Conditions: Surgical Bleeding
Keywords: surgical hemostasis bleeding fibrin sealant fibrinogen thrombin spray dried
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
The purpose of the study is to determine if Raplixa plus Gelfoam is better than Gelfoam alone in stopping mild to moderate bleeding in children having surgery.

Detailed description:

Arms:
arm 1: During a single predefined surgical procedure, participants receive the assigned treatment on an appropriate target bleeding site (TBS). The treatment is topically applied using 1 of the following 3 methods:

* A thin layer of Raplixa is sprinkled directly from the vial onto the TBS, followed by application of Gelfoam.
* A thin layer of Raplixa is sprayed onto the TBS using the RaplixaSpray device, followed by application of Gelfoam.
* Raplixa is applied onto moistened Gelfoam which is then applied to the TBS.

Manual pressure is applied over the treatments using sterile gauze. The amount of Raplixa and Gelfoam used is at the discretion of the investigator, within the maximum of two 1 gram (g) vials of Raplixa that are permitted for each participant.

Thrombin-containing hemostats included in standard of care at the site are permitted as rescue therapy after the 5-minute time-to-hemostasis (TTH) evaluation. arm 2: During a single predefined surgical procedure, participants receive the assigned treatment on an appropriate TBS. Gelfoam is cut to the appropriate size and applied topically, according to the manufacturer's package insert, followed by manual pressure using sterile gauze.

Thrombin-containing hemostats included in standard of care at the site are permitted as rescue therapy after the 5-minute TTH evaluation, if necessary.

Interventions: intervention 1: Raplixa intervention 2: Gelfoam intervention 3: Rescue treatment
Intervention descriptions: intervention 1: Raplixa is a biological product approved for use in adults to help control bleeding from small blood vessels when standard surgical techniques, such as suture, ligature or cautery, are ineffective or impractical. When applied to a bleeding site, Raplixa is dissolved in the blood and a reaction starts between the fibrinogen and thrombin proteins. This results in the formation of blood clots to help stop the bleeding. intervention 2: Gelfoam Sterile Sponge is a medical device (USP, Pfizer) intended for application to bleeding surfaces as a hemostatic. It is a water-insoluble, off-white, nonelastic, porous, pliable product. It may be cut without fraying, used wet or dry, and is able to absorb many times its weight in blood and other fluids. intervention 3: Thrombin-containing hemostats included in standard care at the site

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: A Phase 2, Randomized, Single-Blind, Controlled Trial of 
Topical Raplixa™ (Fibrin Sealant [Human]) in Intraoperative 
Surgical Hemostasis in a Pediatric Population 
NCT Number: NCT02117349 
Document Date: Protocol Version 4: 13-July-2016 
 
 
 


 
 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Single-Blind, Controlled Trial of Topical Raplixa™ 
(Fibrin Sealant [Human]) in Intraoperative Surgical Hemostasis in a 
Pediatric Population 
 
Protocol No.: FC-007 
Date of Original Protocol: 
31 January 2014 
Date of Protocol Amendment 1: 
13 March 2014 
Date of Protocol Amendment 3: 
06 October 2014 
Date of Protocol Amendment 4: 
13 July 2016 
 
Sponsor 
Mallinckrodt Pharmaceuticals 
675 McDonnell Boulevard 
Hazelwood, MO 63042 
United States of America 
 
This document contains confidential information of Mallinckrodt Pharmaceuticals.  
Acceptance of this document constitutes agreement by the recipient that no unpublished 
information contained herein will be published or disclosed without prior written approval 
by Mallinckrodt Pharmaceuticals. This document may be disclosed to appropriate 
Institutional Review Boards/Independent Ethics Committees under the condition that they 
are requested and kept confidential. Do not copy or distribute without written permission 
from the Sponsor.  
CONFIDENTIAL 
 


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CORRESPONDING PROTOCOL AND PROTOCOL AMENDMENT VERSION NUMBERS 
–THE MEDICINES COMPANY/MALLINCKRODT, INC 
Medicines Company 
MNK Interpretation 
Notes 
Version 1.0, Protocol Date: 
31 January 2014 
Original Protocol:  
31 January 2014 
 
Version 2.0, Protocol Date: 
13 March 2014 
Protocol Amendment 1:  
13 March 2014 
Additionally issued a document 
on 23 July 2014 titled “Protocol 
Administrative Letter” 
Version 3.0,  
06 October 2014 
Protocol Amendment 2:  
06 October 2014 
 
Version 4.0,  
17 December 2015 
Protocol Amendment 3: 
17 December 2015 
Protocol submitted to Agency for 
feedback, no comments received 
Version 5.0, 17 July 2016 
Protocol Amendment 4: 
13 July 2016 
Protocol submitted to Agency for 
feedback, no recommendations 
for revisions received 
 
 


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PROTOCOL AMENDMENT 4 DATED 13 JULY 2016 
SUMMARY OF CHANGES 
The intention of this amendment is to address feedback from regulatory agencies and to improve 
subject enrollment.  
1. Sponsor revised to Mallinckrodt Pharmaceuticals and all sponsor contact information 
updated. 
2. Format and content revised globally to provide clarity. 
3. Global change in product names: Fibrocaps to Raplixa, Fibrospray delivery device to 
RaplixaSpray device and all references to F+G were revised to R+G. 
4. Revised the primary contact to be the Medical Monitor and moved the contact information 
for the Safety Physician to the list of additional contacts. 
5. Revised the contact information for the Clinical Trial Manager. 
6. Revised background information to include an additional product approved for hemostasis in 
the pediatric population.  
7. Added reference to Raplixa® package insert. 
8. Reduction in the number of subjects in the study from 108 to 87 subjects. 
9. The Evaluable population revised to the ITT Population. The ITT Population was denoted as 
the primary population for the efficacy analysis. A description of the analysis of the primary 
endpoint has been added. 
10. The safety population modified to be subjects who are exposed to any amount of study drug 
instead of subjects who received at least one dose of study drug. 
11. After simultaneous enrollment of the first 2 older cohorts and a review of their safety 
information by the Independent Data Monitoring Committee (IDMC), enrollment will then 
proceed in a sequential manner for the 2 younger cohorts with IDMC approval.  
12. Spinal and Renal surgical procedures added as two additional surgical indications in which 
Raplixa may be evaluated. 
13. Added the surgery type of “scoliosis surgery” under the spinal surgery type under the section 
“Diagnosis and Main Criteria for Selection." 
14. Clarified blood products allowed during 24 hours prior to treatment with study drug/product. 
Subject should not receive any whole blood, fresh frozen plasma (FFP), cryoprecipitate, or 
platelets within 24 hours prior to study drug. Packed red blood cell (PRBC) transfusions are 
allowed. 
15. Thrombin-containing hemostats (recombinant or human plasma-derived products) may be 
administered, if needed as part of the tiered approach for rescue treatment to achieve 
hemostasis  
16. Efficacy interim analysis of the data will not be performed. 
17. Pregnancy test performed on the day of surgery instead of at baseline. 
18. Day 30 blood sample for immunogenicity testing will not be collected in infants less 
6 months of age and testing will not be done on any samples from infants less than 6 months 
of age. 
19. Days 60 and 90 evaluations were removed from the study. However, should a subject return 
to the investigator between Day 30 and Day 90 for a routine follow-up visit (not scheduled 
for the purpose of the study), the investigator will record any update in the subject’s safety 
information and report such information to the Sponsor using the data collection forms 
provided. 


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20. Added a second data lock date to ensure the capture of safety data from visits after Day 30 
but before Day 90. 
21. Updated the definition, handling and regulatory reporting for device-associated events to be 
fully compliant with the current regulations in the US, Europe, and Canada. 
22. Removed Appendix A (Package Insert for Gelfoam, Absorbable Gelatin Sponge, USP) from 
protocol.  


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PROTOCOL AMENDMENT 3 DATED 6 OCTOBER 2014 
SUMMARY OF CHANGES 
 
The following significant changes were made to protocol FC-007 version 2.0. All changes are 
reflected in version 3.0 of the protocol dated 06-Oct-2014. 
Items in italics were added, while strikethrough text (i.e., text) has been deleted. 
1. Additional background information and reference added to support the rationale for revising 
the approach to subject enrollment. (section:1.1.) 
Although there are physiologic differences in the levels of coagulation & fibrinolytic proteins 
over the maturation of children compared to adults, near adult levels are achieved by most 
children by 6 months of age, and these differences, are considered to be physiologic, i.e., 
something that is normal, not due to anything pathologic nor significant in terms of causing 
illness (7, 8). 
To date, there are only two fibrin sealants, RecothromR and TisseelR, used in the adult 
population, that have also been approved by global regulatory agencies as an adjunct 
hemostatic agent in the pediatric population. Both of these fibrin sealants were studied in 
very small pediatric populations (<30 subjects) which simultaneously enrolled all subjects 
across age groups as they presented to clinical research centers. The efficacy and safety 
profile was similar to data observed in the adult population. There was also no observation 
of enhanced immunogenic responses in the pediatric populations supporting the summary 
basis for approval. As Fibrocaps is in the same biological class (fibrin sealant with a 
comparable mechanism of action and biological activity) as RecothromR and TisseelR, it is 
expected that Fibrocaps will not only be found to be a more convenient formulation, but just 
as safe, effective, and non-immunogenic, as Fibrocaps treatment in the adult population, and 
RecothromR & TisseelR in the pediatric population. 
2. Simultaneous enrollment across all four age groups is allowed. This was changed from 
enrollment utilizing a step-wise sequential approach by age cohort. (sections: protocol 
synopsis, 3.1) 
Methodology:  
Recruitment will occur in a step wise, sequential approach with subjects from the 2 oldest 
age cohorts enrolled first. Subjects will be enrolled, simultaneously, across four different 
age groups as they present to clinical sites: 1) 11 years of age to less than 18 years of 
age; 2) 2 years of age to less than 11 years of age; 3) 6 months of age to less than 2 years 
of age; or 4) 36 weeks gestational age to less than 6 months of age.  
3. The IDMC is afforded more flexibility in approving continued enrollment in a given age 
cohort. (sections: protocol synopsis, 1.1, 3.1, 10.5.1) 
Methodology: 
Following completion of Visit 5, Day 30, for 6 subjects treated with Fibrocaps plus 
gelatin sponge within one of the four age cohort groups, the Independent Data 
Monitoring Committee will review all available safety data and verify that the observed 
safety profile supports continued subject enrollment within that given age cohort which 
has enrolled 6 Fibrocaps treated subjects. During this IDMC review, the IDMC will have 
the authority to approve continued enrollment within a cohort which has enrolled less 


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than 6 Fibrocaps treated subjects, if the safety assessment warrants this with a favorable 
benefit to risk outcome for the subjects. 
      10.5.1. 
Independent Data Monitoring Committee  
 
An independent data monitoring committee (IDMC) comprising external experts in 
pediatric surgery, hematology, and statistics will be charged with monitoring the trial for 
safety. Two IDMC meetings are planned: the first after 6 subjects aged 11 to less than 18 
years have been treated with Fibrocaps and followed for 30 days for safety. The second 
IDMC meeting will occur after 6 subjects aged 2 to less than 11 years have been treated with 
Fibrocaps and followed for 30 days for safety. IDMC meetings will occur after 6 subjects 
have been treated with Fibrocaps and followed for 30 days for safety in any of the 4 age 
cohorts (i.e., once 6 subjects are enrolled in 1 of the 4 age cohorts, the IDMC will convene 
once that data set is ready for review). The IDMC will review all available safety data and 
verify that the observed safety profile supports continued subject enrollment within that given 
age cohort which has enrolled 6 Fibrocaps treated subjects. During this IDMC review, the 
IDMC will have the authority to approve continued enrollment within a cohort which has 
enrolled less than 6 Fibrocaps treated subjects, if the safety assessment warrants this with a 
favorable benefit to risk outcome for the subjects.  
 
4. A minimum number of subjects per age cohort are no longer required.(section: protocol 
synopsis) 
Number of Subjects:  
The study will enroll a total of approximately 108 subjects. with at least 6 subjects from 
each age cohort. Approximately 36 subjects will be enrolled in each surgical indication.  
 
5.  Soft Tissue Surgeries related to burn donor skin grafts are further clarified. (sections: protocol 
synopsis, 4.0) 
 
Soft tissue Surgery 
The TBS will be identified during the soft tissue dissection related to the primary 
operative procedure. Primary operative procedures include but are not limited to: lower 
anterior resections, abdominal perineal resections, donor skin graft site (split-thickness-
meshed, split-thickness-non-meshed, full thickness, and composite graft) in limited burn 
patients, breast mass excision, cleft lip repair, and hernia repair. 
 
6. Renal and Spinal Surgery indications added. (sections: protocol synopsis, 4.0) 
3. Renal Surgery – Nephrectomy associated with diffuse oozing from the 
retroperitoneal wall 
4. Spinal Surgery – Laminectomy, spinal fusion, or other appropriate pediatric spinal 
surgeries associated with mild to moderate bleeding requiring an adjunct fibrin sealant 


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7. Inclusion Criteria clarifications added regarding acceptable gestational age for the newborn 
cohort. (sections: protocol synopsis, 4.2) 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject age is 36 weeks gestational age 0 days through < 18 years of age at time 
of randomization 
 
8. Exclusion Criteria regarding acceptable baseline laboratory values clarified. (sections: protocol 
synopsis, 4.3) 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria 
apply prior to randomization: 
1. Baseline abnormalities of international normalized ration (INR) > 2.5 or  
activated partial thromboplastin time (aPTT) > 100 seconds during screening that 
are not explained by current drug treatment (e.g., warfarin, heparin), or chronic 
disease state necessitating surgery (e.g., end-stage liver disease) 
2. Platelets < 100 x109 PLT/L during screening, unless due to chronic disease state, 
e.g. liver disease/failure, necessitating surgery 
3. Subject has history of heparin induced thrombocytopenia (only for vascular 
subjects where heparin use is required)  
 
9. Added current version of Gelfoam Package Insert dated June, 2013(section: Appendix A) 
 
 
10. Updated Drug Safety Officer Name and Contact Information (section: Title Page) 
 
Drug Safety Officer: 
 
Drug Safety Physician : 
, MD 
 
 
11. Added New Section 8.4 Events of Special Interest (section: 8.4) 
8.4. 
ADVERSE EVENTS OF SPECIAL INTEREST 
During Fibrocaps development, specific categories of AEs were designated as Adverse 
Events of Special Interest (AESI). These are events that are biologically plausibly 
associated with Fibrocaps exposure, have been historically associated with the class of 
topical hemostatic agents, or have been historically associated with drug application 
using air- or gas-pressurized sprayers. The categories of AESI are:  
• 
Surgical site-related events, which includes pain and infection suggestive 
of a higher complication rate  


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• 
Thromboembolic events, which includes acute ischemic events like 
myocardial infarction, deep vein thrombosis and stroke  
• 
Re-bleeding at the TBS, including post-procedural hemorrhage and 
hematomas  
• 
Air emboli-associated events, which includes acute respiratory failure or 
cardiovascular collapse occurring intra-operatively following the use of 
the Fibrospray device  
• 
Hepatitis/HIV infection suggestive of viral transmission through Fibrocaps 
or Tachosil 
The incidence of these AESI will be monitored according to the standard safety 
operating procedure for AEs and will be compared to Gelfoam. In addition, additional 
information will be collected for events of potential air/gas emboli using the Raplixa 
(Fibrocaps) Air or Gas Embolism Adverse Events questionnaire. 
 
12. Section 8.1.4 Additional Reporting Requirements, new text added. 
 
Medication error: Refers to any unintended error in the prescribing, dispensing or 
administration of a medicinal product while in the control of the healthcare 
professional, patient or consumer. Medication errors are an important cause of 
morbidity and mortality and many could be prevented or mitigated. They can fall 
broadly into 4 categories: 
 
1. Wrong medication 
 
2. Wrong dose (including strength, form, timing, concentration, infusion rate and 
amount) 
 
3. Wrong route of administration 
 
4. Wrong patient 
 
Occurrences of medication errors in a study subject should be reported within 24 hours 
using the Medication Error/Overdose form. In cases where a medication error results 
in a serious adverse event, the Serious Adverse Event reporting form should be used to 
report the SAE. Non-serious AEs associated with medication errors should be reported 
in AE page in eCRF. 
 
 


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13. Section 8.1.3 added. 
 
8.1.3. 
Incident (Article 10 of the MDD in the European Union) 
An incident is any malfunction or deterioration in the characteristics and/or 
performance of a device, as well as any inadequacy in the labeling or the instructions 
for use which, directly or indirectly, might lead to or might have led to the death of a 
subject, or user or of other persons or to a serious deterioration in their state of health. 
 
 
 




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PROTOCOL AMENDMENT 2 DATED 13 MARCH 2014 
SUMMARY OF CHANGES 
The following significant changes were made to protocol FC-007 version 1.0. All changes 
are reflected in version 2.0 of the protocol dated 13-Mar-2014. 
The EudraCT number has been confirmed and updated. Minor administrative changes were 
made for consistency and are not all listed here.  No additional assessments or changes in risk 
to the subject have been made. Additional monitoring for anti-fibrinogen antibodies, for 
subjects found positive for anti-thrombin antibodies, is a request from the FDA. 
Items in italics were added, while strikethrough text (i.e., text) has been deleted. 
1. Study Population (Section 1.4) – Clarified to be consistent with EMA agreement 
for the Pediatric Investigational Plan 
The pediatric population will be treated in this study. The ages will be segregated into 4 
groups according to European Medicines Agency (EMA) requirements (EMEA, 
CPMP/ICH/2711/99; FDA, ICH E11, December 2000):  
• Term newborn infants (0–27 days)  
• Infants and toddlers (28 days 23 months)  
• Children (2–11 years)  
• Adolescents (12–17 years) 
 
The ages will be segregated into 4 groups which are generally consistent with the 
European Medicines Agency (EMA) (EMEA, CPMP/ICH/2711/99) and the FDA, 
(ICH E11, December 2000) requirements: 
• Birth to less than 6 months 
• 6 months to less than 2 years 
• Children (2 years to less than 11 years) 
• Adolescents (11 to less than 18 years) 
 
 


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2. Schematic Diagram of Trial Design (Section 3.2, Figure 1) –Included to provide 
overall study schema. 
 
3. Inclusion Criteria (Synopsis, Section 4.2) – Clarified to include sexually active 
teenagers. 
a. If a subject is ≥ 7 years old, or appropriate age as defined by local regulations, 
the subject is may be required to have signed an IRB-approved assent 
document 
b. If subject is a sexually active male or a sexually active female of child-bearing 
potential, subject agrees to use a medically accepted form of contraception 
from the time of consent to completion of all of the follow-up study visits. 
 
4. Laboratory Assessments (Section 7.1.5) and Safety Analysis (Section 10.4.4) – 
included request by the FDA to assess anti-fibrinogen antibodies in subjects with a 
positive anti-thrombin  
a. Section 7.1.5 Laboratory Assessments 
Immunogenicity Sample 
This blood sample will be used for measuring anti-thrombin and anti-fibrinogen 
antibodies in plasma from all subjects treated in the study.  
b. Section 10.4.4 Safety Analysis 
Overall safety, as determined by the incidence, severity and relationship of 
adverse events (AEs), clinical laboratory abnormalities, estimated rates of 
immunogenicity (monitoring for anti-thrombin antibodies and additional 


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monitoring for anti-fibrinogen antibodies will be limited to subjects found positive 
for anti-thrombin antibodies and subjects with unexplained bleeding or clinical 
suspicion of bleeding related to antibody formation) and post-surgery bleeding 
complications.   
 
5. AE Severity (Section 8.1.1.1) – provided clarification of severity grading 
consistent with CTCAE criteria. 
The severity of an AE and the relationship to study drug will be assessed by the 
investigator. The investigator should ensure that any subject experiencing an AE 
receives appropriate medical support until the event resolves. 
Adverse events (AE) will be graded on a 3 point scale and reported as indicated 
on the case report form. The intensity of an AE is defined as follows: 
1 = Mild: Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: Inability to work or perform normal daily activity. 
AE severity will be assessed according to the grading scale in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0: 
a. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
b. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living (ADL)*. 
c. Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
d. Grade 4: Life-threatening consequences; urgent intervention indicated. 
e. Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden 
 
 


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6. Bleeding Events (Section 10.4.4.1) – Section deleted, as the methodology is not 
pertinent to endpoints nor the pediatric population 
The incidence of hemorrhage will be measured by clinically relevant criteria (Global 
Utilization of Streptokinase and Tpa for Occluded Arteries [GUSTO], Thrombolysis 
in Myocardial Infarction [TIMI], and other major bleeding scales) for up to 48 hours. 
Data will be summarized for the following: 
• 
Incidence of hemorrhage by clinically relevant criteria/scales up through 48 
hours  
• 
Incidence of blood product transfusion(s) up through 48 hours, categorized 
according to relationship with coronary artery bypass grafting (CABG) surgery 
 
 


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EMERGENCY CONTACTS 
Emergency Contact Information 
Role in Study  
Name  
Contact Information  
Primary Contact: 
Medical Monitor 
, MD 
Mallinckrodt Pharmaceuticals 
675 McDonnell Boulevard 
Hazelwood, MO 63042 
United States of America 
Telephone: 
 
Cell phone: 
 
E-mail: (not for emergencies):  
 
 
 
Please see next page for additional telephone contact numbers (Page 16). 
Please see Section 8.3 for detailed information regarding the Serious Adverse Event (SAE) 
Reporting Requirements for both the biologics and the devices of this study. 
SAE reporting fax: 
 
SAE confirmation phone: 
 (24-hour call center) 
SAE confirmation email: GlobalPV@mallinckrodt.com 
 




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SIGNATURE PAGE 
 
SPONSOR SIGNATURE 
My signature, in conjunction with the signature of the investigator, confirms the agreement of 
both parties that the clinical study will be conducted in accordance with the protocol and 
applicable laws and other regulations including, but not limited to, the International 
Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the US 
Code of Federal Regulations (CFR), protections for privacy, and generally accepted ethical 
principles for human research such as the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide 
emergency medical care. 
 
 
Sponsor Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 
Sponsor Name (print) 
 
 
 
 
 


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SIGNATURE PAGE 
 
INVESTIGATOR SIGNATURE  
My signature confirms that the clinical study will be conducted in accordance with the 
protocol and applicable laws and other regulations including, but not limited to, the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP), the US Code of Federal Regulations (CFR), protections for privacy, and generally 
accepted ethical principles such as the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide 
emergency medical care. 
 
 
 
Investigator’s Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 
Investigator’s Name and Title (print) 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
Adverse event of special interest 
ALAT/ALT  
alanine aminotransferase 
Alb 
albumin 
aPTT 
activated partial thromboplastin time 
ASAT/AST  
aspartate aminotransferase 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cr 
creatinine 
CRF 
case report form 
DCF 
Data clarification forms 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOS 
end of study visit 
EU 
European Union 
FDA 
Food and Drug Administration 
FFP 
Fresh frozen plasma 
G 
gelatin sponge (control group) 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance Department 
Glu 
glucose 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
IU 
international units 
K 
potassium 
L 
liter 
MDR 
Medical Device Reporting 


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MDV 
Medical Device Vigilance 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
MH 
medical history 
MI 
myocardial infarction 
NA 
sodium 
OBS 
other bleeding sites 
PE 
physical examination 
PI 
Principal Investigator 
PLT 
platelets 
PRBC 
Packed red blood cell 
psi 
pounds per square inch 
PT 
prothrombin time 
PTFE 
polytetrafluoroethylene 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Screen failure 
subject does not meet all inclusion criteria/exclusion criteria 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TBili 
total bilirubin 
TBS 
target bleeding site 
Treated 
treated with Study Treatment (R+G or G) 
TTH 
time to hemostasis 
USA/US 
United States of America 
USP 
United States Pharmacopeia 
USPI 
United States Pharmacopoeia 
WHODD 
WHO Drug Dictionary  
 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Mallinckrodt Pharmaceuticals  
Name of Finished Product: Raplixa™ [Fibrocaps™ (PRO-0601)] 
Name of Active Ingredient: Human Plasma-derived Thrombin and Fibrinogen 
Title of Study: A Phase 2, Randomized, Single-Blind, Controlled Trial of Raplixa in 
Intraoperative Surgical Hemostasis in a Pediatric Population 
Phase of Development: 2 
Study Centers: Up to 25 centers in the United States (US)  
Study Period: 
The estimated study period is approximately 30 months from first subject enrolled to last subject 
completed. 
Estimated date first subject enrolled: December 2014 
Estimated date last subject completed: July 2018 
Objectives:  
The objective of the study is to evaluate the efficacy and safety of Raplixa plus gelatin sponge, as 
compared to gelatin sponge alone, for achieving hemostasis in pediatric subjects undergoing 
hepatic, renal, soft tissue, spinal, or vascular surgery.  
Methodology:  
The study is a Phase 2, multicenter, randomized, single-blind (to subjects), controlled trial 
comparing the efficacy and safety of Raplixa in combination with an absorbable gelatin sponge to 
gelatin sponge alone. The study will enroll subjects undergoing one of the following surgical 
procedures: hepatic, renal, soft tissue, spinal, or vascular surgery.  
Parents/guardians of subjects will provide written informed consent prior to undergoing any 
protocol-related assessments or procedures, which may occur up to 30 days prior to surgery. 
Subjects ≥ 7 years old, or of appropriate age as defined by local regulations, may be required to 
provide assent to participate in the study.  
After establishing eligibility during screening and confirming continued eligibility on the day of 
surgery (Day 1), subjects will be randomized in a single-blinded manner, in a 2:1 ratio, to receive 
study drug (either Raplixa in combination with an absorbable gelatin sponge [active group; R+G] 
or gelatin sponge alone [control group; G]) when an appropriate target bleeding site (TBS) is 
identified. Subjects who are not treated will be withdrawn from the study and may be replaced. 
Reasons for not receiving study drug include, but are not limited to; lack of an appropriate TBS 
for time to hemostasis (TTH) evaluation, severe bleeding, or a change in surgical procedure that 
renders the subject ineligible, after the subject has been randomized. 
Subjects will be enrolled across 4 different age groups, with the 2 oldest age groups being enrolled 
simultaneously: 
• 
Adolescents (11 to less than 18 years). 
• 
Children (2 years to less than 11 years). 
• 
6 months to less than 2 years. 
• 
Birth (≥ 36 weeks gestational age at birth) to less than 6 months. 
During a surgical procedure on Day 1 (Visit 2), subjects will be initially treated with Raplixa plus 
gelatin sponge or gelatin sponge alone at the TBS. The TTH will be assessed every 30 seconds for 
up to 5 minutes. Bleeding appropriate for TTH evaluation is defined as mild to moderate bleeding, 
either on its own or remaining after brisk/severe bleeding has been controlled by standard surgical 
modalities. Subjects may be re-treated with their assigned treatment as necessary during the 5-
minute TTH assessment period, with up to a maximum of 2 vials of Raplixa (2.0 g) in total (for 


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target and non-target bleeding sites). Rescue treatment may be administered if necessary in a 
tiered approach at the TBS or other bleeding sites (OBS) with thrombin-containing hemostats 
permitted after all other treatment options have been attempted after the TTH assessment period 
has elapsed, at the discretion of the Investigator. 
For subjects randomized to Raplixa, at any time after hemostasis has been achieved at the TBS, 
and the 5-minute TTH assessment period has elapsed, the remaining Raplixa may be used at 
additional appropriate OBS that are part of the primary surgical procedure. Importantly, the 
remaining Raplixa should not be used on OBS until after the 5-minute TTH assessment period has 
elapsed in order to ensure that adequate Raplixa is available to use in the event of re-bleeding 
from the TBS. The amount of Raplixa applied and the incidence of hemostasis achieved at OBS 
will be recorded; however, the primary efficacy analysis will not include hemostasis data from the 
OBS. 
Subjects will undergo a safety evaluation consisting of a targeted physical examination and 
clinical laboratory tests on Day 2 (Visit 3). If the subject’s surgery was performed as an outpatient 
procedure, the Visit 3 assessment may be conducted over the phone with the physical examination 
conducted and laboratory tests collected prior to discharge on Day 1. Safety evaluations will also 
be performed on Day 7 (Visit 4) via telephone, if the subject has been discharged, and on  
Day 30 (Visit 5; End of Study Visit). Immunogenicity samples (monitoring for anti-thrombin 
antibodies) will be collected and analyzed at baseline and at Day 30 for all treated subjects, except 
subjects who are less than 6 months old. Additional monitoring for anti-fibrinogen antibodies will 
be limited to subjects found positive for anti-thrombin antibodies and subjects with unexplained 
bleeding or clinical suspicion of bleeding related to antibody formation.  
Number of Subjects:  
The study will enroll a total of up to 87 subjects. 
Diagnosis and Main Criteria for Selection:  
The study will enroll subjects undergoing one of the following surgical procedures: 
1. Hepatic Surgery 
Hepatic wedge resection or anatomic resection of 1 to 5 contiguous hepatic segments, which may 
be combined with surgical procedures involving the pancreas, gall bladder, bile duct or intestines. 
Subjects undergoing living-related liver donation are also eligible. 
2. Renal Surgery 
Nephrectomy associated with diffuse oozing from the retroperitoneal wall. 
3. Soft Tissue Surgery 
The TBS will be identified during the soft tissue dissection related to the primary operative 
procedure. Primary operative procedures include but are not limited to: lower anterior resections, 
abdominal perineal resections, donor skin graft site (split-thickness-meshed, split-thickness-non-
meshed, full thickness and composite graft) in limited burn patients (up to 40% total body surface 
area [TBSA]), breast mass excision, cleft lip repair, and hernia repair. 
Appropriate soft tissue types will include but will not be limited to: loose areolar tissue, fat, 
lymphatic tissue/lymph node beds, and muscle. The TBS will not involve parenchymal, 
gastrointestinal or genitourinary soft tissue, and cardiac, lung or brain tissue, as Raplixa has not 
yet been studied in these tissue types. 
4. Spinal Surgery  
Scoliosis surgery, cervical, thoracic, or lumbar discectomy, corpectomy, laminectomy, lateral or 
interbody fusion. Epidural bleeding typically described as oozing, flowing, or pulsatile, and 
normally requiring topical adjuncts to hemostasis is necessary to be considered eligible. The TBS 
may not be within a bony cavity or other confined area. 
5. Vascular Surgery 
All subjects undergoing vascular surgery should be systemically heparinized according to 
standard procedures. The clamp(s) should be removed to determine if an appropriate TBS with 


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mild to moderate bleeding is present. The clamp(s) should remain off once a TBS is identified and 
during the treatment and assessment of TTH. If protamine reversal is indicated, it should occur 
after the 5-minute TTH assessment period is completed, unless a safety concern dictates that it 
should happen earlier. Appropriate vascular surgical procedures may include, but are not limited 
to: artificial graft (i.e., polytetrafluoroethylene [PTFE] or Dacron) for hemodialysis access 
(including revision procedures), hemangiomas, and vascular injuries (peripheral or abdominal). 
The TBS may not involve the heart or the vessels surrounding the heart. 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject age is ≥ 36 weeks gestational age at birth (for infants) through < 18 years of age at 
time of treatment. 
2. 
Subject’s legal representative (parent or guardian) has signed an institutional review board 
(IRB)-approved informed consent document. 
3. 
If a subject is ≥ 7 years old, or appropriate age as defined by local regulations, the subject 
may be required to have signed an IRB-approved assent document. 
4. 
Subject is scheduled to undergo one of the surgical procedures described in the protocol. 
5. 
If female and of child-bearing potential, subject has a negative pregnancy test on the day of 
surgery 
6. 
If subject is a sexually active male or a sexually active female of child-bearing potential, 
subject agrees to use a medically accepted form of contraception from the time of consent to 
completion of all of the follow-up study visits. 
During Surgery Inclusion Criteria 
1. 
Presence of mild or moderate bleeding/oozing.  
2. 
TBS surface area of ≤ 100 cm2. 
3. 
Subject has not received any whole blood, fresh frozen plasma (FFP), cryoprecipitate, or 
platelets within 24 hours prior to study drug. Packed red blood cell (PRBC) transfusions are 
allowed. 
4. 
Subject has no intra-operative complication other than bleeding which, in the opinion of the 
Investigator, may interfere with the assessment of efficacy or safety. 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria apply prior to 
enrollment: 
1. 
Gestational age of < 36 weeks at birth (for infants less than 6 months). 
2. 
Subject has any clinically-significant congenital coagulation disorder (e.g., hemophilia A or 
B) that may interfere with the assessment of efficacy or pose a safety risk to the subject 
according to the Investigator. 
3. 
Subject has baseline abnormalities of international normalized ratio (INR) > 2.5 or activated 
partial thromboplastin time (aPTT) > 100 seconds during screening that are not explained by 
current drug treatment (e.g., warfarin, heparin), or chronic disease state necessitating surgery 
(e.g., end-stage liver disease). 


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4. 
Subject has aspartate aminotransferase (ASAT/AST) and alanine aminotransferase 
(ALAT/ALT) > 3 times the upper limit of reference range during screening, except for 
subjects undergoing liver resection surgery or with a diagnosis of liver disease where there is 
no upper limit for these analytes due to the nature of their disease. 
5. 
Subject is unwilling to receive blood products or products derived from human blood. 
6. 
Subject has platelets < 100 x109 PLT/L during screening, unless due to chronic disease state, 
e.g., liver disease/failure, necessitating surgery. 
7. 
Subject has known antibodies or hypersensitivity to Raplixa or any of its components, other 
thrombin preparations, or coagulation factors. 
8. 
Subject has known allergy to porcine gelatin. 
9. 
Subject has medical, social, or psychosocial factors that, in the opinion of the Investigator, 
could impact subject safety or compliance with study procedures. 
10. Subject is; 1) currently participating in another clinical study or 2) has participated in 
another clinical study within 30 days of Screening or 3) plans to participate in a clinical 
study prior to completion of the 30-day follow-up period. 
Test Product, Dose and Mode of Administration, Batch Number(s):  
Raplixa contains a spray-dried mixture of human plasma-derived fibrinogen and human 
plasma-derived thrombin powders that was developed under the general guidelines that support 
marketing of fibrin sealant products manufactured for commercial use.  
Raplixa is used without reconstitution and can be applied onto the surgical bleeding site directly 
from the vial or with the use of the RaplixaSpray device, or onto a moistened gelatin sponge that 
is then applied to the surgical bleeding site. Raplixa dissolves readily on contact with aqueous 
fluids (e.g., blood) activating thrombin which triggers an immediate conversion of fibrinogen into 
fibrin, and subsequent clot formation.  
The physicochemical properties of Raplixa make it a unique fibrin sealant that is ready-to-use, 
room-temperature stable and convenient to apply to bleeding sites of various sizes and shapes, 
thus eliminating costly storage, transport, and preparation that is necessary with other currently 
commercially-available fibrin sealants in the US/European Union (EU).  
Duration of Treatment: 
Each subject will be treated during a single surgical procedure and will participate in the study for 
up to 30 days post-surgery. 
Reference Therapy, Dose and Mode of Administration:  
The control arm consists of a gelatin sponge, supplied by the sponsor, and is the same as is used 
with Raplixa. Sites will use Gelfoam® (Absorbable Gelatin Sponge, USP, Pfizer). Sites may use 
their own operating room supply of absorbable gelatin sponge (Gelfoam), if necessary, and must 
record the name, lot number, and expiration date. The gelatin sponge is cut to the appropriate size 
and applied topically, dry or moistened, according to the manufacturer’s package insert, followed 
by manual pressure with sterile gauze. If possible, the gelatin sponge should be left in place, while 
the excess is removed from the bleeding site once hemostasis has been achieved. 


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Criteria for Evaluation:  
Safety:  
Overall safety, as determined by the incidence, severity and relationship of adverse events (AEs), 
clinical laboratory abnormalities, estimated rates of immunogenicity (monitoring for 
anti-thrombin antibodies) collected and analyzed at baseline and at Day 30 for all treated subjects, 
except subjects who are less than 6 months old. Additional monitoring for anti-fibrinogen 
antibodies will be limited to subjects found positive for anti-thrombin antibodies and subjects with 
unexplained bleeding or clinical suspicion of bleeding related to antibody formation and 
post-surgery bleeding complications.  
Study participation ends after the Day 30 visit. However, should a subject return to the 
investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for the 
purpose of the study), the investigator will record any update in the subject’s safety information 
and report such information to the Sponsor using the data collection forms provided. 
Efficacy:  
• 
Percentage/proportion of subjects who reach hemostasis from the first identified TBS 
within 4 minutes of study drug application. 
• 
Restricted mean TTH (during the 5-minute TTH assessment period). 
• 
Through to Visit 5 (End of Study [EOS]) visit: 
o 
Use of alternative hemostatic agents on the TBS. 
o 
Volume of transfused blood (whole blood, fresh frozen plasma (FFP), 
cryoprecipitate, platelets, or packed red blood cell (PRBC). 
o 
Incidence of re-operation for bleeding at the TBS. 
Statistical Methods:  
This is a Phase 2, multicenter, randomized, single blind (for subjects), controlled study to evaluate 
the safety and efficacy of Raplixa (R) in combination with an absorbable gelatin sponge (R+G) to 
gelatin sponge alone (G) for achieving hemostasis in pediatric subjects undergoing hepatic, renal, 
soft tissue, spinal or vascular surgery. Randomization is in a 2:1 ratio between R+G and G groups. 
The sample size estimation is based on data from the completed Phase 3 trial (FC-004). Assuming 
the proportion of subjects achieving hemostasis within 4 minutes in R+G and G are 87% and 60% 
respectively, approximately 87 pediatric subjects (58 in R+G, 29 in G) will provide approximately 
80% power to detect this difference at the one-sided significance level of 0.025 (equivalently, 
2-sided significance level of 0.05) based on a chi-square test for 2 proportions. 
Statistical analyses will be performed using the following subject populations: 
Intent-to-Treat (ITT) population: The ITT population consists of all randomized subjects. This 
population will be the primary population for the efficacy analyses. 
Safety population: All subjects who received any amount of study drug. This population will be 
the primary population for the safety analyses. 
Descriptive statistics and graphical displays will be used to summarize data collected in the 
electronic case report forms (eCRF). Continuous variables will be summarized using mean, 
standard deviation, median, inter-quartile range, minimum and maximum. Categorical variables 
will be summarized using frequency and percentage. Time-to-event variables will be summarized 
using Kaplan-Meier estimates.  
All relevant subjects’ data, including those subjects who are not treated in the study, will be 
presented in data listings. 
 


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TABLE OF CONTENTS 
CORRESPONDING PROTOCOL AND PROTOCOL AMENDMENT VERSION NUMBERS –
THE MEDICINES COMPANY/MALLINCKRODT, INC .......................................................... 2 
EMERGENCY CONTACTS ........................................................................................................... 15 
ADDITIONAL CONTACTS ............................................................................................................ 16 
SIGNATURE PAGE ....................................................................................................................... 17 
SIGNATURE PAGE ....................................................................................................................... 18 
LIST OF ABBREVIATIONS ........................................................................................................... 19 
PROTOCOL SYNOPSIS ................................................................................................................ 21 
1. 
INTRODUCTION................................................................................................................... 30 
 
Background ............................................................................................................ 30 
 
Preclinical Studies ................................................................................... 31 
 
Clinical Studies ........................................................................................ 31 
 
Known and Potential Risks and Benefits ................................................. 33 
 
Study Rationale ...................................................................................................... 33 
 
Study Population ................................................................................................... 34 
2. 
TRIAL OBJECTIVES AND PURPOSE ................................................................................ 35 
3. 
TRIAL DESIGN ..................................................................................................................... 36 
 
Type/Design of Trial .............................................................................................. 36 
 
Schematic Diagram of Trial Design ..................................................................... 38 
 
Endpoints ............................................................................................................... 39 
 
Measures to Minimize/Avoid BiaS ....................................................................... 39 
 
Blinded Study .......................................................................................... 39 
4. 
SUBJECT POPULATION ..................................................................................................... 40 
 
Number of Subjects ............................................................................................... 41 
 
Inclusion Criteria ................................................................................................... 41 
 
Exclusion Criteria .................................................................................................. 41 
 
Withdrawal Criteria ................................................................................................ 42 
 
Withdrawal from Study Drug ................................................................... 43 
 
Withdrawal from Trial ............................................................................... 43 
5. 
TREATMENT OF SUBJECTS .............................................................................................. 44 
 
Study drugs ............................................................................................................ 44 
 
Raplixa ..................................................................................................... 44 
 
Comparator .............................................................................................. 46 


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Packaging and Labeling ........................................................................................ 46 
 
Storage .................................................................................................................... 46 
 
Accountability ........................................................................................................ 47 
 
Concomitant Medications ..................................................................................... 47 
 
Rescue Treatment ................................................................................... 48 
 
Blinding ................................................................................................................... 48 
 
Blinding of Study Medications ................................................................. 48 
 
Method and Maintenance of Blinding ...................................................... 49 
6. 
SCHEDULE AND SEQUENCE OF PROCEDURES ............................................................ 50 
 
Schedule of Events/Assessments By Time Point .............................................. 50 
 
General Conduct of the Trial ................................................................................ 51 
 
Visit 1: Screening Period (Day –30 to Day 1) .......................................... 51 
 
Visit 2: Surgery, Randomization, and Treatment .................................... 52 
 
Visit 3: (Day 2, 16-48 hours post-Treatment): Safety Evaluation ............ 54 
 
Visit 4: (Day 7 ± 2 days): Safety Evaluation ............................................ 54 
 
Visit 5: (Day 30 ± 7 days): Safety Evaluation .......................................... 54 
 
Study Termination ................................................................................................. 55 
7. 
PROTOCOL ASSESSMENTS ............................................................................................. 56 
 
Assessment of Safety ........................................................................................... 56 
 
Adverse Events ....................................................................................... 56 
 
Vital Signs ................................................................................................ 56 
 
Physical Examination .............................................................................. 56 
 
Laboratory Assessments ......................................................................... 56 
 
Assessment of Efficacy ........................................................................................ 57 
 
Time to Hemostasis (TTH) ...................................................................... 57 
8. 
ADVERSE EVENTS ............................................................................................................. 58 
 
Definitions .............................................................................................................. 58 
 
Adverse Event ......................................................................................... 58 
8.1.1.1. 
AE Severity .......................................................................... 58 
8.1.1.2. 
Study Drug Causality ........................................................... 59 
 
Serious Adverse Event ............................................................................ 60 
 
Adverse Device Effects (ADEs) ............................................................... 60 
 
Additional Reporting Requirements ......................................................... 61 
 
Adverse Event of Special Interest (AESIs) .............................................. 62 
 
Complications of the Disease Under Study ............................................. 62 
 
Procedure for Non-Serious Adverse Event Recording ...................................... 63 
 
Procedure for Serious Adverse Event Reporting ............................................... 63 
 
Procedure for Medication error reporting ........................................................... 64 
 
Procedure for Adverse Device Effects (ADEs) reporting .................................. 64 


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Adverse Events of Special Interest ...................................................................... 64 
 
Reporting Events of Pregnancy/lactation ........................................................... 65 
 
POTENTIAL SAFETY UPDATES WITHIN 90 DAYS OF STUDY PRODUCT 
APPLICATION ........................................................................................................ 65 
9. 
DATA COLLECTION ............................................................................................................ 65 
10. 
STATISTICAL PLAN ............................................................................................................ 66 
 
Sample Size ............................................................................................................ 66 
 
Randomization ....................................................................................................... 66 
 
General Statistical Considerations and Definitions ........................................... 66 
 
General Statistical Methods .................................................................... 66 
 
Analysis Populations ............................................................................... 67 
10.3.2.1. 
Intent-to-Treat (ITT) Population ........................................... 67 
10.3.2.2. 
Safety Population ................................................................. 67 
 
Analysis Windows and Baseline .............................................................. 67 
 
Missing Data Handling............................................................................. 67 
 
Statistical Analyses ............................................................................................... 67 
 
Demographic and Baseline Characteristics ............................................ 68 
 
Prior and Concomitant Medications ........................................................ 68 
 
Safety Analysis ........................................................................................ 68 
10.4.3.1. 
Adverse Events .................................................................... 68 
10.4.3.2. 
Laboratory Tests .................................................................. 69 
10.4.3.3. 
Vital Signs ............................................................................ 69 
 
Efficacy Analysis ...................................................................................... 69 
10.4.4.1. 
Primary Efficacy Endpoints .................................................. 69 
10.4.4.2. 
Secondary Efficacy Endpoints ............................................. 69 
11. 
RECORDS RETENTION ...................................................................................................... 70 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................... 71 
 
Monitoring .............................................................................................................. 71 
 
Auditing .................................................................................................................. 71 
 
Protocol Deviations ............................................................................................... 71 
13. 
ETHICS AND RESPONSIBILITY ......................................................................................... 72 
 
Informed Consent .................................................................................................. 72 
 
Institutional Review Board/Ethics Committee .................................................... 72 
14. 
CONFIDENTIALITY .............................................................................................................. 74 
15. 
REFERENCES...................................................................................................................... 75 
 
 


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TABLE OF TABLES 
Table 1: 
Investigational Product ............................................................................................... 44 
Table 2: 
Examples of Other Topical Hemostatic Agents ......................................................... 48 
Table 3: 
Schedule of Events/Assessments ................................................................................ 50 
 
LIST OF FIGURES 
Figure 1:  
Study Schema and TTH Assessment on Visit 2 (Day 1) ............................................ 37 
 


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1. 
INTRODUCTION 
The purpose of this study is to evaluate the use of Raplixa in the pediatric surgical 
population. This study will be conducted in compliance with Good Clinical Practices (GCP) 
including the Declaration of Helsinki and all applicable regulatory requirements. 
 
BACKGROUND 
The use of topical hemostats, such as fibrin sealants comprising plasma-derived fibrinogen 
mixed with biologically active thrombin, has been reported since the mid-1940s (1). 
Commercially-available fibrin sealants have been licensed in the United States and provide 
an alternative approach to achieve hemostasis during surgical procedures when bleeding 
cannot be controlled by standard surgical or mechanical techniques (2-6). Fibrin sealants 
mimic the last stage of the human coagulation system to support local hemostasis as they 
generate semi-rigid, cross-linked fibrin clots that bind the surface of injured tissues to seal 
surfaces, support sutures, and/or improve repair or healing of the tissues. The mechanism of 
action of Raplixa, like that of other fibrin sealants, is based on thrombin’s enzymatic activity 
that catalyzes the conversion of fibrinogen into fibrin monomers that polymerize 
spontaneously to form a fibrin clot. The thrombin in Raplixa also activates endogenous factor 
XIII which crosslinks fibrin to create a firm and dissolution-resistant clot that promotes local 
and rapid hemostasis at the site of application. Because Raplixa dissolves in blood at the 
bleeding site, blood cells, platelets, and circulating plasma proteins are incorporated into the 
clot that resembles the natural fibrin clot that is formed during endogenous blood 
coagulation. As with other fibrin sealants, Raplixa is degraded and metabolized similar to the 
process by which intrinsic degradation of natural clots of fibrinogen and thrombin occurs.  
Raplixa and the RaplixaSpray device are approved for use in adults by the European Union 
(March 2015) and by the FDA (April 2015):  
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00
2807/human_med_001854.jsp&mid=WC0b01ac058001d124 
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Appro
vedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM445346.pdf 
Raplixa is indicated as an adjunct to hemostasis for mild to moderate bleeding in adults 
undergoing surgery when control of bleeding by standard surgical techniques (such as suture, 
ligature, and cautery) is ineffective or impractical. Raplixa is used in conjunction with an 
absorbable gelatin sponge (USP) and is applied directly or using the RaplixaSpray device (7). 
Although there are physiologic differences in the levels of coagulation & fibrinolytic proteins 
over the maturation of children compared to adults, near adult levels are achieved by most 
children by 6 months of age, and these differences are considered to be physiologic, i.e., 
something that is normal, not due to anything pathologic nor significant in terms of causing 
illness (8, 9).  


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In current practice, typical fibrin sealants consist of human plasma-derived thrombin and 
fibrinogen that are filled and stored separately to avoid thrombin’s enzymatic activity on 
fibrinogen before application to the intended site of action. In addition, most 
commercially-available products are stored frozen and must be thawed or reconstituted 
before they can be applied to a wound site. To improve the convenience and flexibility of 
use, Raplixa has been designed as a room temperature stable, ready-to-use powder fibrin 
sealant that dissolves and activates on contact when sprayed onto a bleeding or oozing wound 
site. 
To date, there are 3 topical hemostats, Recothrom® and Tisseel® used in the adult population, 
that have also been approved by regulatory agencies as adjuncts to hemostasis in the pediatric 
population. These products were studied in very small pediatric populations (≤ 30 subjects) 
which simultaneously enrolled all subjects across age groups as they presented to clinical 
research centers. The efficacy and safety profile was similar to data observed in the adult 
population. There was no observation of enhanced immunogenic responses in the pediatric 
populations supporting the summary basis for approval. As Raplixa is a pharmacologically 
active topical hemostat approved for use in pediatric patients as are Recothrom® and 
Tisseell®, it is expected that Raplixa will have a similar safety, efficacy, and 
non-immunogenic profile in pediatric patients as Raplixa treatment in the adult population.  
 
Preclinical Studies 
Raplixa was shown to be effective in multiple animal models of mild and moderate surgical 
bleeding. The use of Raplixa was effective alone, but appeared to be enhanced in certain 
models when used in combination with a pressure sheet. Raplixa was locally and 
systemically non-toxic, and did not promote intra-abdominal adhesion formation when 
applied to non-target organs. In addition, the RaplixaSpray device was shown to have a low 
risk of producing air emboli when used correctly and incorrectly during hepatic resection 
surgery. The nonclinical efficacy and safety data generated support the clinical development 
of Raplixa and the RaplixaSpray device to promote hemostasis in surgical bleeding. For 
additional information please refer to the Investigator’s Brochure (IB) and the Raplixa 
package insert. 
 
Clinical Studies 
Two Phase 2 trials (Verhoef, et al) (10) and one Phase 3 trial (Bochicchio, et al) (11) have 
been performed in different surgical indications to evaluate the efficacy and safety of 
Raplixa. The trials were performed in accordance with the clinical trial designs 
recommended by the CHMP for fibrin sealants (Guideline on the Clinical Investigation of 
Plasma Derived Fibrin Sealant/Haemostatic products; CPMP/BPWG/1089/00) and the FDA 
(Guidance for Industry: Efficacy Studies to Support Marketing of Fibrin Sealant Products 
Manufactured for Commercial Use, May 1999). 


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The clinical safety and efficacy of Raplixa were initially evaluated in 2 Phase 2 studies 
(FC-002 US and FC-002 NL) in surgical indications where adjuncts to hemostasis are 
required to control bleeding: spinal surgery, major hepatic resection, and peripheral vascular 
surgery (i.e., peripheral arterial bypass surgery and arteriovenous graft formation for 
hemodialysis access). Each of these types of surgery is characterized by diffuse and difficult 
to control, mild to moderate bleeding, frequently requiring the use of adjuncts to hemostasis.  
In FC-002 NL, 56 subjects undergoing hepatic resection surgery were randomized 2:1 to 
receive Raplixa plus gelatin sponge (n=39) or gelatin sponge alone (n=17). In the 
Intent-to-Treat (ITT) analysis, a statistically significant reduction in the meantime to 
hemostasis (TTH) was observed with Raplixa, as compared to gelatin sponge alone 
(2.2 minutes vs 4.4 minutes, p=0.004). In FC-002 US, 70 subjects undergoing spinal, 
vascular, or general surgery were randomized 2:1 to Raplixa plus gelatin sponge (n=47) or 
gelatin sponge alone (n=23). A statistically significant reduction in the mean TTH was also 
observed with Raplixa in the ITT analysis, as compared to gelatin sponge alone (1.9 minutes 
vs 4.8 minutes, p<0.001). 
The safety profile of Raplixa plus gelatin sponge across both FC-002 studies (n=86) was 
considered acceptable. The most common (>10% of subjects) treatment-emergent adverse 
events (TEAEs) being post-operative pain, constipation, nausea, edema, vomiting and 
hypokalemia. The majority of TEAEs were classified as mild or moderate in intensity. 
Thirty-five treatment-emergent serious AEs (TESAEs) were reported, with 25 reported from 
subjects undergoing liver resection surgery and only one considered possibly related to 
Raplixa by the Investigator. There were no observed Raplixa-associated trends or safety 
signals related to changes in vital signs, physical examinations, coagulation laboratory 
parameters or anti-thrombin neutralizing antibodies.  
A total of 721 subjects undergoing hepatic resection, spinal surgery, vascular surgery and 
soft tissue dissection surgery were randomized in FC-004, a Phase 3, international, 
multi-center, single-blind, controlled trial (11). All primary and secondary efficacy endpoints 
in this study were met, with the median TTH for each surgery type being significantly shorter 
with Raplixa plus gelatin sponge than with gelatin sponge alone (p<0.0001). In all surgical 
indications, a significantly higher proportion of subjects achieved hemostasis at 3 and 
5 minutes after application with Raplixa plus gelatin sponge than with gelatin sponge alone 
(p<0.0001). Results of the Phase 3 study indicated that Raplixa and the RaplixaSpray device 
appeared to be safe and well tolerated. The adverse events (AEs) reported in the trial were 
consistent with those expected in subjects undergoing spinal, vascular, hepatic resection, and 
soft tissue dissection surgical procedures under general anesthesia and the nature of the 
subjects’ underlying diseases. 


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Known and Potential Risks and Benefits 
This is the first trial of Raplixa in a pediatric population. Raplixa and the RaplixaSpray 
device are approved for use in adults by the European Union (March 2015) and by the FDA 
(April 2015):  
Contraindications for Raplixa use are as follows. 
Do not use: 
• Intravascularly. 
• For the treatment of severe or brisk arterial bleeding. 
• In patients known to have anaphylactic or severe systemic reactions to human blood 
products.  
The Warnings and Precautions for Raplixa/RaplixaSpray device are as follows: 
• Thromboembolic events may result from intravascular application of Raplixa.  
• Air or gas embolism can occur when using air- or gas-pressurized sprayers to 
administer fibrin sealants. Operate the device according to the manufacturer’s 
instructions.  
• Raplixa may carry a risk of transmitting infectious agents, such as viruses, and 
theoretically, the Creutzfeldt-Jakob disease (CJD) agents, despite manufacturing steps 
designed to reduce the risk of viral transmission.  
• Allergic type hypersensitivity reactions may occur. If allergic type hypersensitivity 
symptoms occur, discontinue administration immediately. 
Please consult the United States Pharmacopoeia (USPI) for further information.  
 
STUDY RATIONALE 
This study is being conducted to determine the safety and efficacy of Raplixa for achieving 
hemostasis in pediatric subjects undergoing hepatic, renal, soft tissue, spinal, or vascular 
surgery. Raplixa and the RaplixaSpray device are approved for use in adults, but have not 
previously been evaluated in pediatric subjects. Topical hemostats, Recothrom® and Tisseel®, 
have previously been evaluated and approved by regulatory agencies for use in pediatric 
patients. The safety profile of these products in pediatric patients was similar to that in adult 
patients and there was no observation of enhanced immunogenic responses in the pediatric 
population. As Raplixa is a pharmacologically active topical hemostat as are Recothrom® and 
Tisseel ®, it is expected that Raplixa will have a similar safety, efficacy, and 
non-immunogenic profile in pediatric patients as Raplixa treatment in the adult population. 


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STUDY POPULATION 
Pediatric subjects will be treated in this study, with the 2 oldest age groups enrolled 
simultaneously first. Subjects will be segregated into 4 age groups which are generally 
consistent with the European Medicines Agency (EMA) (EMEA, CPMP/ICH/2711/99) and 
the FDA (ICH E11, December 2000) requirements: 
• Adolescents (11 to less than 18 years). 
• Children (2 years to less than 11 years). 
• 6 months to less than 2 years. 
• Birth (≥ 36 weeks gestational age at birth) to less than 6 months. 


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2. 
TRIAL OBJECTIVES AND PURPOSE 
The objective of the study is to evaluate the efficacy and safety of Raplixa plus gelatin 
sponge, as compared to gelatin sponge alone, for achieving hemostasis in pediatric subjects 
undergoing hepatic, renal, soft tissue, spinal, or vascular surgery. 


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3. 
TRIAL DESIGN 
 
TYPE/DESIGN OF TRIAL 
This is a Phase 2, multicenter, randomized, single-blind, controlled trial comparing the 
efficacy and safety of Raplixa in combination with an absorbable gelatin sponge to gelatin 
sponge alone, in pediatric subjects undergoing hepatic, renal, soft tissue, spinal, or vascular 
surgery. The study will enroll approximately 87 subjects at up to 25 sites in the US. 
Informed consent will be obtained from parents/guardians for each subject before any 
protocol-related assessments or procedures are conducted. Subjects 7 years and older, or of 
an appropriate age as defined by local regulations, may be required to provide assent to 
participate in the study.  
Eligible subjects will be randomized in a 2:1 ratio to receive treatment with Raplixa in 
combination with an absorbable gelatin sponge (active group; R+G) or gelatin sponge alone 
(control group; G) when an appropriate target bleeding site (TBS) is identified. Subjects who 
are not treated with study drug will be withdrawn from the study and may be replaced.  
Reasons for not receiving study drug include, but are not limited to; lack of an appropriate 
TBS for time to hemostasis (TTH) evaluation, severe bleeding, or a change in surgical 
procedure that renders the subject ineligible, after the subject has been randomized. 
Subjects will be enrolled across 4 different age groups, with the 2 oldest age groups enrolled 
simultaneously: 1) 11 years of age to less than 18 years of age; 2) 2 years of age to less than 
11 years of age; 3) 6 months of age to less than 2 years of age; or 4) ≥ 36 weeks gestational 
age at birth to less than 6 months of age. Following completion of Visit 5, Day 30, for 
6 subjects treated with Raplixa plus gelatin sponge within 1 of the 2 oldest age groups, the 
Independent Data Monitoring Committee (IDMC) will review all available safety data and 
verify that the observed safety profile supports continued subject enrollment. Study 
enrollment will not be stopped during the IDMC review. After the IDMC review, this body 
will notify the study team if the safety assessment shows that there is a favorable benefit-to-
risk outcome to continue enrollment in the two older cohorts, and whether it is acceptable to 
initiate sequential enrollment in the two lower age cohorts.  
During a surgical procedure on Day 1 (Visit 2), subjects will be initially treated with up to 
one vial of Raplixa (1.0 g) plus gelatin sponge or gelatin sponge alone at the TBS. The TTH 
will be assessed every 30 seconds for up to 5 minutes. Bleeding appropriate for TTH 
evaluation is defined as mild to moderate bleeding, either on its own or remaining after 
brisk/severe bleeding has been controlled by standard surgical modalities. Subjects may be 
retreated with their assigned treatment as necessary during the 5-minute TTH assessment 
period, with up to a maximum of 2 vials of Raplixa (2.0 g) in total (for target and non-target 
bleeding sites). Rescue treatment may be administered at the TBS or OBS if necessary in a 


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tiered approach after the 5-minute TTH assessment period has elapsed, at the discretion of 
the Investigator (see Section 5.5 for details). 
For subjects who are randomized and receive Raplixa, at any time after hemostasis has been 
achieved at the TBS and the 5-minute TTH assessment period has elapsed, the remaining 
Raplixa may be used at additional appropriate OBS that are part of the primary surgical 
procedure. Importantly, the remaining Raplixa should not be used on OBS until after the 5-
minute TTH assessment period has elapsed in order to ensure that adequate Raplixa is 
available to use in the event of re-bleeding from the TBS. The amount of Raplixa applied and 
the incidence of hemostasis achieved at OBS will be recorded; however, the primary efficacy 
analysis will not include hemostasis data from the OBS. 
Subjects will undergo a safety evaluation consisting of a targeted physical examination and 
clinical laboratory tests on Day 2 (Visit 3). If the subject’s surgery was performed as an 
outpatient procedure, the Visit 3 assessment may be conducted over the phone with the 
physical examination conducted and laboratory tests collected prior to discharge on Day 1. 
Safety evaluations will also be performed on Day 7 (Visit 4), via telephone, if the subject has 
been discharged, and on Day 30 (Visit 5; End of Study visit). Immunogenicity samples 
(monitoring for anti-thrombin antibodies) will be collected and analyzed at baseline and at 
Day 30 for all treated subjects, except subjects who are less than 6 months old. Additional 
monitoring for anti-fibrinogen antibodies will be limited to subjects found positive for anti-
thrombin antibodies and subjects with unexplained bleeding or clinical suspicion of bleeding 
related to antibody formation. 
A subject’s study participation ends after the Day 30 visit. However, should a subject return 
to the investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for 
the purpose of the study), the investigator will record any update in the subject’s safety 
information and report such information to the Sponsor using the data collection forms 
provided. 




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ENDPOINTS 
The study endpoints are: 
Safety 
• Overall safety, as determined by the incidence, severity and relationship of adverse 
events (AEs) with a study product or a study procedure, clinical laboratory 
abnormalities, estimated rates of immunogenicity (monitoring for anti-thrombin 
antibodies) collected and analyzed at baseline and at Day 30 for all treated subjects, 
except subjects who are less than 6 months old. Additional monitoring for anti-
fibrinogen antibodies will be limited to subjects found positive for anti-thrombin 
antibodies and subjects with unexplained bleeding or clinical suspicion of bleeding 
related to antibody formation and post-surgery bleeding complications.  
Efficacy 
• Percentage/proportion of subjects who reach hemostasis from the first identified TBS 
within 4 minutes of study drug application. 
• Restricted mean TTH (during the 5-minute TTH assessment period). 
• Through to Visit 5, EOS visit: 
o Use of alternative hemostatic agents on the TBS. 
o Volume of transfused blood (whole blood, fresh frozen plasma (FFP), 
cryoprecipitate, platelets, or packed red blood cell (PRBC). 
o Incidence of re-operation for bleeding at the TBS. 
 
MEASURES TO MINIMIZE/AVOID BIAS 
 
Blinded Study  
Sealed, blinded envelopes will be provided by an external statistician, who also holds the 
randomization lists during the study. Only after the surgeon has identified an appropriate 
TBS, in the operating room, and notified the study coordinator that the site has been 
identified and he/she is ready for the treatment designation, will the Investigator/designee 
open a randomization envelope which corresponds with the type of surgical procedure the 
subject is undergoing. The time of randomization is subsequently recorded. If a 
randomization envelope has been opened and the subject does not receive the assigned study 
drug, this envelope may not be used for another subject. 


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4. 
SUBJECT POPULATION 
The study will enroll subjects undergoing one of the following surgical procedures: 
1. 
Hepatic Surgery  
Hepatic wedge resection or anatomic resection of 1 to 5 contiguous hepatic segments, which 
may be combined with surgical procedures involving the pancreas, gall bladder, bile duct or 
intestines. Subjects undergoing living-related liver donation are also eligible. 
2. 
Renal Surgery 
Nephrectomy associated with diffuse oozing from the retroperitoneal wall. 
3. 
Soft Tissue Surgery 
The TBS will be identified during the soft tissue dissection related to the primary operative 
procedure. Primary operative procedures include but are not limited to: lower anterior 
resections, abdominal perineal resections, donor skin graft site (split-thickness-meshed, 
split-thickness-non-meshed, full thickness, and composite graft) in limited burn patients (up 
to 40% total body surface area [TBSA]), breast mass excision, cleft lip repair, and hernia 
repair. 
Appropriate soft tissue types will include but will not be limited to: loose areolar tissue, fat, 
lymphatic tissue/lymph node beds, and muscle. The TBS will not involve parenchymal, 
gastrointestinal or genitourinary soft tissue, cardiac, lung or brain tissue, as Raplixa has not 
yet been studied in these tissue types. 
4. 
Spinal Surgery 
Scoliosis surgery, cervical, thoracic, or lumbar discectomy, corpectomy, laminectomy, lateral 
or interbody fusion. Epidural bleeding typically described as oozing, flowing, or pulsatile, 
and normally requiring topical adjuncts to hemostasis is necessary to be considered eligible. 
The TBS may not be within a bony cavity or other confined area. 
5. 
Vascular Surgery 
All subjects undergoing vascular surgery should be systemically heparinized according to 
standard procedures. The clamp(s) should be removed to determine if an appropriate TBS 
with mild to moderate bleeding is present. The clamp(s) should remain off once a TBS is 
identified and during the treatment and assessment of TTH. If protamine reversal is 
indicated, it should occur after the 5-minute TTH assessment period is completed, unless a 
safety concern dictates that it should happen earlier. Appropriate vascular surgical procedures 
may include, but are not limited to: artificial graft (i.e., polytetrafluoroethylene [PTFE] or 
Dacron) for hemodialysis access (including revision procedures), hemangiomas, and vascular 
injuries (peripheral or abdominal). The TBS may not involve the heart or the vessels 
surrounding the heart. 


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NUMBER OF SUBJECTS  
Approximately 87 subjects will be evaluated for efficacy and safety at up to 25 centers 
located in the US. 
 
INCLUSION CRITERIA 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject age is ≥ 36 weeks gestational age at birth (for infants) through < 18 years of 
age at time of treatment. 
2. Subject’s legal representative (parent or guardian) has signed an institutional review 
board (IRB)-approved informed consent document. 
3. If a subject is ≥ 7 years old, or appropriate age as defined by local regulations, the 
subject may be required to have signed an IRB-approved assent document. 
4. Subject is scheduled to undergo one of the surgical procedures described in the 
protocol. 
5. If female and of child-bearing potential, subject has a negative pregnancy test on the 
day of surgery (baseline). 
6. If subject is a sexually active male or a sexually active female of child-bearing 
potential, subject agrees to use a medically accepted form of contraception from the 
time of consent to completion of all of the follow-up study visits. 
During Surgery Inclusion Criteria 
1. Presence of mild or moderate bleeding/oozing.  
2. TBS surface area of ≤ 100 cm2. 
3. Subject has not received any whole blood, fresh frozen plasma (FFP), cryoprecipitate, 
or platelets within 24 hours prior to study drug. Packed red blood cell (PRBC) 
transfusions are allowed. 
4. Subject has no intra-operative complication other than bleeding which, in the opinion 
of the Investigator, may interfere with the assessment of efficacy or safety. 
 
EXCLUSION CRITERIA 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria apply prior 
to enrollment: 
1. Gestational age of < 36 weeks at birth (for infants less than 6 months). 
2. Subject has any clinically-significant congenital coagulation disorder (e.g., 
hemophilia A or B) that may interfere with the assessment of efficacy or pose a safety 
risk to the subject according to the Investigator. 


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3. Subject has baseline abnormalities of international normalized ratio (INR) > 2.5 or 
activated partial thromboplastin time (aPTT) > 100 seconds during screening that are 
not explained by current drug treatment (e.g., warfarin, heparin) or chronic disease 
state necessitating surgery (e.g., end stage liver disease). 
4. Subject has aspartate aminotransferase (ASAT/AST) and alanine aminotransferase 
(ALAT/ALT) > 3 times the upper limit of reference range during screening, except 
for subjects undergoing liver resection surgery or with a diagnosis of liver disease 
where there is no upper limit for these analytes due to the nature of their disease. 
5. Subject is unwilling to receive blood products or products derived from human blood 
6. Subject has platelets < 100 x109 PLT/L during screening, unless due to chronic 
disease state, e.g., liver disease/failure, necessitating surgery. 
7. Subject has known antibodies or hypersensitivity to Raplixa or any of its components, 
other thrombin preparations, or coagulation factors. 
8. Subject has known allergy to porcine gelatin. 
9. Subject has medical, social, or psychosocial factors that, in the opinion of the 
Investigator, could impact subject safety or compliance with study procedures. 
10. Subject is; 1) currently participating in another clinical study or 2) has participated in 
another clinical study within 30 days of screening or 3) plans to participate in a 
clinical study prior to completion of the 30-day follow-up period. 
 
WITHDRAWAL CRITERIA 
Subjects are free to withdraw consent and discontinue participation in the study at any time. 
If a subject decides to discontinue participation, he/she will be contacted in order to obtain 
information about the reason(s) for discontinuation and collection of any potential AEs. A 
subject’s participation may be discontinued at any time at the discretion of the Investigator if 
the subject is uncooperative, major protocol violations or deviations from the treatment plan 
dictated by the protocol are identified, the Investigator feels that it is in the subject’s best 
interest to be withdrawn from the study, the subject is lost to follow-up after multiple 
attempts at contacting the subject, or the study is terminated by the sponsor.  
A clear, concise reason should be recorded in the electronic case report form (eCRF) for all 
discontinued subjects. Subjects discontinued from the study due to an AE should be followed 
until the AE has abated, or is felt to be clinically stable by the Investigator. Follow-up for 
these subjects may require additional tests or medical procedures as deemed appropriate by 
the Investigator, and/or referral to the general physician or a medical specialist. All study 
data from early withdrawals or discontinued subjects will be retained and, if appropriate, 
used in the final study analyses. Subjects withdrawn or discontinued from the study may be 
replaced if the statistical powering of the study is impacted. 
It is imperative to obtain complete follow-up data for all treated subjects. Every attempt 
should be made to collect follow-up information except for those subjects who specifically 


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withdraw consent for release of such information. All procedures and laboratory specimens 
or tests requested for evaluation following administration of study drug should be carried out 
when possible, according the protocol. Subjects who are enrolled but not treated with study 
drug will be withdrawn from the study and may be replaced. 
 
Withdrawal from Study Drug 
Due to the nature of treatment there will be no withdrawals from study drug. 
 
Withdrawal from Trial 
Reasons that a subject may discontinue participation in this study may include one of the 
following: 
• Adverse event(s). 
• Death. 
• Subject withdrew consent. 
• Physician decision. 
• Lost to follow-up. 


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5. 
TREATMENT OF SUBJECTS 
 
STUDY DRUGS 
 
Raplixa 
Table 1: 
Investigational Product 
Product Name: 
Raplixa™ [Fibrocaps™ (PRO-0601)])] 
Dosage Form: 
Dry powder 
Unit Dose 
1.0 g/vial 
Route of Administration 
Topical 
Physical Description 
White to off-white powder 
Manufacturer 
Nova Laboratories, Ltd 
 
Raplixa is a ready-to-use powder consisting of a blend of spray-dried human plasma-derived 
fibrinogen and thrombin particles with trehalose and calcium chloride with a concentration of 
79 mg fibrinogen and 699 international units (IU) thrombin per gram Raplixa (1 vial). 
The RaplixaSpray device is classified as a Class II device in the US. The device has been 
designed and manufactured according to International Organization for Standardization 
(ISO) 13485:2003 and 21 CFR 820 compliant processes to achieve simple, rapid delivery in 
the surgical environment onto a bleeding/oozing site. The device complies with the 
requirements of Medical Device Directive 93/43/EC as revised by 2007/42/EC for 
investigational devices. The delivery device uses a ball bearing mechanism to mobilize and 
subsequently deliver Raplixa via the outlet to the target site when the operating button is 
pressed. A part of this airflow is vented off through the back of the device, while the 
remaining airflow is used to deliver the Raplixa to the bleeding surface in a narrow plume. 
The device is supplied with two interchangeable nozzles: one rigid (attached to the device) 
and one flexible nozzle designed for use in hard to reach bleeding sites. The surgeon may 
switch the nozzles prior to or during use depending on the location of the bleeding site. 
Raplixa Preparation 
Prior to surgery, 2 vials of Raplixa and 2 to 3 gelatin sponges will be in the operating room. 
At sites using the RaplixaSpray device, 2 RaplixaSpray kits that contain the device, flexible 
nozzle and air filter, one regulator with a hose assembly with site specific connectors (both 
supplied by the Sponsor), and a central air supply or medical grade pressurized air will be 
available in the operating room. The second RaplixaSpray device is used as a back-up as 
needed. 
The RaplixaSpray device will be connected to an air filter that is connected to a regulator set 
to a pressure of 1.5 bar (22 pounds per square inch [psi]), which is connected to either a 
central air supply or to a tank containing medical grade pressurized air. A vial of Raplixa will 


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be taken from the packaging in a sterile manner, then uncapped just prior to use and attached 
to the RaplixaSpray device by inverting the device and connecting the upright vial to the 
device. The device should be turned upright and the powder visualized in the well of the 
device prior to use. The application should start within 60 minutes after preparation.  
For sites sprinkling Raplixa directly from the vial onto the TBS, the rubber stopper should be 
removed from the vial just prior to use to prevent the Raplixa from absorbing moisture from 
the air. 
The gelatin sponges will be prepared according to the manufacturers’ instructions. 
Raplixa Administration 
Two vials are allocated for each subject randomized to R+G. One vial (1.0 g) should be used 
for the initial treatment of the TBS regardless of the mode of administration used. The 
remaining one vial may be used as needed for the retreatment of the TBS that continues to 
bleed during the 5-minute TTH assessment period or, after hemostasis at the TBS has been 
achieved, applied to OBS that are part of the primary operative procedure. Importantly, all of 
the remaining Raplixa should not be used on OBS until after the 5-minute TTH assessment 
period has elapsed in order to ensure that adequate Raplixa is available for re-treatment of the 
TBS if required. 
For treating large bleeding surface areas like those frequently encountered during liver and 
soft tissue surgical procedures, Raplixa is applied topically using the RaplixaSpray device as 
a thin layer of powder onto the bleeding surface. The device may be used at the discretion of 
the Investigator for small bleeding sites. The RaplixaSpray device should be held a minimum 
of 5 cm from the bleeding site when applying Raplixa by pushing the actuator button of the 
delivery device. Raplixa should be applied accurately and rapidly to the TBS. After Raplixa 
application, an absorbable gelatin sponge (dry or moistened) is applied, and held in place 
using light manual pressure with a sterile gauze sponge. Once hemostasis has been achieved, 
the gelatin sponge may be left in place with the excess carefully removed. 
For smaller bleeding surface areas, Raplixa may be applied using the RaplixaSpray device or 
by sprinkling a thin layer of powder directly from the vial onto the TBS followed by an 
appropriately-sized gelatin sponge (dry or moistened) and light manual pressure with sterile 
gauze OR sprinkled directly from the vial onto an appropriately-sized, moistened gelatin 
sponge that is applied promptly to the TBS followed by light manual pressure applied with 
sterile gauze. This latter method of application is only appropriate for surgical procedures 
that have small bleeding surface areas. Once hemostasis has been achieved, the gelatin 
sponge may be left in place with the excess carefully removed. 
The amount of Raplixa used (% of the vial contents) should be estimated and recorded on the 
eCRF. 


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Comparator 
The control arm consists of Gelfoam® (Absorbable Gelatin Sponge, USP, Pfizer), an 
approved hemostatic device in the US and is the same as is used with Raplixa. Gelfoam will 
be provided to the US sites by the Sponsor; however, sites may use their own operating room 
supply of Gelfoam, if necessary, and must record the name, lot number, and expiration date. 
The gelatin sponge is cut to the appropriate size and applied topically, dry or moistened, 
according to the manufacturer’s package insert, followed by manual pressure with sterile 
gauze. If possible, the gelatin sponge should be left in place, while the excess is removed 
from the bleeding site once hemostasis has been achieved. The appropriately-sized gelatin 
sponge may be moistened prior to application to the bleeding site, with moistened gelatin 
sponge recommended for irregularly-shaped bleeding areas. The gelatin sponge should be 
held in place with light manual pressure using sterile gauze, consistent with manufacturer’s 
directions, and according to the protocol instructions. Subjects may be retreated with gelatin 
sponge as necessary during the 5-minute observation period. Once hemostasis has been 
achieved, the gelatin sponge may be left in place with the excess carefully removed. 
 
PACKAGING AND LABELING 
Study drug is provided by the Sponsor. Medication labels will comply with regulatory 
requirements. The storage conditions for each medication provided will be described on the 
medication label. 
Raplixa raw materials, fibrinogen and thrombin, are supplied by CSL Behring. Raplixa is 
manufactured under aseptic conditions by Nova Laboratories, Ltd. and the final product 
labeled by 
, according to GMP requirements. Raplixa is packaged 
in 6 mL type I medical grade glass vials with white aluminum tear-off crimp caps (primary 
packaging) and a single foil pouch (secondary packaging).  
The RaplixaSpray kit consists of a sterilized RaplixaSpray device with rigid nozzle, a 
sterilized flexible nozzle, and a sterile air filter, which is supplied separately from the 
Raplixa. 
The gelatin sponges will remain in the original packaging labeled with the manufacturer’s lot 
number, and an additional label specifying the clinical trial identification number and 
Sponsor. 
 
STORAGE 
Raplixa will be shipped to the pharmacy at each study site under controlled temperature with 
a temperature monitor. Upon receipt the shipment must be stored in a secured area at 
controlled room temperature (2°C–25°C). The RaplixaSpray kit will be shipped under 
ambient conditions. Upon receipt, the shipment should be stored in a secured area. 


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ACCOUNTABILITY 
The Investigator or designee must maintain an inventory record of study drug received and 
all administered to assure the regulatory authorities and Sponsor that the investigational new 
drug will not be dispensed to any person who is not a subject under the terms or conditions 
set forth in this protocol.  
The study drug supplied for use in this study is to be prescribed only by the Principal 
Investigator or designated sub-investigators and may not be used for any purpose other than 
that outlined in this protocol. 
Study supplies will be shipped to the study site following receipt by the Sponsor or designee 
of written IRB approval and other appropriate study documentation as required. 
Study drug and associated supplies are to be tracked and documented from the time of receipt 
at the site through subject dosing and return to the Sponsor or designee or destroyed at the 
site (as instructed by the Sponsor). All supplies, including partially used or empty vials, 
should be tracked. Accountability logs and specific instructions will be provided by the 
Sponsor or designee and should contain the identification of the subject to whom the drug 
was dispensed and the date, lot number and quantity of the drug dispensed to the subject. The 
site may use their own accountability form, if similar information is collected on their form. 
All unused vials of study drug are to be retained at the site until inventoried by the Sponsor 
or designee. All vials used in the operating room may be destroyed, and should be 
documented. The Sponsor or designee will conduct drug accountability during the course of 
the study. Disposition of the used study drug during the course of the study should be 
handled according to the Sponsor's instructions and either disposed of, destroyed at the site, 
or returned to the Sponsor or designee. Appropriate site standard operating procedures will 
be followed for destruction of used study drug at the study site.  
The Sponsor or designee will conduct final drug accountability at site closure. All used and 
unused study drug vials should be handled according to the Sponsor's instructions and either 
returned to the Sponsor or designee, or destroyed at the site. 
In the event that study drug needs to be returned for any reason, the site will receive a written 
request listing the drug lot number(s) to be returned and the reason for the return request. 
 
CONCOMITANT MEDICATIONS 
Subjects may continue all normally prescribed medication regimens during this trial, and 
must notify the investigator when changes are made to their medication regimens. 
Medications will be coded using the WHO drug dictionary. 


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Rescue Treatment 
If hemostasis is not achieved TBS during the 5-minute TTH assessment period, 
administration of additional study drug (no more than 2 vials of Raplixa [2.0 g] total), or 
other topical hemostats are permitted.  If hemostasis cannot be achieved at an OBS or 
Raplixa is not indicated for use at the OBS, rescue treatment, if needed, should follow a 
tiered approach: 
1. Additional study drug or surgical hemostatic measures (e.g., suture, cautery, and 
ligature) should be considered first. 
2. Followed by thrombin-free topical hemostats. 
3. Finally, thrombin-containing hemostats (recombinant or human plasma-derived 
products) may be administered, if needed. 
A list of examples of thrombin-free and thrombin-containing hemostatic agents is provided in 
Table 2. 
Table 2: 
Examples of Other Topical Hemostatic Agents 
Thrombin-Free 
Thrombin-Containinga 
CoSeal™ 
Surgifoam™ 
Ultrafoam™ 
Gelfoam® 
Instat™ 
BioGlue® 
DuraSeal® 
Bone wax® 
 
CoStasis®/Vitagel™ 
Crosseal™ 
Tisseel® 
Fibrin sealant produced by the blood bank or in the 
operating room 
Evicel™ 
Evithrom™ 
Recothrom® 
Surgiflo® 
Tachosil® 
Artiss® 
 
a. Investigators should consider the use of products containing thrombin, only after other rescue alternatives fail. 
 
BLINDING 
Subjects will be randomized in a single-blinded manner. Randomization will be done in a 2:1 
ratio (active:control).  
 
Blinding of Study Medications 
Study drugs will be blinded to study subjects but not to the Investigators, the study site 
personnel, or the Sponsor’s study team. 


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Method and Maintenance of Blinding 
Sealed, blinded envelopes will be provided by an external statistician, who also holds the 
randomization lists during the study. Only after the surgeon has identified an appropriate 
TBS, in the operating room, and notified the study coordinator that the site has been 
identified and he/she is ready for the treatment designation, will the Investigator/designee 
open a randomization envelope and record the time of randomization. If a randomization 
envelope has been opened and the subject does not receive the assigned study drug, this 
envelope may not be used for another subject.  
All randomized subjects will be blinded through the end of the study. 
 


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6. 
SCHEDULE AND SEQUENCE OF PROCEDURES 
 
SCHEDULE OF EVENTS/ASSESSMENTS BY TIME POINT 
Table 3: 
Schedule of Events/Assessments 
Visit 
1 
2 
3 
4 
5 
Event 
Screening/Baseline 
(Days -30 to 1) 
Surgery 
(Day 1) 
Follow-upa 
(16-48 hours post-
treatment) 
Follow-upi 
(Day 7 ± 2 days) 
EOSn 
(Day 30 ± 7 days) 
Informed Consent/bAssentb 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Medical History 
X 
Xc 
 
 
 
Weight, Height 
X 
 
 
 
 
Vital Signsd 
X 
Xe 
 
 
X 
Physical Examination (PE)  
X 
 
Xm 
 
Xm 
Complete Blood Count (CBC) with differentialf 
X 
 
X 
 
 
Blood Chemistry Panelg 
X 
 
X 
 
 
Coagulation Panelh 
X 
 
X 
 
X 
Pregnancy Testj 
 
X 
 
 
 
Immunogenicity Samplek 
X 
 
 
 
X 
Intra-operative Eligibility  
 
X 
 
 
 
Treatment and TTH Measurement 
 
X 
 
 
 
Documentation of Surgical Procedure 
 
X 
 
 
 
Adverse Eventsl 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
a. 
For outpatient procedures, Visit 3 may be conducted over the phone with the PE conducted and laboratory tests collected prior to discharge on Day 1. 
b. 
Informed consent and assent (if defined & required by local regulations) may be signed up to 30 days prior to surgery. 
c. 
Review and record any changes in medical conditions since screening visit. 
d. 
Vital signs include resting blood pressure (BP), pulse rate and temperature.  
e. 
Only vital signs, collected pre-operatively. 
f. 
Includes RBC, hemoglobin, hematocrit, platelets and white blood cell (WBC) count with differential. 
g. 
Na, K, blood urea nitrogen (BUN)/urea, Cr, Glu, Alb, AST, ALT, total bilirubin (Tbili). 
h. 
Prothrombin time (PT), aPTT, INR.  
i. 
If the subject has been discharged prior to Day 7, this visit can be a phone call. 
j. 
For females of child-bearing potential only. 
k. 
Immunogenicity samples should not be drawn on infants < 6 months of age. 
l. 
Adverse events are collected from the time of consent. 
m. 
Focused physical examination that is specific for the type of surgery performed and signs and symptoms since the last visit. 
n. 
Study participation ends after the Day 30 visit. However, should a subject return to the investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for the purpose of the 
study), the investigator will record any update in the subject’s safety information and report such information to the Sponsor using the data collection forms provided. 


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GENERAL CONDUCT OF THE TRIAL 
Written informed consent will be obtained from subjects’ parents/guardians before the 
performance of any protocol-specific procedure. Further details related to informed 
consent are found in Section 13.1. 
 
Visit 1: Screening Period (Day –30 to Day 1) 
The Screening Visit will take place within 30 days of surgery. Following informed 
consent, the following screening assessments and procedures will be done: 
1. Allocation of a nine digit number, which is composed of the 6-digit site number 
and incremental subject number. 
2. Documentation of: 
a. Demography: date of birth, gender and ethnic origin. 
b. Medical history, including bleeding and surgical history.  
c. Concomitant medications.  
d. Assess and record AEs. 
3. Review of inclusion/exclusion criteria to confirm subject eligibility. 
4. Blood samples drawn for screening clinical laboratory tests (results may be 
obtained from clinical laboratory tests measured for routine clinical care prior to 
consent provided they were measured within 30 days of surgery) and results 
reviewed prior to enrollment. 
a. Hematology: includes RBC, hemoglobin, hematocrit, platelet count, and 
white blood cell (WBC) count with differential. 
b. Coagulation: prothrombin time (PT), aPTT, INR. 
c. Blood chemistry panel: sodium, potassium, blood urea nitrogen 
(BUN)/urea, creatinine, glucose, albumin, AST/ASAT, ALT/ALAT, total 
bilirubin. 
5. Blood sample for immunogenicity testing (do not draw in infants < 6 months old). 
6. Physical examination (PE). 
7. Weight and height. 
8. Vital signs (pulse rate, resting systolic and diastolic blood pressures [BP], and 
temperature). 
9. If a subject is ineligible for the clinical trial, they will be deemed a screen failure 
and their demographic data and specific reason for ineligibility will be captured on 
the applicable eCRF page(s).  


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Visit 2: Surgery, Randomization, and Treatment 
Pre-Operative 
Pre-operative procedures and assessments include: 
1. Review eligibility. 
2. Review and record concomitant medications. 
3. Assess and record AEs. 
4. Measure and record vital signs. 
5. Pregnancy Test - only for females of childbearing potential (must document in 
the subject’s source document the reason for the inability to become pregnant). 
6. Assess and record changes to baseline health status (changes in health or medical 
conditions since the screening visit). 
Surgery, Randomization and Treatment 
The surgery will be carried out according to the local standardized surgical practices; 
these are not covered within this protocol. Subjects will be randomized after the start of 
surgery to reduce potential bias. 
1. Confirm subject eligibility: 
a. Subject has not received any whole blood, fresh frozen plasma (FFP), 
cryoprecipitate, or platelets between screening and study drug. Packed red 
blood cell (PRBC) transfusions are allowed. 
b. There is a TBS with mild or moderate bleeding/oozing. The bleeding intensity 
will be assessed by the Investigator according to the following description: 
 
 
Mild: Oozing and/or capillary leakage 
 
 
Moderate: Gradual and steady flow 
c. There are no significant intra-operative complications other than bleeding 
which, in the opinion of the Investigator, may interfere with assessment of 
efficacy or safety. 
d. The TBS surface area is ≤ 100 cm2. 
NOTE: If subjects do not meet these intra-operative criteria, they will be deemed 
screen failures and their demographic data and specific reason for ineligibility 
will be captured on appropriate eCRF pages.  
2. Randomize subject to treatment group when an eligible TBS is identified. Record 
the time the subject was randomized. 
3. Subject treatment, based on randomization (TTH clock starts as soon as the 
application of the assigned treatment begins). 


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a. Raplixa + Gelatin Sponge Group: Rapidly apply Raplixa using one of the 
following three methods: 
i. Sprinkle a thin layer of Raplixa directly from the vial onto the TBS 
followed by application of a gelatin sponge (wet or dry). 
ii. Spray a thin layer of Raplixa onto the TBS using the RaplixaSpray 
device followed by application of a gelatin sponge (wet or dry). 
iii. Apply Raplixa onto a moistened absorbable gelatin sponge that is 
then applied to the TBS. 
Light manual pressure using sterile gauze should follow for all three 
application methods. 
b. Gelatin Sponge Group: Apply gelatin sponge followed by light manual 
pressure using sterile gauze. 
4. Begin measurement of TTH (Figure 1). Assessment of hemostasis will be made 
by carefully lifting the sterile gauze pad and checking for bleeding through or 
around the gelatin sponge. Start the first assessment at 30 seconds and repeat 
every 30 seconds until hemostasis has been achieved or 5 minutes has elapsed, 
whichever comes first. In the event that the application takes longer than 30 
seconds, the first TTH assessment should commence at the next scheduled time 
point (i.e., 1 minute). 
a. During this 5-minute assessment period, no further interventions except 
re-application of Raplixa or a gelatin sponge onto the TBS are allowed, 
unless the surgeon determines it is medically necessary for the subject’s 
well-being. 
b. When hemostasis has been achieved, record as TTH. 
c. Once TTH has been reached, it is not necessary to continue assessments 
every 30 seconds, however, the stopwatch should remain running until the 
end of the 5-minute assessment period. 
5. Re-application of Treatment 
Re-application of Raplixa or a gelatin sponge to the TBS being used for TTH 
assessment is allowed within the 5-minute assessment period if hemostasis has 
not been achieved. If necessary, the original gelatin sponge should be carefully 
removed or peeled back to expose the bleeding area to allow the rapid 
re-application of Raplixa. The entire gelatin sponge may be removed and replaced 
if necessary. 
6. Treatment of Other Bleeding Sites 
At any time after hemostasis has been achieved at the TBS, and the 5-minute TTH 
assessment period has elapsed, the remaining Raplixa may be used at additional 
appropriate OBS that are part of the primary surgical procedure. Importantly, the 


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remaining Raplixa should not be used on an OBS until after the 5-minute 
assessment period has elapsed in order to ensure that adequate Raplixa is 
available to use in the event of re-bleeding from the TBS. 
Post-Operative Assessments  
1. Record the number of Raplixa vials used to treat the TBS and OBS separately.  
2. Record the number of RaplixaSpray devices used. 
3. Record concomitant medication usage, including blood products. Medications to 
induce and maintain anesthesia should not be recorded in the eCRF; however, all 
medications given for treatment-emergent AEs during surgery should be recorded. 
4. Assess and record AEs. 
5. Focused physical examination and collection of the Visit 3 hematology, 
coagulation, and blood chemistry samples prior to discharge for subjects 
undergoing outpatient procedures. 
 
Visit 3: (Day 2, 16-48 hours post-Treatment): Safety Evaluation  
Subjects undergoing outpatient procedures may be seen in the office or contacted by 
phone by study personnel to evaluate the subject’s post-operative condition, medication 
usage and AEs. The following assessments and procedures will be performed on subjects 
hospitalized at least overnight following their surgery:  
1. 
Focused physical examination.  
2. 
Collect hematology, coagulation panel, and blood chemistry panel samples prior 
to hospital discharge. 
3. 
Record concomitant medication use, including blood products. 
4. 
Assess and record AEs. 
 
Visit 4: (Day 7 ± 2 days): Safety Evaluation  
The following assessments/procedures will be performed via telephone call if the subject 
has been discharged: 
1. 
Record concomitant medication use, including blood products. 
2. 
Assess and record AEs. 
 
Visit 5: (Day 30 ± 7 days): Safety Evaluation 
The following assessments/procedures will be performed: 
1. Physical examination. 
2. Vital signs. 
3. Collect coagulation panel. 


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4. Collect a blood sample for immunogenicity testing (Note: Should not be collected 
in infants < 6 months of age). 
5. Record concomitant medication use, including blood products. 
6. Assess and record AEs. 
Study participation ends after the Day 30 visit. However, should a subject return to the 
investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for 
the purpose of the study), the investigator will record any update in the subject’s safety 
information and report such information to the Sponsor using the data collection forms 
provided.   
 
STUDY TERMINATION 
The Sponsor reserves the right to terminate the study at any time. In terminating the 
study, the Sponsor and the Investigator(s) will ensure that adequate consideration is given 
to the protection of the subjects’ interests. If the study is terminated, the subject(s) will be 
followed for all safety assessments up to the EOS visit. Should the study/center(s) be 
closed prematurely, all study materials (except for study documentation that must remain 
on site) must be returned to the Sponsor. The Investigator will retain all study 
documentation until notification is given by the Sponsor for its destruction. 


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7. 
PROTOCOL ASSESSMENTS 
Demographics, medical history, and baseline demographic information will be collected 
during screening, and will include age, sex and race/ethnicity. 
Medical history (MH) includes all ongoing medical or surgical issues. Remote medical 
and surgical history > 5 years from the time of screening should only be included if 
considered relevant to the current surgery (e.g., previous similar surgery and outcomes) 
or the mechanism of action of Raplixa (e.g., history of thromboembolic events, bleeding 
events or other coagulation disorders). The MH should also include all prescription 
medications that the subject is currently taking at the time of Informed Consent. Those 
medications that are related to the mechanism of action of Raplixa (e.g., previous 
thrombin or fibrin sealant treatment) within the past 30 days should also be collected. 
Vitamins and other nutritional supplements need not be recorded since they are not 
expected to affect the subject’s safety or the efficacy of Raplixa during the trial. 
 
ASSESSMENT OF SAFETY 
 
Adverse Events  
Subjects will be carefully monitored for adverse events by the Investigator during the 
designated study period (see Section 8 for details).  
 
Vital Signs 
Vital signs include resting blood pressures, pulse rate and temperature. 
 
Physical Examination 
The targeted physical examination should include a focused examination relating to the 
subject’s medical history and current surgical plans. During follow-up, the examination 
should include the surgical site, which may include general, respiratory, cardiovascular, 
abdominal, extremities and brief neurologic evaluations as appropriate. Recording of the 
height and weight should occur at baseline only. 
 
Laboratory Assessments 
The laboratory assessments will be collected according to the Schedule of Assessments 
(Table 3). 
Hematology - Complete Blood Count (CBC) with Differential:  
Includes RBC, hemoglobin, hematocrit, platelet count, and white blood cell (WBC) count 
with differential. 
Blood Chemistry: 
Includes sodium, potassium, BUN/urea, creatinine, glucose, albumin, AST/ASAT, 
ALT/ALAT, and total bilirubin. 


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Coagulation Panel: 
Includes PT, aPTT and INR. 
Pregnancy Test: 
All female subjects of child-bearing potential will have a pregnancy test (serum or urine). 
Immunogenicity Sample: 
This blood sample will be used for measuring anti-thrombin and anti-fibrinogen 
antibodies in plasma from all subjects treated in the study. An immunogenicity sample 
should not be collected in infants < 6 months of age due to immature immune system 
which is indicative of the presence of maternal antibodies. 
 
ASSESSMENT OF EFFICACY  
 
Time to Hemostasis (TTH) 
A TBS with mild to moderate bleeding and a surface area of ≤ 100 cm2 will be identified, 
treated according to the assigned study drug, and used to measure TTH. Study drug 
should be applied as rapidly as possible to the TBS. 
The measurement of TTH will begin at t=0, which is the time R+G study drug 
application to the TBS is started and will end when hemostasis has been achieved or the 
5-minute TTH assessment period ends. If hemostasis has not been achieved within 5 
minutes, the subject will be considered a treatment failure and the surgeon will 
implement additional hemostatic measures, including surgical interventions or the use of 
alternative topical hemostatic agents or devices. See Section 5.5 for a list of example 
rescue treatments. 
TTH will not be measured at OBS treated with study drug, but whether or not hemostasis 
was achieved and the approximate amount of study drug used will be recorded as 
described above. 


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8. 
ADVERSE EVENTS  
 
DEFINITIONS 
 
Adverse Event 
Per ICH guidelines section E2A, Adverse Event means any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product/used 
medical device and which does not necessarily have to have a causal relationship with 
this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product/medical device, whether or not considered related to 
the medicinal product/medical device. 
In this study, AEs are collected from the moment the subject is consented. AEs which 
occur between screening and treatment are always considered unrelated to the study drug 
and devices, but could be considered protocol related.  
For subjects who are considered screen failures (i.e., do not meet all inclusion 
criteria/exclusion criteria), AEs will not be recorded in the eCRF.  
Planned hospital admissions and/or surgical operations for an illness or disease that 
existed before the drug was given or the subject was treated in a clinical study are not to 
be considered as AEs. 
Adverse events or abnormal test findings will be followed until the event (or its sequelae) 
or the abnormal test finding resolves or stabilizes at a level acceptable to the 
Sponsor/Investigator. 
8.1.1.1. 
AE Severity 
The severity of an AE and the relationship to study drug will be assessed by the 
investigator. The investigator should ensure that any subject experiencing an AE receives 
appropriate medical support until the event resolves. 
AE severity will be assessed according to the grading scale in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*. 


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Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
8.1.1.2. 
Study Drug Causality 
The relationship of an AE to study drug and/or device will be assessed with consideration 
to the following criteria: 
• Temporal relationship to the initiation of study drug. 
• Response of the event to withdrawal of study drug. 
• AE profile of concomitant therapies. 
• Clinical circumstances during which the AE occurred. 
• Subject’s clinical condition and medical history.  
Categorization* of causality will be designated by the investigator as stated below: 
1. Unrelated - A clinical event, including laboratory test abnormality, reported as an 
adverse reaction, which lacks a reasonable time sequence between study drug 
administration and the occurrence of the event(s) or for which medical history, 
concomitant medications or other drugs provide a more likely explanation. 
Response to withdrawal of the study drug should not support a relationship 
between the study drug and the event. 
2. Unlikely related - A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations. 
3. Possibly related - A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, which may possibly 
be attributed to concurrent disease or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal (de-challenge). Information on 
study drug withdrawal may be lacking or unclear. Re-challenge information is not 
required to fulfill this definition. 
4. Definitely related - A clinical event, including laboratory test abnormality, 
occurring in a plausible time relationship to study drug administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals. The 


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response to withdrawal of the study drug (de-challenge) should be clinically 
plausible. The event must be clinically definitive using a satisfactory re-challenge 
procedure if deemed necessary. 
* For the purposes of regulatory reporting, categories ‘3’ and ‘4’ will be 
considered “related.” 
 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred (it does not include an event 
that, had it occurred in a more severe form, might have caused death), 
• Results in a significant, persistent or permanent change, impairment, damage or 
disruption in the subject's body function/structure, physical activities and/or 
quality of life, 
• Requires in-subject hospitalization or prolongs hospitalization, 
• Is a congenital anomaly/birth defect, or 
• Is another medically significant event that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above (e.g., allergic 
bronchospasm requiring intensive treatment in an emergency department or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse). 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or 
measure of the intensity of an AE, while the criteria for serious AEs are indications of 
adverse subject outcomes for regulatory reporting purposes. A severe AE need not 
necessarily be considered serious and a serious AE need not be considered severe. For 
example, nausea that persists for several hours may be considered severe nausea, but not 
an SAE. On the other hand, a myocardial infarction (MI) that may be considered minor 
could also be an SAE if it prolonged hospitalization. 
 
Adverse Device Effects (ADEs)  
ADEs include any AE resulting from insufficiencies or inadequacies in the instructions 
for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. It also includes any event that is a 
result of a use error or intentional misuse. 
In accordance with 21 CFR 803 in the US, a medical device manufacturer (in this case 
the sponsor) is required to report to the FDA when it learns that any of its devices may 


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have caused or contributed to a death or serious injury. The sponsor must also report to 
the FDA when it becomes aware that its device has malfunctioned and would be likely to 
cause or contribute to a death or serious injury if the malfunction were to recur. 
Under the FDA Medical Device Reporting Requirements, a Serious Injury/Serious Illness 
[§803.53(c)(2)] is defined as “ an injury or illness that is life threatening, even if 
temporary in nature; results in permanent impairment of a body function or permanent 
damage to a body structure; or necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage to a body structure”.  
A reportable malfunction of a medical device [§803.3(m)] is defined as “a failure of the 
device to meet its performance specifications or otherwise perform as intended. 
Performance specifications include all claims made in the labeling for the device. A 
malfunction should be considered reportable if any one of the following is true: the 
chance of a death or serious injury resulting from a recurrence of the malfunction is not 
remote; the consequences of the malfunction affect the device in a catastrophic manner 
that may lead to a death or serious injury; the malfunction causes the device to fail to 
perform its essential function and compromises the device's therapeutic, monitoring or 
diagnostic effectiveness which could cause or contribute to a death or serious injury, or 
other significant adverse device experiences.”  
An incident for Medical Device Vigilance (MDV) in the European Union is any 
malfunction or deterioration in the characteristics and/or performance of a device, as well 
as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a subject, or user or of other persons or to 
a serious deterioration in their state of health. 
 
Additional Reporting Requirements 
Occurrences of events of overdose, drug misuse and drug abuse are considered 
“important medical events” that should also be reported within 24 hours using the 
appropriate reporting form. These events should be reported regardless of their 
association with other adverse events or serious adverse events.  
Abuse of a medicinal product: Persistent or sporadic, intentional excessive use of 
medicinal products which is accompanied by harmful physical or psychological effects 
[DIR 2001/83/EC Art 1(16)]. 
Medication error: Refers to any unintended error in the prescribing, dispensing or 
administration of a medicinal product while in the control of the healthcare professional, 


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patient or consumer. Medication errors are an important cause of morbidity and mortality 
and many could be prevented or mitigated. They can fall broadly into 4 categories: 
1. Wrong medication. 
2. Wrong dose (including strength, form, timing, concentration, infusion rate and 
amount). 
3. Wrong route of administration. 
4. Wrong patient. 
Occurrences of medication errors in a study subject should be reported within 24 hours 
using the Medication Error/Overdose form. In cases where a medication error results in a 
serious adverse event, the Serious Adverse Event reporting form should be used to report 
the SAE. Non-serious AEs associated with medication errors should be reported in AE 
page in eCRF. 
Misuse: Intentional and inappropriate use of a medicinal product/device not in 
accordance with the prescribed or authorized dose, route of administration, and/or the 
indication(s) or not within the legal status of its supply (e.g., without prescription for 
medicinal products subject to medical prescription). 
Overdose: Administration of a quantity of a medicinal product given per administration 
or per day which is above the maximum recommended dose according to the reference 
safety information for the investigational product or comparator as applicable. This also 
takes into account cumulative effects due to overdose. 
 
Adverse Event of Special Interest (AESIs) 
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, which warrants ongoing 
monitoring and rapid communication by the investigator to the Sponsor (Section 8.6). 
 
Complications of the Disease Under Study  
Certain symptoms are considered typical outcomes following surgery and thus are 
expected side effects. Clinical events that are considered standard post-operative 
occurrences will be reported as AEs if they are considered untoward or unfavorable. In 
cases where the event is not considered as untoward or unfavorable it must be recorded as 
such in the source document. Consistency in reporting adverse events from all 
participating sites will be ensured through appropriate training and monitoring and 
investigators will be required to report all untoward or unfavorable events as adverse 
events based on their clinical judgment. 


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PROCEDURE FOR NON-SERIOUS ADVERSE EVENT RECORDING 
All non-serious AEs that occur during the designated study period from consent up to 
EOS visit (Day 30 ± 7 days) following study drug administration must be assessed and 
recorded on the source documents and eCRF regardless of causal relationship to the study 
drug. 
Study participation ends after the Day 30 visit. However, should a subject return to the 
investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for 
the purpose of the study), the investigator will record any update in the subject’s safety 
information and report such information to the Sponsor using the data collection forms 
provided.  
 
PROCEDURE FOR SERIOUS ADVERSE EVENT REPORTING 
All SAEs involving the study biologics, the reportable malfunctions, serious injuries, 
death and incidents involving the biologic-application devices that occur during the 
designated study period from consent up to 90 days following study drug administration 
must be reported to Mallinckrodt Pharmaceutical’s Global Pharmacovigilance 
Department (GPV) within 24 hours of awareness of the event using the provided study 
specific SAE/AESI Report Form and Device Reporting Form, respectively. The 
completion and processing of the Reporting Forms should follow the instructions in the 
provided Report Form completion guidelines. In addition to completing the Report 
Forms, each SAE/AESI, Medical Device Reporting (MDR) reportable malfunction, 
serious injury, death or Medical Device Vigilance (MDV) incident must be entered on the 
appropriate page of the CRF.  
When death occurs due to a SAE, the cause of death must be reported as the SAE. The 
outcome of the causal SAE should be designated as “fatal.”  
The investigator must assess the causality for each SAE and incident. 
The Sponsor or its representative will contact the investigator, if necessary, to clarify any of 
the event information. The investigator should provide any follow-up information for the 
event to the Sponsor on an SAE/AESI Report Form or a Device Reporting Form as soon 
as it becomes available. 
If the investigator becomes aware of a SAE that occurs post-study period, that he or she 
wishes to report to the Sponsor (e.g., an event suspected to be causally related to the 
study biologics or the application devices), the event should be reported through the 
process described above as soon as possible.  
Where appropriate, if required by local regulations or procedures, the investigator should 
report these events to the Institutional Review Board (IRB)/Ethics Committee (EC) 
and/or appropriate regulatory authority in addition to the Sponsor. 


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PROCEDURE FOR MEDICATION ERROR REPORTING 
Medication errors with or without an AE should be recorded as medication errors in the 
eCRF as described in Section 8.2. 
Medication errors with a SAE should be recorded as medication errors in the eCRF and 
reported to the Sponsor Pharmacovigilance Department as described in Section 8.3. 
A missing dose (refer to Section 12.3) should be reported as a medication error if it was 
an “unintended error” as defined in Section 8.1.4. 
 
PROCEDURE FOR ADVERSE DEVICE EFFECTS (ADES) REPORTING 
Any AE related to the use of an investigational medical device should be reported within 
24 hours using the Device Incident Report Form. In cases where an ADE occurs with a 
Serious Adverse Event, the SAE/AESI Report Form should be used to report the SAE 
and the Device Report Form should be used to report the ADE. When an ADE occurs 
without any concurrent SAE, the Device Report Form may be submitted alone.   
 
ADVERSE EVENTS OF SPECIAL INTEREST 
The AESI(s) listed below have been identified for the study product(s) in this protocol. 
Non-serious AESIs should be reported from the site to the sponsor within 72 hours and 
serious AESIs should be reported from the site to the sponsor within 24 hours. In both 
instances, the reporting procedure provided in Section 8.3 should be followed. The 
SAE/AESI Report Form, along with a targeted questionnaire when applicable, should be 
utilized for reporting the AESI even if a serious outcome may not apply. The SAE/AESI 
report form should indicate that the reported event is an AESI. 
AESIs for this study product/protocol are as follows:  
• Surgical site-related events, which includes inflammation, pain, foreign body 
reaction, and infection suggestive of a higher complication rate.  
• Thromboembolic events, which includes acute ischemic events like pulmonary 
embolism, myocardial infarction, deep vein thrombosis and stroke.  
• Re-bleeding at the TBS, including post-procedural hemorrhage, hematomas and 
compression/obstruction of the adjacent structures secondary to the hematomas. 
• Air emboli-associated events, which includes acute respiratory failure or 
cardiovascular collapse occurring intra-operatively during or following the use of 
the RaplixaSpray device.  
o Additional information will be collected for events of potential air/gas 
emboli using the Raplixa Air or Gas Embolism Adverse Events 
questionnaire. 


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• Blood-borne pathogenic diseases such as hepatitis/HIV infection or prion disease 
suggestive of viral or prion transmission from Raplixa. 
 
REPORTING EVENTS OF PREGNANCY/LACTATION  
Occurrences of pregnancy/lactation exposure in a study subject or study subject’s partner 
should also be reported within 24 hours using the Pregnancy Reporting form. In cases 
where a pregnancy occurs with a Serious Adverse Event, the SAE/AESI Report form 
should be used to report the SAE and the Pregnancy Reporting form should be used to 
report the pregnancy. When a pregnancy occurs without any concurrent SAE, the 
Pregnancy Reporting form may be submitted alone. The pregnancy must be followed 
through to outcome of pregnancy. Any pregnancy discovered from the time of consent to 
follow-up must be reported. 
 
POTENTIAL SAFETY UPDATES WITHIN 90 DAYS OF STUDY PRODUCT 
APPLICATION 
Study participation ends after the Day 30 visit. However, should a subject return to the 
investigator between Day 30 and Day 90 for routine follow-up visits (not scheduled for 
the purpose of the study), the investigator will record any update in the subject’s safety 
information and report such information to the Sponsor using the data collection forms 
provided.   
9. 
DATA COLLECTION 
An electronic data capture (EDC) system will be used for this trial. All users will be 
trained on the technical features of the EDC as well as the content of the eCRF by 
qualified personnel prior to gaining access to the EDC. A User ID/Password will be 
granted after training. This ID is not to be shared amongst the study staff. All users must 
have a unique account to enter or review data. The eCRF should be filled out by the site 
within 48 hours after a visit. It is not expected that the eCRF will serve as source for any 
data collected in this trial. If there is a reason for a site to do so, it must be approved by 
MDCO and documented in the site files. 
Prior to the database being locked, the investigator or designee will review, approve and 
sign/date each completed eCRF. This signature serves as attestation of the Investigator’s 
responsibility for ensuring that all data entered into the eCRF are complete, accurate and 
authentic. After the end of the trial, a copy of the data will be provided to the site. This 
copy will contain the final data, an audit trail of activity on the data, and any queries and 
answers that were posted for data clarification.  
A second data lock date will be set to ensure the capture of safety data from routine or 
unspecified visits after the Day 30 visit but before Day 90. 


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10. STATISTICAL PLAN 
This is a Phase 2, multicenter, randomized, single-blind, controlled trial in pediatric 
subjects undergoing hepatic, renal, soft tissue, spinal, or vascular surgery. Subjects will 
be recruited from up to 25 sites in the US. Subjects who qualify for entry into the study 
will be randomly assigned in a 2:1 ratio to receive either Raplixa plus gelatin sponge 
(R+G) or gelatin sponge alone (G). The objective of this study is to evaluate the safety 
and efficacy of Raplixa plus gelatin sponge, as compared to gelatin sponge alone, for 
achieving hemostasis in pediatric subjects undergoing hepatic, renal, soft tissue, spinal, or 
vascular surgery.  
A separate Statistical Analysis Plan (SAP) document will provide more detailed 
specifications for data analysis and presentation. 
 
SAMPLE SIZE 
The sample size estimation is based on data from the completed Phase 3 trial (FC-004). 
Assuming the proportion of subjects achieving hemostasis within 4 minutes in R+G and 
G are 87% and 60% respectively, approximately 87 pediatric subjects (58 in R+G, 29 in 
G) will provide approximately 80% power to detect this difference at the one-sided 
significance level of 0.025 (equivalently, 2-sided significance level of 0.05) based on a 
chi-square test for 2 proportions.  
 
RANDOMIZATION  
Subjects will be randomized in a 2:1 ratio to the treatment groups R+G and G alone. 
Sealed, blinded envelopes will be provided by an external statistician, who also holds the 
randomization lists during the study. Only after the surgeon has identified an appropriate 
TBS, in the operating room, and notified the study coordinator that the site has been 
identified and he/she is ready for the treatment designation, will the Investigator/designee 
open a randomization envelope and record the time of randomization. If a randomization 
envelope has been opened and the subject does not receive the assigned study drug, this 
envelope may not be used for another subject. 
 
GENERAL STATISTICAL CONSIDERATIONS AND DEFINITIONS 
 
General Statistical Methods 
All study-collected data will be summarized by treatment group using descriptive 
statistics, graphs, and/or raw data listings. Descriptive statistics for continuous variables 
will include number of subjects (n), mean, standard deviation (SD), median, quartiles (Q1 
and Q3), minimum (min) and maximum (max) values. Analysis of categorical variables 
will include frequency and percentage. For time-to-event endpoints such as TTH, the 
Kaplan-Meier method will be used to estimate the survival distribution for each treatment 
group.  


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Analysis Populations 
Two subject populations will be used for data analyses and/or presentations. 
10.3.2.1. Intent-to-Treat (ITT) Population 
The ITT population consists of all randomized subjects. This population will be the 
primary population for the efficacy analyses. 
10.3.2.2. Safety Population 
The safety population consists of all subjects who are exposed to any amount of study 
drug. Treatment classification will be based on the actual treatment received. This will be 
the primary population for the safety analyses. 
 
Analysis Windows and Baseline 
The observational period for the study includes Visit 1 (screening/baseline from  
Day -30 to Day 1), to Visit 5 (Day 30 ±7 days, End of Study). An additional unscheduled 
observational period between Days 30 and 90 will be used to collect safety data from 
routine follow-up visits (not scheduled for the purpose of the study), if any such data 
were to be captured. Any event occurring after the defined observational period, even if 
collected on the eCRF, will not be included in the planned statistical analysis. However, 
all data, including that reported after the defined observational period, will be included in 
the subject data listings.  
Unless otherwise specified, for evaluations that are collected at multiple occasions prior 
to initiation of study drug, the latest evaluation will be considered the "Baseline" 
evaluation for analysis. 
 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from 
the associated analysis. 
 
STATISTICAL ANALYSES 
Summaries by treatment group will represent subject data across study sites. Descriptive 
statistics, graphs, and subject data listings will be used to summarize the data collected. 
For continuous variables, descriptive statistics will include the number of subjects 
reflected in the calculation (n), mean, standard deviation (SD), median, quartiles (Q1 and 
Q3), minimum (min), and maximum (max). Frequencies and percentages will be 
displayed for categorical data. Subject data listings will be presented by study sites, 
treatment group, surgery type, age cohort and subject number. 
Unless otherwise specified, the primary population for efficacy analyses will be the ITT 
population; confirmatory analyses for efficacy will be performed using the safety 
population. All safety analyses will be performed using the safety population. 


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Demographic and Baseline Characteristics 
Demographic variables will include age (continuous and by age cohort), sex, race, height, 
and weight. Baseline disease characteristics will include reason for surgery and related 
co-morbidities. 
Subject demographics and baseline characteristics will be summarized by treatment 
group using the evaluable and safety populations. 
 
Prior and Concomitant Medications 
Summaries of each prior (pre-baseline) medication and concomitant (baseline or later) 
medication will be provided by treatment. Medications will be coded using the WHO 
Drug Dictionary. Subjects will be counted only once within each period by medication. 
 
Safety Analysis 
Overall safety, as determined by the incidence, severity and relationship of adverse 
events (AEs), clinical laboratory abnormalities, estimated rates of immunogenicity 
(monitoring for anti-thrombin antibodies and additional monitoring for anti-fibrinogen 
antibodies will be limited to subjects found positive for anti-thrombin antibodies and 
subjects with unexplained bleeding or clinical suspicion of bleeding related to antibody 
formation) and post-surgery bleeding complications.   
10.4.3.1. Adverse Events 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. An AE (classified as preferred term) occurring during 
the study will be counted as a treatment emergent AE (TEAE) when it is not present at 
baseline or present at baseline but increased in severity after the initiation of study drug.  
Summaries of the number and percentage of subjects with at least one SAE, MDR 
reportable events (malfunction, serious injury, or death), or MDV incident, and the 
number and percentage of subjects with at least one Grade 3, 4, or 5 AE, classified by 
MedDRA preferred term and system organ class, will be provided.  
Adverse events of special interest as listed below will be summarized by treatment group. 
Details of the AEs of special interest are in Section 8.6: 
• Surgical site-related events.  
• Thromboembolic events.  
• Re-bleeding at the bleeding sites. 
• Gas embolism events.  
• Blood borne pathogenic diseases suggestive of pathogen transmission from 
Raplixa.  
 


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Listings will be presented for subjects with SAEs/AEs leading to a treatment 
discontinuation or death.  
The estimated rate of immunogenicity will be reported for both treatment arms. No 
immunogenicity data will be collected for, or reported on, children less than 6 months of 
age. 
10.4.3.2. Laboratory Tests 
Laboratory values will be summarized by treatment group, including changes and percent 
ages of changes from baseline at each time point. Shift tables summarizing the counts and 
percentages of subjects who were normal at baseline, but became abnormal subsequently 
will be provided. 
10.4.3.3. Vital Signs 
Change and percent change from baseline in vital signs will be summarized descriptively 
at each scheduled time point by treatment group. 
 
Efficacy Analysis 
10.4.4.1. Primary Efficacy Endpoints 
The primary efficacy endpoint is: 
• Proportion of subjects who reach hemostasis at the first identified TBS within 
4 minutes of study drug application. 
If a subject achieves hemostasis at any point within 4 minutes of study drug application, 
they will be considered a “success”. All other subjects will be considered a “failure”. 
The primary endpoint will be analyzed with the ITT population. Comparison of the 
overall response between treatment arms will be made using logistic regression. This will 
include the estimation of the overall response rates, with 95% confidence intervals, for 
each treatment arm. Surgical type may also be included in the analysis model as a 
potential covariate in order further assess the endpoint.  
Additional details of this analysis will be described in the SAP.  
10.4.4.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Restricted mean TTH (during the 5-minute TTH assessment period) 
• Through Visit 5, EOS visit: 
o Use of alternative hemostatic agents on the TBS.  
o Volume of transfused blood (whole blood, fresh frozen plasma (FFP), 
cryoprecipitate, platelets, or packed red blood cell (PRBC). 
o Incidence of re-operation for bleeding at the TBS. 
The analysis of these variables will be described in the SAP. 


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11. RECORDS RETENTION 
FDA regulations require all investigators participating in clinical drug trials to 
maintain detailed clinical data for one of the following periods: 
• 
At least 2 years following the date on which a Biologics License Application 
(BLA) is approved by the FDA, or 
• 
Two years after the Sponsor notifies the investigator that no further 
application is to be filed with the FDA. 
Similarly, ICH guidelines require that essential documents be retained until at least 
2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
To comply with these requirements, the investigator will not dispose of any records 
relevant to this study without either (1) written permission from the Sponsor or (2) 
providing an opportunity for the Sponsor to collect such records. The investigator 
shall take responsibility for maintaining adequate and accurate hard copy source 
documents of all observations and data generated during this study, including any 
data clarification forms (DCFs) received from the Sponsor. Such documentation is 
subject to inspection by the Sponsor or its agents, the FDA and/or other regulatory 
agencies. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
MONITORING 
The Sponsor has ethical, legal and scientific obligations to carefully follow this study in 
accordance with established research principles and applicable regulations. The 
investigator, as part of his responsibilities, is expected to cooperate with the Sponsor in 
ensuring that the study adheres to the protocol and GCP requirements.  
As part of a concerted effort to fulfill these obligations, the Sponsor's monitor will visit 
the center(s) during the study in accordance with the Monitoring Plan set forth for this 
trial. The investigator will permit the Sponsor to monitor the study as frequently as is 
deemed necessary and provide access to medical records/source documents to ensure that 
data are being recorded adequately, that data are verifiable and that protocol adherence is 
satisfactory.  
 
AUDITING 
The Sponsor may conduct audits at the study center(s). Audits will include, but not be 
limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of CRFs with source documents. The investigator agrees to permit audits 
conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also inspect the investigator during or after the 
study. The investigator should contact the Sponsor immediately if this occurs, and must 
permit regulatory authority inspections. 
 
PROTOCOL DEVIATIONS 
This study will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety, and well-being of the subject requires immediate 
intervention, based on the judgment of the investigator (or a responsible, appropriately 
trained professional designated by the investigator). In the event of a significant deviation 
from the protocol due to an emergency, accident, or mistake, the investigator or designee 
must contact the Sponsor, or their agent, at the earliest possible time by telephone. This 
will allow an early joint decision regarding the subject’s continuation in the study. The 
investigator and the Sponsor will document this decision. The IRB/EC will be informed 
of all protocol changes by the investigator in accordance with the IRB/EC established 
procedure. No deviations from the protocol of any type will be made without complying 
with all the IRB/EC established procedures. Protocol deviations captured in the eCRF 
will be documented and listed per site and recorded in the Clinical Study Report. 


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13. ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard 
operating procedures and/or guidelines, the United States Food and Drug Administration 
(FDA) regulations, the International Conference on Harmonization (ICH) GCP 
guidelines, the Declaration of Helsinki and other local regulations, as applicable. 
 
INFORMED CONSENT 
Written informed consent will be obtained from parents/guardians for all subjects before 
any study-related procedures (including any pre-treatment procedures) are performed. 
Subjects 7 years and older, or of an appropriate age as defined by local regulations, may 
be required to sign an IRB-approved assent form. The investigator(s) has both ethical and 
legal responsibility to ensure that each subject (and their guardian or legally authorized 
representative) being considered for inclusion in this study is given a full explanation of 
the protocol. This shall be documented on a written informed consent form, which shall 
be approved by the same IRB or EC responsible for approval of this protocol. Each 
informed consent form shall include the elements required by ICH, Part E6, Section 4.8 
and any applicable local regulations. The investigator agrees to obtain approval from the 
Sponsor of any written informed consent form used in the study, preferably prior to 
submission to the IRB or EC.  
Once the appropriate essential information has been provided to the parents/guardians 
and the subject (as required) and fully explained by the investigators (or a qualified 
designee) and it is felt that the parents/guardians and the subject (as required) understands 
the implications of participating, the parents/guardians and the subject (as required) and 
the investigator (or designee) shall sign the IRB or EC approved written informed 
consent form. The parents/guardians and the subject (as required) shall be given a copy of 
the signed informed consent form, and the original shall be filed appropriately, according 
to the institution. A second copy may be filed in the subject's medical record, if allowed 
by the institution. 
 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
This protocol, the written informed consent and assent forms (if applicable) and any 
materials presented to subjects shall be submitted to the IRB or EC identified with this 
responsibility. Notification in writing of approval must come from the IRB or EC 
chairman or secretary, to the investigator, either as a letter or as a copy of the appropriate 
section of the IRB or EC meeting minutes where this protocol and associated informed 
consent form were discussed. The investigator will not participate in the decision. If the 
investigator is an IRB or EC member, the written approval must indicate such non-
participation in the voting session. The investigator will submit status reports to the IRB 
or EC as required by the governing body. The IRB or EC must be notified by the 


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investigator in writing of the interruption and/or completion of the study; the investigator 
must promptly report to the IRB or EC all changes in research (protocol amendments) 
and will not make such changes without IRB or EC approval, except where necessary to 
eliminate apparent immediate hazards to human subjects. In cases where it is necessary to 
eliminate immediate hazards to subjects, the IRB or EC must then be notified of the 
change as per local requirements. The investigator is required to maintain an accurate and 
complete record of all written correspondence to and received from the IRB or EC and 
must agree to share all such documents and reports with the Sponsor. 


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14. CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must 
not be disclosed to any persons not directly concerned with the study without written 
prior permission from the Sponsor. However, authorized regulatory officials and Sponsor 
personnel will be allowed full access to the records. All medications provided and subject 
bodily fluids and/or other materials collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by the Sponsor. 
Only unique subject numbers in CRFs will identify subjects. Their full names may, 
however, be made known to a product regulatory agency or other authorized official if 
necessary. 
With respect to the clinical trial data that is received from countries in the European 
Economic Area and Switzerland, MDCO has certified adherence to the US-European 
Union (EU) and the US-Swiss Safe Harbor Principles. 
 


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15. REFERENCES 
1. Cronkite, EP, EL Lozner, and J Deaver. Use of thrombin and fibrinogen in skin 
grafting. 1944, JAMA 124:976-978. 
2. Radosevich, M, HI Goubran, and T Burnouf. Fibrin sealant: scientific rationale, 
production methods, properties, and current clinical use. 1997, Vox Sang, Vol. 
72(3):133-43. 
3. Spotnitz, WD and Burks, S. Hemostats, Sealants, and Adhesives: Components of 
the Surgical Toolbox. 2008, Transfusion 48:1502-1516. 
4. EVICEL® US Package Insert, May 2007. 
5. TISSEEL US Package Insert, December 2007. 
6. TachoSil® US Package Insert, March 2010. 
7. Raplixa® US Package Insert, April 2015. 
8. Revel-Vilk, S. The conundrum of neonatal coagulopathy. 2012, ASH Education 
Book, Vol 2012, and No.1:450-454. 
9. Andrew M., Vegh P., Johnston M., Bowker J., Ofosu F., and Mitchell L. 
Maturation of the hemostatic system during childhood. 1992, Blood, 80:1998-
2005. 
10. Verhoef C, Singla N, Moneta G, et al. Fibrocaps for surgical hemostasis: two 
randomized, controlled Phase II trials. 2015, J Surg Res, 194:679-87. 
11. Bochicchio GV, Gupta N, Porte RJ, et al. The FINISH-3 trial: a Phase 3, 
international, randomized, single-blind, controlled trial of topical Fibrocaps in 
intraoperative surgical hemostasis. 2015, J Am Coll Surg, 220:70-81.