Clinical trial NCT02891070
Conditions: Cerebrospinal Fluid Leak
Keywords: Cranial Surgery Cerebrospinal Fluid Leak Tisseel
Sponsor: Baxter Healthcare Corporation
Start date: 2016-10-11; Completion date: 2018-08-22
Enrollment: 224 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the safety and efficacy of FS VH S/D 500 s-apr for use as an adjunct to sutured dural repair in cranial surgery.

Detailed description:

Arms: arm 1: FS VH S/D 500 s-apr (Tisseel), single use treatment, intraoperative arm 2: DuraSeal Dural Sealant, single use treatment, intraoperative
Interventions: intervention 1: FS VH S/D 500 s-apr intervention 2: DuraSeal Dural Sealant
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol: 3599-001 
Study Title: 
A Randomised Controlled Study to Evaluate the Efficacy and Safety of 
Fibrin Sealant, Vapour Heated, Solvent/Detergent Treated 
(FS VH S/D 500 s-apr) Compared to DuraSeal Dural Sealant as an Adjunct 
to Sutured Dural Repair in Cranial Surgery. 
Study Number: 
3599-001 
Study Phase: 
Phase 3 
Product Name: 
Fibrin sealant, vapour heated, solvent/detergent, 500 IU/mL thrombin, 
synthetic aprotinin, frozen (referred to as FS VH S/D 500 s-apr in this 
protocol) 
IND Number: 
013204 
EudraCT Number 
2015-005535-40 
Indication: 
The use of FS VH S/D 500 s-apr as an adjunct to suture repair sealing in 
dura mater closure 
Investigators: 
Multicenter study 
Sponsor: 
Baxter Healthcare Corporation 
One Baxter Parkway  
Deerfield, Illinois 60015, USA 
Sponsor Contact: 
Baxter Healthcare Corporation 
Clinical & HEOR, Global Science & Technology 
Holger-Crafoord-Straße 26 
72379 Hechingen, Germany 
Phone: 
Sponsor’s EU Legal 
Representative: 
Baxter R&D Europe SPRL 
Boulevard René Branquart 80 
7860 Lessines, Belgium 
Medical Monitor: 
Baxter Healthcare Corporation 
Clinical & HEOR, Global Science & Technology 
25212 W. IL. Route 120, RTL-10 
Round Lake, Illinois 60073, USA 
ClinicalTrials.gov Identifier: NCT02891070




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SYNOPSIS 
Sponsor: 
Baxter Healthcare Corporation 
Name of Finished Product: 
Fibrin sealant, vapour heated, solvent/detergent, 500 IU/mL thrombin, synthetic aprotinin, frozen 
(referred to as FS VH S/D 500 s-apr in this synopsis). 
Name of Active Ingredient: 
Test product: Fibrinogen (human), thrombin (human), aprotinin (synthetic), and calcium chloride. 
Control device: Polyethylene glycol (PEG) ester solution, and trilysine amine solution. 
Study Title: 
A Randomised Controlled Study to Evaluate the Efficacy and Safety of Fibrin Sealant, Vapour Heated, 
Solvent/Detergent Treated (FS VH S/D 500 s-apr) Compared to DuraSeal Dural Sealant as an Adjunct to 
Sutured Dural Repair in Cranial Surgery. 
Study Number: 
3599-001 
Study Phase: Phase 3  
Primary Objective:  
To evaluate the efficacy of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as an adjunct to 
sutured dural closure. 
Secondary Objective: 
To evaluate the safety of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as an adjunct to 
sutured dural closure.  
Study Design: 
This study is a Phase 3, prospective, controlled, randomised, single-blind (patient), multicenter study to 
evaluate the safety and efficacy of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as an 
adjunct to sutured dural closure in a total of 202 evaluable patients undergoing elective cranial surgery 
for the treatment of a pathological condition (eg, benign/malignant tumours, vascular malformations, or 
Chiari type 1 malformations) specifically located in the posterior fossa (PF) or supratentorial (ST) 
regions. 
Eligible patients will sign an informed consent (IC), and undergo elective cranial surgery of the PF or ST 
region with either craniotomy or craniectomy with planned durotomy. During the surgery, the patients 
will be evaluated according to intra-operative inclusion/exclusion criteria for further eligibility. If 
eligible, the patients will be evaluated upon completion of the primary suturing of the dura (with or 
without non-autologous duraplasty or autologous tissue). Only if intra-operative cerebrospinal fluid 
(CSF) leak is confirmed (spontaneous CSF leak or CSF leak after Valsalva manoeuvre; 25 cm H2O for 
up to 5 - 10 seconds), the patient will be randomised to treatment with either FS VH S/D 500 s-apr or 
DuraSeal Dural Sealant (control) in a 1:1 allocation ratio stratified by center and surgical regions (PF or 
ST). After treatment, a final assessment for intra-operative CSF leak (spontaneous CSF leak or CSF leak 
after Valsalva manoeuvre) will be conducted to evaluate the intra-operative watertight dura closure.  
Two applications of the study products are allowed. In the event that 2 applications are used, the 
Valsalva manoeuvre must be repeated. In the case of continuous intra-operative CSF leak at the final 
assessment, a rescue therapy for sealing any CSF leaks may be applied according to the surgeon’s 
choice/institutional practice (eg, other fibrin sealants [FSs] except FS VH S/D 500 s-apr or DuraSeal 
Dural Sealant). 
Study Population:  
Approximately 476 patients will be screened in order to randomise approximately 224 patients (with a 
minimal number of 56 PF procedures) and have 202 evaluable patients age ≥18 years, both genders, to 


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undergo elective craniotomy/craniectomy for pathological processes in the PF or ST region (eg, benign 
or malignant tumours, vascular malformation, or Chiari type 1 malformations) and who were 
demonstrated to have persistent CSF leakage following the completion of primary closure of the dural 
incision will be enrolled in this study. 
The study will be conducted in 4 countries (United States, Spain, Germany, and Czech Republic). 
Additional countries may be involved in the trial. 
Test Product and Dose:  
FS VH S/D 500 s-apr frozen 4 mL syringe 
Mode of administration:  
FS VH S/D 500 s-apr will be applied to the sutured dural line on a dry surface. Two applications will be 
allowed in order to obtain watertight sealing of suture line.  
The neurosurgical procedures will be performed according to the standard practices applicable to each 
indication. The dura will be closed with suture types and needle sizes according to the surgeon’s 
preference. Special care will be taken to ensure that if tenting sutures are used, they do not perforate the 
dura. Patients having gaps/defects between dura edges that are >2 mm after primary suturing will be 
excluded due to the limitations of FS VH S/D 500 s-apr. 
FS VH S/D 500 s-apr will be prepared according to the protocol and applied in a thin layer with 5 mm 
on each side of the suture line ensuring that all suture holes are covered.  
Approximately 2 mL of FS VH S/D 500 s-apr will be used to cover a suture line 10 cm long and 1 cm 
wide (10 cm2), as per the package insert. After application of FS VH S/D 500 s-apr, the surgeon will 
wait 3 minutes before testing for CSF leak in order to achieve sufficient polymerization. 
In the control group, DuraSeal Dural Sealant will be prepared and applied according to the instructions 
in the protocol appendix. 
Duration of Treatment:  
The patient’s continuation in the clinical study is defined at randomisation and ends upon completion of 
the scheduled final Follow-up visit on post-operative Day 60 (±3 days). According to clinical 
experience, the incidence of CSF leaks are rare, however when they do occur the majority are detected 
within 60 days. Therefore, the follow-up period is deemed appropriate. The period between enrolment 
(i.e., signed IC) and surgery will not exceed 30 days; screening procedure results are valid for 30 days. 
After 30 days, the laboratory tests, the review of systems, and the physical examination must be 
repeated. Post-operative follow-up visits are scheduled to take place on the day before discharge or on 
post-operative Day 5 (±2 days), whichever is first, on post-operative Day 30 (±3 days), and on 
post-operative Day 60 (±3 days) (last study visit), and safety evaluations will be recorded during this 
time period including post-operative CSF leaks (clinical observation, diagnostic testing, or need for 
surgical intervention to treat CSF leak or pseudomeningocele). 
Assessments: 
Primary efficacy assessments 
The primary assessment is the proportion of patients who have neither of the following: 
Intra-operative CSF leakage from dural repair after up to two FS VH S/D 500 s-apr/control applications 
during Valsalva manoeuvre (25 cm H2O for up to 5 - 10 seconds) 
Post-operative CSF leakage within 30 (+3) days post-operatively 
Secondary efficacy assessments 
• 
Incidence of intra-operative CSF leakage following final Valsalva manoeuvre 
• 
Incidence of CSF leaks within 30 (+3) days post-operatively 
• 
Time in surgery (minutes)  
• 
Time from dural closure (application of investigational product) until end of surgery 
• 
Length of stay in hospital (days) 


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Safety Assessments: 
• 
Incidence of CSF leaks within 60 (+3) days post-operatively 
• 
Incidence of adverse events (AEs) up to 60 (+3) days post-operatively 
• 
Incidence of surgical site infections (SSIs) according to the United States (US) National 
Healthcare Safety Network (NHSN) within 30 (+3) days post-operatively 
• 
Number of unplanned interventions within 30 (+3) days post-operatively 
• 
Abnormal laboratory values and vital signs (e.g., elevated white blood cell [WBC] count, fever 
[temperature >100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial pressure 
<60]) 
Statistical Methods:  
Sample Size Calculation: 
In this non-inferiority (NI) study, the proportions of patients meeting the composite primary endpoint are 
assumed to be 
% for FS VH S/D 500 s-apr and 
% for DuraSeal Dural Sealant; the NI margin is 
defined as 10%, the 1-sided Type 1 error rate (α) is 2.5%, the statistical power (1-β) is 80%. One interim 
analysis after 50% of patients complete the study is assumed, resulting in an overall sample size of 
202 evaluable patients. To reach this number, 112 patients will be randomised to each treatment group 
(ie, 224 total patients)  
Planned Statistical Analysis: 
Primary efficacy endpoint analysis:  
The primary composite efficacy endpoint, proportion of patients not meeting the 2 criteria (ie, no 
intra-operative CSF leakage and no post-operative CSF leakage), will be investigated by a 2-sided test 
for non-inferiority using logistic regression, taking into account the following covariates: study center 
and surgery region. Non-inferiority of FS VH S/D 500 s-apr to DuraSeal Dural Sealant will be assessed 
using the confidence interval approach and a NI margin of 10%.  
Secondary efficacy endpoint analyses:  
The logistic regression approach used for the primary efficacy endpoint will also be used to calculate the 
proportions of: incidence of intra-operative CSF leakage following final Valsalva manoeuver and the 
incidence of CSF leaks within 30 (+3). 
The time in surgery, time from dural closure until the end of surgery, and the length of stay in hospital 
will be compared between the 2 treatment groups using a Wilcoxon rank sum test.   
Safety endpoint analyses: 
The logistic regression approach used for the primary endpoint will also be used to calculate the 
proportions of: incidence of CSF leaks within 60 (±3) days post-operatively, and incidence of SSIs 
according to NHSN within 30 (±3) days post-operatively.  
The number of unplanned interventions within 30 (±3) days post-operatively will be compared between 
the 2 treatment groups using a Wilcoxon rank sum test.  
Listings will be prepared for laboratory results and vital signs.  
Date of Protocol Amendment 2: 06 Nov 2017 
Prepared in: Microsoft Word 2013 
 


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Table of Contents 
SYNOPSIS ..........................................................................................................................3 
LIST OF ABBREVIATIONS AND TERMS ................................................................10 
1. INTRODUCTION........................................................................................................13 
1.1 Background ............................................................................................................13 
1.2 Description of Investigational Product ................................................................15 
1.2.1 Approved Therapeutic Indications ...............................................................16 
1.2.2 Contraindications ...........................................................................................16 
1.3 Clinical Condition/Indication ...............................................................................16 
1.4 Evaluation of Anticipated Risks and Benefits of the IP to Humans .................16 
2. STUDY OBJECTIVES ................................................................................................17 
2.1 Primary Objective ..................................................................................................17 
2.2 Secondary Objective ..............................................................................................17 
3. INVESTIGATIONAL PLAN .....................................................................................18 
3.1 Overall Study Design and Plan .............................................................................18 
3.2 Overall Study Design .............................................................................................18 
3.3 Rationale for Study Design and Control Group .................................................19 
3.4 Study Duration and Dates .....................................................................................20 
4. STUDY POPULATION SELECTION ......................................................................22 
4.1 Study Population ....................................................................................................22 
4.2 Inclusion and Exclusion Criteria (General) ........................................................22 
4.2.1 Inclusion Criteria (General) ..........................................................................22 
4.2.2 Exclusion Criteria (General) .........................................................................23 
4.3 Inclusion and Exclusion Criteria (Intra-operative) ............................................24 
4.3.1 Inclusion Criteria (Intra-operative) ..............................................................25 
4.3.2 Exclusion Criteria (Intra-operative) .............................................................25 
4.4 Removal of Patients from Therapy, Assessment, or Study ................................25 
5. STUDY TREATMENTS .............................................................................................27 
5.1 Enrolment, Randomisation, and Assignment to a Treatment Group ...............27 
5.2 Randomisation .......................................................................................................27 
5.3 Description of Treatments.....................................................................................27 
5.3.1 Investigational Product ..................................................................................27 
5.3.2 Control .............................................................................................................28 
5.3.3 Valsalva Manoeuvre .......................................................................................28 


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5.3.4 Antibiotic Prophylaxis ....................................................................................28 
5.3.5 Rescue Therapy ...............................................................................................28 
5.4 Treatments Administered .....................................................................................28 
5.4.1 Description of Treatment and Assessment of CSF Leak (Including 
Valsalva Manoeuvre) .....................................................................................28 
5.5 Method of Assigning Patients to Treatment Groups ..........................................29 
5.6 Blinding ...................................................................................................................29 
5.7 Concomitant Therapy and Prohibited Medications ...........................................30 
5.7.1 Concomitant Therapy ....................................................................................30 
5.7.2 Prohibited Medications ..................................................................................31 
5.8 Restrictions .............................................................................................................31 
5.8.1 Fluid and Food Intake ....................................................................................31 
5.8.2 Patient Activity Restrictions ..........................................................................31 
5.9 Treatment Compliance ..........................................................................................31 
5.10 Packaging and Labeling ......................................................................................32 
5.11 Storage and Accountability .................................................................................32 
6. STUDY PROCEDURES .............................................................................................33 
6.1 Informed Consent ..................................................................................................33 
6.2 Demographics .........................................................................................................33 
6.3 Medical History ......................................................................................................33 
6.4 Physical Examination ............................................................................................33 
6.5 Neurological Assessment .......................................................................................34 
6.6 Vital Signs ...............................................................................................................34 
6.7 Electrocardiogram .................................................................................................35 
6.8 Clinical Laboratory Tests .....................................................................................35 
6.8.1 Laboratory Parameters ..................................................................................35 
6.8.2 Sample Collection, Storage, and Shipping ...................................................36 
6.8.3 Toxicity Grading Scale ...................................................................................37 
6.8.4 Surgical Site Infections ...................................................................................37 
6.9 Dispensing Study Drug ..........................................................................................37 
6.9.1 FS VH S/D 500-s ..............................................................................................37 
6.9.2 DuraSeal Dural Sealant ..................................................................................38 
6.10 Primary Efficacy Assessments ............................................................................39 
6.11 Secondary Efficacy Assessments ........................................................................39 
6.12 Safety Assessments ...............................................................................................40 
6.13 Adverse Events Assessments ...............................................................................41 
6.13.1 Performing Adverse Events Assessments ...................................................41 
6.13.2 Timing ............................................................................................................42 
6.13.3 Severity ..........................................................................................................42 
6.13.4 Relationship ...................................................................................................43 
6.13.5 Expectedness .................................................................................................44 
6.13.6 Adverse Events of Special Interest ..............................................................44 
6.13.7 Clinical Laboratory Adverse Events ...........................................................44 


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6.13.8 Serious Adverse Events ................................................................................45 
6.13.8.1 Definition ................................................................................................45 
6.13.8.2 Reporting Serious Adverse Events .......................................................45 
6.13.9 Urgent Safety Measures ...............................................................................46 
6.13.10 Untoward Medical Occurrences ................................................................47 
6.13.11 Treatment-emergent Adverse Events .......................................................47 
6.14 Concomitant Medication Assessments ...............................................................47 
6.15 Non-Medical Complaints ....................................................................................47 
6.16 Removal of Patients from the Trial or Study Drug ..........................................47 
6.17 Appropriateness of Measurements.....................................................................48 
7. STUDY ACTIVITIES .................................................................................................49 
7.1 Screening and Study Visits....................................................................................49 
7.2 Pre-operative Screening Visit (Days -30 to -1) ....................................................49 
7.3 Procedures for Day 0 Treatment (Pre-operative) ...............................................49 
7.4 Procedures for Day 0 Treatment (During and After Surgery) ..........................50 
7.5 Procedures for Day 5 (±2 Days) or the Day Before Discharge (Whichever 
Comes First), and Day 30 (±3 Days) .....................................................................51 
7.6 Procedures for Day 60 (±3 Days) and/or Study Completion .............................51 
7.7 Procedures for Unscheduled Follow-up (Between Days 5 [±2] to 60 [±3]) .......51 
8. QUALITY CONTROL AND ASSURANCE.............................................................53 
8.1 Auditing ..................................................................................................................53 
8.2 Non-compliance with the Protocol .......................................................................53 
9. PLANNED STATISTICAL METHODS ...................................................................54 
9.1 General Considerations .........................................................................................54 
9.2 Determination of Sample Size ...............................................................................54 
9.2.1 Justification of Non-Inferiority Margin ........................................................54 
9.3 Analysis Populations ..............................................................................................55 
9.3.1 Full Analysis Set (FAS) ..................................................................................55 
9.3.2 Per Protocol Set (PPS) ....................................................................................55 
9.3.3 Safety Analysis Set ..........................................................................................56 
9.4 Methods of Analysis ...............................................................................................56 
9.4.1 Demographics and Baseline Characteristics ................................................56 
9.4.2 Primary Efficacy Endpoint ............................................................................56 
9.4.3 Secondary Efficacy Endpoints .......................................................................57 
9.4.4 Secondary Safety Endpoints ..........................................................................58 
9.5 Interim Analysis .....................................................................................................59 
10. ADMINISTRATIVE CONSIDERATIONS ............................................................60 
10.1 Investigators and Study Administrative Structure ...........................................60 


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10.2 Institutional Review Board (IRB) or Ethics Committee (EC) Approval ........60 
10.3 Ethical Conduct of the Study ..............................................................................60 
10.4 Patient Information and Consent .......................................................................61 
10.5 Patient Confidentiality ........................................................................................61 
10.6 Training ................................................................................................................61 
10.7 Insurance ..............................................................................................................62 
10.8 Study Monitoring .................................................................................................62 
10.9 Electronic Case Report Forms and Study Records ..........................................62 
10.10 Data Safety Monitoring Board .........................................................................63 
10.11 Protocol Violations/Deviations ..........................................................................63 
10.12 Auditing ..............................................................................................................63 
10.13 Access to Source Documentation ......................................................................64 
10.14 Data Generation and Analysis ..........................................................................64 
10.15 Retention of Data ...............................................................................................65 
10.16 Financial Disclosure ...........................................................................................65 
10.17 Publication and Disclosure Policy ....................................................................65 
11. REFERENCE LIST ...................................................................................................66 
 
List of In-Text Tables 
Table 1. Clinical Laboratory Tests .................................................................................36 
 
List of In-Text Figures 
Figure 1. Intra-operative Study Design .........................................................................19 
 
List of Appendices 
Appendix 1 Study Design with Study Visits (Screening, Days 0, 5, 30, and 60) .........70 
Appendix 2 Schedule of Procedures and Assessments .................................................71 
Appendix 3 Surgical Wound Classification ...................................................................73 
Appendix 4 Clinical Laboratory Assessments ...............................................................74 
Appendix 5 Toxicity Grading Scale for Laboratory Values ........................................77 
Appendix 6 Instructions for Preparation of FS VH S/D 500 s-apr .............................79 
Appendix 7 Instructions for Preparation of DuraSeal Dural Sealant ........................81 
Appendix 8 Surgical Site Infections (SSIs) – CDC/NHSN Definitions .......................84 
Appendix 9 Sponsor Signatures ......................................................................................87 
Appendix 10 Investigator’s Signature ............................................................................88 
 


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LIST OF ABBREVIATIONS AND TERMS  
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase  
aPTT 
Activated partial thromboplastin time 
AST 
Advanced Syringe Technology 
B19V 
Parvovirus B19 
BUN 
Blood urea nitrogen 
CBGB 
Coronary artery bypass grafting surgery 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CRO 
Contract research organisation 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for AEs 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EU 
European Union 
EudraCT 
EudraPharm Clinical Trial 
FAS 
Full analysis set 
FS 
Fibrin Sealant 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A virus 
HbA1c 
Glycated haemoglobin 
HBV 
Hepatitis B virus 
Hct 
Haematocrit 
HCV 
Hepatitis C virus 
HEV 
Hepatitis E virus 
HIV 
Human immunodeficiency virus 
Hgb 
Haemoglobin 
IB 
Investigator’s Brochure 
IC 
Informed consent 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
ICP 
Intracranial pressure 


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ICU 
Intensive care unit 
IND 
Investigational new drug 
INR 
International normalised ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web-response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRP 
Mutual Recognition Procedure 
N 
Number of patients 
NCA 
National Competent Authority 
NHSN 
National Healthcare Safety Network 
NI 
Non-inferiority 
NMC 
Non-medical complaint 
OR 
Odds ratio 
PEG 
Polyethylene glycol 
PF 
Posterior fossa 
PIC 
Patient identification code 
PPS 
Per protocol set 
RCT 
Randomised controlled trial 
RNA 
Ribonucleic acid 
RBC 
Red blood cell  
RR 
Relative risk 
SAE 
Serious adverse event 
SAER 
Serious adverse event report 
S/D 
Solvent/detergent 
SmPC 
Summary of Product Characteristics 
SSI 
Surgical site infections 
ST 
Supratentorial 
ULN 
Upper limit of normal 
US 
United States 
VH 
Vapour heat 
Y/N 
Yes/No 
WBC 
White blood cell 
 


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PR interval 
The interval that extends from the beginning of the P wave (the onset of atrial 
depolarization) until the beginning of the QRS complex 
QRS 
Ventricular depolarization 
QT interval 
The measure of the time between the start of the Q wave and the end of the 
T wave in the heart's electrical cycle. 
 


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1. INTRODUCTION 
1.1 Background 
In neurosurgery, cerebrospinal fluid (CSF) leaks where disruption of the arachnoid and 
the dura mater allows CSF to flow to an extradural space, is an event which may lead to 
severe complications, such as infection, pseudomeningocele, and delayed 
pneumocephalus. Closure of the dura serves as a mechanical and a biological barrier to 
both CSF leaks and to the potential entrance of infectious organisms. Reported incidences 
of post-operative CSF leaks may vary on average from 0.8 to 13%, depending on the type 
of surgery and other factors. Craniotomy and craniectomy in the posterior fossa (PF) 
region may have post-operative CSF leaks ranging from 2% to 11.5%, respectively.1-4 
Cerebrospinal fluid leak rates are reported to be lower in the supratentorial (ST) region 
(6.3%) and during smaller trans-sphenoidal procedures (6.8%), but are much higher in 
infratentorial procedures and extensive skull base procedures (12.8% and 34.6%, 
respectively).5  
Persisting CSF leaks may result in post-operative meningitis in about 3.1% of 
interventions with a mean onset of 12 days after surgery.6 The relative risk (RR) for 
developing meningitis in patients with post-operative CSF leak is increased to a 
RR = 10.6 
Also, the risk of surgical site infections (SSIs) is increased in patients with a 
post-operative CSF leak with an odds ratio (OR) for SSI of 3.5 (95% CI 1.4 - 8.5), 
leading to increased length of stay in the hospital.7 Risk factors for CSF leaks after 
545 cranial surgeries were surgery in the PF region, opened pneumatised spaces, age, size 
of craniotomy, craniectomies, large remaining dural defects, wound closure without using 
muscle sutures, and suture techniques.8 Post-operative CSF leaks will, in most cases, 
eventually cease spontaneously or will heal under conservative management including 
lumbar drainage or with medical treatment to lower the intracranial pressure (ICP). 
Patients who do not respond to conservative/medical treatment may require surgical 
revision to close the persisting CSF leak, introducing discomfort to the patient and 
increased overall costs. In fact, neurosurgical procedures with CSF leaks in 1 study 
increased costs by 141% over procedures that did not have CSF leaks.5 
The first attempt to treat and control CSF leaks is done by the neurosurgeon at the end of 
the surgical intervention when the dural edges are to be closed. The goal is a watertight 
closure of the dura. Defects or large dural gaps might require use of different 
patches/grafts such as autograft, allograft, xenograft, or synthetic grafts.9-16 If the dura 
edges can be met, meticulous suturing of the dura is important to gain a watertight 


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closure and suturing is considered standard of care by neurosurgeons. However, with 
increased ICP, CSF may leak through even small suture holes in the dura, causing a 
persisting CSF leak often already detected during surgery. Regardless of how 
meticulously dura suturing is performed, intra-operative CSF leakage has been shown to 
persist in most patients at a CSF opening pressure >20 cm H2O.17 A pressure of 20 cm 
H2O (equal to 10 - 15 mm Hg) is considered the upper limit of a physiological ICP and 
can easily be exceeded at times (eg, coughing) and can be increased during surgery using 
the Valsalva manoeuvre.18 
To minimize the risk of intra-operative CSF leaks and to potentially reduce 
post-operative CSF leak rates, different techniques and materials have been used in 
conjunction to sutures to provide a watertight sealing of the dural incision; one such 
treatment modality is the use of a fibrin sealant (FS) directly on the suture line to seal the 
suture holes, as well as the approximated dural edge (as long as the gap is <2 mm 
wide). 9-16 Fibrin sealants consist of a group of compounds with 2 main active 
ingredients, fibrinogen and thrombin, that, when mixed, form a fibrin clot. Fibrin sealants 
applied to tissue during surgery have 4 main functions: haemostasis, tissue sealing, tissue 
adhesion, and wound healing.19 These FSs may be in liquid form (eg, Tisseel, Tissucol) 
or as a part of a dry patch.20  
The FS that has been available for the longest time to clinicians in both Europe (since 
1978) and the United States (US; since 1998) is Tisseel (Fibrin Sealant, Vapour Heated, 
Solvent/Detergent Treated 500 synthetic aprotinin [FS VH S/D 500 s-apr], Baxter 
Healthcare Corporation [Baxter], Deerfield, IL, US). Several generations of FSs up to the 
current product FS VH S/D 500 s-apr have been developed, mainly focusing on 
improving the viral safety and handling properties of the product. Thus, the latest FS 
generation FS VH S/D 500 s-apr comprises 2 dedicated virus inactivation steps (ie, 
vapour heat [VH] treatment and solvent/detergent [S/D] treatment), in the manufacture of 
both human plasma-derived product components (fibrinogen and thrombin component). 
Vapour heat is effective in inactivation of lipid-enveloped ribonucleic acid (RNA) 
viruses, such as human immunodeficiency virus (HIV), lipid-enveloped double-stranded 
deoxyribonucleic acid viruses such as pseudorabies virus, and non-enveloped RNA 
viruses such as hepatitis A virus (HAV), while S/D treatment is effective against 
lipid-enveloped RNA and deoxyribonucleic acid viruses, for example hepatitis C virus 
(HCV) and hepatitis B virus (HBV). The main indications for use in the European Union 
(EU) as supportive treatment adjunct to standard surgical techniques are to improve 
haemostasis, to improve wound healing, and to support sutures in vascular surgery and 
gastrointestinal anastomoses and for tissue sealing.19 


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1.2 Description of Investigational Product 
The Investigational Product (IP) for this protocol is FS VH S/D 500 s-apr in its frozen 
presentation. 
FS VH S/D 500 s-apr is a 2-component FS made from pooled human plasma. When 
combined, the 2 components, fibrinogen (human) and thrombin (human), mimic the final 
stage of the blood coagulation cascade.  
Fibrinogen (human) is a sterile, non-pyrogenic, VH- and S/D-treated preparation made 
from pooled human plasma. It is provided as a frozen solution pre-filled into 1 side of a 
dual-chambered syringe (eg, Advanced Syringe Technology [AST]). The main active 
ingredient in the fibrinogen component is human fibrinogen (as clottable protein 
91 mg/mL) contained in a total protein concentration of 96 - 125 mg/mL.19 A fibrinolysis 
inhibitor, aprotinin (synthetic, 3000 KIU1/mL), is included in the fibrinogen component 
to delay fibrinolysis. Other ingredients include: human albumin, L-histidine, niacinamide, 
sodium citrate dihydrate, polysorbate 80 (Tween 80) (0.6 - 1.9 mg/mL), and water for 
injections. 
Thrombin (human) is a sterile, non-pyrogenic, VH- and S/D-treated preparation made 
from pooled human plasma. It is provided as a frozen solution pre-filled into 1 side of a 
dual-chambered syringe (eg, AST). The thrombin component contains the clotting 
activator thrombin (human, 500 IU2/mL) and calcium chloride (40 μmol/mL). Other 
ingredients are: human albumin, sodium chloride, and water for injections.  
FS VH S/D 500 s-apr contains plasminogen, fibronectin, and factor XIII as 
process-related substances. In some countries, factor XIII is classified as an active 
ingredient. 
The use of FS VH S/D 500 s-apr is only topical (application by drip) to cover the dura 
suture line in order to work as a sealant.  
A detailed description of the study product is provided in the Summary of Product 
Characteristics (SmPC)19 of the Mutual Recognition Procedure (MRP) and the US 
Prescribing Information.20  
1 1 EPU (European Pharmacopoeia Unit) corresponds to 1800 KIU (Kallidinogenase Inactivator Unit). 
2 Thrombin activity is determined using the current WHO Standard for thrombin. 


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1.2.1 Approved Therapeutic Indications 
In the EU MRP, according to the SmPC,19 FS VH S/D 500 s-apr is approved for 
supportive treatment where standard surgical techniques appear insufficient:  
•
For improvement of haemostasis.
•
As a tissue glue to improve wound healing or to support sutures in vascular
surgery and in gastrointestinal anastomoses.
•
For tissue sealing, to improve adhesion of the separated tissue (e.g., tissue flaps,
grafts, split skin grafts [mesh grafts]).
The efficacy in fully heparinised patients has been proven. 
In the US, according to the prescribing information,20 the therapeutic indications for 
FS VH S/D 500 s-apr are: 
•
For use as an adjunct to hemostasis in adult and pediatric patients (>1 month of
age) undergoing surgery when control of bleeding by conventional surgical
techniques (such as suture, ligature, and cautery) is ineffective or impractical.
FS VH S/D 500 s-apr is effective in heparinised patients.
•
As a FS indicated as an adjunct to standard surgical techniques (such as suture
and ligature) to prevent leakage from colonic anastomoses following the reversal
of temporary colostomies.
1.2.2 Contraindications 
Known hypersensitivity to any constituents of the product, including aprotinin.21 
1.3 Clinical Condition/Indication 
In this protocol, FS VH S/D 500 s-apr is intended to be used as an adjunct to sutured 
dural repair in cranial surgery in patients undergoing elective cranial surgery for the 
treatment of a pathological condition (eg, benign/malignant tumours, vascular 
malformations, or Chiari type 1 malformations) specifically located in the PF or ST 
regions. 
1.4 Evaluation of Anticipated Risks and Benefits of the IP to Humans 
The efficacy and safety of Baxter’s FSs have also been demonstrated in post-marketing 
experience, as Baxter’s FSs have been commercialised for more than 30 years (also for 


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neurosurgery indication in many countries), with a positive benefit-risk balance, which is 
documented in periodic benefit-risk evaluation reports according to EU and US 
regulations. No safety signal has been identified from the reports on use in neurosurgical 
procedures in the EU; note that there is no neurosurgical procedure indication in the 
US.20 
In this clinical trial, the product will be used according to this protocol and to the 
specifications outlined in the current Investigator’s Brochure (IB) to minimize any risks. 
No increased adverse event (AE) risk has been identified over control treatments in the 
previous clinical trials conducted with the IP. 22 For general information about safety of 
plasma-derived products, please see the IB. With correct handling and application 
technique of the IP, as described in this protocol and in the IB, the anticipated risks to the 
patients in this clinical trial are expected to be minimal. The expected benefit of the IP is 
to provide watertight CSF closure to the suture line and potentially reduce complications 
for the patients due to CSF leaks after the surgical intervention.23,24 These anticipated 
benefits seem to outweigh the potential and minimal risks associated with the use of the 
IP (see the IB for additional details).
2. STUDY OBJECTIVES
The purpose of this study is to provide data on the safety and efficacy of FS VH S/D 500
s-apr compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure in
patients who are undergoing elective cranial surgery for the treatment of a pathological
condition (eg, benign/malignant tumours, vascular malformations, or Chiari type 1
malformations) specifically in the PF or ST region.
2.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of FS VH S/D 500 s-apr 
compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure. 
2.2 Secondary Objective 
The secondary objective of this study is to evaluate the safety of FS VH S/D 500 s-apr 
compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure. 


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3. INVESTIGATIONAL PLAN
3.1 Overall Study Design and Plan 
This study is a Phase 3, prospective, controlled, randomised, single-blind (patient), 
multicenter study to evaluate the safety and efficacy of FS VH S/D 500 s-apr compared 
to DuraSeal Dural Sealant as an adjunct to sutured dural closure in a total of 
202 evaluable patients undergoing elective cranial surgery for the treatment of a 
pathological condition (i.e., benign/malignant tumours, vascular malformations, or Chiari 
type 1 malformations) specifically located in the PF or ST region.  
Eligibility according to general and intra-operative criteria will lead to the final selection 
of the patient into the study, which is determined by the presence of an intra-operative 
CSF leak after primary dural closure with sutures. Upon detection of CSF leak, the 
patient’s randomisation assignment to either IP (FS VH S/D 500 s-apr) or to control 
(DuraSeal Dural Sealant) stratified by center and surgical regions (PF or ST) will be 
applied. 
3.2 Overall Study Design 
Patients who are ≥18 years of age who sign the informed consent (IC) and who meet all 
pre-operative inclusion/exclusion criteria will undergo elective cranial surgery with either 
craniotomy or craniectomy with planned durotomy. Their eligibility for surgery will be 
evaluated on the basis of the routine medical work-up (medical history, physical 
examination/review of systems, laboratory, imaging) and of the screening results for 
general inclusion and exclusion criteria (Section 4.2) during the ≤30-day period prior to 
surgery. 
For a schematic diagram of intra-operative study design, see Figure 1. During surgery 
(Day 0), patients will be evaluated according to intra-operative inclusion and exclusion 
criteria for further eligibility (Section 4.3); if eligible, patients will be evaluated upon 
completion of the primary suturing of the dura. Only if an intra-operative CSF leak is 
observed (spontaneous CSF leak or CSF leak after Valsalva manoeuvre; 25 cm H2O for 
up to 5 - 10 seconds), the patient’s randomisation assignment to 1 of 2 treatments – repair 
with FS VH S/D 500 s-apr or DuraSeal Dural Sealant as an adjunct to dural closure – will 
be applied. Patients with no intra-operative CSF leak will not be enrolled in the trial (ie, 
defined as screen failures). 
See Appendix 1 (Schedule of Procedures and Assessments). 




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The only clinical study data for FS VH S/D 500 s-apr is from a small randomised 
controlled trial (RCT) pilot study (N = 62) conducted by Baxter, where 
FS VH S/D 500 s-apr was used to augment the closure of a dura defect by suturing in a 
patch of autologous fascia, pericranium or suturable collagen-based dura substitute, 
which was the standard of care. The primary endpoint was the incidence of post-operative 
CSF leak at 33 days post-operatively. The results demonstrated no disadvantage with 
adding FS VH S/D 500 s-apr to the standard of care; safety was also shown to be 
comparable to standard of care. During this study, cranial surgery was specifically located 
in the PF region. CSF leakage after primary dura sutures was excluded. It is important to 
note that though the results demonstrated no disadvantage using FS VH S/D 500 s-apr as 
a sealant, the study was very small and likely underpowered to demonstrate any 
superiority effect; thus the study was considered inconclusive. However, 
FS VH S/D 500 s-apr was demonstrated to be safe for neurosurgery. 
Recently, a large (n = 139) and well-powered RCT was conducted. The RCT evaluated a 
similar FS product, containing the same main active ingredients (fibrinogen and 
thrombin) as FS VH S/D 500 s-apr; this study proved superiority of another FS over the 
control treatment (sutures only) in providing a watertight dural closure during surgery.26 
The safety profile was comparable in the 2 groups and, with this trial, an indication for 
“suture line sealing in dura mater closure” was obtained in the EU. 
Baxter believes that FS VH S/D 500 s-apr will perform equivalently to the DuraSeal 
Dural Sealant when used as an adjunct to suturing during surgery. While other clinical 
designs were discussed, the design chosen seems appropriate, as it provides a reasonably 
accurate reflection of the typical usage of FS in clinical practice.  
3.4 Study Duration and Dates 
The overall duration of the study is expected to be 26 months from study initiation (ie, 
first patient enrolled) to study completion (ie, last patient last visit). The recruitment 
period is expected to be 24 months.  
The patient participation period is from pre-operative screening to Day 60 (±3 days) after 
surgery (ie, last study visit), unless prematurely discontinued.  
Day of surgery is defined as Day 0. Scheduled Follow-up visits (Appendix 1) will take 
place on the day before discharge or on Day 5 (±2 days), whichever is first, Day 30 
(±3 days), and on Day 60 (±3 days) after surgery (last study visit). Follow-up visits will 
be advanced if complications occur prior to the scheduled date. According to clinical 


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experience, the incidence of CSF leaks are rare, however when they do occur the majority 
are detected within 60 days. Therefore, the follow-up period is deemed appropriate. 
Patients are strongly encouraged to contact or visit the study site without delay to discuss 
a perceived AE that occurs after the first Follow-up visit and between the scheduled 
Follow-up visits, and to follow the directives of the study site for appropriate action 
(Unscheduled Follow-up visit assessments, see Appendix 1).  
See schematic study overview including the study visits (Days 0, 5, 30, and 60) in 
Appendix 1. 


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4. STUDY POPULATION SELECTION
4.1 Study Population 
Approximately 476 patients will be screened in order to randomise approximately 
224 patients (with a minimal number of 56 PF procedures) and have 202 evaluable 
patients age ≥18 years, both genders, who are to undergo elective 
craniotomy/craniectomy for pathological processes (eg, benign or malignant tumours, 
vascular malformation, or Chiari type 1 malformations) in the PF or ST region and who 
have persistent CSF leakage following the primary attempt at suture closure of the dural 
incision. Randomisation will be stratified by study center and surgical region (PF or ST) 
and will be aimed to achieve an approximate 3:1 ratio (ST:PF) of the 2 surgical regions in 
the randomised study population. The minimal number of PF procedures will be 
approximately 56. 
We have estimated a 
% screen failure rate, based on published literature, using a 
similar method to detect CSF leaks during cranial surgery.27 
The study will be conducted in 4 countries (US, Spain, Germany, and Czech Republic). 
Additional countries may be involved in the trial. 
4.2 Inclusion and Exclusion Criteria (General) 
The general inclusion criteria (1 - 5) and the general exclusion criteria (1 - 20) are to be 
evaluated before each patient undergoes planned surgery. Only patients who meet the 
general inclusion criteria and do not meet the general exclusion criteria are to be 
evaluated further according to the intra-operative inclusion and exclusion criteria 
Section 4.3.  
4.2.1 Inclusion Criteria (General) 
Each patient must meet the following criteria to be enrolled in this study. Any patient not 
meeting all the inclusion criteria will be regarded as a screen failure. 
1. Patients ≥18 years of age undergoing craniotomy/craniectomy for pathological
processes in the PF or ST region
2. Patients must be willing and able to participate in the study and provide written IC
before any protocol specific assessment is performed
3. Patients must be willing to receive peri-operative antibiotic prophylaxis
4. Female patients of childbearing potential must present with a negative serum
pregnancy test, and must agree to employ adequate birth control measures


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[restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices 
or licensed hormonal products] for the duration of their participation in the study 
5. Patients are willing and able to comply with the requirements of the protocol
4.2.2 Exclusion Criteria (General) 
Each patient must not meet the following criteria to be enrolled in this study. Any 
excluded patient will be regarded as a screen failure. 
1. Patients with a dural lesion from a recent surgery that still has the potential for
CSF leakage
2. Patients who had undergone chemotherapy treatment, excluding hormonal
therapy, within 3 weeks prior to the planned procedure, or with chemotherapy
scheduled within 7 days following surgery
3. Patients with radiation therapy to the surgical site or standard fractionated
radiation therapy scheduled within 7 days following surgery
4. Patients with a previous craniotomy/craniectomy within 6 months prior to the
study surgery
5. Use of corticosteroids on a chronic basis (defined as daily use of corticosteroids
for ≥8 weeks) for purposes other than decreasing the symptoms of systemic
chemotherapy (unless if those steroids were discontinued 4 weeks prior to the
planned surgery)
6. Patients with a known hypersensitivity to the components of the IP or control
(human fibrinogen, synthetic aprotinin, human albumin, human FXIII, tri-sodium
citrate, histidine, niacinamide, polysorbate 80, human thrombin, polyethylene
glycol [PEG], trilysine amine)
7. Patients with a known hypersensitivity to US Federal Drug & Cosmetic Blue #1
dye
8. Evidence of an infection indicated by any one of the following: clinical
examination supporting the diagnosis of infection, fever (temperature >100.7°F or
38.2°C), positive urine culture, positive blood culture, positive chest X-ray
consistent with pulmonary infection, or infection along the planned surgical path.
A white blood cell (WBC) count of <20000 cells/µL is permitted if the patient is
being treated with steroids in the absence of all other infection parameters


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9. Female patients of childbearing potential with a positive pregnancy test or intent 
to become pregnant during the clinical study period 
10. Female patients who are nursing 
11. Patients with exposure to another investigational drug or device clinical trial 
within 30 days prior to enrolment or anticipated in the 60-day Follow-up period  
12. Patients with severely altered renal function as confirmed by local laboratory 
reference ranges for serum creatinine and/or hepatic function (alanine 
aminotransferase [ALT], aspartate aminotransferase >3 × upper limit of normal 
[ULN]) 
13. Patients who currently have or have had a compromised immune system (such as 
Acquired Immune Deficiency Syndrome [AIDS]) or autoimmune disease, or were 
on chronic immunosuppressant agents 
14. Patients with uncontrolled diabetes as evidenced by the institution’s standard of 
care (glycated haemoglobin [HbA1c] >7%, blood glucose, etc.)  
15. Patients with traumatic injuries to the head  
16. Patients with dural injury during craniotomy/craniectomy that cannot be 
eliminated by widening the craniotomy/craniectomy to recreate the native dural 
cuff 
17. Patients requiring surgical approaches that would not allow sutured dural closure 
such as trans-sphenoidal or translabyrinthine/-petrosal/-mastoid. Superficial 
penetration of mastoid air cells is allowed 
18. Patients with hydrocephalus, except occlusive hydrocephalus caused by PF 
pathology or incompletely open cerebrospinal fluid pathways, to be treated during 
surgical procedure 
19. Existing CSF (ventricular, etc.) drains, Cushing/Dandy cannulation, or Burr holes 
which damage the dura 
20. Patients with confined bony structures where nerves are present and neural 
compression may result due to swelling 
 
4.3 Inclusion and Exclusion Criteria (Intra-operative) 
The intra-operative inclusion criteria (1 - 3) and the intra-operative exclusion criteria 
(1 - 9) will be evaluated when the patient is in surgery. 


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4.3.1 Inclusion Criteria (Intra-operative) 
1. Patients with surgical wound classification Class I (Appendix 3)
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 IP
3. Patient’s CSF leak was present intra-operatively following completion of primary 
dural closure (with or without non-autologous duraplasty or autologous tissue); 
either spontaneously or upon Valsalva manoeuver (25 cm H2O for up to
5 - 10 seconds) 
4.3.2 Exclusion Criteria (Intra-operative) 
1. Patient has a gap between durotomy edges of >2 mm after primary dural closure
in the judgment of the investigator 
2. Patients requiring the use of implants made of synthetic materials coming into
direct contact with dura
3. Patient has 2 or more separate dural defects
4. Patients with intersecting durotomy scars in the surgical path from a previous
operation that cannot be completely removed by the planned dural resection
5. Placement of Gliadel Wafers
6. Major intra-operative complications that require resuscitation or deviation from
the planned surgical procedure
7. Patients in whom application of the Valsalva manoeuver is not found appropriate
due to increased safety risk
8. Patients requiring the use of other FSs or PEG-based sealants
9. Patients with any other intra-operative findings identified by the surgeon that may
preclude the conduct of the study procedure
4.4 Removal of Patients from Therapy, Assessment, or Study 
Any patient may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the End of Study electronic case report form (eCRF). Assessments to be 
performed at the termination visit (including in cases of withdrawal or discontinuation) 
are described in Section 6.16 and Section 7.6.  


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Discontinuation (ie, complete withdrawal from study participation) may be due to drop 
out (ie, active discontinuation by patient) or loss to follow-up (ie, discontinuation by 
patient without notice or action). Additionally, the investigator and the sponsor have the 
discretion to discontinue any patient from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the patient.  
The data safety monitoring board (DSMB) will upgrade an AE to a serious adverse event 
(SAE) if the AE results in a patient injury that: jeopardizes the patient and may require 
medical or surgical intervention, prolongs the hospitalization, requires intervention to 
prevent permanent impairment or damage, causes disability or permanent damage, causes 
a congenital anomaly/birth defect, is life-threatening, or results in death.  
The study enrolment will be paused and re-evaluated by the DSMB if: 
• 2 or more SAEs occur in the same patient and are directly related to the 
investigational product, across 10 patients, or   
• 20 aggregate SAEs occur that are directly related to the investigational product, or   
• 1 patient death occurs that is directly related to administration of the 
investigational product. 
 
The DSMB is required to define the rule(s) appropriate to restart the study, if the above 
triggering events occur during study conduct. 
Discontinuation may also be due to the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) or Competent Authority’s decision to terminate or suspend 
approval of the study or the investigator. 


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5. STUDY TREATMENTS
5.1 Enrolment, Randomisation, and Assignment to a Treatment Group 
This is a randomised, single-blind (patient), controlled clinical study. In order to 
minimize/avoid bias, patients will be randomly assigned to 1 of 2 treatments: IP 
(FS VH S/D 500 s-apr) OR control (DuraSeal Dural Sealant) with a 1:1 ratio stratified by 
center and surgical regions (PF or ST). 
5.2 Randomisation  
Patients will be randomly assigned to FS VH S/D 500 s-apr or DuraSeal Dural Sealant at 
a ratio of 1:1. Randomisation will be stratified by study center and surgical region (PF or 
ST) with the goal of achieving an approximate 3:1 ratio (ST:PF) of the 2 surgical regions 
in the randomised study population. Randomisation will be controlled via an interactive 
Web-response system (IWRS), 
 using dynamic allocation. On the day 
of surgery (Day 0), upon confirmation of pre-operative eligibility criteria, a member of 
the site study staff other than the surgeon will obtain a treatment assignment from the 
IWRS. Adequate amounts of FS VH S/D 500 s-apr and DuraSeal Dural Sealant will be 
taken into the operating room for potential use as the study treatment. 
Immediately after the patient’s intra-operative eligibility for study treatment has been 
confirmed (ie, spontaneous CSF leak or CSF leak after Valsalva manoeuvre), the 
assigned treatment will be revealed to the surgeon and the assigned IP or control will be 
applied to the CSF leak site. Following surgery, the treatment assignment and the actual 
treatment applied will be entered in the eCRF for the patient. 
If the patient’s eligibility is not confirmed intra-operatively, the operation will be 
performed according to hospital standards. The study site designee will document the 
noncompliant criterion or criteria plus the date and reason(s) for the patient’s exclusion in 
the eCRF, and an entry will be made in the IWRS that the study treatment was not 
administered. 
Details of the IWRS and its use will be described in a separate IWRS instruction manual 
that will be maintained in the trial master file and in each center’s investigator trial file. 
5.3 Description of Treatments 
5.3.1 Investigational Product 
FS VH S/D 500 s-apr is to be applied with cannula by dripping in a thin and continuous 
layer with a 5 mm overlap on each side of the sutured line, ensuring that all suture holes 
are covered (Appendix 6). 


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5.3.2 Control 
The DuraSeal Dural Sealant is to be applied with the DuraSeal System Applicator by 
spraying a thin (1 – 2 mm) coating, ensuring that all suture holes are covered (Appendix 
7). 
5.3.3 Valsalva Manoeuvre 
The Valsalva manoeuvre is to be performed by the anaesthesiologist to increase the 
intra-thoracic pressure (eg, by increasing the positive end-expiratory pressure or by 
giving a large tidal volume and hold the inflating pressure) to approximately 25 cm H2O 
constantly for up to 5 - 10 seconds to transiently elevate the ICP and test for any CSF 
leaks. 
5.3.4 Antibiotic Prophylaxis 
All patients, regardless of treatment arm, will have peri-operative antibiotic prophylaxis, 
according to the guidelines at each site. 
5.3.5 Rescue Therapy 
In case of continuous CSF leak in spite of treatment (ie, treatment failure), rescue therapy 
using standard of care is permitted at the surgeon’s choice (including use of other 
sealants, dural patches, etc. [excluding further use of the IP or control in either of the 
2 groups]).  
In case of rescue therapy, the choice of products must be captured in the eCRF (brand 
name of the material used for rescue therapy, application method, amount used). 
5.4 Treatments Administered 
Patients who are ≥18 years of age who have signed the ICF and who are eligible by 
intra-operative inclusion/exclusion criteria will undergo elective cranial surgery with 
durotomy of the PF or ST region with either craniotomy or craniectomy. The 
neurosurgical procedures are to be performed according to the standard practices 
applicable to each indication.  
Treatments will be administered intra-operatively, during dural closure, and consist of 
sutures with FS VH S/D 500 s-apr or sutures with DuraSeal Dural Sealant. 
5.4.1 Description of Treatment and Assessment of CSF Leak (Including Valsalva 
Manoeuvre) 
Dura will be closed with sutures, needle sizes, and suturing techniques according to the 
surgeons’ preference. Suture specification must be captured in the eCRF (type, size, 


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closure technique). Special care will be taken to ensure that if tenting sutures are used, 
they do not perforate the dura. Use of tenting sutures must be captured in the eCRF.  
The surgeon will visually inspect the dural suture line for CSF leakage after application 
of the allocated treatment (FS VH S/D 500 s-apr or DuraSeal Dural Sealant) and after 
waiting at least 3 minutes if the treatment is FS VH S/D 500 s-apr. CSF leaks will be 
defined as any overt flow, seepage, weeping, or sweating of CSF through the dura suture 
line, regardless of volume. Patients who have a CSF leak, as defined by observing a 
spontaneous CSF leak or CSF leak after Valsalva manoeuvre (Section 5.3.3) after 
primary suturing will have their randomisation assignment (Section 5.5) applied. 
If the suture line is watertight (ie, no CSF leak), then the suture line must be inspected 
again after applying the Valsalva manoeuvre (intrathoracic pressure increased to 25 cm 
H2O for up to 5 - 10 seconds; Section 5.3.3). If the suture line after the Valsalva 
manoeuvre is watertight, the treatment is deemed a success, ie, intra-operative CSF leak 
free. 
Note: After the end of the surgical intervention of the brain, physiologic liquids (eg, 
physiological saline) are to be used to prevent any pneumocephalus and to ensure 
evaluation of the primary endpoint (no intra-operative CSF leakage and 30 (±3)-day 
post-operative CSF leakage). 
5.5 Method of Assigning Patients to Treatment Groups 
The patient will be randomised in a 1:1 allocation ratio stratified by center and surgical 
regions (PF or ST) to 1 of 2 treatment arms: 
•
Investigational product: FS VH S/D 500 s-apr
OR 
•
Control: DuraSeal Dural Sealant
5.6 Blinding 
This study will be single-blind (patient), as investigator blinding is not possible due to the 
visual and physical difference between the 2 treatment regimens. Patients will be kept 
blinded throughout the study. In addition, the surgeon performing the surgery will remain 
blinded until intra-operative entry criteria have been confirmed (see Section 5.2).  


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Otherwise, investigators, surgery personnel, site study personnel, clinical research 
organisation personnel, and sponsor personnel will not be blinded. Adequate block size 
will be used to prevent guessing the allocation in the trial and to ensure real blinding. 
Flexible random block sizes will be also used based on the stratification factors (site and 
surgical region), eg, relative small block sizes will be used to maintain balance in small 
strata whereas relative large block sizes will be used in large strata. 
5.7 Concomitant Therapy and Prohibited Medications 
5.7.1 Concomitant Therapy 
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:  
Medications:  
• Prophylactic antibiotics from 1 - 2 days before surgery  
• Thrombosis prophylaxis 
• Standard use of peri-operative steroids (ie, corticosteroids) is permitted. Chronic 
steroid use (defined as daily use of corticosteroids for ≥8 weeks) for the purposes 
of reducing the side effects of chemotherapy and/or radiation therapy for cancer is 
not exclusionary unless the patient is deemed by the investigator to be suffering 
from steroid toxicity (ie, Cushing's syndrome) manifested by symptoms and signs 
such as thin skin, striae, easy bruising, muscle atrophy, upper body obesity, severe 
fatigue, etc.  
• Birth control for women of childbearing potential 
• Anesthetic drugs and drugs used in the operating room such as induction agents, 
volatile anaesthetics, nitrous oxide, narcotics, benzodiazepines, paralytics, 
cardiovascular drugs, antihypertensives, etc. 
Non-drug therapies:  
• Concomitant medications and non-drug therapies received from 30 days before 
enrolment until completion/termination will be recorded on the concomitant 
medications and non-drug therapies eCRFs. 


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5.7.2 Prohibited Medications 
The following medications and non-drug therapies are not permitted before study entry 
(surgery) and during the course of the study (for the time specified below): 
Medications: 
•
Chemotherapy from 3 weeks prior to, and 7 days after, surgery
•
Investigational product from other clinical trials 30 days before and during the
entire study or anticipated in the 60-day Follow-up period.
Non-drug therapies: 
•
Existing CSF drains, Cushing/Dandy cannulation, or Burr holes with damage to
the dura before surgery. CSF drains placed during surgery are allowed.
•
Use of implants or grafts made of synthetic materials coming into direct contact
with dura during surgery
•
Placement of Gliadel Wafers during surgery
•
Radiation therapy for the head within 7 days following surgery
•
Other FSs or PEG-based sealants, unless used as rescue therapy if the assigned
study treatment fails
A patient who has taken any of these medications or received any of these non-drug 
therapies will be excluded according to exclusion criteria (Sections 4.2.2 and 4.3.2). If 
this occurs after randomisation, it will be regarded as a protocol violation. 
5.8 Restrictions 
5.8.1 Fluid and Food Intake 
No special requirements on fluid and food intake are necessary, other than the standard 
procedure (ie, no food or liquids after 12 am on the day of surgery). 
5.8.2 Patient Activity Restrictions 
No special requirements on patient activity are necessary, other than those imposed by 
the investigator or as per standard post-operative procedure. 
5.9 Treatment Compliance 
Not applicable. 


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5.10 Packaging and Labeling 
The FS VH S/D 500 s-apr and DuraSeal Dural Sealant batches used in this study will be 
labeled with the contents, storage instructions, and expiry date, along with other 
information according to the valid regulatory requirements for clinical trials. The study 
product is delivered in cardboard boxes.  
5.11 Storage and Accountability 
The shelf life of FS VH S/D 500 s-apr (frozen) is 24 months, provided that the product is 
shipped and stored at or below -4°F (-20°C). The cooling chain must be maintained 
without interruption until application. The unopened product, thawed in an incubator at 
98.6°F (37°C), may be stored at 98.6°F (37°C) for up to 4 hours. If the solution is not 
used within 4 hours after thawing, FS VH S/D 500 s-apr must be discarded. Do not 
refrigerate or re-freeze. The product must not be used after the expiration date indicated 
on the label. For additional information on these issues, please see the SmPC.19 
The shelf life of DuraSeal Dural Sealant is 12 months, provided that the product is 
shipped and stored below 77°F (25°C). DuraSeal Dural Sealant must be used within 
1 hour of preparation.27 
The investigator will ensure that the IP is stored as specified above and that the storage 
area is secured, with access limited to authorised study personnel. The investigator will 
maintain records that the IP was received, including the date received, drug identity code, 
date of manufacture or expiration date, amount received, and outcome of the product. The 
IPs must be dispensed only at the study site. Records will be maintained that includes the 
patient identification code (PIC), dispensation date, and amount dispensed. All remaining 
partially used and/or unused IP will be destroyed with the permission of the sponsor in 
accordance with applicable laws and study site procedures for waste of biological human 
origin. If the IP is to be destroyed, the investigator will provide documentation in 
accordance with sponsor’s specifications. 


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6. STUDY PROCEDURES 
6.1 Informed Consent 
The investigator or designated personnel must explain the study and the implications of 
participation (e.g., objectives, methods, anticipated benefits, and possible risks) to 
potential patients according to local regulations prior to any trial related activity. Patients 
will be informed that their participation is voluntary and that they may withdraw from the 
study at any time. They will be informed that choosing not to participate or to withdraw 
from the study will not have an impact on the care the patient will receive for the 
treatment of his/her disease. In case the patient is unable to read and write, an impartial 
witness must confirm the informed consent.  
The patient will be given sufficient time to read the informed consent form (ICF) and to 
ask additional questions. After this explanation and before entry in the study, consent 
should be appropriately recorded by means of the patient's personally dated signature (or, 
if applicable, by the signature of an independent witness who certifies the patient's 
consent in writing) and by the investigator’s signature. After having obtained the consent, 
a copy of the signed and dated informed consent must be given to the patient. 
Any patient who provides informed consent and meets the general inclusion/exclusion 
criteria is considered enrolled into the study. 
6.2 Demographics 
Demographic characteristics to be recorded at pre-operative screening will include age, 
sex, race, ethnicity, and physical characteristics such as weight and height. Weight will 
be recorded on Days 0, 5 (±2 days), 30 (±3 days), and 60 (±3 days). Body mass index 
will be calculated as: BMI = (weight in kilograms / (height in meters x height in meters)). 
6.3 Medical History 
During pre-operative screening and on Day 0, the patient’s medical history will be 
described for the following body systems including severity or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; haematopoietic/lymphatic; dermatological; and 
genito-urinary. 
6.4 Physical Examination 
Physical examination will be performed at pre-operative screening, before and after 
administration of the study products during surgery (Day 0), at Day 5 (±2 days), at 
Day 30 (±3 days), at the study completion Day 60 (±3 days), and at any unscheduled 


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follow-up visit on the following body systems with special attention to the general 
appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, and skin.  
During pre-operative screening, if an abnormal condition is detected, the condition will 
be described on the medical history eCRF. At study visits, if a new abnormal condition or 
worsened abnormal pre-existing condition is detected, the condition will be described on 
the AE eCRF. If the abnormal value was not deemed an AE because it was due to an 
error, due to a pre-existing disease, not clinically significant, a symptom of a 
new/worsened condition already recorded as an AE, or due to another issue that will be 
specified, the investigator will record the justification on the AE eCRF. 
6.5 Neurological Assessment 
Neurological assessment will be performed at pre-operative screening, before and after 
administration of the study products during surgery (Day 0), at Day 5 (±2 days), at 
Day 30 (±3 days), at the study completion Day 60 (±3 days), and at an unscheduled 
follow-up visit.  
During pre-operative screening, if an abnormal condition is detected, the condition will 
be described on the medical history eCRF. At study visits, if a new abnormal condition or 
worsened abnormal pre-existing condition is detected, the condition will be described on 
the AE eCRF. If the abnormal value was not deemed an AE because it was due to an 
error, due to a pre-existing disease, not clinically significant, a symptom of a 
new/worsened condition already recorded as an AE, or due to another issue that will be 
specified, the investigator will record the justification on the AE eCRF. 
6.6 Vital Signs 
Vital signs will include body temperature (tympanic; °C), respiratory rate (breaths/min), 
pulse rate (beats/min), and systolic and diastolic blood pressure (mm Hg). Blood pressure 
will be measured when patients are in the supine position.  
Vital signs will be measured at pre-operative screening, before and after administration of 
the study products during surgery (Day 0), at Day 5 (±2 days), at Day 30 (±3 days), at the 
study completion Day 60 (±3 days), and at any unscheduled follow-up visit.  
Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 6.12 
and record the medical diagnosis [preferably], symptom, or sign on the AE eCRF).  


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Additional tests and other evaluations required to establish the significance or aetiology 
of an abnormal value, or to monitor the course of an AE should be obtained when 
clinically indicated. Any abnormal value that persists should be followed at the discretion 
of the investigator.  
6.7 Electrocardiogram 
A resting 12-lead electrocardiogram (ECG) will be performed at pre-operative screening 
and on Days 0, 5 (±2 days), 30 (±3 days), and 60 (±3 days). Patients should be rested for 
at least 5 minutes in the supine position before the ECG evaluation. Electrocardiograms 
will be performed before blood sample collection. 
Parameters that will be recorded include: heart rate, ventricular polarization (QRS), the 
interval that extends from the beginning of the P wave (the onset of atrial depolarization) 
until the beginning of the QRS complex (PR interval), the uncorrected measure of the 
time between the start of the Q wave and the end of the T wave in the heart's electrical 
cycle (QT interval), and rhythm analysis.  
The pre-operative screening ECG is not necessary if a recent ECG is available as of 
≤3 months before planned surgery.  
6.8 Clinical Laboratory Tests  
6.8.1 Laboratory Parameters  
Clinical laboratory parameters will be assessed at pre-operative screening and at Days 0, 
5 (±2 days), 30 (±3 days), 60 (±3 days), and any unscheduled follow-up visit (see 
Appendix 4 for tests and timing). For evaluation of clinical laboratory findings, the 
investigator will use the Common Terminology Criteria for AEs (CTCAE) toxicity 
grading scale Version 4.03 as described in Appendix 5.  
Women of childbearing potential will be required to take a blood beta-human chorionic 
gonadotropin (β-hCG) test at pre-operative screening and a urine β-hCG test the day of 
surgery (Day 0).  
Patients will be in a seated or supine position during blood collection. Clinical laboratory 
tests that will be conducted are presented in Table 1. 


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Table 1. Clinical Laboratory Tests 
Serum Chemistry 
Haematology 
Coagulation 
Spinal Fluid Leak 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate  
Bilirubin (total and direct) 
Blood urea nitrogen 
C-reactive protein
Calcium
Chloride
Creatinine
Glucose
Glycated haemoglobin
(HbA1c)
Potassium
Sodium
Total protein
Haemoglobin 
Haematocrit 
Red blood cell (RBC) 
count 
Platelet count 
White blood cell (WBC) 
count and differential  
Prothrombin time 
Activated partial 
thromboplastin time 
(aPTT) 
International 
normalised ratio 
(INR) 
Beta-2 
(β2)-transferrin 
(CSF) / Beta-trace 
protein (CSF) 
Serology 
Pregnancy Test 
Human 
immunodeficiency 
virus (HIV), 
hepatitis A virus 
(HAV), hepatitis B 
virus (HBV), 
hepatitis C virus 
(HCV), hepatitis E 
virus (HEV), 
parvovirus B19 
(B19V)  
Beta-human 
chorionic 
gonadotropin 
(β-hCG) (blood or 
urine) 
6.8.2 Sample Collection, Storage, and Shipping 
Blood will be obtained for assessment of haematology and clinical chemistry parameters 
at pre-operative screening, day of surgery (Day 0), Day 5 (±2 days), Day 30 (±3 days), 
and at study completion (Day 60 [±3 days]). At study completion, only limited 
haematology and clinical chemistry parameters will be taken (Appendix 4). Also, if an 
Unscheduled Follow-up visit occurs between the date of discharge and study completion 
(Day 60 [±3 days]), haematology and clinical chemistry parameters will be repeated. 
Haematology and clinical chemistry assessments will be performed at the investigational 
site. See Appendix 4 for specific details. 


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6.8.3 Toxicity Grading Scale 
Laboratory values will be evaluated according to the CTCAE Version 4.03 toxicity 
grading scale and captured on the eCRF by the investigator. Grades 3 and 4 will be 
considered AEs and reported appropriately. The laboratory parameters and the 
corresponding grading scale are provided in Appendix 5. Laboratory parameters not 
covered by the CTCAE toxicity scale will be evaluated according to normal values 
assigned by the local laboratory.  
6.8.4 Surgical Site Infections 
The surgeon or designated physician will evaluate the patients for SSIs on Follow-up 
visits at Days 5 (±2 days), 30 (±3 days), and 60 (±3 days), and at unscheduled visits 
according to the US Centers for Disease Control and Prevention (CDC)/National 
Healthcare Safety Network (NHSN) guidelines found in Appendix 8. 
6.9 Dispensing Study Drug 
6.9.1 FS VH S/D 500-s 
The IP for this protocol is FS VH S/D 500 s-apr in its frozen presentation and must be 
thawed and prepared using the method described in Appendix 6. When applying 
FS VH S/D 500 s-apr, the investigator will apply the IP by dripping the FS onto the 
suture lines. Use of the spray FS formulation (which utilises pressurized gas in the 
dispensing mechanism) is prohibited during neurosurgery, due to the risk of 
pneumocephalus, as well as other associated risks, such as air embolism, tissue rupture, 
or gas entrapment with compression, which may be life-threatening.  
Approximately 2 mL FS VH S/D 500 s-apr will be needed to cover a suture line 10 cm 
long and 1 cm wide (10 cm2), as per the package insert. Before application, the wound 
surface should be as dry as possible. Only a thin layer of FS VH S/D 500 s-apr should be 
applied. Excessive thickness of the fibrin layer may interfere with the product’s efficacy 
and the wound healing process. After application of FS VH S/D 500 s-apr, the IP must 
rest 3 minutes before the test for CSF leak is evaluated (visual inspection/Valsalva 
manoeuvre) in order for the IP to polymerize and get sufficient tensile strength.  
If needed, a second application of FS VH S/D 500 s-apr is allowed as evaluated by the 
surgeon; however, avoid re-application of FS VH S/D 500 s-apr to a pre-existing 
polymerized FS VH S/D 500 s-apr layer because FS VH S/D 500 s-apr may not adhere 
firmly to a polymerized layer. If a second application of FS VH S/D 500 s-apr is given, it 
is mandatory to wait for additional 3 minutes before evaluating for CSF leaks (visual 


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inspection/Valsalva manoeuvre). There is a maximum of 2 allowable applications of the 
IP. 
Important for application of the IP:  
• The IP must be warmed to 37°C and maintained at that temperature until ready to 
apply. 
• Keep the dura surface adjacent to the suture as dry as possible immediately before 
and during application of the IP.  
• Expel the first 5 drops from the syringe then begin IP application. 
• Apply the IP in a thin layer only.  
• In order to provide optimised polymerization, it is important that the IP is not 
interfered with or manipulated during the resting time of 3 minutes.  
 
If application is interrupted, clogging will occur immediately in the cannula. Replace the 
application cannula with a new one immediately before application is resumed.  
It is important to note that the sealer protein and thrombin solutions are denatured by 
alcohol, iodine, or heavy metal ions. If any of these substances have been used to clean 
the wound area, the area must be thoroughly rinsed before application of 
FS VH S/D 500 s-apr. The wound surface and margins should be as dry and clear of 
clots, fluids, hemostatic agents, and loose connective tissue as possible Oxidized 
cellulose-containing preparations may reduce the efficacy of FS VH S/D 500 s-apr and 
should not be used as carrier materials. Additionally, the safety and efficacy of the 
combined use of FS VH S/D 500 s-apr with other biocompatible carrier materials has not 
been evaluated in controlled clinical trials. 
6.9.2 DuraSeal Dural Sealant 
The control for this protocol, DuraSeal Dural Sealant, must be prepared using the method 
described in Appendix 7. When applying the DuraSeal hydrogel, the investigator will 
apply the product by using the DuraSeal Systems applicator to spray the hydrogel onto 
the suture lines. DuraSeal must be used within 1 hour of preparation. 
Before application, the wound surface and margins (2 – 3 mm) around the durotomy edge 
should be as dry and clear of clots, fluids, hemostatic agents, and loose connective tissue 
as possible. Only a thin layer (1 – 2 mm) of the DuraSeal hydrogel should be applied.  
After application of the hydrogel, the patient will be evaluated for CSF leakage (visual 


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inspection/Valsalva manoeuvre) in order for the product to polymerize and get sufficient 
tensile strength.  
If needed, a second application of the DuraSeal hydrogel is allowed as evaluated by the 
surgeon; however, avoid re-application of the DuraSeal hydrogel to a pre-existing 
polymerized DuraSeal because the hydrogel may not adhere firmly to a polymerized 
layer. If a second application of DuraSeal is given, the patient will be evaluated for CSF 
leakage (visual inspection/Valsalva manoeuvre). There is a maximum of 2 allowable 
applications of the control.  
If application is interrupted and the spray tip is plugged, remove the spray tip, wipe the 
applicator tip, and attach a new spray tip and continue delivery. Hydrogel application 
beyond the edges of the dural margin may be removed with scissors or mechanical 
disruption. Irrigation immediately after the sealant has solidified is permitted. 
6.10 Primary Efficacy Assessments 
The primary assessment is defined as the proportion of patients who have neither of the 
following:  
• Intra-operative CSF leakage from dural repair after up to 
two FS VH S/D 500 s-apr/control applications during Valsalva manoeuvre 
(25 cm H2O for up to 5 - 10 seconds) 
• Post-operative CSF leakage within 30 (+3) days post-operatively. 
 
Success is defined as: an intra-operative watertight closure of the dura after suturing 
during surgery after test with the Valsalva manoeuvre (25 cm H2O for up to 
5 - 10 seconds) and no CSF leakage within 30 (+3) days post-operatively.  
Failure is defined as: an intra-operative non-watertight closure, which consists of any 
overt flow, seepage, weeping, or sweating of CSF through the dura suture line, regardless 
of volume, during surgery or within 30 (+3) days post-operatively.  
6.11 Secondary Efficacy Assessments 
Secondary efficacy assessments will include:  
• Incidence of intra-operative CSF leakage following final Valsalva manoeuvre 
• Incidence of CSF leaks within 30 (+3) days post-operatively 
• Time in surgery (minutes) 


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• Time from dural closure (application of IP) until end of surgery 
• Length of stay in hospital (days) 
 
All post-operative CSF leaks will be primarily diagnosed based on a detailed history and 
physical examination including neurological examination. Although not standard of care 
post-operatively, imaging tests such as computed tomography/magnetic resonance 
imaging will only be considered if there is a high clinical suspicion of CSF leakage. For 
example, if CSF leaks externally (eg, incisional leaks, otorrhea, or rhinorrhea), or if there 
is any bulging suggesting subcutaneous fluid collection at the incision site, needle 
aspiration and the beta-2 transferrin test or beta-trace protein will be used to confirm the 
presence of CSF. 
6.12 Safety Assessments 
The following secondary safety assessments will be performed during this study:  
• Incidence of CSF leaks within 60 (+3) days post-operatively 
• Incidence of AEs up to 60 (+3) days post-operatively  
• Incidence of SSI according to US NHSN within 30 (+3) days post-operatively  
• Number of unplanned interventions within 30 (+3) days post-operatively 
• Laboratory values and vital signs (e.g., elevated WBC count, fever [temperature 
>100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial 
pressure <60]).  
Adverse events will be evaluated as described in Section 6.13.  
Unplanned interventions include the management of meningitis and a deep infection, 
minimally invasive procedures, the return to the operating room for neurosurgical 
complications other than a CSF leak or pseudomeningocele formation, or those related to 
the patient’s pre-existing condition during the 30-day follow-up period following original 
surgical procedure. 
Surgical site infections will be evaluated by the surgeon or designated physician 
according to CDC/NHSN criteria as specified in Appendix 8. 
Vital signs and laboratory values will be evaluated as described in Sections 6.6 and 6.8. 


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6.13 Adverse Events Assessments 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product (IP). 
(ICH E6 [R2]).  
An elective procedure/surgery that occurs during the course of the study (ie, prior to 
signing the ICF), but is being performed for a documented pre-existing condition and was 
pre-planned prior to study entry will not qualify as an AE.  If, however, there is an 
increase in the severity, duration, or frequency of a pre-existing disease, the event must 
be described on the AE eCRF. 
An AE can result from the use of the study product or control in accordance with the 
protocol, as well as from an accidental or intentional misuse of the study product/control 
or any other treatment error such as unintentional administration or use of another 
product during the course of the study.  
6.13.1 Performing Adverse Events Assessments 
During the course of the study, the investigator or designee will routinely monitor and 
solicit each patient for the occurrence of any AEs, no matter how common they are for a 
particular patient and regardless of the causality. All AEs (initial, follow-up) will be 
entered in the eCRF and SAEs (initial, follow-up, upgraded AEs, revisions/amendments) 
will simultaneously be submitted using a paper SAE Report (SAER) Form.    
If a definitive diagnosis has been medically established by the investigator, this diagnosis 
should then be recorded as the AE. If a definitive diagnosis has not been medically 
established, the signs and symptoms should then be recorded as the AEs using standard 
medical terminology, in order to avoid the use of vague, ambiguous, or colloquial 
expressions.  
If a patient experiences an AE, but also additionally a complication of the AE (eg, 
myocardial infarction with congestive heart failure), both the AE and the additional 
medical complication should be collected and recorded on CRFs as separate AEs.  
Each AE will be evaluated by the investigator for seriousness, severity, and causal 
relationship to IP/control exposure or study procedure.  


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For each AE, the outcome (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (ie, none, drug/device withdrawn, not applicable (AE occurred 
before drug/device application), or unknown) will also be recorded on the AE eCRF. If 
the severity rating for an ongoing AE changes before the event resolves, the stop date of 
this AE will be recorded and a new AE report will be entered with the new severity 
rating.  
Deviations from the protocol-specified dosage (including use of more than the maximum 
2 allowable applications of IP/control), treatment errors (including incorrect route of 
administration, use of an incorrect product, and deviations from the protocol-defined 
dosing and application schedule), failures of expected pharmacological actions, and 
unexpected therapeutic or clinical benefits will be followed with regards to occurrence of 
AEs, lack of efficacy, and/or other observations because these events may be reportable 
to regulatory authorities. 
6.13.2 Timing 
In this study, all SAEs and related AEs will be recorded and reported to Baxter Global 
Pharmacovigilance within 24 hours of awareness beginning at the time the ICF is signed 
until the event has resolved, stabilized, or returned to baseline or for 30 days after the 
patient’s study completion/termination visit, whichever comes first. If an investigator 
becomes aware of an SAE occurring in a patient after study completion, the SAE must be 
reported on the SAER Form within 24 hours after awareness; no additional reporting on 
eCRFs is necessary. 
Adverse events occurring prior to the initiation of the first study procedure will be 
recorded as signs and symptoms in the patient’s medical history. Adverse events 
occurring between pre-operative screening and the administration of study treatment will 
be considered as unrelated to study treatment.  
For events assessed as not related or unlikely related and occurring within 2 weeks after 
administration of IP/control, the investigator shall provide the alternative etiology. These 
causality definitions will also be used to assess the relationship of an AE with a 
study-related procedure(s), if necessary. 
6.13.3 Severity 
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:  


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• Mild: The AE is a transient discomfort and does not interfere in a significant 
manner with the patient’s normal functioning level and/or the AE resolves 
spontaneously or may require minimal therapeutic intervention.  
• Moderate: The AE produces limited impairment of function and may require 
therapeutic intervention and/or the AE produces no sequela/sequelae.  
• Severe: The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern and/or the AE produces 
sequela/sequelae, which require (prolonged) therapeutic intervention.  
 
These severity definitions will also be used to assess the severity of an AE with a 
study-related procedure(s), if necessary. 
6.13.4 Relationship 
Causality is a determination of whether there is a reasonable possibility that the 
IP/control is etiologically related to/associated with the AE. Causality assessment 
includes, assessment of temporal relationships, de-challenge/re-challenge information, 
association (or lack of association) with underlying disease, presence (or absence) of a 
more likely cause, and physiological plausibility. For each AE, the investigator will 
assess the causal relationship between the IP/control and the AE using his/her clinical 
expertise and judgment according to the following most appropriate algorithm for the 
circumstances of the AE: 
• Not related (both circumstances must be met).  
1. Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs.  
2. Is not associated with the IP/control (ie, does not follow a reasonable temporal 
relationship to the administration of IP/control or has a much more likely 
alternative aetiology). 
• Unlikely related (either 1 or both circumstances are met). 
a. Has little or no temporal relationship to the IP/control. 
b. A more likely alternative aetiology exists. 
• Possibly related (both circumstances must be met).  
a. Follows a reasonable temporal relationship to the administration of IP/control.  


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b. An alternative aetiology is equally or less likely compared to the potential 
relationship to the IP/control. 
• Probably related (both circumstances must be met).  
a. Follows a strong temporal relationship to the administration of IP/control, 
which may include but is not limited to the following:  
a. Reappearance of a similar reaction upon re-administration (positive 
re-challenge).  
b. Positive results in a drug sensitivity test (skin test, etc.).  
c. Toxic level of the IP/control as evidenced by measurement of the 
IP/control concentrations in the blood or other bodily fluid. 
b. Another aetiology is unlikely or significantly less likely. 
 
6.13.5 Expectedness 
The only expected AEs that may be related to the IP/control in this study is the reaction 
to the IP/control (i.e., allergic reaction), which will be evaluated and if observed, 
standard-of-care will be applied. Patients with an aprotinin allergy will be excluded from 
the study. 
A suspected unexpected serious adverse reaction is any adverse reaction that is classified 
as serious and is suspected to be caused by the investigational drug but is not consistent 
with the information found in the product current IB.  For the purposes of this study, each 
unexpected AE experienced by a patient undergoing neurosurgical intervention will be 
recorded on the AE eCRF. 
6.13.6 Adverse Events of Special Interest 
Patients will be closely monitored for any signs of sterile meningitis during surgery and 
follow-up visits. In case signs and symptoms of sterile meningitis are present during the 
study, the investigator will assess these symptoms, and order and review diagnostic 
procedures, as appropriate, to confirm the diagnosis.  
6.13.7 Clinical Laboratory Adverse Events 
The investigator’s assessment of each relevant laboratory value will be recorded on the 
eCRF. For each abnormal laboratory value, the investigator will determine whether the 
value is considered clinically significant or not. For clinically significant values, the 
investigator will indicate if the values constitute a new AE and record the sign, symptom, 
or medical diagnosis on the AE eCRF. The investigator will also record on the AE eCRF 


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whether the clinically significant values are symptoms or related to previously recorded 
AEs, are due to pre-existing diseases, or are due to other issues. Adverse events that are 
grade 3 and 4 will be considered AEs and reported appropriately. The laboratory 
parameters and the corresponding grading scale are provided in Appendix 4. Additional 
tests and other evaluations required to establish the significance or aetiology of an 
abnormal value or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. 
Any seroconversion result for HIV, HAV, HBV, HCV, hepatitis E virus (HEV), or 
parvovirus B19 (B19V) shall be re-tested. 
6.13.8 Serious Adverse Events 
6.13.8.1 Definition 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: death, life-threatening AE, hospitalization, or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Moreover, reviewed and confirmed seroconversion for HIV, HAV, HBV, HCV, HEV, or 
B19V will also be important medical events that shall qualify as an SAE. 
6.13.8.2 Reporting Serious Adverse Events 
The investigator will report all SAEs to the pharmacovigilance safety desk of the contract 
research organisation (CRO). The CRO will verify that the applicable laws/requirements 
for reporting SAEs to the Institutional Review Boards (IRBs)/Ethics Committees (ECs) 
are followed by the sponsor (Baxter). The sponsor will expedite the SAER forms to the 
appropriate regulatory authority(ies).   


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•
ALL SAEs ARE TO BE REPORTED TO THE CRO’S SAFETY DESK ON THE
SAER FORM WITHIN 24 HOURS AND TRANSMITTED ALONG WITH
ANY DE-IDENTIFIED SUPPORTING DOCUMENTATION IN THE
ENGLISH LANGUAGE TO THE SPONSOR WITHIN 24 HOURS OF
BECOMING AWARE OF THE EVENT
See SAER form for contact information. 
Further details are also available in the study team roster. 
For definitions and information on the assessment of these events, refer to the following: 
•
Section 6.13, Adverse Events Assessments
•
Section 6.13.1, Performing Adverse Events Assessments
•
Section 6.13.8, Serious Adverse Events 
6.13.9 Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect patients participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following:  
•
Immediate change in study design or study procedures
•
Temporary or permanent halt of a given clinical trial or trials
•
Any other immediate action taken in order to protect clinical trial participants
from immediate hazard to their health and safety.
The investigator may take appropriate urgent safety measures in order to protect patients 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorisation from the sponsor. In the 
event(s) of an apparent immediate hazard to the patient, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The investigator 
will also ensure the responsible IRB/EC and national competent authority (NCA) is 
notified of the urgent measures taken in such cases according to local regulations. The 
CRO should verify that the responsible IRB/EC and the sponsor (Baxter) have been 
informed of the event in an expedited manner as stated above. 


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6.13.10 Untoward Medical Occurrences 
Untoward medical occurrences occurring before the first exposure to IP/control are not 
considered AEs; however, each serious untoward medical occurrence experienced before 
the first IP/control exposure (ie, from the time of signed ICF up to but not including the 
first IP/control exposure) will be described on the SAER form. 
6.13.11 Treatment-emergent Adverse Events 
A treatment-emergent AE is defined as any AE that occurs after the onset of study 
treatment administration through the end of the study. 
6.14 Concomitant Medication Assessments 
Ongoing prior medications will be recorded as concomitant medication once the study 
treatment has been initiated. During treatment, concomitant medications and therapies 
(including dose, frequency, start and stop dates, and indication for use), will be recorded 
in the eCRF by study site personnel on a daily basis. 
6.15 Non-Medical Complaints 
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety, and performance of the product but does 
not result in an AE. Non-medical complaints include but are not limited to the following: 
• A failure of a product to exhibit its expected pharmacological activity and/or 
design function (eg, reconstitution difficulty).  
• Missing components.  
• Damage to the product or unit carton.  
• A mislabelled product (eg, potential counterfeiting/tampering).  
• A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims. 
 
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, the defective product(s) will be returned to 
the sponsor for inspection and analysis according to procedures. 
6.16 Removal of Patients from the Trial or Study Drug 
A patient is considered to have completed the study when he/she ceases active 
participation in the study because the patient has, or is presumed to have, completed all 


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study procedures according with the protocol (with or without protocol deviations). Any 
other cases are classified as discontinuation. 
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation eCRF, including: Completed, AE (eg, death), 
discontinuation by patient (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the patient], dropout), physician decision (eg, pregnancy, progressive 
disease, protocol violation[s], recovery), study terminated by sponsor, or other (reason to 
be specified by the investigator [eg, technical problems]). Screening failures will be 
recorded on the Screening Failures form. Regardless of the reason, all data available for 
the patient up to the time of completion/discontinuation should be recorded on the 
appropriate eCRF. 
Every effort will be made to have discontinued patients complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a patient terminates participation in the study and does 
not return for the completion/termination visit, his/her last recorded assessments shall 
remain recorded with his/her last visit. The reason for discontinuation will be recorded 
and the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. If additional assessments are required, the 
assessments shall be recorded separately. Assessments to be performed at the termination 
visit (including cases of withdraw or discontinuation) can be found in Appendix 2 
(Schedule of Study Procedures and Assessments) and Appendix 4 (Clinical Laboratory 
Assessments). 
In the event of patient discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor.  
6.17 Appropriateness of Measurements 
Measurements to be performed during the course of the study (with the following 
exceptions) are standard for the indication or patient population under study:  
•
The Valsalva manoeuvre, while not standard, is necessary to assess
intra-operative CSF leakage that may not be easily identified on visual inspection.


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7. STUDY ACTIVITIES
7.1 Screening and Study Visits 
The study site is responsible for maintaining an enrolment/screening log that includes all 
patients enrolled. The log will also serve to document the reason for screening failure.  
The overall study design is illustrated in Appendix 1. Details on the procedures to be 
performed at each study visit, including screening, can be found in Appendix 2 (Schedule 
of Study Procedures and Assessments) and Appendix 4 (Clinical Laboratory 
Assessments). 
7.2 Pre-operative Screening Visit (Days -30 to -1) 
•
Obtain IC.
•
During the pre-operative screening visit, the investigator will determine if the 
patient meets all pre-operative inclusion criteria and none of the pre-operative 
exclusion criteria.
•
Record demographics (including weight, height, and body mass index), medical 
history, physical examination results, an assessment of neurological status, vital 
signs, and ECG results.
•
Measure baseline clinical laboratory values (see Appendix 4).
•
Record AEs.
•
Record concomitant medications and non-drug therapies. 
7.3 Procedures for Day 0 Treatment (Pre-operative) 
•
Re-assess patient to confirm that the patient is ready for surgery and meets the 
pre-operative inclusion criteria and none of the exclusion criteria. No changes in 
health status have occurred between the initial screening and the day of surgery 
that would affect the patient and/or study conduct.
•
Record medical history, physical examination results, an assessment of 
neurological status, vital signs, and weight.
•
Perform a urine screening for pregnancy test (for women of childbearing 
potential). If screening occurred more than 48 hours prior to performing the 
operation, baseline clinical laboratory values (see Appendix 4) will be measured.
•
Record AEs. 


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• Record concomitant medications and non-drug therapies. 
• Perform pre-operative randomisation (surgeon remains blinded to treatment until 
intra-operative screening is complete, as described in Section 7.4) 
 
7.4 Procedures for Day 0 Treatment (During and After Surgery) 
• Perform intra-operative screening for inclusion and exclusion criteria and a check 
for CSF leak after placing primary suture. 
• Randomised treatment is revealed to the surgeon 
• Apply IP or control treatment to the CSF leak site. 
• Administer peri-operative antibiotic. 
• Collect the following surgery details: 
• Start (skin cut), 
• Start (application of IP/control), 
• End (last skin suture), 
• Length of sutured durotomy (cm), 
• Surgical complications, 
• Suture type used for dura closure (brand, type, size), 
• Suture closure technique (eg, continuous simple, continuous locked, 
interrupted), 
• Use of autologous or non-autologous dural material, 
• Use of tenting sutures (Yes/No), 
• Rescue therapy (Yes/No, if Yes: reason, brand, type, technique). 
• Assess primary endpoint part 1: check for CSF leakage (Yes/No) after up to two 
IP/control applications during the Valsalva manoeuver (up to 25 cm H2O for up to 
5 - 10 seconds). Any visible CSF is considered positive for CSF leak. 
• Post-operatively, monitor vital signs and perform physical examination, 
neurological assessment, and ECG. 
 


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7.5 Procedures for Day 5 (±2 Days) or the Day Before Discharge (Whichever Comes 
First), and Day 30 (±3 Days) 
•
Record physical examination results, an assessment of neurological status, vital 
signs, ECG, and weight.
•
Measure clinical laboratory values (see Appendix 4).
•
Assess primary endpoint part 2: check for CSF leakage.
•
Assess surgical site.
•
Document any need for surgical revision.
•
Check drain duration and output, if present.
•
Document the number of unplanned interventions.
•
Record AEs.
•
Record concomitant medications and non-drug therapies. 
7.6 Procedures for Day 60 (±3 Days) and/or Study Completion 
•
Record physical examination results, an assessment of neurological status, vital 
signs, ECG, and weight.
•
Measure clinical laboratory values (see Appendix 4).
•
Perform assessment of CSF leak.
•
Assess surgical site.
•
Document any need for surgical revision.
•
Document length of stay and number of days in the intensive care unit (ICU).
•
Document the number of unplanned interventions.
•
Record AEs.
•
Record concomitant medications and non-drug therapies. 
7.7 Procedures for Unscheduled Follow-up (Between Days 5 [±2] to 60 [±3]) 
•
Record physical examination results, an assessment of neurological status, and 
vital signs.
•
Measure clinical laboratory values (see Appendix 4).
•
Perform assessment of CSF leak.
•
Assess surgical site. 


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• Document any need for surgical revision. 
• Record AEs. 
• Record concomitant medications and non-drug therapies. 


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8. QUALITY CONTROL AND ASSURANCE 
8.1 Auditing 
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP), the IRB/IEC and applicable regulatory guidelines/requirements. The 
investigator will permit auditors to visit the study site, as described in the Clinical Study 
Agreement. Auditing processes specific to the study will be described in the auditing 
plan. 
8.2 Non-compliance with the Protocol 
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the patient. In the event(s) of an apparent immediate hazard to the patient, the 
investigator will notify the CRO immediately by phone and will confirm notification to 
the CRO in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The investigator will also ensure the responsible IRB/EC/NCA is notified 
of the urgent measures taken in such cases according to local regulations.  
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the CRO may terminate the investigator’s participation. The CRO will notify 
the IRB/EC and applicable regulatory authorities of any investigator termination. 


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9. PLANNED STATISTICAL METHODS
9.1 General Considerations 
The Statistical Analysis Plan (SAP) is a separate document that will provide a more 
technical and detailed elaboration of the principal features stated in the protocol. Any 
deviations from the planned analyses will be described and justified in the final clinical 
trial report. 
9.2 Determination of Sample Size 
This study is designed to show non-inferiority (NI) of FS VH S/D 500 s-apr compared to 
DuraSeal Dural Sealant based on the primary composite efficacy endpoint. The 
proportion of patients meeting the composite primary endpoint is assumed to be 
% for 
FS VH S/D 500 s-apr and 
% for DuraSeal. Using a non-inferiority margin of 10% 
(the largest clinically acceptable difference), a 1-sided Type 1 error rate (α) of 2.5%, a 
statistical power (1-β) of 80%, that one interim analysis is performed after 50% of the 
patients complete the study, the sample size estimation results in 202 evaluable patients. 
Assuming a group sequential design utilising O’Brien-Fleming boundaries, the study may 
be stopped early for futility if a p-value >0.2486 is observed at the interim. The 
estimation of sample size was performed using 
 software (
, 
).  
The primary analysis will be performed on the per protocol set (PPS). Assuming that the 
PPS is 10% less than the total number of randomised patients, 112 patients per treatment 
group should be randomised, and there will be 224 patients in total. 
9.2.1 Justification of Non-Inferiority Margin 
The 10% NI margin is mainly based on literature review, the screening of multiple key 
opinion leaders (clinical judgment), and a previous clinical study for a comparable 
product that led to biologic license application (BLA) approval.  
•
Literature review (Weber 2012)8: In a retrospective analysis of 1395 cranial 
surgeries, post-operative CSF leaks occur in approximately 7.7%, across all types 
of cranial surgeries. However, tight dural sutures by inspection were followed by 
CSF leaks in 4.7%. Tight suturing of the dura mater with additional securing and/
or augmentation of the suture by a different technique (covering with muscle or 
fascia flab, gelitta, fibrin glue, hydrogel gel, or others) is performed 68% of the 
time. The subgroups with different dural closure augmentation techniques 


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(fleece-bound sealant, glue, dural-plasties, etc.) were too small to detect any 
statistically demonstrable effect on CSF leaks after cranial surgery. 
• Clinical judgment: Based upon discussion with clinicians (neurosurgeons) on the 
use of dural sealants as an adjunct to suture line, the consensus was that NI could 
be claimed if the maximum difference of success rate (ie, CSF leakage free) 
between the new treatment (Tisseel) and the current treatment (DuraSeal) is 10%, 
with the assumption that the proportion of patients meeting the composite primary 
endpoint is at least 85.0% for DuraSeal.   
• Previous clinical study: A 10% NI margin was used in a previous Phase III 
pivotal, NI study. In this study, a new dural sealant (Adherus) was compared to 
the same control (DuraSeal) and the study design including patient population, 
eligibility criteria, and the primary endpoint was very similar to the current 
Tisseel study.29 Thus, the assumed proportion of 90.6% for DuraSeal in the 
current Tisseel study is based on results of this previous study evaluating Adherus 
and DuraSeal. 
 
9.3 Analysis Populations  
9.3.1 Full Analysis Set (FAS) 
The patients who were randomised and treated with at least 1 dose of IP/control will be 
included in the Full Analysis Set (FAS).   
9.3.2 Per Protocol Set (PPS) 
The patients included in the FAS without any major protocol deviations, which could 
impact the primary endpoint assessment, will be included in the Per Protocol Set (PPS). 
The PPS is defined by the following:  
• Patients who meet all inclusion criteria and do not meet any exclusion criteria.  
• Patients who are randomised and treated according to the randomisation scheme.  
• Patients with no major protocol deviations which could impact the primary 
endpoint assessment.  
• Availability of primary endpoint assessment.  
 


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Furthermore, any other major protocol violations, such as serious unforeseen violations 
deemed to invalidate the data and affect the conclusions of the study, will lead to the 
exclusion of patients from the PPS. 
9.3.3 Safety Analysis Set 
The patients who received at least 1 dose of IP/control will be included in the Safety 
Analysis Set. Patients will be analysed as treated (in case of incorrect randomisations). 
9.4 Methods of Analysis 
The efficacy endpoints will be analysed for the FAS and the PPS, with the PPS being 
considered as primary and the FAS as supportive.   
The safety endpoints will be analysed for the safety data using the safety analysis set.  
Categorical data will be summarised using frequencies and percentages, while continuous 
data will be presented using descriptive summary statistics (the number of patients [N], 
mean, standard deviation, median, minimum, and maximum).  
No imputation of missing data will be performed, unless otherwise specified. 
All efficacy and safety endpoints will be listed in patient data listings. 
9.4.1 Demographics and Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented 
for the FAS population by treatment group and total in order to assess the degree of 
similarity achieved. 
9.4.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients who have neither of the 
following: 
• Intra-operative CSF leakage from dural repair after up to two 
FS VH S/D 500 s-apr/control applications during Valsalva manoeuver (25 cm 
H2O for up to 5 - 10 seconds) 
• Post-operative CSF leakage within 30 (+3) days post-operatively 
 
The specific hypotheses of the proportion difference to be tested are as follows: 
H0: PFS – PDS ≤ -0.10 


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Ha: PFS – PDS > -0.10 
where 
PFS = the proportion of patients not meeting the 2 criteria (ie, no intra-operative CSF 
leakage and no post-operative CSF leakage) for the FS VH S/D 500 s-apr treatment 
group, and 
PDS = the proportion of patients not meeting the 2 criteria (ie, no intra-operative CSF 
leakage and no post-operative CSF leakage) for the DuraSeal Dural Sealant treatment 
group. 
The primary composite efficacy endpoint, proportion of patients not meeting the 
2 criteria (ie, no intra-operative CSF leakage and no post-operative CSF leakage), will be 
investigated by a 2-sided test for non-inferiority using logistic regression, taking into 
account the following covariates: study center and surgery region. Non-inferiority of FS 
VH S/D 500 s-apr to DuraSeal Dural Sealant will be assessed using the confidence 
interval approach and a NI margin of 10%.  
9.4.3 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
• Incidence of intra-operative CSF leakage following final Valsalva manoeuver 
• Incidence of CSF leaks within 30 (+3) days post-operatively 
• Time in surgery (minutes) 
• Time from dural closure (application of IP) until end of surgery 
• Length of stay in hospital (days)  
 
The logistic regression approach used for the primary efficacy endpoint will also be used 
to calculate the proportions of patients with incidence of intra-operative CSF leakage 
following final Valsalva manoeuver and incidence of CSF leaks within 30 (+3) days 
post-operatively.  
The time in surgery, time from dural closure until end of surgery, and the length of stay 
in hospital will be compared between the 2 groups using a Wilcoxon rank sum test.  


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9.4.4 Secondary Safety Endpoints 
The secondary safety endpoints are the following: 
• Incidence of CSF leaks within 60 (+3) days post-operatively 
• Incidence of AEs up to 60 (+3) days post-operatively 
• Incidence of SSIs according to US NHSN within 30 (+3) days post-operatively 
• Number of unplanned interventions within 30 (+3) days post-operatively 
• Laboratory values and vital signs (e.g., elevated WBC count, fever [temperature 
>100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial 
pressure <60]). 
 
The logistic regression approach used for the primary efficacy endpoint will be used to 
calculate the proportions of patients with: incidence of CSF leaks within 60 (+3) days 
post-operatively, and incidence of SSIs according to NHSN within 30 (+3) days post-
operatively. The duration and incidence of each laboratory and vital sign abnormality will 
be recorded. Abnormal laboratory values will be observed, followed, and managed by the 
investigator for a return to baseline, per standard of care. 
The number of unplanned interventions within 30 (+3) days post-operatively will be 
compared between the 2 treatment groups using a Wilcoxon rank sum test.  
An AE overview summary table will be prepared including the number of patients 
reporting an AE, the percentage of patients (%) with an AE, and the number of events 
reported, for the following categories:  
1. Deaths.  
2. SAEs.  
3. AEs leading to withdrawal.  
4. Severe AEs.  
5. Related AEs. 
6. AEs of special interest. 
 
Adverse events will be tabulated by body system using the Medical Dictionary for 
Regulatory Activities (MedDRA). The table will display the total number of patients 
reporting an AE, the percentage of patients (%) with an AE, and the number of events 


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reported by system organ class (SOC) and preferred term. In addition, tables will be 
summarised by SOC, preferred term, and severity.  
These tables will be produced for: 
• All AEs. 
• AEs with an incidence ≥5% of patients in any treatment arm. 
• Non-serious AEs with an incidence ≥5% of patients in any treatment arm. 
• AEs by causality (related/unrelated). 
• AEs leading to death. 
• AEs by severity. 
• SAEs. 
• AEs leading to withdrawal. 
 
Listings will be prepared for: 
• All AEs sorted by center and patient.  
• SAEs. 
• AEs leading to death. 
• AEs leading to withdrawal. 
• Laboratory results and vital signs. 
 
9.5 Interim Analysis 
An interim analysis will be conducted after the completion of 50% of patients. A group 
sequential design utilising O’Brien-Fleming boundaries will be carried out. Basic 
demographic tables will be produced during the interim analysis. The study may be 
stopped early for futility if a p-value >0.2486 is observed. If the study is stopped early, a 
full analysis of all of the data will be produced. 


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10. ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The investigator will comply with the protocol (which has been approved/given 
favourable opinion by the IRB/EC/NCA), ICH GCP, the ethical principles of the 
Declaration of Helsinki, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. Whenever the term ‘investigator’ is noted in the protocol text, 
it may refer to either the principal investigator at the site, or an appropriately qualified, 
trained and delegated individual of the investigational site. Sub-investigators or other 
authorised study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required. 
10.2 Institutional Review Board (IRB) or Ethics Committee (EC) Approval 
Before the enrolment of patients into this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information to be provided will be 
reviewed and approved/given favourable opinion by the IRB/EC and applicable 
regulatory authorities. The IB will be provided for review and/or approval by the 
IRB/EC, if required. The IRB/EC’s composition will be documented and filed in to the 
respective investigator’s study file. The study will commence only upon the sponsor’s 
receipt of approval/favourable opinion from the IRB/EC and, if required, upon the 
sponsor’s notification of applicable regulatory authority(ies) approval, as described in the 
Clinical Study Agreement.  
If the protocol, any other information given to the patient or any other study documents 
(eg, IB, Investigational Medicinal Product Dossier) is substantially amended, the revised 
documents will be reviewed and approved/given favourable opinion by the IRB/EC and 
applicable regulatory authorities, where applicable. Any substantial protocol amendment 
will only be implemented upon the sponsor’s receipt of approval and, if required, upon 
the sponsor’s notification of applicable regulatory authority(ies) approval. 
10.3 Ethical Conduct of the Study 
This study will be conducted in accordance with the following guidelines: 
• Declaration of Helsinki (current version). 
• Current ICH Guidelines (ICH E6) for GCP Guidelines. 
• Basic principles defined in US 21 Code of Federal Regulations Part 312. 


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• IRBs/IECs requirements. 
• All local legal requirements of the countries, where the study is being conducted.  
 
10.4 Patient Information and Consent 
Investigators will choose patients for enrolment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients must personally sign and date an ICF before entering into the study according 
to applicable regulatory requirements and ICH GCP. Before use, the ICF will be 
reviewed by the sponsor and approved by the IRB/EC and regulatory authority(ies), 
where applicable. The ICF will include a comprehensive explanation of the proposed 
treatment without any exculpatory statements, in accordance with the elements required 
by ICH GCP and applicable regulatory requirements. Patients will be allowed sufficient 
time to consider participation in the study. By signing the ICF, patients agree that they 
will complete all evaluations required by the study, unless they withdraw voluntarily or 
are terminated from the study for any reason. 
The sponsor will provide to the investigator, in written form, any new information that 
significantly bears on the patients’ risks associated with IP exposure. The IC will be 
updated, if necessary. This new information and/or revised ICF, which have been 
approved by the applicable IRB/EC and regulatory authorities, where applicable, will be 
provided by the investigator to the patients who consented to participate in the study. 
10.5 Patient Confidentiality 
The investigator will comply with applicable patient privacy regulations/guidance as 
described in the Clinical Study Agreement. 
10.6 Training 
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting 
by Baxter staff, at the study site, and/or by instruction manuals. In addition, the study 
monitor will be available for consultation with the investigator and will serve as the 
liaison between the study site and the sponsor. A Baxter representative may be present 
for the first surgery for each site. 


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10.7 Insurance 
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the 
start of the clinical study. For patients treated according to the clinical study protocol, 
injury possibly arising from participating in this study is covered by the liability 
insurance of the sponsor, unless malpractice from the investigator.  
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
sponsor’s requirements. When reviewing data collection procedures, the discussion will 
also include identification and documentation of source data items. 
The sponsor/designee will monitor the site activity to verify that the: 
a. Data are authentic, accurate, and complete. 
b. Supporting data may be requested.  
c. Safety and rights of patients are being protected. 
d. Study is conducted in accordance with the currently approved protocol (including 
study treatment being used in accordance with the protocol). 
 
Any other study agreements, ICH GCP, IRBs/IECs, and all applicable regulatory 
requirements are met. The investigator and the head of the medical institution (where 
applicable) agrees to allow the monitor direct access to all relevant documents. 
10.9 Electronic Case Report Forms and Study Records 
Study documentation may include information defined as “source data”, records detailing 
the progress of the study for each patient, signed ICFs, correspondence with the IRB/EC 
and the study monitor/sponsor, enrolment and screening information, eCRFs, SAER 
forms, laboratory reports (if applicable), and queries. 
The investigator will comply with the procedures for data recording and reporting.  
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the eCRFs. The case report forms will be provided in electronic form. 
Electronic case report forms will be provided by the sponsor/designee, only authorised 
study site personnel will record or change data on the eCRFs. Changes to an eCRF will 


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require documentation of the reason for each change in the source documents. An 
identical (electronic/paper) version of the complete set of eCRFs for each patient will 
remain in the investigator file at the study site in accordance with the data retention 
policy and contractual obligations. 
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP and local legal requirements) and the standard 
operating procedures of the sponsor. Data management and control processes specific to 
the study will be described in the data management plan. 
10.10 Data Safety Monitoring Board 
This study will be monitored by an independent unblinded DSMB. The DSMB will be 
composed of 3 members, 2 members who are recognized experts in the field of 
neurosurgery clinical care and research and 1 member who is a biostatistician. One (1) of 
the members shall serve as chairperson of the DSMB. The DSMB neurosurgeons will not 
be involved in enrolling or treating study patients. 
The DSMB will monitor ongoing safety data (AEs and laboratory test results). The 
DSMB will review safety and efficacy data from the study after 50% of the patients have 
been completed, and will have the discretion to recommend stopping the trial due to 
safety, efficacy, or futility concerns. The rules to pause the study enrolment and 
re-evaluate the study are presented in Section 4.4. 
10.11 Protocol Violations/Deviations 
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the patient. In the event(s) of an apparent immediate hazard to the patient, the 
investigator will notify the sponsor immediately by phone and will confirm notification to 
the sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The investigator will also ensure the responsible IRB/EC and the 
responsible NCA, if applicable, is notified of the urgent measures taken in such cases 
according to local regulations. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the IRB/EC and applicable regulatory authorities of any investigator termination. 
10.12 Auditing 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s 
(or a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess 


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the performance of the study at the study site and of the study documents originating 
there. The investigator/institution will be informed of the audit outcome. In addition, 
inspections by regulatory health authority representatives and IRB(s)/EC(s) are possible. 
The investigator should notify the sponsor immediately of any such inspection. The 
investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector 
to discuss findings and any issues. Audits and inspections may occur at any time during 
or after completion of the study.  
10.13 Access to Source Documentation 
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the hospital records, 
medical records, clinical and office charts, laboratory notes, memoranda, evaluation 
checklists, outcomes reported by patients, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, 
X-rays, patient files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical study. 
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the IRB/EC, and inspections by 
applicable regulatory authorities, as described in the Clinical Study Agreement. If 
contacted by an applicable regulatory authority, the investigator will notify the sponsor of 
contact, cooperate with the authority, provide the sponsor with copies of all documents 
received from the authority, and allow the sponsor to comment on any responses, as 
described in the Clinical Study Agreement. 
10.14 Data Generation and Analysis 
The study data will be entered into a validated, audit-trailed, Part 11 compliant Electronic 
Data Capture system. Computerised data checks will be used to supplement manual 
review to check for data omissions, inconsistencies, and out of range values. 


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10.15 Retention of Data 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the Clinical Study Agreement. 
10.16 Financial Disclosure 
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and patient compensation policies, if applicable, as described in the Clinical Study 
Agreement. 
10.17 Publication and Disclosure Policy 
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 


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11. REFERENCE LIST 
1. 
Merkus P, Taibah A, Sequino G, Sanna M. Less than 1% cerebrospinal fluid 
leakage in 1,803 translabyrinthine vestibular schwannoma surgery cases. Otol 
Neurotol. 2010;31(2):276-283.  
2. 
Becker SS, Jackler RK, Pitts LH. Cerebrospinal fluid leak after acoustic neuroma 
surgery: a comparison of the translabyrinthine, middle fossa, and retrosigmoid 
approaches. Otol Neurotol. 2003;24(1):107-112.  
3. 
Cappabianca P, Cavallo LM, Esposito F, Valente V, De Divitiis E. Sellar repair in 
endoscopic endonasal trans-sphenoidal surgery: results of 170 cases. Neurosurgery. 
2002;51(6):1365-1371; discussion 1371-1372.  
4. 
Legnani FG, Saladino A, Casali C, et al. Craniotomy vs. craniectomy for posterior 
fossa tumours: a prospective study to evaluate complications after surgery. Acta 
Neurochir (Wien). 2013;155(12):2281-2286.  
5. 
Grotenhuis JA. Costs of postoperative cerebrospinal fluid leakage: 1-year, 
retrospective analysis of 412 consecutive nontrauma cases. Surg Neurol. 
2005;64(6):490-493, discussion 493-494.  
6. 
Allen KP, Isaacson B, Kutz JW, Purcell PL, Roland PS. The association of 
meningitis with postoperative cerebrospinal fluid fistula. J Neurol Surg B Skull 
Base. 2012;73(6):401-404.  
7. 
Chiang HY, Kamath AS, Pottinger JM, et al. Risk factors and outcomes associated 
with surgical site infections after craniotomy or craniectomy. J Neurosurg. 
2014;120(2):509-521.  
8. 
Kehler U, Hirdes C, Weber C, Spuck S, Tronnier V, Kundt G. CSF leaks after 
cranial surgery-a prospective multicenter analysis. Innovative Neurosurgery. 
Online. August 12, 2012.  
9. 
Parízek J, Mĕricka P, Husek Z, et al. Detailed evaluation of 2959 allogeneic and 
xenogeneic dense connective tissue grafts (fascia lata, pericardium, and dura mater) 
used in the course of 20 years for duraplasty in neurosurgery. Acta Neurochir 
(Wien). 1997;139(9):827-838.  


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10. 
Messing-Jünger AM, Ibáñez J, Calbucci F, et al. Effectiveness and handling 
characteristics of a three-layer polymer dura substitute: a prospective multicenter 
clinical study. J Neurosurg. 2006;105(6):853-858.  
11. 
Filippi R, Schwarz M, Voth D, Reisch R, Grunert P, Perneczky A. Bovine 
pericardium for duraplasty: clinical results in 32 patients. Neurosurg Rev. 
2001;24(2-3):103-107.  
12. 
Cosgrove GR, Delashaw JB, Grotenhuis JA, et al. Safety and efficacy of a novel 
polyethylene glycol hydrogel sealant for watertight dural repair. J Neurosurg. 
2007;106(1):52-58.  
13. 
Ahn JY, Kim SH. A new technique for dural suturing with fascia graft for 
cerebrospinal fluid leakage in trans-sphenoidal surgery. Neurosurgery. 
2009;65(6 Suppl):65-71; discussion 71-62.  
14. 
Acerbi F, Genden E, Bederson J. Circumferential watertight dural repair using 
nitinol U-clips in expanded endonasal and sublabial approaches to the cranial base. 
Neurosurgery. 2010;67(2 Suppl Operative):448-456. 
15. 
Chi JH, Sughrue M, Kunwar S, Lawton MT. The "yo-yo" technique to prevent 
cerebrospinal fluid rhinorrhea after anterior clinoidectomy for proximal internal 
carotid artery aneurysms. Neurosurgery. 2006;59(1 Suppl 1):ONS101-107; 
discussion ONS101-107.  
16. 
Litvack ZN, West GA, Delashaw JB, Burchiel KJ, Anderson VC. Dural 
augmentation: part I-evaluation of collagen matrix allografts for dural defect after 
craniotomy. Neurosurgery. 2009;65(5):890-897; discussion 897.  
17. 
Kenning TJ, Willcox TO, Artz GJ, Schiffmacher P, Farrell CJ, Evans JJ. Surgical 
management of temporal meningoencephaloceles, cerebrospinal fluid leaks, and 
intracranial hypertension: treatment paradigm and outcomes. Neurosurg Focus. 
2012;32(6):E6.  
18. 
Dunn LT. Raised intracranial pressure. J Neurol Neurosurg Psychiatry. 
2002;73(Suppl 1):i23-27.  
19. 
Baxter Healthcare Corporation. Summary of product characteristics (SmPC) 
TISSEEL VH S/D 500 s-apr (frozen). MRP Version AT/H/0317/001/II/044/G, 
Oct 2016. 


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20. 
Baxter Healthcare Corporation. US Prescribing Information. TISSEEL [Fibrin 
Sealant]. November 2014. 
21. 
Baxter Healthcare Corporation. Company Core Safety Information. TISSEEL 
Fibrin Sealant 500. Ccsi20820160108. 
22. 
Spotnitz WD, Burks S. Hemostats, sealants, and adhesives III: a new update as well 
as cost and regulatory considerations for components of the surgical toolbox. 
Transfusion. 2012;52(10):2243-2255.  
23. 
Hutchinson RW, Mendenhall V, Abutin RM, Muench T, Hart J. Evaluation of 
fibrin sealants for central nervous system sealing in the mongrel dog durotomy 
model. Neurosurgery. 2011;69:921–928. 
24. 
Parker SR, Harris P, Cummings TJ, George T, Fuchs H, Grant G. Complications 
following decompression of Chiari malformation Type I in children: Dural graft or 
sealant. J Neurosurg Pediatr. 2011;8:177–183. 
25. 
European Medicines Agency. Guideline on core SmPC for plasma-derived fibrin 
sealant/haemostatic products. EMA/CHMP/BPWP/598816/2010 rev. 1. London, 
United Kingdom. 2015. 
26. 
European Medicines Agency. Assessment report invented name Evicel. Procedure 
No. EMEA/H/C/000898/II/0021. EMA/474697/2013. London, United Kingdom; 
2013.  
27. 
Green AL, Arnaud A, Batiller J, Eljamel S, Gauld J, Jones P, et al. A multicenter, 
prospective, randomised, 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. 
28. 
Confluent Surgical, Inc. DuraSeal Dural Sealant System instructions for use. Rev B 
2005.  
29. 
Mehrotra DV, Railkar R. Minimum risk weights for comparing treatments in 
stratified binomial trials. Stat Med. 2000;19(6):811-825. 
30. 
Center for Devices and Radiological Health of the Food (CDRH), Drug 
Administration (FDA). Approval letter for P130014 Adherus® AutoSpray Dural 
Sealant. 30 March 2015.  


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31.
Centers for Disease Control and Prevention, National Center for Infectious
Diseases. Guideline for Prevention of Surgical Site Infection. Infection Control and
Hospital Epidemiology. 1999;20(4):248-278.
32.
Centers for Disease Control and Prevention (CDC), National Healthcare Safety
Network (NHSN). Surgical site infection (SSI) event. Procedure associated Module
SSI. January 2016.


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Appendix 1 Study Design with Study Visits (Screening, Days 0, 5, 30, 
and 60) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent from eligible patients ≤30 days 
prior to surgery  
(Pre-operative Screening) 
Patients ineligible 
are screen failures 
Pre-operative screening for inclusion and 
exclusion criteria (Pre-operative Screening) 
Patients ineligible 
are screen failures 
Randomization (Day 0) 
IP: Treatment with  
FS VH S/D 500 s-apr 
Control: DuraSeal  
Dural Sealant 
Unscheduled 
Follow-up visit(s) 
anytime in between 
hospital discharge and 
Day 60 (±3) 
First Follow-up Visit Day 5: 
On the day before discharge or 
on post-operative Day 5 (±2) 
Second Follow-up Visit  
Day 30: On post-operative 
Day 30 (±3) 
Final Follow-up Visit Day 60: 
On post-operative Day 60 (±3) 
Intra-operative screening for inclusion and 
exclusion criteria + CSF leak (Day 0)  
(Intra-operative Screening) 
Assessment of intra-operative 
component of primary endpoint 
Treatment Assignment Disclosure to the surgeon 
Assessment of 
post-operative 
component of 
primary 
endpoint 











































SAP_001.pdf: 
ClinicalTrials.gov Identifier: NCT02891070


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Table of Contents 
1. SIGNATURE PAGE ......................................................................................................4 
2. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................5 
3. INTRODUCTION..........................................................................................................6 
4. TRIAL OBJECTIVES ..................................................................................................6 
4.1 Primary Objectives ..................................................................................................6 
To evaluate the efficacy of FS VH S/D 500 s-apr compared to DuraSeal Dural 
Sealant as an adjunct to sutured dural closure. ....................................................6 
4.2 Secondary Objectives ..............................................................................................7 
4.3 Exploratory Objectives ............................................................................................7 
5. STUDY DESIGN AND CONDUCT CONSIDERATIONS .......................................7 
5.1 Study Design .............................................................................................................7 
5.2 Baseline definition ....................................................................................................7 
5.3 Sample Size ...............................................................................................................7 
5.3.1 Justification of Non-Inferiority Margin ..........................................................8 
5.4 Randomization Procedure ......................................................................................9 
5.5 Efficacy Assessments ...............................................................................................9 
5.6 Safety Assessments .................................................................................................10 
5.7 Completion and Discontinuation ..........................................................................11 
6. STUDY POPULATIONS ............................................................................................11 
6.1 Subject Disposition ................................................................................................11 
6.2 Analysis Populations ..............................................................................................12 
6.3 Protocol Deviations ................................................................................................12 
7. STATISTICAL ANALYSIS .......................................................................................12 
7.1 General ....................................................................................................................12 
7.2 Handling of Missing Data......................................................................................13 
7.3 Data Safety Monitoring Board .............................................................................13 
7.4 Interim Analysis .....................................................................................................13 
7.5 Pooling Strategy for Study Sites ...........................................................................13 
7.6 Visit Windows/Unscheduled Visits .......................................................................14 
7.7 Other Issues ............................................................................................................14 
7.8 Changes to Planned Analyses Described in the Clinical Investigation Plan ....14 


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8. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...............................14 
9. SURGERY DETAILS AND EXPOSURE .................................................................14 
9.1 Planned Surgery Details ........................................................................................14 
9.2 Intraoperative Details ............................................................................................14 
9.3 Rescue Therapy Details (listing only)...................................................................16 
9.4 Post-operative Clinical Assessment of CSF Leak ...............................................16 
9.5 Surgical Revision ....................................................................................................17 
9.6 Surgical Site Infection ...........................................................................................17 
10. EFFICACY .................................................................................................................17 
10.1 Primary Efficacy Assessment .............................................................................17 
10.2 Secondary Efficacy Assessment ..........................................................................18 
11. SAFETY ......................................................................................................................18 
12. REFERENCES ...........................................................................................................20 
13. LIST OF TABLES, FIGURES AND LISTINGS ....................................................20 
13.1 List of Tables ........................................................................................................20 
13.2 List of Listings ......................................................................................................22 
 
List of Appendices 
No table of figures entries found. 




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2. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADE 
adverse device effect 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIP 
clinical investigation plan 
CRO 
contract research organization  
DSMB 
data safety monitoring board 
eCRF 
electronic case report form 
FAS 
full analysis set 
ICF 
informed consent form  
IWRS 
interactive web-response system 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMC 
non-medical complaint 
OC 
oxidized cellulose 
PPS 
per-protocol analysis set 
SADE 
serious adverse device event 
SAE 
serious adverse event 
SAER 
serious adverse event report 
SI 
serious injury 
SD 
standard deviation 
SE 
standard error  
TBS 
target bleeding site 
TTH 
time to hemostasis 
UADE 
unanticipated adverse device effect 
WHO 
World Health Organization 
 


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3. INTRODUCTION 
This Statistical Analysis Plan is intended to describe the planned statistical analysis of 
project 3599-001. 
In neurosurgery, cerebrospinal fluid (CSF) leaks where disruption of the arachnoid and 
the dura mater allows CSF to flow to an extradural space, is an event which may lead to 
severe complications, such as infection, pseudomeningocele, and delayed 
pneumocephalus. Closure of the dura serves as a mechanical and a biological barrier to 
both CSF leaks and to the potential entrance of infectious organisms.  
To minimize the risk of intra-operative CSF leaks and to potentially reduce post-
operative CSF leak rates, different techniques and materials have been used in 
conjunction to sutures to provide a watertight sealing of the dural incision; one such 
treatment modality is the use of a fibrin sealant (FS) directly on the suture line to seal the 
suture holes, as well as the approximated dural edge. 
The Investigational Product (IP) for this protocol is FS VH S/D 500 s-apr in its frozen 
presentation. FS VH S/D 500 s-apr is a 2-component fibrin sealant (FS) made from 
pooled human plasma. When combined, the 2 components, fibrinogen (human) and 
thrombin (human), mimic the final stage of the blood coagulation cascade.  
In this protocol, FS VH S/D 500 s-apr is intended to be used as an adjunct to sutured 
dural repair in cranial surgery in patients undergoing elective cranial surgery for the 
treatment of a pathological condition (eg, benign/malignant tumours, vascular 
malformations, or Chiari type 1 malformations) specifically located in the PF or ST 
regions. 
4. TRIAL OBJECTIVES 
The purpose of this study is to provide data on the safety and efficacy of FS VH S/D 500 
s-apr compared to DuraSeal Dural Sealant as an adjunct to sutured dural closure in 
patients who are undergoing elective cranial surgery for the treatment of a pathological 
condition (eg, benign/malignant tumors, vascular malformations, or Chiari type 1 
malformations) specifically in the PF or ST region. 
4.1 Primary Objectives 
To evaluate the efficacy of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as 
an adjunct to sutured dural closure. 
 


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4.2 Secondary Objectives 
To evaluate the safety of FS VH S/D 500 s-apr compared to DuraSeal Dural Sealant as 
an adjunct to sutured dural closure. 
4.3 Exploratory Objectives 
Not applicable. 
5. STUDY DESIGN AND CONDUCT CONSIDERATIONS 
5.1 Study Design 
This is a phase 3, prospective, randomized, controlled, single-blind (patient) multicenter 
study to evaluate the safety and efficacy of FS VH S/D 500 s-apr compared to DuraSeal 
Dural Sealant as an adjunct to sutured dural closure in a total of 202 evaluable patients 
undergoing elective cranial surgery for the treatment of a pathological condition (i.e., 
benign/malignant tumors, vascular malformations, or Chiari type 1 malformations) 
specifically located in the PF or ST region. 
Eligibility according to general and intra-operative criteria will lead to the final selection 
of the patient into the study, which is determined by the presence of an intra-operative 
CSF leak after primary dural closure with sutures. Upon detection of CSF leak, the 
patient’s randomization assignment to either IP (FS VH S/D 500 s-apr) or to control 
(DuraSeal Dural Sealant) stratified by center and surgical regions (PF or ST) will be 
applied. 
5.2 Baseline definition 
Baseline values are not applicable for effectiveness measures. Safety measures of clinical 
laboratory parameters and vital signs will be evaluated with respect to initial values taken 
during the screening visit. 
5.3 Sample Size 
The number of subjects in a clinical trial should always be large enough to provide a 
reliable answer to the questions addressed. This number is usually determined by the 
primary objective of the trial. If the sample size is determined on some other basis, then 
this should be made clear and justified. For example, a trial sized on the basis of safety 
questions or requirements or important secondary objectives may need larger numbers of 
subjects than a trial sized on the basis of the primary efficacy question (see ICH E1A). 
This study is designed to show non-inferiority (NI) of FS VH S/D 500 s-apr compared to 
DuraSeal Dural Sealant based on the primary composite efficacy endpoint. The 






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for up to 5 - 10 seconds) and no CSF leakage within 30 (+3) days post-
operatively. 
• Failure is defined as: an intra-operative non-watertight closure, which consists 
of any overt flow, seepage, weeping, or sweating of CSF through the dura 
suture line, regardless of volume, during surgery or within 30 (+3) days post-
operatively. 
Secondary efficacy assessments will include: 
• Incidence of intra-operative CSF leakage following final Valsalva manoeuvre 
• Incidence of CSF leaks within 30 (+3) days post-operatively 
• Time in surgery (minutes) 
• Time from dural closure (application of IP) until end of surgery 
• Length of stay in hospital (days) 
All post-operative CSF leaks will be primarily diagnosed based on a detailed history and 
physical examination including neurological examination. Although not standard of care 
post-operatively, imaging tests such as computed tomography/magnetic resonance 
imaging will only be considered if there is a high clinical suspicion of CSF leakage. For 
example, if CSF leaks externally (eg, incisional leaks, otorrhea, or rhinorrhea), or if there 
is any bulging suggesting subcutaneous fluid collection at the incision site, needle 
aspiration and the beta-2 transferrin test will be used to confirm the presence of CSF.   
5.6 Safety Assessments 
The following secondary safety assessments will be performed during this study: 
• Incidence of CSF leaks within 60 (+3) days post-operatively 
• Incidence of AEs up to 60 (+3) days post-operatively 
• Incidence of SSI according to US NHSN within 30 (+3) days post-operatively 
• Number of unplanned interventions within 30 (+3) days post-operatively 
• Laboratory values and vital signs (e.g., elevated WBC count, fever [temperature 
>100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial 
pressure <60]). 
Unplanned interventions include meningitis, the management of a deep infection, 
minimally invasive procedures, and the return to the operating room for neurosurgical 
complications other than a CSF leak or pseudomeningocele formation, or those related to 
the subject’s pre-existing condition during the 30-day follow-up period following original 
surgical procedure. 


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Surgical site infections will be evaluated by the surgeon or designated physician 
according to CDC/NHSN criteria. 
5.7 Completion and Discontinuation 
A patient is considered to have completed the study when he/she ceases active 
participation in the study because the patient has, or is presumed to have, completed all 
study procedures according with the protocol (with or without protocol deviations). Any 
other cases are classified as discontinuation.  
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation eCRF, including: Completed, AE (eg, death), 
discontinuation by patient (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the patient], dropout), physician decision (eg, pregnancy, progressive 
disease, protocol violation[s], recovery), study terminated by sponsor, or other (reason to 
be specified by the investigator [eg, technical problems]).   
Regardless of the reason, all data available for the patient up to the time of 
completion/discontinuation should be recorded on the appropriate eCRF. 
Every effort will be made to have discontinued patients complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a patient terminates participation in the study and does 
not return for the completion/termination visit, his/her last recorded assessments shall 
remain recorded with his/her last visit. The reason for discontinuation will be recorded 
and the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. 
6. STUDY POPULATIONS 
6.1 Subject Disposition 
The number of subjects who signed informed consent (enrolled), met the pre- and intra-
operative inclusion and exclusion criteria (eligible), were randomized, and withdrew 
early will be displayed for subject disposition. Early withdrawals will be summarized 
according to reason for withdrawal. Subjects who have been assigned a treatment based 
on pre-operative criteria, but were found not eligible intraoperatively are not considered 
to be randomized (for more detail on randomization see section 5.4). 


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6.2 Analysis Populations 
Two types of analyses of effectiveness are planned: analysis of the full analysis set (FAS) 
and of the per-protocol analysis set (PPS). The primary efficacy analysis will be carried 
out on the PPS. The analysis using the FAS will be used as a supportive analysis. 
Assessment of safety will be carried out on all subjects treated (safety analysis set). 
• Full analysis set: The FAS will consist of all subjects who were randomized and 
treated with at least 1 dose of IP/control. Subjects will be analyzed as randomized. 
• Per-protocol analysis set: The PPS is defined as a subset of the FAS. Subjects 
with any major deviation that may impact the primary efficacy parameter will be 
excluded from the per-protocol analysis set (see section 6.3 for more detail on 
protocol deviations leading to exclusion). 
Safety analysis set: The safety analysis set will consist of all subjects who are treated 
with IP/Control. Subjects will be analyzed as treated. 
6.3 Protocol Deviations 
Protocol deviations will be classified as minor or major deviations and reviewed at a data 
review meeting. Subjects with any major deviation that may impact the primary efficacy 
parameter will be excluded from the per-protocol analysis set, including the following: 
• Violations inclusion and/or exclusion criteria (pre and/or intra-operative 
assessment) 
• Use of prohibited medication known to influence the primary endpoint 
• Randomization or treatment errors 
• Improper administration of study product  
• Improper assessment of the primary endpoint 
7. STATISTICAL ANALYSIS  
7.1 General 
The analyses described in this SAP refer to Amendment 2 of the Clinical Investigation 
Plan (dated 2015 Nov 09). Unless otherwise noted, all analyses will be performed using 
. 
Copyright© 2002-2012, 
 and all other 
 Inc. product 
or service names are registered trademarks or trademarks of 
, 
USA. All Rights Reserved. If not specified otherwise, data will be presented by planned 


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treatment group and overall. Safety data will be summarized by actual treatment and 
overall. Continuous variables will be summarized by the following sample statistics: 
number of non-missing observations, mean, standard deviation (SD), median, minimum 
and maximum. Categorical variables will be presented by their absolute frequency and 
percentage (based on the number of subjects in the respective group). 
7.2 Handling of Missing Data 
Only subjects for whom endpoint data are available will be included in the statistical 
analysis. Missing values will be neither replaced nor estimated in the primary analysis. 
7.3 Data Safety Monitoring Board 
This study will be monitored by an independent unblinded DSMB. The DSMB will be 
composed of 3 members, 2 members who are recognized experts in the field of 
neurosurgery clinical care and research and 1 member who is a biostatistician. One (1) of 
the members shall serve as chairperson of the DSMB. The DSMB neurosurgeons will not 
be involved in enrolling or treating study subjects.  
 
The DSMB will monitor ongoing safety data (AEs and laboratory test results). The 
DSMB will review safety and efficacy data from the study after 50% of the subjects have 
been completed, and will have the discretion to recommend stopping the trial due to 
safety, efficacy, or futility concerns. The stopping rules are presented in Section 7.4. 
7.4 Interim Analysis 
An interim analysis will be conducted after the completion of 50% of patients. A group 
sequential design utilizing O’Brien-Fleming boundaries will be carried out. Basic 
demographic tables will be produced during the interim analysis. Predicted values for the 
primary outcome will be produced from a logistic regression equation containing terms 
for treatment, site and surgical region (supratentorial or posterior fossa). A one-sided two 
sample t-test will be performed to compare the lower bound of the difference (active – 
control) between treatments in the mean predicated proportions against the null value of -
0.1, to test whether the mean predicted value for Tisseel is less than -0.1 less than the 
mean predicted value for Duraseal. The study may be stopped early for futility if a p-
value >0.2486 is observed. If the study is stopped early, a full analysis of all of the data 
will be produced.  
7.5 Pooling Strategy for Study Sites 
Generally, the data of all study sites will be analyzed together. The logistic regression 
model for the efficacy analysis will use study site as a factor. In the case of study sites 


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with fewer than 5 subjects, those study sites may be combined into entities of similar size 
for the purpose of including in the logistic regression model as a factor.  
7.6 Visit Windows/Unscheduled Visits 
For tabulation, values will be summarized according to the planned time point as 
recorded in the eCRF. Data recorded at unscheduled visits will only be listed. 
7.7 Other Issues 
Not applicable. 
7.8 Changes to Planned Analyses Described in the Clinical Investigation Plan 
Not applicable. 
8. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 Demographic and baseline variables as collected in the eCRF will be summarized 
according to the general principles as detailed above. Demographics will include sex, 
race, ethnicity, age (years), height (cm), weight (kg) and BMI (kg/m2). Medical history 
will be coded using MedDRA and incidences will be tabulated by System Organ Class 
and Preferred Term. Previous medication (stopped before the surgery) and concomitant 
medication and non-drug therapies (ongoing at the time of surgery or started between 
surgery and end of study participation) will be coded using WHO Drug Dictionary 
(medications) and MedDRA (non-drug therapies) and tabulated by ATC Term and 
Preferred Term. 
9. SURGERY DETAILS AND EXPOSURE 
The following information on the surgery will be tabulated and/or provided in a listing.  
9.1 Planned Surgery Details 
• Hospitalization for planned study surgery admission/discharge dates (listing only) 
• Duration of hospital stay for planned study surgery (days, to nearest half day) 
• Indication for surgery (categories TBD)  
• Surgery type [craniotomy with planned durotomy, craniectomy with planned 
durotomy] 
• Surgery region [posterior fossa, supratentorial] 
9.2 Intraoperative Details 
• Length of sutured durotomy (cm) 
• Needle type used for closure (listing only) 


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o Atraumatic needle 
o Ethicon (atraumatic needle 12 or 17, fibre 5/0, 70 cm) 
o Type E6 / 0.6x16 (surgical needles) 
o TF taper needle 
o RB-1 needle 
o Cylindric 
o Cylindric taper 17mm (HR17) 
o Round bodied 
o CV-23 Taper ½ 17mm; RB-1 plus 17 mm ½ 
o Other (specified) 
• Suture material (listing only) 
o Neuolon 4-0 suture 
o Vicril 
o Absorbable (polyglactin) 
o Silk, braided, coated, non-absorbable (polyester) 
o SurgiPro II (Monofilament PP)  
o Ethicon-Ethiban Excel 4.0 PE non-resorbable 
o Other (specified) 
• Suture technique (listing only) 
o Continuous simple 
o Continuous locked 
o Interrupted 
o Other (specified) 
• Tenting sutures used [yes/no] (listing only) 
• Dural material used [yes/no] (listing only) 
• Dural closure method  
o Suture + autologous material 
o Suture + non-autologous material 
o Suture + other material 
o Suture only 
• Type of material used [autologous, non-autologous, other (specified)] (listing 
only) 
o If type of material used is autologous, specify [fascia, muscle, 
pericranium] 
o If type of material used is non-autologous, specify [dura patch, hemostasis 
matrix, other (specified)] 
• Surgery start date/time (first skin cut) (listing only) 


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• Primary dura closure date/time (listing only) 
• Surgery end date/time (last skin suture) (listing only) 
• Duration of surgery (min) (date/time of last skin suture – date/time of first skin 
cut) 
• Duration from dural closure to end of surgery (min) (date/time of last skin suture 
– primary dura closure date/time) 
• Drainage left after surgery 
• Any surgical complications 
• Actual treatment applied  
• Number of study product applications 
• Start/stop times of study product application(listing only) 
• Volume of treatment applied (mL) (listing only) 
• Type of CSF leak [spontaneous, following Valsalva] (listing only) 
• If applicable, time of Valsalva maneuver (listing only) 
• If applicable, time of watertight closure (listing only) 
• If applicable, type of leak [overflow, seepage, weeping, sweating] (listing only) 
• Rescue therapy needed 
9.3 Rescue Therapy Details (listing only) 
• Reason for rescue therapy  
• Time of rescue therapy 
• Time watertight dura closure achieved 
• Actions performed to achieve watertight dura closure 
• Brand name of material used to achieve water tight dura closure 
• Material type 
• Suture technique 
9.4 Post-operative Clinical Assessment of CSF Leak 
The following information will be tabulated and/or provided in a listing, by date/visit of 
assessment (Visit 3, 4, 5 or Unscheduled).  
• CSF Leak observed  
• Type of CSF leak, if applicable (listing only)Drain duration (days) 
• Output volume (mL) 
• Beta2-transferrin result 
• MRI/CT Done 


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• MRI/CT findings, if applicable (listing only) 
• Surgical revision required 
9.5 Surgical Revision 
• Indication for surgical revision (listing only) 
• Procedure description (listing only) 
• Start date/time:End date/time (listing only) 
• Complications associated with surgical revision 
9.6 Surgical Site Infection 
The following information will be tabulated and/or provided in a listing, by date/visit of 
assessment (Visit 3, 4, 5 or Unscheduled).  
• Signs of surgical site infection observed 
• Type of surgical site infection, if applicable 
10. EFFICACY 
10.1 Primary Efficacy Assessment 
The primary efficacy analysis will be carried out on the PPS. The analysis using the FAS 
will be supportive. The primary efficacy endpoint is the proportion of patients who have 
neither of the following: 
• Intra-operative CSF leakage from dural repair after up to two FS VH S/D 500 s-
apr/control applications during Valsalva manoeuver (25 cm H2O for up to 5 - 10 
seconds) 
• Post-operative CSF leakage within 30 (+3) days post-operatively 
The specific hypotheses of the proportion difference to be tested are as follows: 
H0: PFS – PDS ≤ -0.10 
Ha: PFS – PDS > -0.10 
PFS = the proportion of patients not meeting the 2 criteria (ie, no intra-operative CSF 
leakage and no post-operative CSF leakage) for the FS VH S/D 500 s-apr treatment 
group, and 
PDS = the proportion of patients not meeting the 2 criteria (ie, no intra-operative CSF 
leakage and no post-operative CSF leakage) for the DuraSeal Dural Sealant treatment 
group. 


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The primary composite efficacy endpoint, proportion of patients not meeting the 2 
criteria (ie, no intra-operative CSF leakage and no post-operative CSF leakage), will be 
investigated by a 2-sided test for non-inferiority using logistic regression, taking into 
account the following covariates: study center and surgery region. The null hypothesis 
will be tested against the alternative using logistic regression, taking into account the 
following covariates: study center and surgery region (supratentorial or posterior fossa). 
The method described in reference 1 will be used: The parameters of the fitted logistic 
regression model will be used to predict the success rate of all subjects for both Tisseel 
and Duraseal treatment. The average response rate per group will be calculated as well as 
the difference between the two rates. The standard error of the difference will be derived 
using the delta method in order to construct a 95% confidence interval. A non-inferiority 
margin of 10% (the largest clinically acceptable difference) will be used; thus, if the 
lower bound of the 2 sided 95% CI (based on normal approximation) around the 
difference in proportions (Tisseel group – Duraseal group) is greater than -10% in the 
final analysis, Tisseel will be declared non-inferior to Duraseal. 
10.2 Secondary Efficacy Assessment 
The secondary efficacy endpoints are the following: 
• Incidence of intra-operative CSF leakage following final Valsalva manoeuver 
• Incidence of CSF leaks within 30 (+3) days post-operatively 
• Time in surgery (minutes) 
• Time from dural closure (application of IP) until end of surgery 
• Length of stay in hospital (days) 
The logistic regression approach used for the primary efficacy endpoint will also be used 
to calculate the proportions of patients with incidence of intra-operative CSF leakage 
following final Valsalva manoeuver and incidence of CSF leaks within 30 (+3) days post-
operatively. The time in surgery, time from dural closure until end of surgery, and the 
length of stay in hospital will be compared between the 2 groups using a Wilcoxon rank 
sum test. 
11. SAFETY  
The secondary safety endpoints are the following: 
• Incidence of CSF leaks within 60 (+3) days post-operatively 
• Incidence of AEs up to 60 (+3) days post-operatively 
• Incidence of SSIs according to US NHSN within 30 (+3) days post-operatively 


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• Number of unplanned interventions within 30 (+3) days post-operatively 
• Laboratory values and vital signs (e.g., elevated WBC count, fever [temperature 
>100.7°F or 38.2°C], tachycardia [pulse >100], hypotension [mean arterial 
pressure <60]). 
The logistic regression approach used for the primary efficacy endpoint will be used to 
calculate the proportions of patients with: incidence of CSF leaks within 60 (+3) days 
post-operatively, and incidence of SSIs according to NHSN within 30 (+3) days 
postoperatively. The number of unplanned interventions within 30 (+3) days post-
operatively will be compared between the 2 treatment groups using a Wilcoxon rank sum 
test.  
The duration and incidence of each laboratory and vital sign abnormality will be 
recorded. Abnormal laboratory values will be observed, followed, and managed by the 
investigator for a return to baseline, per standard of care. Clinical laboratory parameters 
and vital signs will be summarized by visit and treatment group. Absolute values and 
changes from baseline will be presented. Shift tables for baseline vs. worst post baseline 
assessment (normal, abnormal/not clinically significant, abnormal/clinically significant) 
will be generated for laboratory parameters.  
An AE overview summary table will be prepared including the number of patients 
reporting an AE, the percentage of patients (%) with an AE, and the number of events 
reported, for the following categories: 
1. Deaths. 
2. SAEs. 
3. AEs leading to withdrawal. 
4. Severe AEs. 
5. Related AEs. 
6. AEs of special interest. 
Adverse events will be tabulated by body system using the Medical Dictionary for 
Regulatory Activities (MedDRA). The table will display the total number of patients 
reporting an AE, the percentage of patients (%) with an AE, and the number of events 
reported by system organ class (SOC) and preferred term. In addition, tables will be 


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summarized by SOC, preferred term, severity grade (mild, moderate, and severe) and 
relatedness to treatment (“possibly related” or “probably related” AEs, and AEs with 
missing information on relatedness will be considered “related”; “unlikely related” or 
“not related” AEs will be considered “not related”). These tables will be produced for: 
• All AEs 
• AEs with an incidence ≥5% of patients in any treatment arm 
• Non-serious AEs with an incidence ≥5% of patients in any treatment arm 
• AEs by causality (related/unrelated) 
• AEs leading to death 
• AEs by severity 
• SAEs 
• AEs leading to withdrawal 
Listings will be prepared for: 
• All AEs sorted by center and patient 
• SAEs 
• AEs leading to death 
• AEs leading to withdrawal 
• Laboratory results and vital signs 
12. REFERENCES 
1. 
Covariate-Adjusted Difference in Proportions from Clinical Trials Using Logistic 
Regression and Weighted Risk Differences, Miaomiao Ge, L. Kathryn Durham, R. 
Daniel Meyer, Wangang Xie, Neal Thomas, Drug Information Journal vol. 45, no. 
4, pp. 481-493, 2011 
13. LIST OF TABLES, FIGURES AND LISTINGS 
13.1 List of Tables 
Applicable 
Analysis 
Populations 
Table 
Number 
Table Name 
NA 
14.1.1 
Subject Disposition 
PPS 
14.1.2.1 
Demographic and Baseline Characteristics 
FAS 
14.1.2.2 
Demographic and Baseline Characteristics 
Safety 
14.1.2.3 
Demographic and Baseline Characteristics 


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PPS 
14.1.3.1 
Vital Signs 
FAS 
14.1.3.2 
Vital Signs 
Safety 
14.1.3.3 
Vital Signs 
PPS 
14.2.1.1.1 
Primary Efficacy Assessment - CSF Leakage, Intra- and Post-
Operative 
FAS 
14.2.1.1.2 
Primary Efficacy Assessment - CSF Leakage, Intra- and Post-
Operative 
PPS 
14.2.1.2.1 
Primary Efficacy Assessment - CSF Leakage, Intra- and Post-
Operative Model Results 
FAS 
14.2.1.2.2 
Primary Efficacy Assessment - CSF Leakage, Intra- and Post-
Operative Model Results 
PPS 
14.2.2.1 
Secondary Efficacy Assessments 
FAS 
14.2.2.2 
Secondary Efficacy Assessments  
PPS 
14.2.3.1 
Summary of Planned Surgery Intra-operative Details 
FAS 
14.2.3.2 
Summary of Planned Surgery Intra-operative Details 
PPS 
14.2.4.1 
Summary of Planned Surgery Post-operative Details 
FAS 
14.2.4.2 
Summary of Planned Surgery Post-operative Details 
PPS 
14.2.5.1 
Listing of Observed Post-Operative CSF Leak Details 
FAS 
14.2.5.2 
Listing of Observed Post-Operative CSF Leak Details 
Safety 
14.3 
Secondary Safety Assessments 
Safety 
14.3.1.1 
Summary of Adverse Events  
Safety 
14.3.1.2 
Summary of Adverse Events (Serious and Non-Serious) by System 
Organ Class and Preferred Term 
Safety 
14.3.1.3 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety 
14.3.1.4 
Summary of Adverse Events (Serious and Non-Serious) by System 
Organ Class, Preferred Term and Severity 
Safety 
14.3.1.5 
Summary of Adverse Events (Serious and Non-Serious) by System 
Organ Class, Preferred Term and Relation to Study Product 
Safety 
14.3.1.6 
Summary of Adverse Events (Serious and Non-Serious) by System 
Organ Class, Preferred Term and Relation to Study Procedure 
Safety 
14.3.1.7 
Summary of Adverse Events of Special Interest (Serious and Non-
Serious) by System Organ Class and Preferred Term 
Safety 
14.3.1.8 
Summary of Adverse Events (Serious and Non-Serious) with Incidence 
>= 5% by System Organ Class and Preferred Term 
Safety 
14.3.1.9 
Summary of Non-Serious Adverse Events with Incidence >= 5% by 
System Organ Class and Preferred Term 
Safety 
14.3.1.10 
Summary of Adverse Events Leading to Death by System Organ Class 
and Preferred Term 
Safety 
14.3.1.11 
Summary of Adverse Events Leading to Withdrawl by System Organ 
Class and Preferred Term 
Safety 
14.3.2.1 
Listing of Serious Adverse Events 
Safety 
14.3.2.2 
Listing of Adverse Events of Special Interest 


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Safety 
14.3.2.3 
Listing of Adverse Events Leading to Discontinuation from the Study 
Safety 
14.3.4.1.1 
Shift Table of Hematology Laboratory Parameters 
Safety 
14.3.4.1.2 
Hematology Laboratory Summary 
Safety 
14.3.4.1.3 
Listing of Abnormal Hematology Laboratory Values 
Safety 
14.3.4.2.1 
Shift Table of Chemistry Laboratory Parameters 
Safety 
14.3.4.2.2 
Chemistry Laboratory Summary 
Safety 
14.3.4.2.3 
Listing of Abnormal Chemistry Laboratory Values 
Safety 
14.3.4.3.1 
Shift Table of Coagulation Parameters 
Safety 
14.3.4.3.2 
Coagulation Laboratory Summary 
Safety 
14.3.4.3.3 
Listing of Abnormal Coagulation Laboratory Values 
Safety 
14.3.4.4.1 
Shift Table of Serology Laboratory Parameters 
Safety 
14.3.4.4.2 
Serology Laboratory Summary 
13.2 List of Listings 
Listing 
Number 
Listing Name 
16.2.1 
Subject Disposition 
16.2.2 
Protocol Deviations 
16.2.3 
Patients excluded from PP 
16.2.4.1 
Subject Demographics 
16.2.4.2 
Subject Vital Signs 
16.2.4.3 
Subject ECG Results 
16.2.4.4 
Medical History 
16.2.4.5 
Concomitant Medications and Non Drug Therapies by Coded 
Drug Term 
16.2.5 
Study Treatment Application 
16.2.6.2 
Planned Surgery Intra-operative Details 
16.2.6.3 
Rescue Therapy 
16.2.6.4 
Planned Surgery Post-Operative Details 
16.2.6.5 
Surgical Revision 
16.2.6.6 
Surgical Site Infection 
16.2.6.7 
Other Interventions 
16.2.6.8 
Hospitalizations 
16.2.7 
Treatment Emergent Adverse Events 
16.2.8.1 
Subject Laboratory Hematology Results 
16.2.8.2 
Subject Laboratory Chemistry Results 
16.2.8.3 
Subject Laboratory Coagulation Results 
16.2.8.4 
Subject Laboratory Serology Results