructive 
surgery (eg, facelift, burn scar surgery).  

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Placement of a central venous access device may qualify as a major surgical procedure if the 
complexity of the procedure and patient require ≥ 5 days of coagulation factor replacement.  
Minor Surgical Procedures: Minor surgical or other invasive procedures typically require <5 
days of factor replacement and usually involve the skin, mucous membranes, or superficial 
connective tissue and include, but are not limited to, the following: placement of a PICC or 
other central venous access device, isotopic synovectomies, tooth extractions, and skin 
biopsies. Patients who are about to undergo invasive procedures, including lumbar puncture, 
arterial blood gas determination, bronchoscopy with brushings or biopsy, and gastrointestinal 
endoscopy with biopsy are allowed in the study as well; these are also regarded as minor 
procedures.  
4.2 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study.  
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 (as confirmed at screening by the institutional lab, with 
the exception being for patients <12 kg where samples will only be collected centrally), 
OR  
b.  an inhibitor  test BU <5 (as confirmed at screening by the institutional lab, with the 
exception being for patients <12 kg where samples will only be collected centrally) but 
expected to have an anamnestic response to FVIII or FIX, as demonstrated by a  history 
of a high-responding inhibitor manifested by a previous  anamnestic response, defined as 
a peak inhibitor titer > 5 BU after re-exposure to factor concentrates, precluding the use 
of FVIII or FIX products to treat or prevent bleeding, OR 
c. an inhibitor test BU <5 (as confirmed at screening by the institutional lab, with the 
exception being for patients <12 kg where samples will only be collected centrally) but 
expected to be refractory to FVIII or FIX, as demonstrated by the patient’s history of 
previous failure to respond to FVIII or FIX concentrates, even in the absence of a 
documented anamnestic response, precluding the use of FVIII or FIX products to treat or 
prevent bleeding episodes. 
3. be ≥6 months to ≤75 years of age; different age restrictions may apply per local 
regulation and ethical considerations (enrollment of children <12 years of age will not 
begin until after review of data from the PERSEPT 2 study by the DMC) 
4. be scheduled for an elective surgical or other invasive procedure 
5. be capable of understanding and willing to comply with the conditions of the protocol OR 
in the case of a patient <18 years of age, parent(s)/legal guardian(s) must be capable of 
understanding and willing to comply with the conditions of the protocol  
6. have read, understood, and provided written Informed Consent (patient and/or 
parent(s)/legal guardian(s) if the patient is <18 years of age) or Assent, if applicable 
4.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study.  

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1. have any coagulation disorder other than hemophilia A or B 
2. be immunosuppressed (ie, the patient should not be receiving systemic 
immunosuppressive medication; CD4 counts at screening should be >200/µl) 
3. known intolerance to LR769 or any of its excipients 
4. currently receiving ITI therapy 
5. have a known allergy or hypersensitivity to rabbits 
6. have platelet count <100,000/µL 
7. have received an investigational drug within 30 days of the planned first LR769 
administration, or is expected to receive such drug during participation in this study (with 
the exception of patients who are or were participating in another LR769 study, eg, a 
study assessing the treatment of bleeding episodes with LR769) 
8. have a clinically relevant hepatic (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT] >3 times the ULN and/or renal impairment (creatinine >2 times 
the ULN) 
9. have a history of arterial and/or venous thromboembolic events (such as myocardial 
infarction, ischemic strokes, transient ischemic attacks, DVT, or PE) within 2 years prior 
to the planned first dose of LR769, uncontrolled arrhythmia, or current New York Heart 
Association (NYHA) functional classification score of stages II – IV 
10. have an active malignancy (those with non-melanoma skin cancer are allowed) 
11. have any life-threatening disease or other disease or condition which, according to the 
investigator’s judgment, could imply a potential hazard to the patient, or interfere with 
the trial participation or trial outcome (eg, a history of non-responsiveness to bypassing 
products) 
12. be using aspirin, NSAIDS, herbs, natural medications, or other drugs with platelet 
inhibitory properties within one week prior to surgery and for the duration of treatment 
with LR769 
13. have active gastric or duodenal ulcer disease  
  

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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  
5.2.1 
Selection and Timing of Dose for Each Patient 
The treatment regimen used in this study is selected based on a Phase 1b study assessing the 
pharmacokinetic (PK) and pharmacodynamic (PD) effects of 3 doses of LR769 (25, 75, 
225 µg/kg) in hemophilia A or B patients, as well as from a Phase 3 study which confirmed 
the clinical efficacy of 75 and 225 µg/kg LR769 for the treatment of bleeding episodes 
predicted based upon the PK/PD correlation in the Phase Ib trial.   Based upon the 
demonstrated PK/PD relationship as well as the efficacy noted for achieving hemostasis in 
mild/moderate bleeding episodes, the initial dosing will employ 75 µg/kg prior a minor 
surgical procedure. However, to account for the more extensive tissue damage in major 
surgical procedures and resulting greater hemostatic challenge, a dose of 200 µg/kg before a 
major surgical procedure will be used.  These doses are expected to provide a PD effect that 
will be sufficient to effectively prevent excessive bleeding during and after surgical/invasive 
procedures and achieve and maintain hemostasis.  Additional doses for the post-procedure 
setting are outlined in detail in Sections 5.2.2 and 5.2.3 below. 
 
Preliminary efficacy and safety results of  a study (RB-FVIIa-006-13, PERSEPT 1) in patients 
12 years and older provide evidence that on-demand LR769 doses of 75 µg/kg every 2-3 
hours effectively control bleeding episodes in hemophilia A or B patients with inhibitors. The 
available results of this study and of the Phase 1b study completed earlier are more 
extensively described in the current LR769 Investigator’s Brochure.  
 
5.2.2 
Treatment for Major Surgical Procedures 
The initial dose of LR769 (200 µg/kg) will be followed by repeated administration of 
75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours after completion of the 
procedure. The minimum duration of LR769 treatment for major procedures will be 5 days, 
according to the frequency listed in the table below.  

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Table 1. 
Dose(s) and Dosing Schedule(s) for Major Surgical Procedures 
Day 
Dose 
Recommended Frequency 
Day 0 (within 2 minutes of 
surgical incision or 
invasive procedure) 
200 µg/kg  
 
Initial dose 
Day 0 (post first dose) – 48 
hours 
75 µg/kg 
Every 2 hours (±5 minutes) 
Days 3- 4 
75 µg/kg 
Intervals of up to every 4 
hours but not more 
frequently than every 2 
hours 
Days 5-6 
75 µg/kg 
Intervals of up to every 6 
hours but not more 
frequently than every 2 
hours 
Days 7-10 
75 µg/kg 
Intervals of up to every 8 
hours but not more 
frequently than every 2 
hours 
Day 11 to Last 
Administration of LR769 
75 µg/kg 
Intervals of up to every 12 
hours but not more 
frequently than every 2 
hours 
 
NOTE: If clinically indicated because of oozing or similar findings suggesting the need for 
more frequent LR769 infusions, the treatment interval may be shortened in consecutive doses 
within the guidelines stated in Table 1. 
If the patient requires further treatment with LR769 after hospital discharge, the patient will 
administer LR769 at home according to the investigator’s judgment and the dosing 
guidelines specified in Table 1. The patient will be provided with LR769 and directions for 
its storage, reconstitution and administration along with a patient diary in which to record 
LR769 administration.  
If physical therapy is planned, an IV bolus dose of 75 µg/kg of LR769 administered within 
≤2 minutes is recommended each time before the therapy begins. Similarly, before drain or 
suture removal, an IV bolus dose of 75 µg/kg of LR769 administered within ≤2 minutes is 
recommended.  
5.2.3 
Treatment for Minor Surgical or Other Invasive Procedures 
The initial dose of LR769 (75 µg/kg) will be followed by repeated administration of 
75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours. The minimum duration 

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of LR769 infusion for minor procedures will be 2 days, according to the frequency listed in 
the table below.  
Table 2. 
Dose(s) and Dosing Schedule(s) for Minor Surgical or Other Invasive 
Procedures 
Day 
Dose 
Recommended Frequency 
Day 0 (within 2 minutes of 
surgical incision or invasive 
procedure) 
75µg/kg 
Initial dose 
Day 0 (post first dose) – 48 
hours 
75 µg/kg 
Every 2 hours (±5 minutes) 
initially. Interval may be 
increased upon the 
investigator’s judgment  
Day 3 to Last Administration of 
LR769 
75 µg/kg 
Intervals of up to every 24 
hours but not more 
frequently than every 2 
hours  
*For less invasive procedures, such as PICC or Port-a-Cath placement and for procedures such as dental 
extractions, the patient may be treated for ≤48 hours if the investigator or designee determines this shorter 
duration of treatment is sufficient to achieve hemostasis.  
 
NOTE: If clinically indicated because of oozing or similar findings suggesting the need for 
more frequent LR769 infusions, the treatment interval may be shortened in consecutive doses 
within the guidelines stated in Table 2. 
5.2.4 
All Procedures 
If the patient requires further treatment with LR769 after discharge, the patient will 
administer LR769 at home according to the investigator’s judgment and the dosing 
guidelines in Sections 5.2.2 and 5.2.3. The patient will be provided with LR769 and 
directions for its storage, reconstitution and administration along with a patient diary in 
which to record LR769 administration.  
5.3 
Method of Assigning Patients to Treatment Groups 
The method of assigning patients to treatment groups is not applicable as this is a study with 
a single treatment group.  
5.4 
Blinding 
Not applicable.  

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5.5 
Concomitant Therapy 
All concomitant therapies, including the use of blood products such as red blood cells, 
platelets, fresh frozen plasma, fibrinogen, etc, will be recorded in the patients’ medical 
records and/or patients’ diaries and in the eCRF. Concomitant therapies, including date, time, 
and dose, will be recorded from 30 days prior to screening and throughout the study until the 
end of the follow-up period.  
5.6 
Restrictions 
5.6.1 
Prohibited Medications 
All aspirin, NSAIDs, herbs, natural medications, or any other drug with platelet inhibitory 
properties must be discontinued at least 1 week prior to elective surgical or other invasive 
procedure and for the duration of treatment with LR769.   
Additional restrictions to concomitant therapies include the use of other sources of FVIIa, 
such as aPCC (FEIBA®) or NovoSeven®. These products may be used only if the response to 
LR769 is considered insufficient (ie, treatment failure), in which case these bypassing agents 
may be used for rescue therapy.  
Other agents for the prevention of excessive bleeding during surgical or other invasive 
procedures, such as antifibrinolytics, are allowed and will be recorded on the eCRF.  
5.6.2 
 Prior Therapy 
At least 24 hours must have passed between the last administration of a FVIIa-containing 
product (aPCC (FEIBA®) or (NovoSeven®) and the first LR769 administration.  
5.6.3 
Prior Gastrointestinal Distress/Ulcers 
Patients with active gastric or duodenal ulcer disease are not allowed to participate in this 
study, in accordance with Exclusion Criterion 13. 
5.6.4 
 Fluid and Food Intake 
No restrictions on fluid or food intake apply.  
5.6.5 
Patient Activity Restrictions 
Patients should not undergo physical therapy before the fourth day post-surgical or invasive 
procedure.  If physical therapy is planned, an IV bolus dose of 75 µg/kg of LR769 
administered within ≤2 minutes is recommended each time before the therapy begins. 
Similarly, before drain or suture removal, an IV bolus dose of 75 µg/kg of LR769 
administered within ≤2 minutes is recommended.  

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5.7 
Treatment Compliance 
All patients will be treated with LR769 in the hospital or outpatient treatment center prior to, 
during, and immediately after the surgical or other invasive procedure. Patients may be 
discharged from the hospital or outpatient treatment center and treated at home at the 
investigator’s discretion. During the patient’s hospitalization for the procedure, compliance is 
managed by the site staff. If the patient continues treatment with LR769 after discharge from 
the hospital or outpatient treatment center, he will be given a patient diary in which to record 
the exact dose and time of LR769 administration.  
5.8 
Packaging and Labeling 
LR769 will be supplied in clear glass vials as lyophilized powder in 1 mg and 5 mg. The 
vials will be labeled using multilingual labels which will comply with local regulations and 
requirements. Vials will be packed in an outer box. In addition, prefilled syringes with water 
for injection for reconstitution as well as supplies for reconstitution and administration of 
LR769 will be provided. Study staff will refer to a separate Pharmacy Manual that will 
describe the appropriate directions, and patients will refer to “Instructions for Use.” if 
discharged home while still on treatment. 
5.9 
Storage and Accountability 
LR769 must be stored in a safe and secure place at the study center or at home. LR769 is to 
be stored at 36° to 86° F (2-30°C), is not to be frozen, and must be protected from light. The 
investigator is fully responsible for LR769 stored at the study center. Access at the study 
center will be strictly limited to the investigator and designated staff. Neither the investigator 
nor designated staff may provide LR769 to any patient not in the study. Dispensing of LR769 
may be delegated, e.g., to a hospital pharmacy, as locally applicable. Patients who are given 
LR769 for home administration will be instructed to return the used and any unused vials to 
the site.  
All LR769 received at the investigational site will be documented on LR769 drug 
accountability forms. This documentation must be available for review by the monitor at the 
monitoring visit to confirm proper LR769 management.  
5.10 Investigational Product Retention at Study Site 
All used and unused vials of LR769 will be retained until drug accountability has been 
performed by the monitor. For this purpose, the investigator or designated staff will keep all 
used vials, including those returned by patients who administered LR769 at home, for the 
accountability check by the monitor (unless local regulation does not allow this).  
All unused vials will be returned or destroyed according to the instructions of the Sponsor at 
the end of the study. A separate pharmacy manual will be prepared that will describe the 
appropriate procedures.  

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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All patients 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 their personal data, and that their 
medical records may be reviewed for study purposes by authorized individuals other than 
their treating physician. It will be emphasized that participation is voluntary and that the 
patient is allowed to refuse further participation in the protocol whenever he wants. Once the 
patient completely understands the study and its procedures and risks, he will be asked to 
sign and date the Informed Consent. Study procedures may not begin until after the Informed 
Consent is signed and dated.  
If the patient is younger than 18 years of age, his parent(s)/legal guardian(s) will receive the 
same information. His parent(s)/legal guardian(s) will sign and date the Informed Consent.  
The patient may, depending on his age, receive age-appropriate information as well as be 
asked to sign and date an Assent form. Age of providing information and Assent form may 
differ among institutions and will be determined by local law and Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) requirements.  
Once the Informed Consent and/or Assent has been signed and dated by the patient and/or 
parent(s)/legal guardian(s), the patient is considered enrolled in the study.  
6.2 
Medical History 
The medical history of each patient will be obtained. Specific information will be recorded in 
the source records and on the eCRF relating to any prior or existing medical 
conditions/surgical procedures involving the following: infectious diseases (including viral 
infections, such as hepatitis and human immunodeficiency virus [HIV]), allergies including 
allergic responses to LR769 and its excipients (arginine HCl, isoleucine, trisodium citrate 
dihydrate, glycine, lysine HCl, polysorbate 80), metabolic/endocrine/nutritional, 
hematopoietic, musculoskeletal, dermatologic, head/ears/eyes/nose/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 and patient bleeding history will be collected. This will include the following: 
type of hemophilia (A or B), history of bleeding episodes, severity (mild, moderate or 
severe), inhibitor level, date of first detection of inhibitors, concomitant medication use, and 
response to FVIII or FIX if applicable in case of either anamnestic or refractory response to 
factor administration.  
Demographics (date of birth, race/ethnicity, and sex) will also be collected.  

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6.3 
Physical Examination 
6.3.1 
All findings from physical examinations 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. Postoperative 
Assessments 
The patient will be followed postoperatively according to the site’s standard of care. 
Postoperative assessments include assessing patient’s incision or procedure site for 
inflammation, bleeding, infection, oozing, and discoloration.  
6.4 
Vital Signs 
Vital signs will 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 
Electrocardiography 
6.5.1 
12-Lead Electrocardiograms 
A standard 12-lead electrocardiogram (ECG) will be performed in supine position at 
Screening, and will be reviewed for any clinically relevant abnormalities by a qualified 
physician prior to the first administration of LR769.  
6.6 
Clinical Laboratory Tests 
After the sponsor authorizes enrollment of patients <12 years old, the investigator will 
contact the Medical Monitor regarding any such patient 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.  
 If the local lab is unable to perform analyses from the recommended volumes, the PSI 
medical monitor or lab specialist should be contacted in order to discuss possible volumes. In 
such cases blood volumes will be calculated individually, taking into account patient’s 
weight and applicable requirements in order not to exceed 1% at any single time and 3% 
within 4 weeks. 
Table 3 includes estimates for the amount of blood to be drawn for pediatric patients who 
weigh <12 kg.  
 

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Table 3. 
Total Amounts (mL) of Blood Taken During the Study for Patients 
<12 kg 
  
Screena 
Pre 
Surgery 
24 hrs post 
procedure 
7-14 days 
post first 
dose 
48 hrs 
post last 
dose 
28 days 
post last 
dose/EOS 
Hematology 
1 
1 
1 
1 
PT and aPTT 
(local lab) 
3 
 
 
 
 
 
Chemistry 
2 
 
2 
 
2 
2 
Factors VIII or IX, 
and Inhibitors  
(central lab only) 
2.8 
Immunogenicity 
and serum storage 
sample 
2 
3 
Immunogenicity 
1.2 
1.2 
Totals 
8.8 
2 
3 
1.2 
4.2 
6 
EOS = end of study 
a Screening visit will be spilt into 2 different days if the total volume of blood drawn is to exceed 0.8 mL/kg at a 
single time.  
Serology not performed for pediatric patients < 12 kg. 
Table 4 includes estimates for the amount of blood to be drawn for pediatric patients who 
weigh ≥12 kg and <27 kg.  

 
 
Table 4. 
Total Amounts (mL) of Blood Taken During the Study for Pediatric 
Patients ≥12 kg and <27 kg 
Screena 
Pre 
Surgery 
24 hrs 
post 
procedure 
7-14 days 
post first 
dose 
48 hrs 
post last 
dose 
28 days post 
last 
dose/EOS 
Hematology 
1 
 
1 
 
1 
1 
PT and aPTT and Factor 
VIII or IX and Inhibitors  
(local lab) 
4.5 
 
 
 
 
 
Serology 
4 
 
 
 
 
 
Chemistry 
2 
 
2 
 
2 
2 
Factors VIII or IX and  
Inhibitors 
(central lab) 
4.2 
 
 
 
 
 
Immunogenicity and  
serum storage sample 
3 
 
 
 
4 
Immunogenicity 
 
 
 
2 
2 
  
Totals 
15.7 
3 
3 
2 
5 
7 
EOS = end of study 
a Screening visit will be spilt into 2 different days if the total volume of blood drawn is to exceed 0.8 mL/kg at a 
single time. 
Table 5 includes estimates for the amount of blood to be drawn for pediatric patients who 
weigh ≥27 kg.  
Table 5. 
Total Amounts (mL) of Blood Taken During the Study for Pediatric 
Patients ≥27 kg 
Screen 
Pre 
Surgery 
24 hrs 
post 
procedure 
7-14 days 
post first 
dose 
48 hrs 
post last 
dose 
28 days post 
last 
dose/EOS 
Hematology 
2 
 
3 
 
3 
3 
PT and aPTT and Factors 
VIII and IX and Inhibitors 
(local lab) 
6 
 
 
 
 
 
Serology 
4 
 
 
 
 
 
Chemistry 
4 
 
5 
 
5 
5 
Factors VIII or IX and 
Inhibitors 
(central lab) 
4.2 
 
 
 
 
 
Immunogenicity and  
serum storage sample 
3 
 
 
 
4 
Immunogenicity 
 
 
 
2 
2 
  
Totals 
20.2 
3 
8 
2 
10 
12 
EOS = end of study 
 

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Table 6includes estimates for the amount of blood to be drawn for adult patients (≥18 years 
old). 
 
Table 6. 
Total Amounts (mL) of Blood Taken During the Study for Adult 
Patients (≥18 Years) 
Screen 
Pre 
surgery 
24 hours 
post 
procedure 
7-14 days 
post first 
dose 
48 hours 
post last 
dose 
28 days 
post last 
dose/EOS 
Hematology 
4 
4 
4 
4 
PT and aPTT and 
Factors VIII and IX 
and Inhibitors  
(local lab) 
8 
Serology 
6 
Chemistry 
8 
8 
5 
5 
Factors VIII or IX 
and Inhibitors 
(central lab) 
5.7 
Immunogenicity,  
serum storage sample 
5 
5 
Immunogenicity 
3 
3 
Totals 
31.7 
5 
12 
3 
12 
14 
EOS = end of study 
 
6.6.1 
Laboratory Parameters 
6.6.1.1 
Clinical Safety Laboratory Tests 
The clinical safety laboratory tests for patients ≥12 kg are presented in Table 7 and will be 
carried out by the local laboratory of the site (FVIII or FIX concentration as well as inhibitor 
testing will also be analyzed at the central laboratory) at Screening. Hematology, chemistry, 
and urinalysis will be repeated as specified in Appendix 1.  

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Table 7. 
List of Laboratory Tests 
Hematology: 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count with 
differential (automated) 
- 
CD4 count1 
 
Urinalysis (dipstick): 
- 
Glucose 
- 
Ketones 
- 
Microscopic examination of 
sediment in case of positive dipstick 
- 
Nitrite  
- 
Occult blood 
- 
Protein 
 
Serology1 
- 
Hepatitis B surface antigen (HBsAg) 
- 
Hepatitis C virus (HCV) 
- 
Human immunodeficiency virus 
(HIV) 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase 
(AST; SGOT) 
- 
Blood urea nitrogen (BUN) or 
urea 
- 
Calcium (Ca) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Gamma-glutamyl transferase 
(GGT) 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Total protein 
- 
Troponins 
 
Coagulation1:  
- 
FVIII2 or FIX3 
- 
FVIII2 or FIX3 inhibitors 
- 
Prothrombin time (PT) 
- 
Activated partial thromboplastin 
time (aPTT) 
Note: laboratory tests may vary depending on the weight of the patient (see Section 6.6). 
1 
At Screening only  
2 
In hemophilia A patients only 
3 
In hemophilia B patients only 
 
6.6.1.2 
Factor and Inhibitor Tests 
The concentration of factor VIII (in hemophilia A patients) and FIX (in hemophilia B 
patients) as well as the titer of inhibitors to FVIII (in hemophilia A patients) or FIX (in 
hemophilia B patients) will be assessed at Screening. The Bethesda assay will be used for 
inhibitor testing. FVIII or FIX and titer of inhibitors to FVIII or FIX tests will be performed 
at the local and central laboratories, except for patients <12 kg where samples will be only 
collected for testing at the central laboratory.  

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6.6.1.3 
Immunogenicity Testing 
Serum samples to test for antibodies against LR769 and any host-related impurities will be 
taken as specified in Appendix 1. 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 identification of patients who are 
generating an immune response to milk proteins as a result of LR769 treatment.  
6.6.1.4 
Storage Samples 
Serum samples will be taken and stored (for a maximum of 5 years after the end of the study) 
for purposes of any safety evaluations deemed necessary in the future (eg, infectious disease 
evaluations). These samples will be stored by the Sponsor (or designee) in a central location.  
6.6.2 
Sample Collection, Storage, and Shipping 
A separate laboratory manual will be prepared that will describe the appropriate sample 
collection, storage, and shipping procedures.  
6.7 
Dispensing Study Drug 
When treatment is taking place in the hospital prior to, during, and after surgery, LR769 will 
be dispensed to the study staff or patient according to the local procedure of the study center. 
If the patient has been discharged home, he will be provided with LR769 and directions for 
its storage, reconstitution and administration.  
6.8 
Efficacy Assessments 
Efficacy Assessments: 
The intraoperative efficacy of LR769 will be assessed by the surgeon/practitioner; all other 
efficacy assessments will be made by the investigator or designee as specified in Appendix 1. 
Assessments for major and minor procedures will be performed at the same timepoints.  
The final assessment (which represents the primary efficacy outcome) will be performed by 
the investigator at the study center 48 (±4) hours after the last dose of LR769 and will be 
based upon the totality of the assessments performed on the patient at each timepoint, also 
taking into consideration the number of (interventions for) bleeding episodes, oozing, blood 
transfusions, and the total amount of LR769 used.  
All efficacy assessments will be recorded in the patient’s source records and on the eCRF.  

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Intraoperative Assessment of Efficacy by Surgeon/Practitioner 
The surgeon/practitioner’s rating of intraoperative efficacy of LR769 will be based on the 
following parameters: 
• Estimated blood loss in the surgical patient as compared to the maximum expected 
volume of blood loss in a patient without a bleeding disorder: 
• Prior to surgery, the surgeon will note if the procedure is major or minor and the type 
of anesthesia that is planned, and estimate the maximum expected volume of blood 
loss based upon the type of surgery and the surgeon/practitioner’s previous 
experience in a patient who does not have a bleeding disorder. After the procedure, 
the surgeon/practitioner will determine the actual characteristics of the procedure and 
estimate the volume of blood lost during the procedure using the following factors as 
a guide: volume of drainage fluid, volume of fluid on sponges and towels, fluid 
replacement given, transfusion requirements, etc. The maximum expected volume of 
blood loss and the estimated volume of blood loss during the procedure will be 
recorded.  
• The surgeon/practitioner will assess the intraoperative hemostasis by comparing the 
estimated intraoperative blood loss with the maximum expected blood loss estimated 
prior to the procedure as well as the amount of fluid replacement given, transfusion 
requirements, hemodynamic stability, etc 
Comments from the surgeon/practitioner may be necessary if extenuating circumstances 
occurred (eg, an artery was briefly severed and required additional time for surgical control 
of the bleeding creating a larger than expected blood loss. 
Taking into account the above parameters, the intraoperative response to treatment will be 
rated as follows: 
• Excellent: intraoperative blood loss similar to or less than expected for this type of 
procedure in a patient who does not have a bleeding disorder and who is undergoing the 
same surgical or other invasive procedure; no blood component transfusion is required 
• Good: intraoperative blood loss that is greater than expected (but not more than 50% 
greater) for this type of procedure in a patient who does not have a bleeding disorder and 
who is undergoing the same surgical or other invasive procedure; no unexpected 
increased blood component transfusion requirement  
• Moderate: intraoperative blood loss that is substantially greater than expected (more than 
50% greater) for this type of procedure in a patient who does not have a bleeding disorder 
and who is undergoing the same surgical or other invasive procedure, not explained by a 
surgical/medical issue other than hemophilia; additional blood component (within 2-fold 
greater than expected) transfusion is necessary  
• Poor: uncontrolled intraoperative blood loss, not explained by a surgical/medical issue 
other than hemophilia, that requires intervention (rescue therapy requirement [bypass 
agent or porcine FVIII], and/or increased blood component [>2-fold greater than 
expected] transfusion, and/or leads to hypotension or unexpected transfer to Intensive 
Care Unit [ICU]) 

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Investigator or Designee Assessment of Hemostasis on Postoperative Days 
• Excellent: postoperative blood loss similar to or less than expected following this type of 
procedure in a patient who does not have a bleeding disorder and who is undergoing the 
same surgical or other invasive procedure; no blood component transfusion is required 
• Good: postoperative blood loss greater than expected following this type of procedure in 
a patient who does not have a bleeding disorder and who is undergoing the same surgical 
or other invasive procedure, not explained by a surgical/medical issue other than 
hemophilia; no unexpected need for blood component transfusion 
• Moderate: postoperative blood loss that is substantially greater than expected following 
this type of procedure in a patient who does not have a bleeding disorder and who is 
undergoing the same surgical or other invasive procedure, not explained by a 
surgical/medical issue other than hemophilia; additional blood component [within 2-fold 
greater than expected] transfusion is necessary 
• Poor: uncontrolled postoperative blood loss, not explained by a surgical/medical issue 
other than hemophilia that requires intervention (rescue therapy requirement [bypass 
agent or porcine FVIII], and/or increased blood component [>2-fold greater than 
expected] transfusion, and/or leads to hypotension or unexpected transfer to Intensive 
Care Unit [ICU]) 
 
6.8.1 
Efficacy Endpoints 
Primary efficacy endpoint: 
• Percentage of surgical or other invasive procedures with a “good” or “excellent” response 
to LR769 treatment 48 (±4) hours after the last administration of LR769 as assessed by 
the investigator 
 
Secondary efficacy endpoints: 
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the investigator or designee for all efficacy timepoints other than the 
primary  
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the investigator 
or designee for all efficacy timepoints  
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the surgeon/practitioner 
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the 
surgeon/practitioner for the intraoperative period 
• Intraoperative blood loss determined by the surgeon/practitioner as compared to the 
surgeon/practitioner’s maximum predicted blood loss 
• Number of events requiring transfusion between start of procedure and 48 (±4) hours 
after last administration of LR769 

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• Changes in hemoglobin between start of procedure and 48 (±4) hours after last 
administration of LR769 
• Amount of LR769 used. Total, and separated by use in hospital, at home, or for specific 
reasons (eg, physical therapy, or other reasons like drain or suture removal) 
• Number and type of bleeding episodes at the surgical site between start of procedure and 
48 (±4) hours after last administration of LR769 
• Number of surgical interventions/re-explorations for bleeding episodes between start of 
procedure and 48 (±4) hours after last administration of LR769 
 
6.9 
Adverse Events Assessments 
6.9.1 
Performing Adverse Events Assessments 
An AE is defined as any undesirable physical, psychological, or behavioral effect 
experienced by a patient or subject 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 LR769 are also regarded as AEs, but will be listed as non-TEAEs. Disease 
signs, symptoms, and/or laboratory abnormalities already existing prior to Informed Consent 
are not considered AEs, unless they recur after the patient has recovered from the 
pre-existing condition or they represent an exacerbation in severity, duration, or frequency.  
All AEs will be recorded in the patient’s source record and on 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 LR769, 
action taken, and outcome will be provided.  
All AEs will be followed up until resolution or 30 days after the last dose or early 
termination, whichever comes first.  
6.9.2 
Timing 
Adverse events will be collected from the time of the signing of the Informed Consent/Assent 
until resolution or 30 days after the last dose or early termination, whichever comes first. At 
each specified timepoint, the patient (or parent/legal guardian) will be asked to report any 
and all AEs experienced since the previous assessment or visit. Specifically, the patient (or 
parent(s)/legal guardian(s) if the patient is a child), will be asked if 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, or redness.  
If an AE occurs in PERSEPT 3 and the patient is still enrolled in PERSEPT 2, the AE should 
only be collected in PERSEPT 3.  If the AE is ongoing at the time of rejoining PERSEPT 2, that 
AE should be only collected in PERSEPT 2 under medical history.  If when rejoining PERSEPT 

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2, there is an exacerbation or recurrence of the AE, this AE should be collected as a new AE 
in PERSEPT 2. 
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 LR769. Treatment for symptom(s) is given. The AE 
produces sequelae, which may also require (prolonged) treatment.  
 
Note: Severe is not equivalent to serious.  
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 LR769 administration and the 
occurrence of the event, the expected pharmacology of LR769, the potential contribution of 
the underlying disease under investigation and/or any other concomitant diseases/medical 
history, evolution of the event when LR769 was withdrawn, and whether the event recurred 
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)  
 

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6.9.5 
Expectedness 
An AE is expected if the nature, severity, and outcome of the event are consistent with the 
reference safety information, ie, the Investigator’s Brochure.  
6.9.6 
Clinical Significance 
Clinical significance is defined as any variation in physical/laboratory findings or AE 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 as 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 this deviation of the 
parameter.  
6.9.8 
Serious Adverse Events 
6.9.8.1 
Definition 
A serious adverse event (SAE) is defined by federal and international regulation as any AE 
occurring at any dose that results in any of the following outcomes: death, life-threatening 
AE, hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE 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 inpatient hospitalization, or the development of 
drug dependency or drug abuse. Any suspected transmission via a medicinal product of an 
infectious agent is also considered a SAE.  
6.9.8.2 
Reporting Serious Adverse Events 
The necessity and time requirements for reporting 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 LR769. In case 
reporting via the eCRF is not available, the SAE may be reported via fax in order to meet 
the reporting requirements.  
 

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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 anonymized 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 LR769 
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 LR769, 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 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 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/contract research organization (CRO) to notify the IRB/EC.  
If applicable, SAEs will be reported to the appropriate regulatory agencies by the Sponsor or 
designee. In case the local regulations require notification through the investigator, the 
Sponsor will facilitate this process.  
6.9.9 
Treatment-Emergent Adverse Events 
All AEs that occur after the first administration of LR769 will be regarded as treatment 
emergent (TEAE). All AEs occurring from signing the Informed Consent up to the first 
administration of LR769 will also be collected and will be referred to as non-TEAEs. 
Adverse events that are present prior to the first administration of LR769 but subsequently 
worsen will be considered TEAEs. 
A potential risk associated with the administration of LR769 is the occurrence of an allergic 
or anaphylactic 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 initial administration of LR769 to detect the occurrence of any potential allergic 
reaction. Symptoms of such a reaction may consist of, but are not limited to: 
• Skin redness, rash, hives 

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• 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 will assess 
the patient and determine whether the symptoms are consistent with an acute allergic reaction 
and treat the symptoms accordingly.  
Although reported to be rare in hemophilia patients, a potential risk associated with the 
administration of LR769 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 
LR769 as well as during the follow-up assessments to detect the occurrence of any 
thromboembolic events. Events that may occur are myocardial infarction, ischemic 
cerebrovascular accident, arterial thrombosis (eg, aorta, intestinal), DVT, and 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, computed tomography [CT], magnetic resonance imaging 
[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.  
If an acute allergic reaction or a confirmed thrombotic event occurs in association with the 
administration of the LR769, such event will be reported in the same manner and timelines as 
a SAE (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 Surgical or Invasive Procedure Characteristics 
The surgeon/practitioner will determine the following predicted surgical or invasive 
procedure characteristics and record them prior to the procedure:  
• major or minor  
• maximum expected blood loss in a patient without a bleeding disorder who is undergoing 
this type of procedure  
• type of anesthesia  
 
After the surgery or invasive procedure, the surgeon/practitioner will determine the actual 
characteristics of the procedure and record them: 

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• major or minor  
• duration of procedure 
• estimated blood loss  
• factors that may have influenced bleeding independent of hemostasis, eg, surgical 
complications, difficulties owing to scarring, adhesions, problems with suturing vessels 
• actual type of anesthesia 
• complications 
6.11 Concomitant Medication Assessments 
All concomitant medications (including any blood or blood products) and/or concomitant 
procedures administered or performed during the study will be recorded in the source record 
and subsequently captured in the eCRF (including date, time, type of medication or product, 
and dose or amount).  
6.11.1 
Excluded Medications 
As was stated in Exclusion Criterion 12, the use of aspirin, NSAIDs, herbs, natural 
medications, or other drugs with  platelet inhibitory properties are excluded one week prior to 
surgical procedure and for the duration of treatment with LR769. 
6.12 Study Stopping Rules 
The study will be stopped (ie, cease enrollment as well as treatment of already enrolled 
patients) in the following cases: 
• A confirmed thrombotic event has been reported in any of the patients treated in the study 
• An acute allergic or anaphylactic 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 study. Only after approval of the competent authorities and ECs/IRBs may the study 
continue.  
In addition, the DMC could make a recommendation for study termination due to concerns 
over patient safety or issues relating to data monitoring or quality control. 

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6.13 Removal of Patients from the Trial or Treatment 
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  
• The Sponsor or investigator terminates the study  
• The patient withdraws consent or requests to be discontinued from the study 
• The patient is non-compliant  
 
In case of early withdrawal of the patient, he will be asked to perform the 48 (±4) hour visit 
assessment after last administration of LR769, unless he has withdrawn Informed Consent.  
The investigator may discontinue a patient from LR769 treatment for any of the following 
reasons: 
• AE or SAE possibly related to LR769 treatment 
• A clinically significant change in the patient’s condition that does not allow safe 
administration of LR769 
• Per judgment of the investigator, if an adequate hemostatic response is not achieved with 
LR769, and the bleeding requires continued treatment, the treating physician should stop 
treatment with LR769 and treat the patient with a rescue therapy, such as another 
bypassing agent (e.g., FEIBA® or NovoSeven®) and/or other effective hemostatic 
treatment. The patient remains eligible for treatment with LR769 for a new surgical 
procedure taking into account the pharmacodynamic half-life of the rescue therapy given. 
 
6.14 Replacement of Patients 
Patients who are removed from the study will only be replaced if their removal results in the 
minimum number of surgical or other invasive procedures/patients needed for the study not 
being met.  
6.15 Other Study Procedures 
There are no other study procedures.  
6.16 Appropriateness of Measurements 
Efficacy assessments are performed according to existing guidelines and published literature 
(Shapiro and Cooper, 2012; Shapiro, 2014; Shapiro et al., 1998; Giangrande et al., 2009). In 
this study, response to treatment with LR769 will be assessed intraoperatively by the 
surgeon/practitioner and postoperatively by the investigator or designee.  

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7 
STUDY ACTIVITIES 
All study activities can be found in the Schedule of Events (see Appendix 1).  
7.1 
Screening (Days -21 to -1) 
• Informed consent signature 
• Determine eligibility 
• Demographics  
• Medical history 
• Physical examination  
• Clinical safety laboratory tests (hematology, coagulation, serology, chemistry, 
urinalysis), by local laboratory - per weight requirement 
• FVIII/FIX and inhibitor testing, by central laboratory (as confirmed at screening by the 
institutional lab, with the exception being for patients <12 kg where samples will only be 
collected for testing at the central laboratory) 
• Vital signs  
• 12-lead ECG 
• Assessment of concomitant medication 
• Assessment of AEs 
 
7.2 
Surgery/Invasive Procedure and LR769 Treatment 
7.2.1 
Before Surgery/Invasive Procedure 
• Confirm eligibility 
• Physical examination (excluding height, including weight, which is the weight to be used 
for calculating dose of LR769) within 24 hours before the procedure 
• An IV bolus dose of 75 µg/kg (for a minor surgery or other minor invasive procedure) or 
200 µg/kg (for a major surgery or other major invasive procedure) of LR769 
administered within ≤2 minutes before the surgical incision or start of the invasive 
procedure.  
• Predicted surgery/invasive procedure characteristics  
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature [sublingual 
or tympanic]) 
• Assessment of concomitant medications 
• Assessment of AEs 
• Immunogenicity sample (including storage serum sample for future use) 
 

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7.2.2 
During Surgery/Invasive Procedure 
After the initial IV bolus dose of LR769 during the surgical or other invasive procedure, 
patients will be given repeated IV bolus doses of 75 µg/kg of LR769 administered over 
≤2 minutes at least 2 hours apart.  
7.2.3 
Surgeon/Practitioner’s Assessment 
Immediately after completion of the procedure, the surgeon will: 
• Determine the actual surgery/invasive procedure characteristics (major or minor, duration 
of procedure, factors that may have influenced bleeding independent of hemostasis, 
actual type of anesthesia, and complications) 
• Estimate the blood loss 
• Assess the intraoperative efficacy of LR769 
 
The patient’s intraoperative response to treatment with LR769 will be assessed by the 
surgeon/practitioner and recorded as “excellent,” “good,” “moderate,” or “poor.” Further 
details regarding the criteria for the surgeon/practitioner’s assessment of intraoperative 
efficacy are provided in Section 6.8. The surgeon/practitioner will also record any AEs and 
concomitant medications. 
7.3 
After Surgery/Invasive Procedure 
The patient will be followed postoperatively according to the site’s standard of care. 
Treatment with LR769 following completion of the surgery or invasive procedure will be 
administered according to the specifications in Section 5.2.2 (major surgical procedures) or 
Section 5.2.3 (minor surgical or other invasive procedures).  
7.3.1 
24 Hours ± 2 Hours After Completion of Procedure 
• Clinical safety laboratory tests (hematology, chemistry, urinalysis), by local laboratory; 
per weight requirement 
• Administration of 75 µg/kg of LR769 according to the administration schedule 
determined by the investigator 
• Postoperative assessment 
• Vital signs 
• Efficacy assessment by investigator or designee if treatment with LR769 is ongoing; 
assessment may be made by phone if the patient has been discharged home 
• Assessment of concomitant medications 
• Assessment of AEs (including thromboembolic assessments) 
 

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7.3.2 
Every 24 Hours ± 2 Hours After Completion of Procedure 
• Efficacy assessment by investigator or designee as long as treatment with LR769 is 
ongoing); assessment may be made by phone if the patient has been discharged home 
• Postoperative assessment 
• Assessment of concomitant medications 
• Assessment of AEs (including thromboembolic assessments) 
 
7.3.3 
7-14 Days After Start of Treatment with LR769 
A sample for immunogenicity will be taken 7-14 days after start of treatment. Depending on 
the timing (length of time since the patient’s first dose of LR769), this visit may be combined 
with another specified visit. 
7.4 
Last Dose of LR769 
• Last administration of LR769 (for end of treatment only) 
• Efficacy assessment by investigator or designee 
• Assessment of concomitant medications 
• Postoperative assessment 
• Assessment of AEs (including thromboembolic assessments) 
 
7.5 
Early Termination Procedures 
• Efficacy assessment by investigator or designee 
• Assessment of concomitant medications 
• Postoperative assessment 
• Vital signs 
• Clinical safety laboratory tests (hematology, chemistry, urinalysis) by local laboratory; 
per weight requirement 
• Assessment of AEs (including thromboembolic assessments) 
• Immunogenicity sample (including storage serum sample for future use) 
• Physical Examination (excluding height) 
 
7.6 
Follow-Up Visits 
7.6.1 
48 Hours ± 4 Hours After the Last Dose of LR769 
• Clinical safety laboratory tests (hematology, chemistry, urinalysis), by local laboratory; 
per weight requirement 

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• Review of patient diaries and final study drug accountability (including used vials 
returned by the patient) 
• Vital signs 
• Efficacy assessment by investigator  
• Assessment of concomitant medications 
• Postoperative assessment 
• Physical examination (excluding height)  
• Assessment of AEs (including thromboembolic assessments) 
• Immunogenicity sample  
 
7.6.2 
28 Days ± 3 Days After the Last Dose of LR769 
• Clinical safety laboratory tests (hematology, chemistry, urinalysis), by local laboratory; 
per weight requirement 
• Assessment of concomitant medications 
• Assessment of AEs (including thromboembolic assessments) 
• Immunogenicity sample (including storage serum sample for future use) 
 

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8 
QUALITY CONTROL AND ASSURANCE 
This study is sponsored by LFB USA Inc. The Sponsor will delegate specific tasks regarding 
the conduct of this study to a 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 
All data collected in this study will be displayed using summary tables and patient data 
listings. Continuous variables will be summarized using descriptive statistics, specifically the 
mean, median, standard deviation, minimum, and maximum. Categorical variables will be 
summarized by frequencies and percentages.  
9.2 
Determination of Sample Size 
The sample size was determined based on adaptations of international guidelines for 
coagulation factors in agreement with US and EU authorities.  
9.3 
Analysis Populations  
The Efficacy Population is defined as all patients who receive LR769 treatment, undergo a 
surgical or invasive procedure, and have at least 1 efficacy assessment.  
The Safety Population is defined as all patients who receive at least 1 dose of LR769.  
All efficacy analyses will be performed on the Efficacy Population and all safety analyses 
will be performed on the Safety Population.  
9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics for all patients will be summarized using 
descriptive statistics for continuous variables and frequencies and percentages for categorical 
variables.  
9.5 
Efficacy Endpoints 
Efficacy results will be reported as descriptive statistics. Surgeries will be examined overall 
as well as by major procedures and minor procedures separately. 
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of surgical or other invasive procedures with 
a “good” or “excellent” response to LR769 treatment as assessed by the investigator at the 
study center 48 (±4) hours after the last administration of LR769; this assessment will be 
based upon the totality of assessments performed on the patient at each timepoint also taking 
into consideration the surgeon’s intraoperative hemostatic assessment, the number of 
(interventions for) bleeding episodes, oozing, blood transfusions, and the amount of LR769 
used. 
A point estimate of this endpoint will be calculated together with a Clopper-Pearson exact 
95% confidence interval. 

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9.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the investigator or designee for all efficacy timepoints other than the 
primary  
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the investigator 
or designee for all efficacy timepoints  
• Percentages of success as defined as the combination of “good” and “excellent” 
responses by the surgeon/practitioner  
• Percentages of “poor,” “moderate,” “good,” and “excellent” response by the 
surgeon/practitioner for the intraoperative period 
• Intraoperative blood loss determined by the surgeon/practitioner as compared to the 
surgeon/practitioner’s maximum predicted blood loss 
• Number of events requiring transfusion between start of procedure and 48 (±4) hours 
after last administration of LR769 
• Changes in hemoglobin between start of procedure and 48 (±4) hours after last 
administration of LR769 
• Amount of LR769 used. Total, and separated by use in hospital, at home, or for specific 
reasons (eg, physical therapy, or other reasons like drain or suture removal 
• Number and type of bleeding episodes at the surgical site between start of procedure and 
48 (±4) hours after last administration of LR769 
• Number of surgical interventions/re-explorations for bleeding episodes between start of 
procedure and 48 (±4) hours after last administration of LR769 
 
Point estimates will be computed together with 95% confidence intervals for the proportion 
of successes, mean difference between intraoperative blood loss and surgeon/practitioner’s 
maximum predicted blood loss, proportion of events requiring transfusion, mean hemoglobin 
level at each timepoint, mean amount of LR769 used, and mean number of surgical 
interventions/re-explorations for bleeding episodes. Clopper-Pearson exact confidence 
intervals will be used for dichotomous endpoints; confidence intervals for continuous 
variables will be based on the normal approximation.  
9.6 
Safety Endpoints and Analysis 
Safety endpoints include the following: 
• Analysis (including relationship to LR769, severity, and outcome) of AEs/SAEs between 
first LR769 administration and 28 (±3) days after last administration of LR769 
• Analysis of treatment-emergent thromboembolic events between start of procedure and 
28 (±3) days after last administration of LR769 

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• Analysis of allergic and anaphylactic reactions between start of procedure and 28 (±3) 
days after last administration of LR769 
• Analysis of treatment-emergent antibodies against LR769 or host-related impurities 
between start of procedure and 28 (±3) days after last administration of LR769 
 
All AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). 
The number and percentage of patients with any treatment-emergent AEs (TEAEs) and any 
treatment-emergent serious AEs (SAEs) will be presented for all patients. 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 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.  
The number and percentage of patients with any treatment-emergent thromboembolic event 
and/or allergic and anaphylactic reactions will be presented for all patients.  
For vital signs and clinical laboratory test results (continuous parameters), descriptive 
statistics for the actual value at each timepoint and the change from baseline to each post 
baseline timepoint will be tabulated. 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. Descriptive statistics for immunogenicity data will also be produced for the 
specified timepoints. 
9.7 
Interim Analysis 
There are no planned interim analyses for this 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 investigators 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 investigators will review all study-related documents including the protocol and the 
current version of the Investigator’s Brochure. It is obligatory 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/CRO must submit and, where necessary, obtain approval from the 
IRB/IEC for all subsequent protocol amendments and changes to the Informed 
Consent/Assent form. The Principal Investigator/CRO will 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/CRO 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 GCP: 
Consolidated Guidance” dated April 1996. These practices are consistent with the principles 

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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. Patients or the 
parent(s)/legal guardian(s) 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 or patient’s parent(s)/legal 
guardian(s) in a language that is easily understood by the patient or the parent(s)/legal 
guardian(s). 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 
agrees or the parent(s)/legal guardian(s) agrees to allow a child 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 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 IRB or IEC requirements.  
10.5 Patient Confidentiality 
Patient participation is voluntary and patients or a patient’s parent(s)/ legal guardian(s) may 
refuse to participate or withdraw from the study at any time and for any reason. Patients 
and/or their parent(s)/legal guardian(s) will be informed that information about them/their 
child 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 
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 verification of 100% of data captured in the eCRF. For this study, source 
documents include but are not limited to the Informed Consent/Assent Form, patient’s 
medical records, patient diaries, laboratory results, reports of SAE’s, 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 investigators must ensure 
the accuracy and completeness of the recorded data and provide a signature on the 
appropriate eCRFs. The investigator’s 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 Data Monitoring Committee (DMC) is responsible for the oversight of patient safety. 
The DMC will consist of 3 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 
immediate serious adverse drug reactions and quarterly review of SAE listings. In addition 
the DMC will review the data and recommendation from the DMC in the PERSEPT 2 
pediatric study to determine whether enrollment of patients <12 years of age is appropriate 
for this study. 
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 study, 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 primary endpoints, 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.  
10.10 Criteria for Terminating Study 
The Sponsor reserves the right to terminate the study but intends only to exercise this right 
for valid scientific or administrative reasons and reasons related to patient safety and 

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protection. Investigators and the associated IRB/IEC will be notified in the event of 
termination.  
Possible reasons for study termination include: 
• DMC recommendation 
• 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 LR769 
 
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 important 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 LR769 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 (eg, original laboratory reports) 
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).  
10.14 Retention of Data 
The investigator/institution should maintain the trial documents as specified in ICH E6 GCP 
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 investigator withdraws responsibility for maintaining 

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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 LR769. These documents will 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 regulations on the documentation and disclosure of any potential financial 
conflicts will be adhered to.  
10.16 Publication and Disclosure Policy 
The study will be listed in the public database on clinical studies www.clinicaltrials.gov 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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Appendix 1 
Schedule of Events 
Evaluation 
Screening 
Days 
-21 to -1 
Procedures + LR769 Treatment 
Follow-Up Visits 
Pre 
Proce-
dure 
Immedi-
ately 
Postopera-
tive  
24 (±2) hrs 
after 
procedure 
completion 
Every 
24 (±2) hrs 
after 
procedure 
completion 
7-14 days 
after 1st 
dose of 
LR7699 
Last 
Dose of 
LR769 
Early 
Termi-
nation 
48 (±4) 
hrs after 
last dose 
28 (±3) 
days 
after last 
dose  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics and 
Detailed Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination1 
X 
X8 
 
 
 
 
 
X 
X 
 
Safety Lab Tests 
 
 
 
 
 
 
 
 
 
 
Hematology, chemistry, 
urinalysis (local lab) 
X 
 
 
X 
 
 
 
X 
X 
X 
Coagulation10, 
serology12  
X 
 
 
 
 
 
 
 
 
 
LR769 Administration2 
 
X 
 
 
 
Surgical/Invasive 
Procedure Characteristics3 
 
X 
X 
 
 
 
 
 
 
 
Postoperative Assessment4 
 
 
 
X 
X 
 
X 
X 
X 
 
Vital Signs5 
X 
X 
 
X 
 
 
 
X 
X 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 

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Evaluation 
Screening 
Days 
-21 to -1 
Procedures + LR769 Treatment 
Follow-Up Visits 
Pre 
Proce-
dure 
Immedi-
ately 
Postopera-
tive  
24 (±2) hrs 
after 
procedure 
completion 
Every 
24 (±2) hrs 
after 
procedure 
completion 
7-14 days 
after 1st 
dose of 
LR7699 
Last 
Dose of 
LR769 
Early 
Termi-
nation 
48 (±4) 
hrs after 
last dose 
28 (±3) 
days 
after last 
dose  
Efficacy Assessments6 
 
 
 
 
 
 
 
 
 
 
Surgeon’s Assessment 
 
 
X 
 
 
 
 
 
 
 
Investigator’s 
Assessment 
 
 
 
X 
X 
 
X 
X 
X 
 
Adverse Event 
Assessment 
X 
X10 
Concomitant Medication 
X 
X 
Immunogenicity 
 
X7 
 
 
 
X9 
 
X7 
X 
X7 
1 
Height will be measured at screening only.  
2 
Initial dose of 75 µg/kg (minor surgery or other minor invasive procedure) or 200 µg/kg (major surgery or other major invasive procedure) of LR769 will 
be administered as an IV bolus dose within ≤2 minutes prior to surgical incision or start of the invasive procedure; subsequent doses of 75 µg/kg of LR769 
will be administered as an IV bolus dose of LR769 within ≤2 minutes during and after surgical or other invasive procedure; duration of treatment will be 
dependent on the type of procedure and the patient’s status in accordance with Table 1 and Table 2.  
3 
Surgical/invasive procedure characteristics: Predicted surgery/invasive procedure characteristics: major or minor, maximum expected blood loss in a patient 
without hemophilia, type of anesthesia. Actual surgery/invasive procedure characteristics: major or minor, duration, estimated blood loss, factors that may 
have influenced bleeding independent of hemostasis, actual type of anesthesia, and complications.  
4 
Patients will be followed postoperatively according to the site’s standard of care. 
5 
Vital sign measurements will include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature (sublingual or tympanic); if the 
patient is discharged before the 24 (±2) hour time point vital signs will be taken at that time.  
6 
Intraoperative efficacy will be assessed by the surgeon/practitioner immediately after completion of the procedure and recorded; the primary efficacy 
endpoint will be determined by the investigator at 48 (±4) hours after last dose of LR769; all other efficacy assessments will be determined by the 
investigator or designee 
7 
Including storage serum sample for potential future use (eg, viral serology) 
8 
Weight taken within 24 hours prior to surgery or invasive procedure will be used for calculating the dose of LR769  
9 
Depending on the timing (length of time since the patient’s first dose of LR769), this assessment may be combined with a pre-specified visit 

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10
FVIII or FIX and titer of inhibitors to FVIII or FIX will at local and central lab. Only central lab for patients <12 kg. 
11
Patients will be assessed for signs and symptoms of thromboembolic events, such as pulmonary embolism (eg, shortness of breath, chest pain) or deep vein 
thrombosis (eg, calf pain, swelling/edema, and redness). 
12
Serology not performed for patients <12 kg.

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Biggs R (1952) Christmas disease: a condition previously mistaken for haemophilia. Br Med 
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Tachdjian R, Cooper DL, Shapiro AD (2012) Multidisciplinary management of patients with 
haemophilia with inhibitors undergoing surgery in the United States: perspectives and best 
practices derived from experienced treatment centres. Haemophilia 18:971-981 
Giangrande PL, Wilde JT, Madan B, Ludlam CA, Tuddenham EG, Goddard NJ, Dolan G, 
Ingerslev J (2009) Consensus protocol for the use of recombinant activated factor VII 
[eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients 
with inhibitors. Haemophilia 15:501-508 
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 
Obergfell A, Auvinen MK, Mathew P (2008) Recombinant activated factor VII for 
haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the 
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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 
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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 
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Shapiro A (2014) Long-term outcomes from orthopaedic surgery in haemophilia: are we 
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Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA (1998) Prospective, 
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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 
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Teitel JM, Carcao M, Lillicrap D, Mulder K, Rivard GE, St-Louis J, Smith F, Walker I, 
Zourikian N (2009) Orthopaedic surgery in haemophilia patients with inhibitors: a practical 
guide to haemostatic, surgical and rehabilitative care. Haemophilia 15:227-239 
Valentino LA, Carcao M, Mathew P, Leissinger CA, Berntorp E, Blanchette V, Escuriola-
Ettingshausen C, Ewenstein B, Ewing N, Gringeri A, Hoots WK, Negrier C (2009) The 
application of bypassing-agent prophylaxis in haemophilia A patients with inhibitors: a 
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White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J (2001) 
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