A Single-Blinded, Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair
Phase: PHASE3
Conditions: Cerebrospinal Fluid Leak
Sponsor: Ethicon, Inc.

Protocol BIOS-14-002 
 
CONFIDENTIAL 
Version: Amendment 3 – 16 May 2016 
 
 
A Single-Blinded, Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® 
Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair 
 
The EVICEL® Neurosurgery Phase III Study 
 
Protocol Number: BIOS-14-002 
 
Original Protocol: October 2, 2014 
Amendment 1: 12 February 2015 
Amendment 2: 17 November 2015 
Amendment 3: 16 May 2016 
 
 
Sponsor: 
ETHICON Inc. 
P.O. Box 151, 
Route 22 West, 
Somerville, NJ 08876 
 
 
Responsibilities for the conduct of this clinical study have been transferred from  
Ethicon Inc. to: 
 
Johnson & Johnson Medical Pty Ltd. 
1-5 Khartoum Road 
North Ryde, NSW 2113 
Australia 
 
Ethicon, a division of J&J Medical Ltd. 
Simpson Parkway, Kirkton Campus 
Livingston, EH54 0AB 
United Kingdom 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations.  In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them.  These restrictions on disclosure will apply equally to all future information supplied to you which is indicated as privileged 
or confidential.   
 

Protocol BIOS-14-002 
 
CONFIDENTIAL 
Version: Amendment 3 – 16 May 2016 
 
EudraCT number 2014-003954-15 
 
Page 2 of 40 
 
A Single-Blinded, Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® 
Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair 
 
 
Protocol Number: BIOS-14-002 
 
Original Protocol:  October 2, 2014 
Amendment 1: 12 February 2015 
Amendment 2: 17 November 2015 
Amendment 3: 16 May 2016 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________ 
 
______________ 
Richard Kocharian, MD, PhD 
 
 
Date 
Franchise Medical Director  
ETHICON™ Biosurgery 
 
 
___________________________ 
 
______________ 
Nicolas Aguirre  
 
 
 
Date 
Associate Director, Ethicon Clinical R&D 
Ethicon, Inc. 
 
 
COMPLIANCE STATEMENT 
This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements. 
 
 
 

Protocol BIOS-14-002 
 
CONFIDENTIAL 
Version: Amendment 3 – 16 May 2016 
 
EudraCT number 2014-003954-15 
 
Page 3 of 40 
 
A Single-Blinded Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® 
Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair 
 
 
Protocol Number: BIOS-14-002 
 
Original Protocol:  October 2, 2014 
Amendment 1: 12 February 2015 
Amendment 2: 17 November 2015 
Amendment 3: 16 May 2016 
 
 
 
 
 
 
 
 
 
 
___________________________ 
 
______________ 
EU Coordinating Investigator Signature  
Date 
 
 
___________________________ 
Coordinating Investigator Name (printed) 
 
 
 
 
 
 
 
 
 
 
COMPLIANCE STATEMENT 
This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements. 
 
 

Protocol BIOS-14-002 
 
CONFIDENTIAL 
Version: Amendment 3 – 16 May 2016 
 
EudraCT number 2014-003954-15 
 
Page 4 of 40 
 
A Single-Blinded, Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® 
Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair 
 
 
Protocol Number: BIOS-14-002 
 
Original Protocol:   October 2, 2014 
Amendment 1: 12 February 2015 
Amendment 2: 17 November 2015 
Amendment 3: 16 May 2016 
 
 
 
 
 
 
Investigator Agreement: 
I have read this protocol and agree to conduct the study as outlined herein.  I will provide copies of the 
protocol and all pertinent information to all individuals responsible to me who assist in the conduct of this 
study.  I will discuss this material with them to ensure they are fully informed regarding the investigational 
product and the conduct of the study.   
 
 
 
 
 
 
 
 
___________________________ 
 
______________ 
Investigator Signature  
 
 
Date 
 
 
___________________________ 
Investigator Name (printed) 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol BIOS-14-002 
 
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Table of Contents 
Synopsis ........................................................................................................................................................ 8 
Schedule of Events ...................................................................................................................................... 13 
1. 
Introduction ........................................................................................................................................ 14 
2. 
Study Objectives ................................................................................................................................. 16 
3. 
Overview of Study Design ................................................................................................................... 16 
4. 
Study Population ................................................................................................................................. 17 
4.1  
General Considerations ............................................................................................................... 17 
4.2 
Inclusion Criteria ......................................................................................................................... 17 
4.3  
Exclusion Criteria ......................................................................................................................... 17 
5. 
Randomization .................................................................................................................................... 18 
5.1 
Overview ..................................................................................................................................... 18 
5.2 
Procedures .................................................................................................................................. 19 
6. 
Investigational Product and Comparators .......................................................................................... 19 
6.1 
EVICEL® Fibrin Sealant ................................................................................................................ 19 
6.1.1 
Formulation ......................................................................................................................... 19 
6.1.2 
Labeling and Packaging ....................................................................................................... 20 
6.1.3 
Application Device .............................................................................................................. 20 
6.1.4 
Accessory Tips ..................................................................................................................... 20 
6.1.5 
Pressure Regulators ............................................................................................................ 21 
6.1.6 
Shipping, Handling, and Storage Conditions ....................................................................... 21 
6.1.7 
Preparation ......................................................................................................................... 21 
6.1.8 
Dose, Route, and Duration of Administration .................................................................... 21 
6.2  
DuraSeal® Dural Sealant System ................................................................................................. 21 
6.3 
Investigational Product Dispensation and Accountability .......................................................... 22 
6.4  
Concomitant Medications ........................................................................................................... 22 
6.4.1 
Documentation of Concomitant Medications .................................................................... 22 
7. 
Study Evaluations ................................................................................................................................ 22 
7.1 
Study Procedures ........................................................................................................................ 22 
7.1.1 
Screening ............................................................................................................................. 22 
7.1.2 
Baseline ............................................................................................................................... 23 
7.1.3 
Surgical Procedure .............................................................................................................. 23 

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7.1.4 
Post-Surgery through Hospital Discharge ........................................................................... 25 
7.1.5 
30-Day Follow-up (-/+7 days) .............................................................................................. 25 
7.1.6 
60-Day Follow-up (-/+14 days) ............................................................................................ 25 
7.2 
Procedures for Handling Biological Samples .............................................................................. 26 
7.2.1 
Laboratory Tests.................................................................................................................. 26 
7.3 
Premature Withdrawal of Subjects from the Study ................................................................... 26 
8. 
Statistical Methods ............................................................................................................................. 26 
8.1 
Sample Size Determination ......................................................................................................... 26 
8.2 
Data Analysis ............................................................................................................................... 27 
8.2.1 
Analysis Sets ........................................................................................................................ 27 
8.3 
Effectiveness ............................................................................................................................... 27 
8.3.1 
Effectiveness Variables ....................................................................................................... 27 
8.3.2 
Methods of Analysis ............................................................................................................ 27 
8.4 
Safety .......................................................................................................................................... 28 
8.4.1 
Safety Variables/Criteria ..................................................................................................... 28 
8.4.2 
Methods of Analysis ............................................................................................................ 28 
8.5  
Handling of Missing Data ............................................................................................................ 28 
8.6  
Health Economics ........................................................................................................................ 29 
9. 
Safety .................................................................................................................................................. 29 
9.1  
Adverse Event ............................................................................................................................. 29 
9.2  
Serious Adverse Event................................................................................................................. 29 
9.3  
Relationship ................................................................................................................................ 30 
9.4  
Severity ....................................................................................................................................... 30 
9.5  
Collection of Adverse Events ...................................................................................................... 30 
9.6  
Adverse Event Reporting ............................................................................................................ 30 
9.7 
Device Complaint Handling ......................................................................................................... 31 
10. 
Regulatory Obligations .................................................................................................................... 31 
10.1  
Informed Consent ................................................................................................................... 31 
10.2  
Institutional Review Boards/Ethics Committees..................................................................... 32 
10.3  
Data Management .................................................................................................................. 32 
10.3.1 Electronic Data Capture (EDC) ................................................................................................. 32 
10.3.2 Data Collection ......................................................................................................................... 32 

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10.3.3 Data Correction ........................................................................................................................ 32 
10.3.4 Source Documentation ............................................................................................................ 33 
10.4  
Study Monitoring and Auditing ............................................................................................... 33 
10.5  
Sponsor Obligations ................................................................................................................ 33 
10.5.1 
Monitoring .......................................................................................................................... 33 
10.5.2 
Regulatory Requirements ................................................................................................... 34 
10.5.3 
Liability and Insurance Conditions ...................................................................................... 34 
11. 
Investigator Obligations .................................................................................................................. 34 
11.1 
Financial Disclosure ..................................................................................................................... 34 
11.2 
Audit and Inspection ................................................................................................................... 34 
11.3 
Confidentiality of Subject Records .............................................................................................. 34 
11.4  
Record Retention .................................................................................................................... 34 
12. 
Changes to the Protocol .................................................................................................................. 34 
12.1 
Protocol Amendments ................................................................................................................ 34 
12.2 
Clinical Trial Termination ............................................................................................................ 34 
12.3  
Use of Information and Publication ........................................................................................ 35 
13. 
Contact Details ................................................................................................................................ 36 
14. 
References ...................................................................................................................................... 37 
Appendix I: CDC/NHSN Criteria for Defining a Surgical Site Infection (SSI) ................................................ 38 
Appendix II: U.S. Center for Disease Control (CDC) Guideline for Prevention of SSI Surgical Wound 
Classification ............................................................................................................................................... 40 
 
 
 
 

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Version: Amendment 3 – 16 May 2016 
 
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A Single-Blinded, Randomized, Controlled Study to Evaluate the Safety and Effectiveness of EVICEL® 
Fibrin Sealant (Human) Compared to a Hydrogel Sealant as an Adjunct to Sutured Dural Repair 
 
Synopsis 
 
OBJECTIVE: 
The objective of this study is to evaluate the safety and efficacy of EVICEL® 
Fibrin Sealant (Human) for use as an adjunct to sutured dural repair in cranial 
surgery 
 
INVESTIGATIONAL  
PRODUCT: 
EVICEL® Fibrin Sealant (Human) 
 
STUDY DESIGN: 
This is a single-blinded, randomized, controlled study evaluating EVICEL® as 
an adjunct to sutured dural closure compared to DuraSeal™ Dural Sealant 
System.   
 
 
Approximately 230 subjects undergoing posterior fossa or supratentorial 
procedures (craniectomy or craniotomy) will be enrolled in the trial. At least 
60 subjects undergoing posterior fossa procedures will be randomized. 
 
Upon completion of the sutured dural repair, the closure will be evaluated 
for intraoperative cerebrospinal fluid (CSF) leakage with a baseline Valsalva 
maneuver performed to an intra-thoracic pressure between 20-25 cm H2O 
for 5-10 sec. If a spontaneous leak is apparent immediately after dural 
closure, no Valsalva maneuver will be performed.   
 
Subjects who have a CSF leak will be stratified by surgical procedure, 
posterior fossa or supratentorial approach, and then randomized to either 
EVICEL® Fibrin Sealant or DuraSeal™ Dural Sealant System in a 1:1 allocation 
ratio. 
 
Subjects will be followed post-operatively through discharge and again at 30 
(-/+ 7 days) days and 60 (-/+14) days post-surgery.  The incidence of CSF leaks 
for the primary endpoint will be assessed up to the 30 day post-operative 
follow-up period.  A CSF leak will be reported as detected by any of the 
following: clinical observation, diagnostic testing, imaging or the need for 
surgical intervention to directly treat a CSF leak. 
 
STUDY POPULATION: 
Subjects at least 18 years of age undergoing craniotomy or craniectomy 
surgery for pathological processes in the supratentorial procedures or 
posterior fossa (such as benign or malignant tumors, vascular and Chiari 1 
malformations).   
 
PROCEDURE: 
Subjects Randomized to EVICEL® 
 
For subjects randomized to receive EVICEL®, a thin layer will be applied to 
cover the entire length of the suture line and the adjacent area to assure 

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complete coverage of the suture line including all suture holes.  If necessary, 
a second layer of EVICEL® may be applied. A cure time should be allotted 
between layers to allow for the EVICEL® clot formation and stabilization. CSF 
leakage will be evaluated with the Valsalva maneuver performed to an intra-
thoracic pressure between 20-25 cm H2O for 5-10 sec.   
 
 
If a CSF leakage is still apparent a second treatment (up to two layers) with 
EVICEL® may be applied.  CSF leakage will be re-evaluated with the Valsalva 
maneuver as described above.   
 
If watertight closure is achieved for EVICEL® treatment, no further treatment, 
including the use of onlays, will be allowed. 
 
If watertight closure is not evident after the final Valsalva maneuver, the 
subject will be deemed a failure and surgeon may revert to his/her standard 
of care for closure, this can include additional treatment with EVICEL® if 
clinically appropriate.  The use of other fibrin sealants is not permitted.     
 
Subjects randomized to EVICEL® may not have their dura treated with 
DuraSeal™ Dural Sealant System or any other PEG based or fibrin sealants.   
 
Subjects Randomized to DuraSeal™  
For subjects randomized to DuraSeal™, the assigned product will be applied 
to the entire length of the suture line, including all suture holes, according to 
the manufacturer’s instruction for use. CSF leakage will be evaluated with the 
Valsalva maneuver performed to an intra-thoracic pressure between 20-25 
cm H2O for 5-10 seconds.   
 
If a CSF leakage is still apparent, continue treatment with DURASEAL™ per 
manufactures directions. CSF leakage will be re-evaluated with the Valsalva 
maneuver as described above.  If watertight closure is achieved for 
DuraSeal™ treatment, no further treatment, including the use of onlays, will 
be allowed.   
 
If watertight closure is not evident after the final Valsalva maneuver, the 
subject will be deemed a failure and surgeon may revert to his/her standard 
of care for closure, this can include additional treatment with DuraSeal™, if 
clinically appropriate.  The use of fibrin sealants is not permitted.     
 
Subjects randomized to DuraSeal™ may not have their dura  treated with 
EVICEL® Fibrin Sealant or any other PEG based or fibrin sealants.   
 
  
 
                                          
 
PRIMARY ENDPOINT: 
The primary endpoint is the proportion of subjects that do not have a CSF 
leak during surgery and up to the 30-day (-/+ 7) post-operative period.  

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A subject is declared as a success when the following conditions are met: 
• 
absence of intra-operative CSF leak following final Valsalva maneuver, 
and  
• 
absence of CSF leak or Pseudomeningocele in the surgical area during the 
30-day (-/+ 7) follow-up period. 
 
 
A confirmed CSF leak or pseudomeningocele is diagnosed by physical 
examination, diagnostic testing, imaging study or the need for surgical 
intervention to directly treat a CSF leak during the 30-day (-/+ 7 days) follow-
up at the location where randomized treatment was applied.   
 
SECONDARY ENDPOINTS: 
 
- 
Incidence of Intra-operative CSF leakage following final Valsalva maneuver. 
- 
Incidence of post-operative CSF leakage within 30 (-/+7) days post-
operatively. 
- 
Incidence of post-operative CSF leakage within 60 (-/+ 14) days post-
operatively. 
- 
Incidence of adverse events. 
- 
Incidence of surgical site infections (SSI) according to NNIS definition and CDC 
classification within 30 days (-/+7) post-operatively (See Appendix I and II). 
 
SAFETY: 
Adverse events will be collected from time of randomization, throughout the 
60 day (-/+ 14) follow-up period after the procedure.   
 
 
STATISTICAL DESIGN: 
This is a non-inferiority trial using a one-sided alpha 0.025 and 90% power.  
The assumed success rate in the both arms is 95%.6,14   
  
STUDY HYPOTHESIS: 
The statistical hypothesis for testing the treatment difference is presented 
as follows: 
 
• 
H0: Δ ≤ -0.10 tested against the alternative hypothesis  
• 
Ha: Δ > -0.10.  
 
 
where: 
• 
Δ is the difference between the success rates of Experimental and Control 
(Experimental minus Control) 
• 
-0.10 is the non-inferiority difference  
• 
The assumed proportion of successes for Control is 0.95 
 
 
PC is the proportion of success in DuraSeal™ Control subjects and PE is the 
proportion of success in EVICEL® subjects. 
 
 
SAMPLE SIZE: 
The number of randomized subjects required for this trial is 202 subjects (101 
per treatment arm) from centers in North America, Europe, and Asia-Pacific.  

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There will be approximately 30 global sites. In order to account for potential 
missing follow-up information (drop-outs), approximately 230 subjects will 
be enrolled. At least 60 subjects undergoing posterior fossa procedures will 
be randomized.  
 
 
Two hundred and two (202) evaluable subjects (101 per arm) will achieve 90% 
power to detect a non-inferiority margin difference in group proportions of -
0.10.  The proportion of successes in the Control group is 0.95. The proportion 
of successes in EVICEL® group is assumed to be 0.85 under the null hypothesis 
of inferiority.  The power was computed for the case when the actual 
proportion of successes in the EVICEL® group is 0.95.  The one-sided 
significance level of the test is 0.025. 
 
 
If the lower limit of the one-sided 97.5% confidence interval for Δ is greater 
than -0.10, then it will be concluded that Experimental is considered to be 
non-inferior to Control.  
 
INCLUSION CRITERIA: 
 
Pre-Operative 
1. Subjects  ≥18 years of age undergoing craniotomy/craniectomy for pathological processes in the 
supratentorial region or posterior fossa (such as benign or malignant tumors, vascular 
malformation, and Chiari 1 malformations); 
2. Subjects or legally authorized representatives must be willing to participate in the study and 
provide written informed consent. 
 
Intra-Operative 
1. Surgical wound classification Class I (refer to Appendix II). Superficial penetration of mastoid air 
cells during partial mastoidectomy is permitted. 
2. The cuff of native dura along the craniotomy edge on each side is adequate, based on surgeon’s 
judgment, to facilitate suturing and to allow for sufficient surface area for adherence of the 
investigational product 
3. Presence of intra-operative cerebrospinal fluid (CSF) leakage following primary dural closure or 
after Valsalva maneuver  
 
EXCLUSION CRITERIA: 
Pre-Operative 
1. Subjects with a cranial dural lesion from a recent surgery that still has the potential for CSF 
leakage. 
2. Chemotherapy within 30-days prior to enrollment or scheduled within 7 days following surgery. 
3. Radiation therapy to the head within 30-days prior to enrollment or scheduled within 7 days 
following surgery. 
4. A previous craniotomy/craniectomy within 6 months prior to the study surgery. 
5. Known hypersensitivity to the components (such as human fibrinogen, arginine hydrochloride, 
glycine, sodium chloride, sodium citrate, calcium chloride, human thrombin, human albumin, 
mannitol and sodium acetate) of the investigational product. 
6. Subjects with a known allergy to FD&C Blue #1 dye in DuraSeal  

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7. Subjects with an infection present at the surgical site 
8. Subjects with an infection indicated by any one of the following: clinical diagnosis of infection, 
fever, positive urine culture, positive blood culture, positive chest X-ray. 
9. Female subjects of childbearing potential with a positive pregnancy test or intent to become 
pregnant during the clinical study period. 
10. Female subjects who are nursing.  
11. Exposure to another investigational drug or device clinical trial within 30 days prior to enrollment 
or anticipated in the 60 day follow-up period. 
12. Subjects with severely altered renal or hepatic function, with a compromised immune system or 
autoimmune disease who can NOT receive DuraSeal™. 
13. Subjects with penetrating traumatic injuries to the head with damage to the dura.   
 
Intra-Operative 
1. Dural injury during craniotomy/craniectomy that cannot be eliminated by widening the 
craniotomy/craniectomy to recreate the native dural cuff. 
2. Patient has a gap between durotomy edges of greater than 2mm after primary dural closure. 
3. Approaches that would not allow sutured dural closure such as trans-sphenoidal or trans-
labyrinthine-/petrosal/-mastoid. Superficial penetration of mastoid air cells is allowed.  
4. Use of implants made of synthetic materials coming into direct contact with dura (e.g., PTFE 
patches, shunts, ventricular and subdural drains, existing CSF drains). 
5. Use of other fibrin sealants or PEG-based sealants on the dural closure.  Approved fibrin sealants 
may be used for hemostasis if not in contact with the dura. 
6. Hydrocephalus, except occlusive hydrocephalus caused by posterior fossa pathology or 
incompletely open cerebrospinal fluid pathways to be treated during the planned surgical 
procedure. 
7. Placement of Gliadel Wafers 
8. Intersecting durotomy scars in the surgical path from a previous operation that cannot be 
completely removed by the planned dural resection. 
9. Two or more separate cranial dural defects, including defects from ventricular cannulation and 
ventriculo-peritoneal shunting  
10. Subjects with any other intra-operative findings identified by the surgeon that may preclude the 
conduct of the study procedure. 
11. Confined bony structures where nerves are present where neural compression may result due 
to swelling.  
 
 
 

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Schedule of Events 
 
Procedures 
Screening1 
(within 30 days 
prior to 
procedure) 
 
Baseline1 
(within 24 
hours prior to 
procedure)  
Surgical 
Procedure  
 
Post-Surgery 
to Hospital 
Discharge 
30-Day Follow 
Up  
(-/+7 days) 
60-day Follow 
Up  
(-/+14 days) 4 
Inclusion/Exclusion  
X 
X 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
Physical Exam  
X 
 
 
X 
X 
 
Laboratory tests 
 
X 
 
X3 
X 
 
Pregnancy Tests 
 (if applicable) 
 
X 
 
 
 
 
Sutured Dural Closure 
 
 
X 
 
 
 
Randomization 
 
 
X 
 
 
 
Treatment Application 
 
 
X 
 
 
 
Valsalva Maneuver 
 
 
X 
 
 
 
Intra-Operative Details 
 
 
X 
 
 
 
Perioperative 
Information2 
 
 
X 
X 
 
 
CSF Leak Assessment 
 
 
X 
X 
X 
 
Surgical Site Infection 
Evaluation 
 
 
 
X 
X 
 
Wound Healing 
Assessment 
 
 
 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
1. 
Screening and Baseline visits can be the same visit as long as all study procedures are completed. At least one set of laboratory tests 
and pregnancy test are needed within 7-days prior to the procedure.  
2. 
Including but not limited to, Length of stay (ICU and overall LOS),  
3. 
Within 72 hours prior to discharge. Labs taken closest to discharge should be used. 
4. 
60 day follow-up visit may be in-person or over the phone.  

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1. Introduction 
 
Many neurosurgical procedures require that the surgeon pass through the dura mater to gain access to 
the neural elements, which constitute part of the central nervous system. Despite advances in 
neurosurgical techniques and the development of new methods to repair dura mater defects, 
cerebrospinal fluid (CSF) leakage is one of the most challenging complications of cranial surgery.1 
Meticulous dural repair should include an intraoperative watertight closure as protection from post-
operative CSF leakage.1   CSF leaks can lead to other serious complications like meningitis and delayed 
wound healing.1-3   
 
Following cranial neurosurgical procedures (craniotomy or craniectomy) that require a dural incision, 
current dural closure techniques to obtain an intraoperative watertight closure include but are not limited 
to:  
 
1. Primary suture closure of the durotomy  
2. Augmentation or onlay patching of the dural incision with synthetic or biologic patches  
3. Adjunctive use of various products designed for prophylactic use or to treat persistent CSF leak 
after primary sutured dural closure  
a. Additional suture repair 
b. Synthetic Sealants (e.g. polyethylene glycol, etc)  
c. Biological Sealants, e.g fibrin sealants, glutaraldehyde crosslinked bovine albumin  
d. Autologous tissue buttresses or duraplasty materials, e.g. fat, muscle, peri-cranium, etc.  
e. Gelatin pads or other resorbable biomaterials  
 
Fibrin sealants have been widely used for various neurosurgical indications, in particular as an adjunct to 
dura repair, for more than 20 years. 4-6     Even though there has been a long history of fibrin sealant use 
in this area, there is a limited number of multicenter, prospective, controlled randomized clinical studies 
published. Nevertheless, the published literature does include number of retrospective studies with 
historical controls and few randomized trials which provide support of clinical efficacy of fibrin sealants in 
dura mater sealing. 5-6         
 
Fibrin sealants are typically derived from biologic sources consisting of blood coagulation factors (i.e. 
thrombin and fibrinogen) and may contain additional components. They are typically marketed as surgical 
hemostats and wound support products. Their main role is to mimic the final step in the coagulation 
pathway to form a stable, physiological fibrin clot that assists in healing. 7  
 
EVICEL® Fibrin Sealant (Human) 
 
EVICEL® is a fibrin sealant manufactured by Omrix Biopharmaceuticals Ltd., Israel and is approved for 
marketing in the EU (approved via the Centralized Procedure in October 2008), the US (since 2006) and in 
numerous other countries worldwide.   
 
EVICEL® is a human plasma derived fibrin sealant consisting of two components: (1) Human Fibrinogen 
(named also Biologically Active Component 2 (BAC2)).(2) Human Thrombin containing calcium.8-9  The 
sealant components are administered to the surgical site by spraying or dripping using a single use 
applicator device. The applicator device consists of two syringes connected by a syringe holder and bridge.  

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The syringes are linked to a tri-lumen catheter or other available accessory tip device via a closed-system 
vial-transfer device.  
 
EVICEL’s current indication is the following in the US and EU: 
US: EVICEL® is a fibrin sealant indicated as an adjunct to hemostasis for use in patients undergoing 
surgery, when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) 
is ineffective or impractical.8 
 
EU:  Supportive treatment in surgery where standard surgical techniques are insufficient, for 
improvement of haemostasis. Suture support for haemostasis in vascular surgery and for suture line 
sealing in dura mater closure.9 
 
The safety and hemostatic efficacy of EVICEL® and its predecessors (QUIXIL/CROSSEAL) have been 
investigated in numerous clinical trials in different clinical settings (retroperitoneal or intra-abdominal, 
liver, vascular surgery, etc.).10-12 QUIXIL/CROSSEAL was similar to EVICEL® except that QUIXIL/CROSSEAL 
contained tranexamic acid (TA) as a stabilizer and thus were contraindicated for use in neurosurgery and 
procedures where dura mater or CSF contact could occur due to TA potential neurotoxic effects that has 
been demonstrated in experimental in-vivo studies.13  Information from clinical studies indicated no 
particular safety concerns.10-12   
 
EVICEL®’s EU indication for suture line sealing in dura mater closure was supported by multicenter, 
prospective, controlled, randomized clinical study which demonstrated EVICEL safe and effective as an 
adjunct to dural sutures to provide watertight closure of the dura mater in cranial surgery.  The study 
further demonstrated that EVICEL was superior to the control (i.e. adjunctive dural closure techniques 
using additional repair sutures only) in achieving intra-operative watertight closure of the dura. One 
hundred and thirty-nine subjects were randomized: 89 to EVICEL and 50 to Control. Intra-operative 
watertight closure was achieved in 92.1% EVICEL-treated subjects versus 38.0% in the control group; a 
treatment difference of 54.1% (p < 0.001). The treatment differences in the supratentorial and posterior 
fossa strata were 49.1% and 75.7%, respectively (p < 0.001). The incidence of adverse events was similar 
between treatment groups. No deaths or unexpected serious adverse drug reactions were reported. The 
CSF leakage from the dural repair site within 30 days post-operatively was 2.2% and 2.0% in EVICEL and 
control groups, respectively.  The clinical study indicated no particular safety concerns in regard to dura 
mater closure.6  
 
DuraSeal™ Dural Sealant System 
DuraSeal™ Dural Sealant System is a commercially available synthetic sealant that is intended for use as 
an adjunct to sutured dural repair during cranial surgery to provide watertight closure. 
 
The product is a synthetic absorbable sealant (with applicator) composed of two solutions, a polyethylene 
glycol (PEG) ester solution and a rilysine amine solution. When these two solutions are mixed together, 
the precursors cross link to form a hydrogel sealant. 
 
DuraSeal™ Dural Sealant System is approved in the US (since 2005), EU (since 2003) and numerous 
countries world-wide.  DuraSeal™ ’s  current indication is the following in the US and EU: 
 

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US: The DuraSeal Dural Sealant System is intended for use as an adjunct to sutured dural repair during 
cranial surgery to provide watertight closure.14 
EU: The DuraSeal Sealant System is intended for use as an adjunct to standard methods of dural repair, 
such as sutures, to provide watertight closure.15 
 
EVICEL® Neurosurgery Phase III Study 
This clinical study is a non-inferiority study designed to evaluate the safety and efficacy of EVICEL® for use 
as an adjunct to sutured dural repair in cranial surgery as compared to DuraSeal™ Dural Sealant System.  
The study will assess both achievement of intra-operative watertight closure of the dural suture line and 
the occurrence of post-operative CSF leaks.   This study will provide additional data to support the 
development of EVICEL® for use in tissue sealing and suture support in neurosurgery and surgical 
procedures where contact with cerebrospinal fluid or dura mater may occur. 
 
2. Study Objectives 
The objective of this study is to evaluate the safety and efficacy of EVICEL® Fibrin Sealant (Human) for 
use as an adjunct to sutured dural repair in cranial surgery. 
 
The primary endpoint is the proportion of subjects that do not have a CSF leak during surgery and up to 
the 30-day (-/+ 7) post-operative period.  
 
A subject is declared as a success when the following conditions are met: 
• 
absence of intra-operative CSF leak following final Valsalva maneuver, and  
• 
absence of CSF leak or Pseudomeningocele in the surgical area during the 30-day (-/+ 7) follow-
up period. 
 
A confirmed CSF leak or pseudomeningocele is diagnosed by physical examination, diagnostic testing, 
imaging study or the need for surgical intervention to directly treat a CSF leak during the 30-day (-/+ 7 
days) follow-up at the location where randomized treatment was applied.   
 
The secondary endpoints of the study include:  
 
• 
Incidence of intra-operative CSF leakage following final Valsalva maneuver. 
• 
Incidence of post-operative CSF leakage within 30 (-/+7) days post-operatively. 
• 
Incidence of post-operative CSF leakage within 60 (-/+ 14) days post-operatively. 
• 
Incidence of adverse events. 
• 
Incidence of surgical site infections (SSI) according to NNIS definition and CDC classification within 
30 (-/+7) days post-operatively (See Appendix I and II). 
 
3. Overview of Study Design 
This is a single-blinded randomized, controlled study evaluating EVICEL® as an adjunct to sutured dural 
closure compared to DuraSeal™ Dural Sealant System.   
 
Approximately 230 subjects undergoing posterior fossa or supratentorial procedures (craniectomy or 
craniotomy) will be enrolled in the trial with at least 60 subjects undergoing posterior fossa procedures 
being randomized. 
 

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Upon completion of the sutured dural repair, the closure will be evaluated for intraoperative 
cerebrospinal fluid (CSF) leakage with a baseline Valsalva maneuver performed to an intra-thoracic 
pressure between 20-25 cm H2O for 5-10 sec. If a spontaneous leak is apparent immediately after dural 
closure, no Valsalva will be performed.   
 
Subjects who have a CSF leak will be stratified by surgical procedure, posterior fossa or supratentorial 
approach and then randomized to either EVICEL Fibrin Sealant or DuraSeal™ Dural Sealant System in a 1:1 
allocation ratio. 
 
Subjects will be followed post-operatively through discharge and again at 30 (-/+7) days and 60 (-/+14) 
days post-surgery.  For the primary endpoint, the incidence of CSF leaks will be assessed up to the 30 day 
post-operative follow-up period. The incidence of CSF Leak will also be assessed up to the 60 day post-
operative follow-up period.  A CSF leak will be reported as detected by any of the following: clinical 
observation, diagnostic testing, imaging or the need for surgical intervention to directly treat a CSF leak. 
 
4. Study Population 
 
4.1  
General Considerations 
The Investigator is expected to invite all patients expected to meet the pre-operative entry criteria to 
participate in the study.   
 
4.2 
Inclusion Criteria 
Pre-Operative 
1. Subjects  ≥18 years of age undergoing craniotomy/craniectomy for pathological processes in the 
supratentorial region or posterior fossa (such as benign or malignant tumors, vascular 
malformation, and Chiari 1 malformations); 
2. Subjects or legally authorized representatives must be willing to participate in the study and 
provide written informed consent. 
 
Intra-Operative 
1. Surgical wound classification Class I (refer to Appendix II). Superficial penetration of mastoid air 
cells during partial mastoidectomy is permitted. 
2. The cuff of native dura along the craniotomy edge on each side is adequate, based on surgeon’s 
judgment, to facilitate suturing and to allow for sufficient surface area for adherence of the 
investigational product. 
3. Presence of intra-operative cerebrospinal fluid (CSF) leakage following primary dural closure or 
after Valsalva maneuver 
 
4.3  
Exclusion Criteria 
Pre-Operative 
1. Subjects with a cranial dural lesion from a recent surgery that still has the potential for CSF 
leakage. 
2. Chemotherapy within 30-days prior to enrollment or scheduled within 7 days following surgery. 
3. Radiation therapy to the head within 30-days prior to enrollment or scheduled within 7 days 
following surgery. 
4. A previous craniotomy/craniectomy within 6 months prior to the study surgery. 

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5. Known hypersensitivity to the components (such as human fibrinogen, arginine hydrochloride, 
glycine, sodium chloride, sodium citrate, calcium chloride, human thrombin, human albumin, 
mannitol and sodium acetate) of the investigational product. 
6. Subjects with a known allergy to FD&C Blue #1 dye in DuraSeal™. 
7. Subjects with an infection present at the surgical site 
8. Subjects with an infection indicated by any one of the following: clinical diagnosis of infection, 
fever, positive urine culture, positive blood culture, positive chest x-ray.  
9. Female subjects of childbearing potential with a positive pregnancy test or intent to become 
pregnant during the clinical study period. 
10. Female subjects who are nursing.  
11. Exposure to another investigational drug or device clinical trial within 30 days prior to enrollment 
or anticipated in the 60 day follow-up period. 
12. Subjects with severely altered renal or hepatic function, with a compromised immune system or 
autoimmune disease who can NOT receive DuraSeal™. 
13. Subjects with penetrating traumatic injuries to the head with damage to the dura. 
 
 
Intra-Operative 
1. Dural injury during craniotomy/craniectomy that cannot be eliminated by widening the 
craniotomy/craniectomy to recreate the native dural cuff. 
2. Patient has a gap between durotomy edges of greater than 2mm after primary dural closure. 
3. Approaches that would not allow sutured dural closure such as trans-sphenoidal or trans-
labyrinthine-/petrosal/-mastoid. Superficial penetration of mastoid air cells is allowed.   
4. Use of implants made of synthetic materials coming into direct contact with dura (e.g., PTFE 
patches, shunts, ventricular and subdural drains, existing CSF drains.)  
5. Use of other fibrin sealants or PEG-based sealants on the dural closure.  Approved fibrin sealants 
may be used for hemostasis if not  in contact with the dura. 
6. Hydrocephalus, except occlusive hydrocephalus caused by posterior fossa pathology or 
incompletely open cerebrospinal fluid pathways to be treated during the planned surgical 
procedure. 
7. Placement of Gliadel Wafers 
8. Intersecting durotomy scars in the surgical path from a previous operation that cannot be 
completely removed by the planned dural resection. 
9. Two or more separate cranial dural defects, including defects from ventricular cannulation and 
ventriculo-peritoneal shunting 
10. Subjects with any other intra-operative findings identified by the surgeon that may preclude the 
conduct of the study procedure. 
11. Confined bony structures where nerves are present where neural compression may result due 
to swelling.  
 
5. Randomization 
 
5.1 
Overview 
Randomization will be used to avoid bias in the assignment of treatment to each subject, to increase the 
likelihood that attributes of the subject are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.  

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5.2 
Procedures 
Sponsor will provide each site with two sets (Supratentorial or Posterior Fossa Approach) of computer-
generated randomization envelopes, each bearing the sequential subject randomization number, and 
containing the treatment allocation and stratification.     
 
Subjects with a CSF leak will be stratified by surgical procedure, posterior fossa or supratentorial approach.  
Treatment will be assigned randomly to each subject on a 1:1 basis to either EVICEL® or DuraSeal™.  In 
the event that a potential subject fails intra-operative criteria and is not randomized to the study, the 
unused randomization envelope should be returned to the series, and used for the next subject. 
 
This will be a single-blinded study where the subject will be blinded to treatment.  Subjects should remain 
blinded throughout the trial.  Given the differences in appearance of the two treatment groups, it will not 
be possible for the investigator to be blinded to the treatment.  However, to avoid any bias in the conduct 
of the surgical procedure, randomization should only take place after completion of the following steps.  
1. EVICEL® and DuraSeal™ will be available in the OR/theatre for each subject. 
2. The investigator must perform the surgical procedure according to his/her standard of care.  
3. After a CSF leak is identified intra-operatively, randomization should immediately take place.   
 
If the subject is randomized to EVICEL®, then the unopened DuraSeal™ must be removed from the 
OR/theatre. Unopened DuraSeal™ may be returned to storage, as applicable per institutional guidelines 
and product storage instructions.  If the subject is randomized to DuraSeal™, the unused EVICEL® product 
should be disposed of according to institutional procedures. Accountability information must be 
documented for this unused study product. 
 
6. Investigational Product and Comparators 
 
6.1 
EVICEL® Fibrin Sealant  
 
6.1.1 
Formulation 
EVICEL® is a human plasma-derived fibrin sealant. EVICEL® consists of two components: a concentrate of 
Human Fibrinogen (referred to as Biological Component 2; BAC2) and a solution of Human Thrombin, 
which incorporates calcium. No material of animal origin is present in the product.  A purpose- designed 
application device is used to apply EVICEL® to the surgical site by spraying or dripping. The applicator 
device has been designed to ensure even mixing of the two components. 
 
 Composition of EVICEL® 
 
Human Fibrinogen  
 
Human Thrombin 
Active Ingredient 
Concentrate of human 
fibrinogen (55-85 mg/mL)* 
Human thrombin (800-1200 
IU/mL) 
 
Other ingredients 
Arginine 
hydrochloride, 
Glycine, Sodium chloride, 
Sodium 
citrate, 
Calcium 
Calcium 
chloride, 
Human 
albumin, 
mannitol, 
Sodium 
acetate, Water for injection 
(WFI). 

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chloride, Water for injection 
(WFI) 
 
 
*In EU, specified as 50-90 mg/mL human clottable protein containing mainly fibrinogen and 
fibronectin..  Each mL of Evicel® contains 11.6-12.9 mg sodium. 
 
6.1.2 
Labeling and Packaging 
The investigational product will have two vials contained within a single box. The product will be labeled 
according to local regulatory requirements and may contain the following information:  
• 
Name, address and telephone number of Sponsor  
• 
Protocol number  
• 
EudraCT number  
• 
Vial contents (volume of solution and concentration of active ingredients)  
• 
Storage conditions  
• 
Reference to the Package Leaflet for instructions of preparation and use in the Investigator’s 
Brochure  
• 
“For Clinical Trial Use Only”  
• 
“Caution: New Drug—Limited by Federal Law to Investigational Use”  
• 
Lot number   
• 
Expiry date  
 
6.1.3 
Application Device 
The application device is commercially available in the US, EU and multiple other countries.  It will be 
used according to its intended instructions and is not considered an investigational product in regions 
where available.  The applicator will be labeled according to local regulatory requirements, and may 
contain the following information: 
• 
Name, address and telephone number of Ethicon, Inc. 
• 
Protocol number 
• 
“For Clinical Trial Use Only” 
 
6.1.4 
Accessory Tips 
Certain accessory tips are commercially available in several countries.  They will be used according to their 
intended instructions and are not considered as an investigational product in regions where available.   
 
There will be three accessory tips provided for use with the application device: 
• 
Standard yellow tip (provided with application device) 
• 
4cm tip (control tip)  
• 
Airless Spray Tip 
 
Accessory tips may be used according to surgeon preference.  Tips will be used in accordance with their 
Product Assembly Guide.  Depending on its regulatory status and local regulatory requirements, the 
product will be labeled according to local regulatory requirements, and may contain the following 
information: 
• 
Name, address and telephone number of Ethicon, Inc. 
• 
Protocol number 
• 
“For Clinical Trial Use Only” 

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6.1.5 
Pressure Regulators 
Pressure regulators may be supplied by request.  The pressure regulators are commercially available.  They 
will be used according to their intended instructions and are not considered an investigational product.   
 
6.1.6 
Shipping, Handling, and Storage Conditions 
Distribution of EVICEL® to the clinical sites will be performed by a qualified distribution center with proper 
inventory and quality control capabilities once all the necessary documentation and approvals are 
obtained.  For distribution in the EU, a qualified person (QP) release will be done prior to distribution.  
 
The two components of the EVICEL® Kit are frozen, and must be stored at –18°C or colder.  EVICEL® will be 
shipped to each site on dry ice during which the temperature will be monitored continuously.  Once at 
the site, the product will be stored in a freezer at –18°C or colder, according to the product label. 
 
The application devices, tips, and pressure regulators will be shipped and stored at ambient temperature. 
  
6.1.7 
Preparation 
The two frozen components of EVICEL® (BAC2 and Thrombin) must be thawed before use, using one of 
the following methods: 
• 
2-8°C (refrigerator): vials thaw within one day; or 
• 
20-25°C (room temperature): vials thaw within one hour; or 
• 
37°C; vials thaw within ten minutes and should not be left at 37°C for more than 10 
minutes. The temperature must not exceed 37°C. 
 
Thawed, unopened vials can be stored at 2-8°C for up to 30 days. Thawed vials must not be re-frozen, and 
product taken out of the refrigerator should not be returned to the refrigerator. 
 
After thawing, preparation of the product must occur in a sterile surgical field. The two components 
should be drawn into the application device, following directions enclosed in the application device 
package. Both syringes must be filled with equal volumes, and should not contain air bubbles. Selection 
of the appropriate application/accessory tip will be left to the discretion of the surgeon.  
 
6.1.8 
Dose, Route, and Duration of Administration 
For each subject, at least one kit of EVICEL® will be thawed and available for administration prior to 
randomization.  EVICEL® will be applied to cover the entire length of the suture line and the adjacent area 
of the dura to produce a thin, even layer (approx. 1mm thickness). If necessary, a second layer of EVICEL® 
may be applied.  A cure time of 1-2 minutes should be allotted between applications to allow for the clot 
formation and stabilization. The amount of EVICEL® required depends upon the area of tissue to be 
treated and the method of application.  
 
Application can be made by dripping or spraying in accordance with the EVICEL® Investigator Brochure, 
Accessory Tip Directions and Device and Pressure Regulator IFU. 
 
6.2  
DuraSeal® Dural Sealant System 
DuraSeal® will be stored, handled, prepared, and applied according to its label and instructions for use 
(IFU) or package insert. If necessary, a second layer of DuraSeal™ may be applied.    

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6.3 
Investigational Product Dispensation and Accountability 
A dispensing/accountability log will be kept by the designated study personnel containing information on 
the date of administration, subject ID #, quantity of EVICEL® and DuraSeal™ (if applicable) dispensed, 
details of remaining product, and subsequent destruction (if applicable).  The study monitor will verify 
these logs during the course of the study.  The study product will be stored according to the IB or IFU, 
respectively, and be kept in a secured area with access restricted.  Study product is to be used for study 
subjects only.   
 
6.4  
Concomitant Medications 
 
6.4.1 
Documentation of Concomitant Medications 
Indication and start-stop dates of concomitant medications administered from 24 hours prior to surgery 
up to the 60-day follow-up visit will be recorded.  This will include medications that subjects are using 
chronically.  
 
Anesthetics used for the study surgery and over the counter (OTC) drugs will not be recorded as 
concomitant medication (with the exception of prophylactic aspirin and those administered to treat 
adverse events, which should be documented).  Concomitant medications used to treat Adverse Events 
must also be documented, including OTC medications.  Doses and routes of administration are not 
required to be reported.   
 
7. Study Evaluations 
 
7.1 
Study Procedures 
The schedule of events included in the synopsis summarizes the frequency and timing of the study 
procedures.  All assessments will be performed by the investigator or other study personnel with 
delegation of authority.  Data collected for the subject during the study will be recorded in the subject’s 
medical records, and study worksheets/source documents, as appropriate, and transcribed into the eCRF.     
 
7.1.1 
Screening 
Prospective patients will be screened within 30 days prior to surgery. All prospective patients should be 
listed in the screening and enrollment log. Patients screened but not consented or enrolled should be 
recorded with a reason for not enrolling.  Prior to any study specific procedures, subjects will be 
appropriately consented and the consenting process documented.   Subjects (or legally authorized 
representative) will be asked to sign an Informed Consent Form.  Once the Informed Consent Form is 
signed, study related information, including information obtained as part of standard clinical practice, may 
be collected as part of the protocol.   
 
The following tests and activities will be performed or collected at the screening visit.  The timing of these 
activities may occur based on routine hospital practice and may be done up to the day of, but prior to, the 
study surgery: 
• 
Informed consent process 
• 
Allocation of screening number 
• 
Assessment of pre-operative inclusion and exclusion criteria for subject eligibility 
• 
Documentation of demography (e.g. age, ethnic origin) 

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• 
Physical examination, including  documentation of relevant medical and surgical history 
• 
Documentation of smoking status, alcohol consumption, history (family and personal) of 
thromboembolic events 
 
7.1.2 
Baseline  
The following activities/assessments will be done within 24 hours prior to the procedure.  The timing of 
these activities may occur based on routine hospital practice and may overlap with some of the Screening 
(see Section 7.1.1) activities.   
• 
Review of pre-operative inclusion and exclusion criteria to confirm subject pre-operative 
eligibility.  If the subject is no longer eligible, the reason for screen failure will be documented in 
the source documentation and the screening log  
• 
Documentation of concomitant medications as outlined in Section 6.4 
• 
Documentation of any changes in medical history since the screening visit (if done on a separate 
visit from Baseline).  
• 
Laboratory evaluations – samples can be drawn within 7-days prior to the procedure.  Labs taken 
closest to procedure should be used.  
o Electrolyte, blood urea nitrogen (BUN), creatinine 
o Complete blood count (CBC) with differential 
o Liver function tests 
o Serum or urine pregnancy test (if applicable) 
 
 
7.1.3 
Surgical Procedure 
The investigator will use his or her standard surgical techniques for the surgical procedure. Use of a tissue 
based patch is permitted for primary sutured dural closure if a watertight seal can be achieved.  Upon 
completion of the sutured dural repair, the closure will be evaluated for intraoperative CSF leakage with 
a baseline Valsalva maneuver performed to an intra-thoracic pressure between 20-25 cm H2O for 5-10 
seconds. If a spontaneous leak is apparent immediately after dural closure, no Valsalva maneuver will be 
performed.   
 
Subjects who have a CSF leak will be stratified by surgical procedure, posterior fossa or supratentorial 
approach, and then randomized to either EVICEL® or DuraSeal™ in a 1:1 allocation ratio. 
 
EVICEL® and DuraSeal™ will be available in the OR/theatre for administration prior to randomization for 
each subject.  
 
The following activities/assessments will be done during the surgical procedure: 
• 
Review of inclusion and exclusion criteria to confirm intra-operative eligibility.  If the subject is no 
longer eligible, the reason for screen failure will be documented in the source documentation, the 
screening log, and the eCRF. 
• 
Documentation of concomitant medications as outlined in Section 6.4 
• 
Hospital admission date (for overall Length of Stay) 
• 
Operating room/theatre details: 
o Enter and exit time 
o Procedure time (first incision to final closure) 
• 
Surgical approach – posterior fossa or supratentorial 

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• 
Indication for procedure, (e.g. – A-V malformation, Chiari malformation, aneurysm, epilepsy, 
tumor, other) 
o If tumor, tumor type details (e.g. acoustic neuroma, frontal, meningioma, parietal, 
temporal, other) 
• 
Tissue patch details (e.g. autologous/non-autologus), if applicable 
• 
CSF leakage determination (prior to randomization) 
• 
Randomization and treatment details (see below) 
o EVICEL® Treatment (to be captured for each layer applied) 
▪ 
Method of application (spray or drip)  
▪ 
Accessory tips used (if applicable) 
▪ 
Number of layers applied 
▪ 
Total volume applied 
▪ 
EVICEL® units used 
o DuraSeal™ Treatment 
▪ 
Number of layers applied 
▪ 
Total volume applied 
▪ 
DuraSeal™ units used 
• 
Post-treatment Valsalva maneuver details 
o CSF leakage details (if applicable) – breakthrough CSF leakage, delamination, other 
• 
Rescue treatment (if applicable) 
• 
Adverse events from time of application (through follow-up) 
 
7.1.3.1 Subjects Randomized to EVICEL®  
For subjects randomized to receive EVICEL® Fibrin Sealant (Human), a thin layer will be applied to cover 
the entire length of the suture line and the adjacent, including all suture holes.  If necessary, a second 
layer of EVICEL® may be applied. A cure time of 1-2 minutes should be allotted between layers to allow 
for clot formation and stabilization. CSF leakage will be evaluated with the Valsalva maneuver performed 
to an intra-thoracic pressure between 20-25 cm H2O for 5-10 sec.   
 
If a CSF leakage is still apparent a second treatment (up to two layers) with EVICEL® may be applied.  CSF 
leakage will be re-evaluated with the Valsalva maneuver as described above.  If watertight closure is 
achieved for EVICEL® treatment, no further treatment, including the use of onlays, will be allowed. 
 
If watertight closure is not evident after the final Valsalva maneuver, the subject will be deemed a failure 
and surgeon may revert to his/her standard of care for closure, this can include additional treatment with 
EVICEL® if clinically appropriate.  The use of other fibrin sealants is not permitted.     
 
Subjects randomized to EVICEL® may not have their dura  treated with DuraSeal™ Dural Sealant System 
or any other PEG based or fibrin sealants.   
 
Closure of the remaining layers of the surgical site will be performed according to the surgeon’s standard 
practice.   
 
7.1.3.2 Subjects Randomized to DuraSeal™  
For subjects randomized to DuraSeal™, the assigned product will be applied to the entire length of the 
suture line, including all suture holes, according to the manufacturer’s instruction for use. CSF leakage will 

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be evaluated with the Valsalva maneuver performed to an intra-thoracic pressure between 20-25 cm H2O 
for 5-10 seconds.   
 
If a CSF leakage is still apparent, continue treatment with Duraseal™ per manufactures directions. CSF 
leakage will be re-evaluated with the Valsalva maneuver as described above.  If watertight closure is 
achieved for DuraSeal™ treatment, no further treatment, including the use of onlays, will be allowed.   
 
If watertight closure is not evident after the final Valsalva maneuver, the subject will be deemed a failure 
and surgeon may revert to his/her standard of care for closure, this can include additional treatment with 
DuraSeal™, if clinically appropriate.  The use of fibrin sealants is not permitted.     
 
Subjects randomized to DuraSeal™ may not have their dura treated with EVICEL® Fibrin Sealant or any 
other PEG based or fibrin sealants.   
 
Closure of the remaining layers of the surgical site will be performed according to the surgeon’s standard 
practice.   
   
7.1.4 
Post-Surgery through Hospital Discharge 
Concomitant medications and adverse events will be collected throughout the study.  The following 
additional information will also be collected post-surgery through discharge: 
• 
ICU time in days 
• 
Laboratory evaluations – collected within 72 hours prior to discharge (labs taken closest to 
discharge should be used).   
o Electrolyte, blood urea nitrogen (BUN), creatinine 
o Complete blood count (CBC) with differential 
o Liver function tests 
• 
Physical examination (prior to discharge) 
o Surgical site assessment 
o Wound healing assessment 
• 
Hospital discharge date (for overall Length of Stay) 
 
7.1.5 
30-Day Follow-up (-/+7 days) 
The following information will be collected at the clinical follow-up approximately 30 days following 
surgery: 
• 
Adverse events 
• 
Changes in concomitant medications 
• 
Laboratory evaluations 
o Electrolyte, blood urea nitrogen (BUN), creatinine 
o Complete blood count (CBC) with differential 
o Liver function tests 
• 
Physical examination 
o Surgical site assessment 
o Wound healing assessment 
 
7.1.6 
60-Day Follow-up (-/+14 days) 

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The 60-Day follow-up visit may take place in-person or over the phone. The following information will be 
collected at the clinical follow-up approximately 60 days following surgery: 
• 
Adverse events, including occurrence of CSF Leak 
• 
Changes in concomitant medications 
 
7.2 
Procedures for Handling Biological Samples 
 
7.2.1 
Laboratory Tests 
All laboratory investigations will be performed at the local hospital laboratory.  The volume of blood to be 
taken will be determined according to the standard practices of each hospital.  The normal reference 
ranges must be provided to Sponsor. Laboratory accreditation certificates must be verified. 
 
7.3 
Premature Withdrawal of Subjects from the Study 
All randomized subjects should be encouraged to remain in the study until they have completed all follow-
up visits.  Subjects may discontinue participation in the study at any time and for any reason.  However, if 
the subject decides to discontinue participation in the study, the reason must be documented when 
possible.  Reasons for early withdrawal include, but are not limited to: 
• 
Death; 
• 
Consent withdrawn by the subject; 
• 
Subject refusal to complete study visits and/or procedures; 
• 
Withdrawals due to adverse events 
• 
Lost to follow-up: a certified letter, unless restricted by per local requirements, will be sent to the 
subject at their last known address, after a minimum of three attempts to reach the subject by 
telephone have failed.  If communication via certified letter is unsuccessful, the subject will be 
considered lost to follow-up.  
 
Subjects who discontinue from the study prematurely will not be replaced. 
 
8. Statistical Methods 
The Data Management and Biostatistics groups of Clinical Development at ETHICON will be responsible 
for the overall analysis of data from this protocol. The detailed Statistical Analysis Plan (SAP) will be based 
on and will supplement the statistical design and analysis described in this section. 
 
8.1 
Sample Size Determination 
The number of randomized subjects required for this trial is 202 subjects (101 per treatment arm) from 
centers in North America, Europe, and Asia-Pacific.  There will be approximately 25 global sites. In order 
to account for potential missing follow-up information (drop-outs), approximately 230 subjects will be 
enrolled. At least 60 subjects undergoing posterior fossa procedures will be randomized. 
 
Two hundred and two (202) evaluable subjects (101 per arm) will achieve 90% power to detect a non-
inferiority margin difference in group proportions of -0.10.  The proportion of successes in the Control 
group is 0.95. The proportion of successes in EVICEL® group is assumed to be 0.85 under the null 
hypothesis of inferiority.  The power was computed for the case when the actual proportion of successes 
in the EVICEL® group is 0.95.  The one-sided significance level of the test is 0.025. 
 

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If the lower limit of the one-sided 97.5% confidence interval for Δ is greater than -0.10, then it will be 
concluded that Experimental is considered to be non-inferior to Control.  
 
8.2 
Data Analysis 
The categorical data will be summarized descriptively by frequencies along with associated percentages 
for each group. The continuous variables will be summarized descriptively by number of subjects, mean, 
standard deviation, minimum, and maximum for each group. A two-sided 5% significance level will be 
used for any statistical tests, unless otherwise specified in the protocol. 
 
8.2.1 
Analysis Sets 
There will be three analysis sets defined: 
• 
Evaluable set (or per protocol set) consists of all ITT subjects who have no major protocol 
violations. 
• 
Intent-to-treat set (ITT or full analysis set) consists of all randomized subjects.  
• 
Safety set consists of all subjects who receive a study treatment. 
 
The primary endpoint analysis will be based on the evaluable set.16  Surgical procedure (posterior fossa or 
supratentorial approach) will be utilized as stratification factor in the overall analysis.  
 
Major protocol violations are violations that have an impact on the primary endpoint, or that have an 
impact on the randomization assignment.  These will be determined prior to database lock.  
 
8.3 
Effectiveness 
 
8.3.1 
Effectiveness Variables 
The primary endpoint is the proportion of subjects that do not have a CSF leak during surgery and up to 
the 30-day (-/+7) post-operative period.   A subject is declared as a success when the following conditions 
are met: 
• 
absence of intra-operative CSF leak following Valsalva maneuver, and  
• 
absence of CSF leak or pseudomeningocele in the surgical area during the 30-day follow-up 
period. 
  
The primary effectiveness parameter will be analyzed using the ITT and Per-Protocol analysis sets.  The 
Per-Protocol analysis will be considered primary effectiveness analysis.  
 
There are no secondary effectiveness endpoints for this study.  
 
8.3.2 
Methods of Analysis 
The statistical hypothesis for testing the treatment difference is presented as follows: 
 
▪ 
H0: Δ ≤ -0.10 tested against the alternative hypothesis  
▪ 
Ha: Δ > -0.10.  
 
where: 
▪ 
Δ is the difference between the success rates of Experimental and Control 
(Experimental minus Control) 

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▪ 
-0.10 is the non-inferiority difference  
▪ 
The assumed proportion of successes for Control is 0.95. 
 
PC is the proportion of success in DuraSeal™ Control subjects and PE is the proportion of success in EVICEL® 
subjects. 
 
Two hundred and two (202) evaluable subjects (101 per arm) will achieve 90% power to detect a non-
inferiority margin difference in group proportions of -0.10.  The proportion of successes in the Control 
group is 0.95. The proportion of successes in EVICEL® group is assumed to be 0.85 under the null 
hypothesis of inferiority.  The power was computed for the case when the actual proportion of successes 
in the EVICEL® group is 0.95. 6,14    The one-sided significance level of the test is 0.025. 
 
If the lower limit of the one-sided 97.5% confidence interval for Δ is greater than -0.10, then it will be 
concluded that Experimental is considered to be non-inferior to Control.  
 
For the primary endpoint, the comparability between the surgical procedure (posterior fossa or 
supratentorial approach) subgroups will be evaluated using a logistic regression analysis, with 
success/failure for primary endpoint as dependent variable and with surgical procedure, treatment group 
and interaction between surgical procedure and treatment group as independent variables included in 
the model.  The interaction term will be considered significant at 0.15 significance level in the logistic 
regression.  In addition, the primary endpoint will be compared between treatment groups using a CMH 
Chi-square test adjusting for the surgical procedure.   
 
8.4 
Safety 
 
8.4.1 
Safety Variables/Criteria 
The following will be summarized using the Safety Set: 
• 
Incidence of adverse events 
• 
Laboratory tests 
• 
Incidence of surgical site infections (SSI) according to NNIS definition and CDC classification within 
30 days (-/+ 7) post-operatively. 
• 
Incidence of Intra-operative CSF leakage following final Valsalva maneuver. 
• 
Incidence of post-operative CSF leakage within 30 days (-/+ 7) post-operatively. 
• 
Incidence of post-operative CSF leakage within 60 (-/+ 14) days post-operatively. 
 
8.4.2 
Methods of Analysis 
Adverse events will be summarized descriptively using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.  Laboratory evaluations (baseline and post-surgery samples) will be summarized 
in SI units.  No inferential statistical analysis will be performed for the safety endpoints. 
 
8.5  
Handling of Missing Data 
The primary analysis will be the Per-Protocol analysis.  It is not anticipated that there will be any data 
missing for treated subjects for the primary endpoint, but if there is, sensitivity analyses will be performed 
considering missing data as failures, successes, and as worst-case, with missing data for the EVICEL® group 
considered as failures and missing data for the DuraSeal™ group considered as successes. 
 

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8.6  
Health Economics 
Health Economic data will be collected in this evaluation including products used for this rescue treatment 
(if applicable), Length of Stay, Days in ICU, and OR times.  These data points will be analyzed descriptively.   
 
9. Safety  
 
9.1  
Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  An adverse event (AE, also referred to as an adverse experience) 
can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
a drug, without judgment about causality. 
 
9.2  
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that, in the view of either the 
Investigator or the sponsor, it: 
• 
Results in death; 
• 
Is considered to be life-threatening; 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent of significant disability, incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• 
Results in congenital anomaly or birth defect; 
• 
Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization.  The event may be considered serious when, based on appropriate medical 
judgment, it may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   
 
Life threatening refers to an event in which, in the view of the investigator or sponsor, the subject was at 
immediate risk of death at the time of the event; it does not include an event that might have caused 
death if it were more severe.  All other events that are considered medically serious by the investigator 
should also be reported.  
 
Hospitalization is defined as the patient being admitted and hospitalized for more than 24 hours.  Any 
event requiring inpatient hospitalization (or prolongation of hospitalization) that occurs during the course 
of a subject’s participation in a clinical study must be reported as a SAE, except hospitalizations for the 
following: 
• 
Social reasons in absence of an AE; 
• 
Surgery or procedure planned before entry into the study (must be documented in the case report 
form) 
• 
Emergency room visits unless the subject is admitted. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the AE.  Reasonable possibility means there is evidence to suggest a causal relationship 
between the drug and the AE.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction (an AE caused by a drug).   
 

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Unexpected adverse event or unexpected suspected adverse reaction.  An AE or suspected adverse 
reaction is considered ‘unexpected’ if it is not listed in the investigator brochure or in the product labeling 
(USPI, SmPC etc.,) or is not listed at the specificity or severity that has been observed.  ‘Unexpected’ also 
refers to events that are mentioned as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular 
drug under investigation.   
 
Suspected, unexpected, serious adverse drug reactions (SUSAR) are serious adverse drug reactions that 
are suspected of being related to the drug and are unexpected.   
 
9.3  
Relationship 
The relationship of the product to an AE must be determined using the following classification: 
• 
None: No relationship with investigational product. 
• 
Possible: Reasonable possibility that the event was caused by the investigational product. 
• 
Related: The event was certainly or probably caused by the investigational product.   
 
The relationship of the surgical procedure to an AE must be determined using the following classification: 
• 
None: No relationship to the surgical procedure. 
• 
Possible: Reasonable possibility that the event was caused by the surgical procedure. 
• 
Related: The event was certainly or probably caused by the surgical procedure.   
 
9.4  
Severity 
The following definitions should be used to determine the severity rating of AEs: 
• 
Mild: Awareness of signs of symptoms, but these are easily tolerated and are transient and mildly 
irritating only.   There is no loss time from normal activities and symptoms do not require 
medication or medical evaluation.   
• 
Moderate: Discomfort enough to cause interference with usual activities or require therapeutic 
intervention, such as concomitant medication. 
• 
Severe: Incapacity with inability to work or do usual activities.   
 
9.5  
Collection of Adverse Events 
AEs will be recorded as they are reported, whether spontaneously, volunteered, or in response to 
questioning about well-being.  AEs will be collected from the start of randomization during the procedure, 
through the hospital admission, and until completion of the 60-day follow-up visit.   
 
All AEs will be documented in the subject’s source document (e.g. medical records) and electronic case 
report forms.  All AEs will be followed until completion of the 60-day follow-up visit or until a stable 
resolution, whichever is sooner.    
 
The investigator may also need to consider whether an event is attributable to the investigational product, 
based on insufficiencies or inadequacies in the instructions for use/ IB or as a result of user error.  The 
Investigator must contact the Sponsor should this occur. 
 
9.6  
Adverse Event Reporting 

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It is a requirement that the Investigator promptly report all SAEs (irrespective of relationship to the study 
product) to PAREXEL, the safety monitoring CRO, as soon as possible, but no later than 24 hours after 
becoming aware of the event occurring.  SAE reports must be communicated as follows: 
 
If North America: 
 
PAREXEL International 
1 Federal Street 
Billerica, MA 01821 
United States 
Phone: +1-919-294-5268 
Fax: +1-919-544-3572 
Email: NorthAmerica_Medical@parexel.com 
If Europe or Australia/New Zealand: 
 
PAREXEL International 
Haus 11 
Am Bahnof Westend 11 – 14059 
Berlin, Germany 
Phone: +49 30 30 685 274 
Fax: +49 30 315118 7777 
Email: Medical_Berlin@parexel.com 
 
 
 
The Sponsor will report any SUSARs to the regulatory authorities and IRBs/Ethics Committees within the 
required timeframes of 7 calendar days for fatal or life-threatening SUSARs and 15 calendar days for all 
other SUSARs.   
 
9.7 
Device Complaint Handling 
If a device failure occurs with the EVICEL® applicator device, accessory tips or pressure regulator, a Device 
Complaint Form must be completed and faxed immediately (within 24 hours) to Ethicon at 908-218-5490.  
Included are those complaints related to the applicator devices, accessory tips or pressure regulator that 
have been open but unused (e.g, sterile container was opened inadvertently).  Upon receipt of the 
Complaint Form, instructions will be given on handling/returning of the defective device.  
 
Complaints related to DuraSeal™ should be reported to the manufacturer according to the Package Insert.   
 
10. 
Regulatory Obligations 
 
10.1  Informed Consent 
Prior to participation, Informed Consent will be appropriately obtained and documented.  The study 
procedures and any known or likely risks will be explained to the subjects or subject’s legal representative, 
by the Investigator or individuals delegated the authority by the Principal Investigator.   
 
An IRB/EC approved Informed Consent Form (ICF) will be provided containing all the required information 
per ICH guidelines and applicable regional requirements.  Any questions will be answered and the subject 
will then be given sufficient time to consider their participation in the study before signing a consent form.  
Subjects should receive a signed and dated copy of the ICF. 
 
The Investigator (or designee) will explain that the subjects are completely free to refuse to enter the 
study or to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
 
Each subject will be informed that his/her source medical records may be checked by representatives 
from the Sponsor or from a regulatory agency, in accordance with applicable regulations.  However, they 

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should be made aware that all information will be treated with confidentiality and a subject ID number 
will identify them.   
 
10.2  Institutional Review Boards/Ethics Committees 
The Investigator must submit the protocol, protocol amendments, informed consent forms, any subject 
information sheets, advertising materials and other applicable documents to the appropriate Institutional 
Review Board (IRB) or Ethics Committee (EC) according to local requirements.  Approval from the IRB/EC 
must be obtained prior to starting any study-related procedures.  Investigational product will not be 
shipped to a site until written IRB/EC authorization has been received by the sponsor or its representative.  
 
10.3  Data Management 
 
10.3.1 Electronic Data Capture (EDC) 
An EDC system will be utilized by trial site personnel to transfer trial data from source records (medical 
records and/or source document worksheets) onto common eCRFs (electronic Case Report Forms).  This 
system is a web-based, secure electronic software application.  This system was designed and is developed 
and maintained by Medidata in a manner that is compliant with national and international GCP data 
protection/data privacy and electronic record/electronic signature (e.g., 21 CFR Part 11) regulatory 
requirements.  The EDC system will be used to facilitate the collection of all trial data at the site.  
Designated site personnel will be responsible for entering subject data into the EDC system.  All external 
and Sponsor internal users will be trained on the EDC application at a level dependent on their planned 
function.  An EDC digital User Manual will be available under the help menu within the Medidata® Rave 
website to assist in the collection and entry of source data into the electronic casebook.  A 24/7/365 Help 
Desk Support line staffed by the outsourced vendor will be available to respond to site and monitor 
questions.   
 
10.3.2 Data Collection 
The Investigator must maintain required records on all study subjects.  Data for this study will be recorded 
in the subjects medical records, study-specific worksheets, and on eCRFs provided by the Sponsor in 
accordance with the parameters set forth in ICH Topic E6 for GCP (1.5.96) Guidelines – Responsibilities of 
Sponsor, Monitor, and Investigator with 21 CFR Part 312 and applicable regional requirements.   All data 
on the eCRFs should be recorded from appropriate source documentation.   
 
Each EDC eCRF will be completed by the Principal Investigator (PI) or PI’s designee.  Every effort should be 
made to respond to all monitoring and/or data management questions on each eCRF as completion of the 
data is required by the protocol.  A unique ID number will identify each subject.  A unique ID number will 
be visible on each eCRF.  At no time should the subject name appear on the eCRFs.  Complete data is 
needed in order to provide statistical analysis for each subject.  All data should be recorded accurately 
and completely. The investigator is responsible for reviewing and approving each completed eCRF.  
Assurance of overall review and approval will be documented by the Investigator electronically signing 
each subject’s electronic casebook.   
 
10.3.3 Data Correction 
Required data corrections to eCRFs will be prompted via automated electronic edit checks and/or queries 
manually created by sponsor reviewers.  The change(s), individual making the change(s), and time the 
change(s) were made to the eCRFs will be automatically captured in the audit trail within Medidata® Rave.   

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10.3.4 Source Documentation 
Investigators must keep accurate separate records (other than the eCRFs) of all subjects' visits, being sure 
to include all pertinent study related information.  A statement should be made indicating that the 
subjects have been enrolled in Protocol and have provided written Informed Consent.  Any and all side 
effects and adverse events must be thoroughly documented.  Results of any diagnostic tests conducted 
during the study should also be included in the source documentation.  Telephone conversations with the 
subjects concerning the study must also be recorded. 
 
The Investigator is responsible for maintaining a Subject Identification Log, which will include all subjects 
who provided informed consent (i.e. to include randomized subjects and screening failures). This 
confidential subject identification # provides the link between named subject source records in the subject 
file and anonymous eCRF data provided to SPONSOR. 
 
The Investigator must retain all study related documentation until at least two years after the final 
marketing application is approved, or at least two years have elapsed since the formal discontinuation of 
the clinical study.   If regional regulations differ, the investigator must retain study related documents by 
whichever is longer. Study documents should not be destroyed without prior written agreement between 
the Investigator and SPONSOR.  The sponsor must be notified if the Investigator wishes to assign the study 
records to another party, or move them to another location.  
 
10.4  Study Monitoring and Auditing 
This study will be monitored at all stages of its development by the clinical research personnel employed 
by the Sponsor or its representative.  Monitoring will include site visits, review of eCRF data, and 
telephone communication to assure that the investigation is conducted according to protocol and in order 
to comply with guidelines of Good Clinical Practice.  On-site review of eCRFs will include a review of forms 
for completeness and clarity, and consistency with source documents available for each subject.  Note 
that a variety of original documents, data, and records will be considered as source documents in this 
trial.  
 
The study may be subject to audit by the sponsor or by regulatory authorities.  If such an audit occurs, the 
Investigator must agree to allow access to required subject records.  By signing this protocol, the 
Investigator grants permission to personnel from the Sponsor, its representatives, and appropriate 
regulatory authorities for on-site monitoring of all appropriate study documentation.   
 
 
10.5  Sponsor Obligations 
 
10.5.1 Monitoring 
The monitor or designee will contact and visit the Investigator regularly and must be allowed to monitor 
the trial.  The monitor will visit as soon as possible following enrollment for the first subject and at regular 
intervals during the study (approximately every four to six weeks) as deemed necessary.  It will be 
monitor’s responsibility to inspect study records at regular intervals throughout the study, to verify 
adherence to the protocol and the completeness, correctness and accuracy of all eCRF entries, and ensure 
patient protection.   
 

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10.5.2 Regulatory Requirements 
This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
 
10.5.3 Liability and Insurance Conditions 
In case of any damage or injury occurring to a subject in association with the trial medication, Sponsor has 
product liability insurance.  A copy of this policy is on file at the Sponsor.   
 
11. 
Investigator Obligations 
The investigator is responsible for ensuring that the study is performed in accordance with the protocol, 
current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and country-specific 
requirements. 
 
11.1 Financial Disclosure 
The investigator is responsible for updating the Sponsor if there are any changes that would affect their 
Financial Disclosure during the conduct of the study.   
 
11.2 Audit and Inspection 
The Investigator (and head of institution, if required by regional regulations) will make source data and 
documents for this study available to an appropriately qualified quality assurance auditor mandated by 
Sponsor or to regulatory authority inspectors, after appropriate notification. 
 
11.3 Confidentiality of Subject Records 
The Investigator will ensure that the subjects’ anonymity will be maintained.  On eCRFs or other study 
documents submitted to Sponsor, subjects will not be identified by their names, but by an identification 
code that may consist of a combination of the site, and randomization or subject ID number.  Documents 
not for submission to Sponsor, i.e. Subject Identification Log and original subjects’ informed consent 
forms, will be maintained in the Investigator Site File. 
 
11.4  Record Retention 
The Investigator must retain all study related documentation until at least 2-years after the final indication 
is approved, or at least 2-years have elapsed since the formal discontinuation of the clinical study.   If 
regional regulations differ, the investigator must retain study related documents by whichever is longer. 
Study documents should not be destroyed without prior written agreement between the Investigator and 
Sponsor.  The Sponsor must be notified if the Investigator wished to assign the study records to another 
party or move the records to another location.  The Investigator will take measure to prevent accidental 
or premature destruction of these documents.   
 
12. 
Changes to the Protocol  
 
12.1 Protocol Amendments 
All protocol amendments are required to be submitted for information/consideration to the regulatory 
authorities, IRBs/ECs.  Documentation of approval is required before implementation of amendments.   
 
12.2 Clinical Trial Termination 

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Both the Investigator and Sponsor reserve the right to terminate the study at any time.  Should this be 
necessary, the procedures will be arranged on an individual study basis after review and consultation with 
both parties.  In terminating the study, Sponsor and the Investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interests and safety.   
 
12.3  Use of Information and Publication 
All information concerning study data, Ethicon’s operations, patent application, formulas, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor or Sponsor designee 
to the Investigator and not previously published is considered confidential and remains the sole property 
of Ethicon.  The Investigator agrees to use this information only to accomplish this study and will not use 
it for other purposes without the Sponsor’s written consent.   
 
The Investigator understands that the information developed in the clinical study will be used by Ethicon 
in connection with continued development of the EVICEL® Fibrin Sealant and thus may be disclosed as 
required to other clinical investigators or government regulatory agencies.  To permit the information 
derived from the clinical studies to be used, the Investigator is obligated to provide the Sponsor with all 
data obtained in the study.    
 
Any publication or other public presentation of results from this study requires prior review by Ethicon, 
Inc.  Draft abstracts, manuscripts, and materials for presentation at scientific meetings must be sent to 
the Sponsor at least 30 working days prior to abstract or other relevant submission deadlines.  Authorship 
of publications resulting from this study will be based on generally accepted criteria for major medical 
journals. 
 
The Investigator understands not to use the name of Johnson & Johnson (J&J), Ethicon, ETHICON™ 
Biosurgery, Fibrin Sealant (EVICEL®), EVICEL® Fibrin Sealant, or any of its employees in any publicity, news 
release, or other public announcement, written or oral, whether to the public, press, or otherwise, related 
to this protocol, to any amendment hereto, or to the performance hereunder, without the prior consent 
of Ethicon, Inc.   
 
 
 

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13. 
Contact Details 
 
SPONSOR  
Clinical Development and Medical Affairs 
MEDICAL DIRECTOR 
Richard Kocharian, MD, PhD 
Ethicon Biosurgery 
ETHICON, Inc. 
P.O. Box 151, Route 22 West 
Somerville, NJ 08876-0151, US 
Tel: +908-218-2013 
Fax: +1-908-685-3706 
SENIOR DIRECTOR, 
CLINICAL DEVELOPMENT 
Jonathan Batiller 
ETHICON, Inc. 
P.O. Box 151, Route 22 West 
Somerville, NJ 08876-0151, US 
Tel: +1-908-218-2492  
Fax: +1-908-218-5490 
ASSOCIATE DIRECTOR, 
CLINICAL DEVELOPMENT 
Nicolas Aguirre 
ETHICON, Inc. 
P.O. Box 151, Route 22 West 
Somerville, NJ 08876-0151 US 
Tel: +1-908-218-2933 
Fax: +1-908-218-5490 
GLOBAL PROJECT 
MANAGER 
Kimberly Eason 
ETHICON, Inc. 
P.O. Box 151, Route 22 West 
Somerville, NJ 08876-0151 US 
Tel: +1-908-218-3118 
Fax: +1-908-218-5490 
REGIONAL PROJECT 
MANAGER (NORTH 
AMERICA) 
Cristina Seltzer 
ETHICON, Inc. 
P.O. Box 151, Route 22 West 
Somerville, NJ 08876-0151 US 
Tel: +1-908-218-2611 
Fax: +1-908-218-5490 
REGIONAL PROJECT 
MANAGER (EUROPE) 
Val Jarvis Evans 
Johnson & Johnson Medical Ltd 
Simpson Parkway 
Kirkton Campus 
Livingston, EH54 0AB 
UNITED KINGDOM 
Tel: +44 1509 412374 
Fax: +44 1509 412374 
REGIONAL PROJECT 
MANAGER 
(AUSTRALIA/NEW 
ZEALAND) 
Tania Betts 
Johnson & Johnson medical Pty Ltd 
1-5 Khartoum Road 
North Ryde NSW 2113 
AUSTRALIA 
Tel: +61 2 9815 3365  
Fax: +61 2 9815 4050 
 
 
 
 
 

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14. 
References 
 
1. Walcott BP et al. Incidence of cerebrospinal fluid leak following petrosectomy and analysis of 
avoidance techniques.  J Clin neuroSci 2012 Jan;19(1):92-4 
2. Horowitz G et al. Association between Cerebrospinal Fluid Leak and Meningitis after Skull Base 
Surgery. Otolaryngol Head Neck Surg. 2011 Oct;145(4):689-93. 
3. Kono Y et al. One Thousand Endoscopic Skull Base Surgical Procedures Demystifying the Infection 
Potential: Incidence and Description of Postoperative Meningitis and Brain Abscesses Infect Control 
Hosp Epidemiol. 2011 Jan;32(1):77-83. 
4. Shaffrey C. et al. Neurosurgical Applications of Fibrin Glue: Augmentation of Dural Closure in 134 
Patients. Neurosurgery. 1990 Feburary: 26:207-210. 
5. Kassam A et al. Use of Tisseel Fibrin Sealant in Neurosurgical Procedures: Incidence Cost Benefit 
Analysis in a Restrospective Study. Neurosurgery. 2003 May:53(5): 1102-1105. 
6. Green A. et al. A multicentre, prospective, randomized, controlled study to evaluate the use of a 
fibrin sealant as an adjunct to sutured dural repair. British Journal of Neurosurgery. 2014; Early 
Online 1-7. 
7. Spotntiz W. Fibrin Sealant: Past, Present, and Future: A Brief Review. World J Surg. 2010. 34:632–634 
8. EVICEL® Fibrin Sealant (Human). Prescribing Information. Article No. 80FZ00M3-4. Issued: 01/2014. 
Omrix Biopharmaceuticals Ltd. 
9. EVICEL® Fibrin Sealant (Human). Summary of Product Characteristics. Omrix Biopharmaceuticals N.V. 
10. Fischer C.P. Et al. A Randomized Trial of Aprotinin-Free Fibrin Sealant Versus Absorbable Hemostat. 
CLIN APPL THROMB HEMOST 2011 17: 572 
11. Schwartz M. Comparison of a New Fibrin Sealant With Standard Topical Hemostatic Agents. Arch 
Surg. 2004;139:1148-1154 
12. Chalmers RTA. Et al. Randomized clinical trial of tranexamic acid-free fibrin sealant during vascular 
surgical procedures. British Journal of Surgery 2010; 97: 1784–1789 
13. Dhillon S. Fibrin Sealant  (Evicle® [Quixil®/Crosseal™]) A Review of its Use as Supportive Treatment 
for Haemostasis in Surgery. Drugs 2011; 71 (14): 1893-1915 
14. DuraSeal Sealant System. Instructions for Use (United States). REF: 20 - 2050 / REF: 20 - 2010. LCN 
80-2005-151 Rev B. Confluent Surgical.   
15. DuraSeal Sealant System. Instructions for Use (for products sold outside the United States). REF: DS 
– D- 5005 LCN 
16. HyperBranch Medical Technology, Inc; Safety and Effectiveness of the Adherus Dural Sealant System 
When Used as a Dural Sealant in Cranial Procedures. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). cited date: August 27, 2014. Available from: 
http://clinicaltrials.gov/ct2/show/NCT01158378  NLM Identifier: NCT01158378. 
 
 
 

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Appendix I: CDC/NHSN Criteria for Defining a Surgical Site Infection (SSI) 
 
Superficial Incisional SSI 
Infections occur within 30 days after the operation and infection involves only skin or subcutaneous 
tissue of the incision and at least one of the following: 
1. Purulent drainage, with or without laboratory confirmation, from the superficial incision. 
2. Organisms isolated from an aseptically obtained culture or fluid or tissue from the superficial 
incision. 
3. At least one of the following signs or symptoms of infection: pain or tenderness, localized 
swelling, redness, or heat and superficial incision is deliberately open by surgeon, unless incision 
is culture-negative. 
4. Diagnosis of superficial incisional SSI by the surgeon or attending physician. 
 
Do not report the following conditions as SSI: 
1. Stitch abscess (minimal inflammation and discharge confined to the points of suture 
penetration. 
2. Infection of an episiotomy or newborn circumcision site. 
3. Infected burn wound. 
4. Incisional SSI that extends into the fascial and muscle layers (see deep incisional SSI). 
Note: Specific criteria are used for identifying infected episiotomy and circumcision site and burn 
wounds. 
 
Deep Incisional SSI 
Infections occurs within 30 days after the operation if no implant is left in place or within 1 year if 
implant is in place and the infection appears to be related to the operation and infection involves deep 
soft tissues (e.g., fascial and muscles layers) of the incision and at least one of the following: 
1. Purulent drainage from the deep incision but not from the organ/space component of the 
surgical site. 
2. A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient 
has at least one of the following signs or symptoms: fever (>38°C), localized pain, or tenderness, 
unless site is culture-negative. 
3. An abscess or other evidence of infection involving the deep incision is found on direct 
examination, during reoperation, or by histopathologic or radiologic examination. 
4. Diagnosis of a deep incisional SSI by a surgeon or attending physician. 
Notes: 
1. Report infection that involves both superficial and deep incisional sites as deep incisional SSI. 
2. Report organ/space SSI that drains through the incision as a deep incisional SSI. 
 
Organ/space SSI 
Infections occurs within 30 days after the operation if no implant is left in place or within 1 year if 
implant is in place and the infection appears to be related to the operation and infection involves any 
part of the anatomy (e.g., organs or spaces) other than the incision, which was opened or manipulated 
during an operation and at least one of the following: 
1. Purulent drainage from a drain that is placed through a stab wound into the organ space. 
2. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space. 

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3. An abscess or other evidence of infection involving the organ/space that is found on direct 
examination, during reoperation, or by histological or radiologic examination. 
4. Diagnosis of an organ/space SSI by a surgeon or attending physician. 
 
 

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Version: Amendment 3 – 16 May 2016 
 
EudraCT number 2014-003954-15 
 
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Appendix II: U.S. Center for Disease Control (CDC) Guideline for 
Prevention of SSI Surgical Wound Classification 
 
CLASS I/CLEAN: 
An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, 
genital and urinary tracts are not entered.  Clean wounds are primarily closed and, if necessary, drained 
with closed drainage. Operative incisional wounds that follow non-penetrating (blunt) trauma should be 
included in this category if they meet these criteria. 
 
CLASS II/CLEAN-CONTAMINATED: 
An operative wound in which the respiratory, alimentary, genital and urinary tract is entered under 
controlled conditions and without unusual contamination.  Specifically, operations involving the biliary 
tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection 
or major break in technique is encountered. 
 
CLASS III/CONTAMINATED: 
Open, fresh, accidental wounds, operations with major breaks in sterile technique or gross spillage from 
the gastrointestinal tract, and incisions in which acute, nonpurulent inflammation is encountered. 
 
CLASS IV/DIRTY OR INFECTED: 
Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or 
perforated viscera. This definition suggests that the organisms causing postoperative infection were 
present in the operative field before the operation.