A Prospective, Randomized, Controlled Study to Evaluate the Effectiveness and Safety of CELSTAT as an Adjunct to Hemostasis for Tissue Bleeding in Cardiothoracic, General, and Vascular Surgery.
Phase: NA
Conditions: Bleeding Active
Sponsor: Baxter Healthcare Corporation

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3584-001 CLINICAL INVESTIGATION PLAN
CELSTAT
A Prospective, Randomized, Controlled Study to Evaluate the Effectiveness and 
Safety of CELSTAT as an Adjunct to Hemostasis for Tissue Bleeding in 
Cardiothoracic, General and Vascular Surgery
STUDY 3584-001
Amendment 2: 2015 NOV 09
Prior versions:
Amendment 1: 2015 SEP 04 (identified as Study 3584-001)
Original: 2013 JUN 25 (identified as Study 621001, Revision 1)
Study Sponsor:
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL  60015  USA
Contract Research Organization:
SWITZERLAND

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2. SERIOUS ADVERSE EVENT/SERIOUS INJURY/SERIOUS ADVERSE 
DEVICE EFFECT/DEVICE DEFICIENCY REPORTING
For reporting of serious adverse events (SAEs)/serious injuries (SI), serious adverse 
device effects (SADEs), and device deficiencies that could have led to an SADE to the 
IRBs/IECs/REBs, the investigator will comply with applicable national regulations and 
requirements as laid down in this clinical investigation plan (CIP) or mandated by the 
IRB/IEC/REB and the regulatory authorities.
For information on the definition and assessment of adverse events (AEs), device 
deficiencies, and SADEs, refer to Section 12.3.2.
ALL SAEs/SIs, SADEs, AND DEVICE DEFICIENCIES THAT COULD HAVE
LED TO AN SADE ARE TO BE REPORTED ON THE SERIOUS ADVERSE
EVENT REPORT (SAER) FORM AND FAXED/E-MAILED TO THE CRO 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
REPORTS ON NEW FINDINGS/UPDATES IN RELATION TO ALREADY
REPORTED EVENTS WILL ALSO BE FAXED/E-MAILED TO THE CRO
WITHIN 24 HOURS AFTER BECOMING AWARE OF THEIR OCCURRENCE.
See relevant report form for contact information.
Further details are also available in the study team roster.

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3. UNANTICIPATED ADVERSE DEVICE EFFECT REPORTING
The investigator will comply with applicable requirements for reporting unanticipated 
adverse device effects (UADEs) to the reviewing IRB/IEC/REB. For sites in the United 
States, Food and Drug Administration regulations 21 CFR 812.150(a)(1)for a device 
require investigators to report any UADEs to their IRB no later than 10 working days 
after the investigator first learns of the effect. For the definition of UADEs, refer to 
Section 12.3.2.1.7.
ALL UADEs ARE TO BE REPORTED ON A SAER FORM AND
FAXED/E-MAILED TO THE CRO
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT.
See relevant report form for contact information.
Further details are also available in the study team roster.

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4. SYNOPSIS
INVESTIGATIONAL DEVICE
Name of Investigational 
Device
CELSTAT Absorbable Hemostat
Name(s) of Active 
Ingredient(s)
Oxidized cellulose
CLINICAL CONDITION(S)/INDICATION(S)
Intended for use adjunctively in surgical procedures to assist in the control of capillary, venous and 
small arterial hemorrhage when ligation or other conventional methods of control are impractical or 
ineffective
STUDY ID
3584-001
CLINICAL 
INVESTIGATION 
PLAN TITLE
A prospective randomized, controlled, study to evaluate the effectiveness and 
safety of CELSTAT as an adjunct to hemostasis for tissue bleeding in 
cardiothoracic, general and vascular surgery.
Short Title
Effectiveness and safety of CELSTAT for hemostasis in intraoperative tissue 
bleeding
PLANNED STUDY PERIOD
Initiation
First subject’s enrollment: Q1 2016
Primary Completion
Last subject’s primary outcome assessed: Q1 2017
Study Completion
Last subject’s last visit: Q2 2017
Duration
14 months
STUDY OBJECTIVES AND PURPOSE
Study Purpose
To evaluate the effectiveness and safety of CELSTAT as an adjunct to hemostasis in subjects 
undergoing cardiothoracic, general and vascular surgery as compared to Surgicel Original.
Primary Objective
To assess the hemostatic effectiveness of CELSTAT in comparison to Surgicel based on the proportion 
of subjects in which hemostasis is achieved at 5 minutes after the start of study treatment application
Secondary Objectives
1.
To evaluate additional hemostatic effectiveness parameters of CELSTAT in comparison to 
Surgicel
2.
To evaluate the safety of CELSTAT
STUDY DESIGN
Study Type
Effectiveness, Safety
Control Type
Concurrent (Active)

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Study Indication Type
Treatment
Intervention Model 
2-group, parallel 
Blinding/Masking
Subject-blinded
Study Design
This study is a prospective, controlled, randomized, multicenter study to 
compare effectiveness and safety of CELSTAT versus Surgicel in a total of 
258 randomized subjects (1:1 randomization) undergoing cardiothoracic, 
general or vascular surgery.
Planned Duration of 
Subject Participation
The subject participation period is approximately 15 weeks from enrollment to 
subject completion.
Primary Endpoints
Effectiveness
Proportion of subjects with hemostasis achieved at the target bleeding site (TBS) at 5 minutes after the 
start of application of the study device
Safety
Postoperative rebleeding from the TBS requiring surgical re-exploration during the subject’s study 
participation
Secondary Endpoints
Effectiveness
Time to hemostasis (TTH) at the TBS within the 10-minute assessment period
Proportions of subjects with intraoperative hemostasis at the TBS at 3, 7 and 10 minutes after start of 
the application of the study device
Intraoperative rebleeding from the TBS after occurrence of  hemostasis
Safety
Occurrence of adverse events (AEs)/adverse device effects (ADEs) during the subject’s study 
participation
Clinical laboratory parameters
Vital signs
INVESTIGATIONAL DEVICE(S), DOSE AND MODE OF ADMINISTRATION 
Investigational Device
Dosage form: Oxidized cellulose strip (CELSTAT)
Dosage frequency: Single-use treatment
Mode of Administration: Intraoperative, direct application to the TBS
Comparator 
Dosage form: Oxidized regenerated cellulose strip (Surgicel Original)
Dosage frequency: Single-use treatment
Mode of Administration: Intraoperative, direct application to the TBS
SUBJECT SELECTION
Targeted Number of 
Subjects
258 randomized subjects at approximately 26 sites in the United States (20) and 
Europe (6)
Number of Arms
2 arms

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Inclusion Criteria
Preoperative
1.
Male or female subjects, 18 years or older at the time of signing the informed consent form 
(female subjects of childbearing potential must present with a negative serum pregnancy test, and 
must agree to employ adequate birth control measures [restricted to abstinence, barrier 
contraceptives, intrauterine contraceptive devices or licensed hormonal products] for the duration 
of their participation in the study)
2.
Subject is undergoing planned (non-emergency) cardiothoracic, general or vascular surgery
3.
Subject is willing and able to comply with the requirements of the clinical investigation plan
Intraoperative
Bleeding scale Grade 1 or 2 (mild or moderate) soft tissue, vascular or parenchymal bleeding present at 
the TBS after standard conventional surgical hemostatic methods (eg, ligature, suture, compression, 
cautery) prove to be ineffective or impractical.
Exclusion Criteria
Preoperative
1.
Subject needs emergency surgery
2.
Subject will undergo renal transplantation, or minimally invasive/laparoscopic surgery
3.
Subject will undergo neurological or ophthalmological surgery
4.
Subject will undergo urological or gynecological surgery (except for gynecological surgery in a 
postmenopausal subject or that results in removal of childbearing potential [eg, hysterectomy or 
other permanent sterilization procedure])
5.
Subject has congenital coagulation disorder (eg, hemophilia)
6.
Subject has known hypersensitivity to components of the investigational device
7.
Subject has a clinically significant medical condition (eg, concomitant illness, psychiatric disorder, 
drug/ alcohol abuse), that, in the investigator’s opinion, could adversely affect the safety of the 
subject and/ or compliance with the study procedures
8.
Subject has participated in another clinical study involving an investigational product within 
30 days prior to enrollment, or is scheduled to participate in another clinical study involving an 
investigational product during their participation in this study
9.
Subject is a family member or employee of the investigator
10. Subject is pregnant or lactating at the time of enrollment, or becomes pregnant prior to the planned 
surgery
Intraoperative:
1.
Occurrence of any surgical complication that requires resuscitation or deviation from the planned 
surgical procedure prior to identification of a TBS
2.
Disseminated intravascular coagulopathy
3.
Application of any topical hemostatic product to the TBS prior to application of the study 
treatment
4.
TBS is within an inflamed or actively infected field
5.
TBS is in, around, or in close proximity to foramina in bone, area of bony confinement or the spinal 
cord
6.
Bleeding scale Grade 3 or 4 (severe or life-threatening) bleeding at the TBS
7.
TBS is a non-treated hemorrhage from a visible capillary, vein or small artery, where ligation or 
other conventional means are likely to be effective

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STATISTICAL ANALYSIS
Sample Size Calculation
In this non-inferiority study, the proportions of subjects meeting the primary endpoint are assumed to be 
% for CELSTAT and 
% for Surgicel; the non-inferiority margin is defined as 10%, the 1-sided Type 1 
error rate () is 2.5%; and the statistical power (1-) is 80%. This results in a sample size of 121 evaluable 
subjects per treatment group. To reach this number, 129 subjects are to be randomized per treatment group.
Planned Statistical Analysis
Primary Endpoints
The primary effectiveness endpoint, achievement of hemostasis within 5 minutes, will be investigated by a 
2-sided test for non-inferiority using logistic regression, taking into account the following covariates: study 
center, surgery type (cardiothoracic, general or vascular), and initial bleeding severity (mild or moderate).
Non-inferiority of CELSTAT to Surgicel will be assessed using the confidence-interval approach and a 
non-inferiority margin of 10%.
The difference in the proportion of subjects having postoperative rebleeding during study participation will 
be performed using the same logistic regression model described for the primary efficacy endpoint.
Secondary Endpoints
The logistic regression model used for the primary endpoint will also be performed on the proportions of 
subjects with hemostasis achieved at 3, 7, and 10 minutes after treatment application, and on the proportion 
of subjects with intraoperative rebleeding from the TBS after achievement of hemostasis.
The TTH will be presented by Kaplan-Meier curves. In addition, a log-rank test will be performed to assess 
the difference between the distributions of TTH for CELSTAT and Surgicel.
Descriptive statistics will be generated for the secondary safety endpoints (AEs, clinical laboratory 
parameters and vital signs). Shift tables will be generated for laboratory parameters.

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5. TABLE OF CONTENTS
3584-001 CLINICAL INVESTIGATION PLAN........................................................... 1
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory)/Responsible Party................................ 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT/SERIOUS INJURY/SERIOUS ADVERSE 
DEVICE EFFECT/DEVICE DEFICIENCY REPORTING.................................... 3
3. UNANTICIPATED ADVERSE DEVICE EFFECT REPORTING........................ 4
4. SYNOPSIS..................................................................................................................... 5
5. TABLE OF CONTENTS ............................................................................................. 9
6. LIST OF ABBREVIATIONS .................................................................................... 13
7. BACKGROUND INFORMATION .......................................................................... 14
7.1 Identification and Description of Investigational Device.................................. 14
7.2 Clinical Condition/Indication .............................................................................. 14
7.3 Justification for the Design of the Clinical Investigation.................................. 16
7.3.1 CELSTAT Preclinical Studies...................................................................... 16
7.3.2 Prior CELSTAT Clinical Investigation....................................................... 17
7.3.3 Choice of Surgicel as Comparator ............................................................... 18
7.3.4 Types of Surgery............................................................................................ 19
7.3.5 Primary Effectiveness Endpoint................................................................... 19
7.3.6 Statistical Considerations.............................................................................. 19
7.3.7 Relevant Literature and Data....................................................................... 20
7.4 Anticipated Benefits and Risks of the Investigational Device and Clinical 
Investigation .......................................................................................................... 20
7.5 Compliance Statement.......................................................................................... 21
8. OBJECTIVES OF THE CLINICAL INVESTIGATION....................................... 22
8.1 Primary Objective................................................................................................. 22
8.2 Secondary Objectives ........................................................................................... 22
9. STUDY DESIGN......................................................................................................... 22
9.1 Brief Summary...................................................................................................... 22

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9.2 Overall Study Design............................................................................................ 22
9.3 Duration of Study Period(s) and Subject Participation .................................... 24
9.4 Outcome Measures ............................................................................................... 24
9.4.1 Primary Outcome Measures......................................................................... 24
9.4.1.1 Effectiveness............................................................................................ 24
9.4.1.2 Safety........................................................................................................ 24
9.4.2 Secondary Outcome Measures ..................................................................... 24
9.4.2.1 Effectiveness............................................................................................ 24
9.4.2.2 Safety........................................................................................................ 24
9.5 Factors Influencing the Outcome ........................................................................ 25
9.6 Randomization and Blinding............................................................................... 25
9.6.1 Randomization ............................................................................................... 25
9.6.2 Blinding........................................................................................................... 25
9.7 Suspension or Premature Termination of the Clinical Investigation .............. 26
9.8 Investigational Device(s) and Comparator(s)..................................................... 26
9.8.1 Description and Administration of Treatment ........................................... 26
9.8.1.1 Description of the Investigational Device - CELSTAT ....................... 26
9.8.1.2 Description of Comparator Device – Surgicel...................................... 27
9.8.1.3 Administration of the Study Device...................................................... 28
9.8.2 Number of Investigational Devices and Justification................................. 29
9.8.3 Justification for Use of Comparator(s)........................................................ 29
9.9 Investigational Device Accountability................................................................. 29
9.10 Source Data ......................................................................................................... 30
10. SUBJECTS ................................................................................................................ 30
10.1 Inclusion Criteria................................................................................................ 31
10.2 Exclusion Criteria............................................................................................... 31
10.3 Criteria and Procedures for Subject Withdrawal or Discontinuation .......... 32
11. PROCEDURES......................................................................................................... 33
11.1 Informed Consent and Enrollment ................................................................... 33
11.2 Subject Identification Code................................................................................ 33
11.3 Screening and Study Visits................................................................................. 34
11.4 Medications and Non-Drug Therapies.............................................................. 34
11.5 Subject Completion/Discontinuation ................................................................ 34
11.6 Procedures for Monitoring Subject Compliance............................................. 35
12. ASSESSMENT OF OUTCOMES ........................................................................... 35
12.1 Medical, Medication and Non-Drug Therapy History.................................... 35
12.2 Assessment of Effectiveness ............................................................................... 36
12.3 Assessment of Safety........................................................................................... 38
12.3.1 Postoperative Rebleeding............................................................................ 38
12.3.2 Adverse Events, Adverse Device Effects and Device Deficiencies........... 38

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12.3.2.1 Definitions.............................................................................................. 38
12.3.2.2 Severity .................................................................................................. 42
12.3.2.3 Causality................................................................................................ 42
12.3.2.4 Assessment of Adverse Events............................................................. 43
12.3.2.5 Expedited Adverse Event Reporting................................................... 44
12.3.2.6 Pre-existing Diseases............................................................................. 45
12.3.2.7 Foreseeable Adverse Events................................................................. 45
12.3.2.8 Urgent Safety Measures ....................................................................... 45
12.3.2.9 Untoward Medical Occurrences Not Considered Adverse Events .. 45
12.3.2.10 Non-Medical Complaints ................................................................... 46
12.3.3 Physical Examinations................................................................................. 46
12.3.4 Clinical Laboratory Parameters ................................................................ 47
12.3.4.1 Hematology, Clinical Chemistry and Coagulation............................ 47
12.3.4.2 Other Laboratory Tests ....................................................................... 47
12.3.4.3 Assessment of Laboratory Values....................................................... 48
12.3.5 Vital Signs..................................................................................................... 48
13. STATISTICAL CONSIDERATIONS .................................................................... 49
13.1 Sample Size and Power Calculations ................................................................ 49
13.2 Datasets and Analysis Cohorts .......................................................................... 49
13.3 Handling of Missing, Unused, and Spurious Data........................................... 50
13.4 Methods of Analysis............................................................................................ 50
13.4.1 Primary Outcome Measures....................................................................... 50
13.4.2 Secondary Outcome Measures ................................................................... 51
13.5 Interim Analysis.................................................................................................. 52
14. ACCESS TO SOURCE DATA................................................................................ 52
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 53
15.1 Investigator’s Responsibility.............................................................................. 53
15.2 Training ............................................................................................................... 53
15.3 Monitoring........................................................................................................... 53
15.4 Auditing ............................................................................................................... 53
15.5 Noncompliance with the Clinical Investigation Plan....................................... 54
15.6 Laboratory Standardization.............................................................................. 54
16. ETHICS ..................................................................................................................... 54
16.1 Subject Privacy ................................................................................................... 54
16.2 Ethics Committee and Regulatory Authorities................................................ 54
16.3 Informed Consent ............................................................................................... 55
16.4 Data Safety Monitoring Board .......................................................................... 55

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17. DATA HANDLING AND RECORD KEEPING................................................... 56
17.1 Confidentiality Policy ......................................................................................... 56
17.2 Study Documentation and Case Report Forms ............................................... 56
17.3 Extent of Source Data Verification ................................................................... 56
17.4 Document and Data Retention........................................................................... 57
18. FINANCING AND INSURANCE........................................................................... 57
19. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN .................... 57
20. PUBLICATION POLICY........................................................................................ 57
21. SUPPLEMENTS....................................................................................................... 58
21.1 Study Flow Chart................................................................................................ 58
21.2 Schedule of Study Procedures and Assessments.............................................. 59
22. REFERENCES.......................................................................................................... 60
INVESTIGATOR ACKNOWLEDGEMENT.............................................................. 61
LIST OF TABLES
Table 1. Examples of Cardiothoracic, General and Vascular Surgery Types and 
Associated Possible Tissue Types ............................................................................ 15
Table 2. Bleeding Severity Scale...................................................................................... 23

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6. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADE
adverse device effect
AE
adverse event
CI
confidence interval
CFR
Code of Federal Regulations
CIP
clinical investigation plan
CRO
contract research organization
DSMB
data safety monitoring board
eCRF
electronic case report form
FAS
full analysis set
GCP
Good Clinical Practice
IB
Investigator's Brochure
ICF
Informed consent form
IEC
independent ethics committee
IRB
institutional review board
ISO
International Organization for Standardization
IWRS
interactive Web-response system
MedDRA
Medical Dictionary for Regulatory Activities
NMC 
non-medical complaint
OC
oxidized cellulose
PPS
per-protocol analysis set
REB
research ethics board
SADE
serious adverse device effect
SAE
serious adverse event
SAER
serious adverse event report
SI 
serious injury
SIC
subject identification code
SSRI
selective serotonin re-uptake inhibitor
TBS
target bleeding site
TTH
time to hemostasis
UADE 
unanticipated adverse device effect

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7. BACKGROUND INFORMATION
7.1 Identification and Description of Investigational Device
CELSTAT is a medical device intended for use adjunctively in surgical procedures to 
assist in the control of capillary, venous and small arterial hemorrhage when ligation or 
other conventional methods of control are impractical or ineffective. It is a gamma 
sterilized, absorbable hemostat in a flat form with textile structure of high flexibility. It 
consists entirely of oxidized cellulose (OC) and does not contain any excipients. The 
hemostatic effect is immediate and total hemostasis is usually obtained within several 
minutes after application. CELSTAT is currently marketed in several European countries 
as Traumastem (distributed by Baxter Healthcare Corporation), Traumastem TAF Light 
(distributed by 
 or Traumacel TAF Light (distributed by 
. in the 
Czech Republic). Hereafter in this CIP, the product will be referred to as CELSTAT.
Once applied, CELSTAT absorbs blood, turns brown, and adheres to the wound, thereby 
preventing thrombocytes from being washed out and accelerating hemostasis.1
CELSTAT is 100% absorbable by the body and generally can, but does not have to be, 
left in situ. Results from International Organization for Standardization (ISO) 10993 
testing documented that it causes no adverse immune or inflammatory reactions, is 
accepted by the organism, and does not affect any biological healing processes.
In this study, CELSTAT will be compared to Surgicel Original (marketed as Tabotamp in 
some European countries [see Section 9.8.1.2], referred to as Surgicel for the remainder 
of this document), a commercially available hemostatic agent based on oxidized 
regenerated cellulose, manufactured by Johnson and Johnson's Ethicon subsidiary. For 
study purposes the investigational devices will be traced by means of lot numbers.
7.2 Clinical Condition/Indication
Absorbable hemostats like CELSTAT or Surgicel are used in situations where ligature or 
conventional procedures are either ineffective or impractical. The devices play an 
important role in controlling bleeding during surgery and in minimizing rebleeding in the 
postoperative period, and can have a significant impact on surgical outcomes and 
postoperative complications. 
Both CELSTAT and Surgicel are suitable for use in general and digestive surgery, plastic 
surgery, vascular and thoracic surgery, gynecology, stomatology, and other related fields.
In this study, CELSTAT will be compared to Surgicel as hemostatic adjunct during open 
field cardiothoracic, general and vascular surgery. Target bleeding sites (TBSs) include 

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mild to moderate parenchymal (organ tissue), vascular (small arteries or veins or surgical 
reconnections) and soft tissue (muscle, fat, ligament, connective tissue) bleeding. 
Examples of cardiothoracic, general and vascular surgery and the associated possible 
tissue types are provided in Table 1 (however, this list is not exclusive). Excluded from 
this study are neurological, ophthalmological, urological, and gynecological surgery 
(except in postmenopausal women or for gynecological surgery that results in removal of 
childbearing potential).
Table 1. Examples of Cardiothoracic, General and Vascular Surgery Types and 
Associated Possible Tissue Types
Broad Surgery Types 
Included in Study
Defined Surgery Type 
(examples, not exclusive)
Associated Tissue Types
(examples, not exclusive)
Cardiothoracic
Vascular anastomosis
Vascular
CABG (coronary artery bypass graft)
Vascular, soft tissue
Valvular operations
Vascular
Aneurysm resection or repair
Vascular, soft tissue
General (including 
intraabdominal and
retroperitoneal)
Colectomy
Soft tissue
Retroperitoneal tumor resection
Parenchymal, vascular, soft tissue
Abdominoperineal resection
Vascular, soft tissue
Hepatic resection
Parenchymal, vascular, soft tissue
Lymphadenectomy
Vascular, soft tissue
Vascular
Open repair of aneurysm of aorta 
abdominalis
Vascular
Creation of arteriovenous fistula
Vascular
Aortobifemoral bypass
Vascular
Carotid endarterectomy
Vascular
Femoropopliteal, femorocrural 
bypass
Vascular
Subjects 18 years and older with planned cardiothoracic, general or vascular surgery will 
be recruited.
Subjects eligible for randomization will present with an intraoperative TBS suitable for 
treatment with a hemostatic adjunct, after conventional surgical hemostasis has been 
completed. Male or female subjects of any ethnic group and race may be recruited.

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7.3 Justification for the Design of the Clinical Investigation
The design of this clinical investigation is based on the experience from a previous 
clinical study with CELSTAT, clinical studies with other absorbable hemostatic devices, 
and on preclinical study results with CELSTAT.
Surgicel was chosen as comparator, as it is considered standard among comparable 
marketed devices. CELSTAT or Surgicel will only be applied after primary/conventional 
hemostatic procedures (eg, ligature, suture, compression, cautery) prove to be either 
ineffective or impractical. Treatment of Grade 3 or 4 (severe or life-threatening; see 
Table 2) bleeding is prohibited and subjects with such a bleeding at the TBS will be 
excluded from this study.
According to the anticipated clinical use, this study intends to demonstrate the hemostatic 
effectiveness and safety of CELSTAT in a broad range of open surgical procedures 
including cardiothoracic, general and vascular surgeries.
7.3.1 CELSTAT Preclinical Studies
Nonclinical data were obtained in 22 nonclinical studies investigating the safety and 
efficacy of CELSTAT. In 2 studies on swelling properties and the effects on pH of 
CELSTAT when exposed to neutral buffered media, the swelling and chemical properties 
of CELSTAT were similar to those of Surgicel OriginaI. In 14 biocompatibility and 
toxicology studies, no potential for CELSTAT to cause sensitization, irritation, toxicity, 
or systemic coagulation activation was detected; CELSTAT was determined to be
biocompatible; and no toxicologic risk resulting from exposure to extractable materials 
identified in CELSTAT was found.
Effectiveness of CELSTAT was assessed in 6 nonclinical studies. Three of these studies 
examined the time to hemostasis after CELSTAT application in comparison to 
commercially available hemostatic products (BloodSTOP or Surgicel Original). These 
studies used either a porcine liver square model or a porcine gastrointestinal punch 
biopsy model. In all 3 studies, CELSTAT showed a statistically significantly shorter time 
to hemostasis than the comparator products. CELSTAT was also more successful than 
BloodSTOP in controlling and maintaining hemostasis over time. One study examined 
hemostatic success (bleeding, yes or no) following application of CELSTAT or Surgicel 
Original in a rabbit femoral vein bleeding model. Statistical superiority of CELSTAT to 
Surgicel Original was demonstrated at 30, 60, and 90 seconds after application. Another 
study compared the hemostyptic properties of CELSTAT and Surgicel Original in a pig 
split skin hemostasis model. Bleeding scores were statistically significantly reduced with 

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CELSTAT compared to Surgicel. An additional study on hemostatic effectiveness, local 
tissue response and absorption of CELSTAT versus Surgicel in a rabbit femoral vessel 
bleeding model showed comparability of the 2 devices in effectiveness, local tissue 
response and absorption.
These studies are summarized in the Investigator’s Brochure (IB) for CELSTAT.
7.3.2 Prior CELSTAT Clinical Investigation
The sponsor conducted a pilot clinical study (Study 621101) to evaluate the safety and 
effectiveness of CELSTAT (brand name Traumastem in the study report) as an adjunct to 
hemostasis for tissue bleeding in subjects undergoing open cardiac, intraabdominal
(including retroperitoneal) or pelvic surgery as compared to Surgicel. This was a 
prospective, randomized, positive-controlled, subject-blinded, multicenter study.
In eligible subjects, the study treatment was applied at the TBS after conventional 
surgical hemostasis was completed. The number and size of layers of device used was at 
the discretion of the surgeon. The investigational device did not need to be removed and 
could be left in situ. 
All 82 subjects enrolled achieved hemostasis at the primary TBS within 10 minutes. At 
5 minutes after the start of device application hemostasis was achieved in 51 of 
55 subjects (93%) in the CELSTAT group and in 24 of 27 subjects (89%) in the Surgicel 
group. Median time to hemostasis (TTH) in the CELSTAT group was 117 seconds, 
compared with 158 seconds in the Surgicel group.
The proportion of subjects with any adverse event (AE)/adverse device effect (ADE) was
similar for the CELSTAT and Surgicel groups, with 74.5% (41/55 subjects) and 74.1% 
(20/27 subjects), respectively. Only 3 AEs/ADEs (postprocedural hematoma, 
postprocedural complication, and liver abscess) in the Surgicel group, all occurring in 
1 subject, were considered by the investigator to be related to study treatment. 
The pilot study defined AEs/ADEs of special interest as any of the following:

Postoperative rebleeding

Infection: signs included fever >100°F or >37.8°C after the first 48 hours with 
malaise and or lethargy

Hematoma at the surgical site

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
Change in coagulation parameters (as noted by change from normal or abnormal 
without clinical significance, respectively, at baseline to abnormal or abnormal 
with clinical significance at Day 7 (±1)/Discharge (Visit 3): prothrombin time, 
activated partial thromboplastin time, platelet count

Increased wound healing time (more than 2 weeks) or wound dehiscence

Foreign body reactions and allergic reactions (to device and material); signs of 
inflammation or encapsulation

Embolization (especially vascular surgeries) and associated complications
The Surgicel group had a higher proportion of treatment-emergent AEs/ADEs of special 
interest (22.2%, 6/27 subjects, 6 events), compared with the CELSTAT group (7.3%, 
4/55 subjects, 4 events). In the Surgicel group, the 6 events of special interest were 
wound infections (2 events), postprocedural hematoma (2 events), postprocedural 
hemorrhage, and wound dehiscence; in the CELSTAT group, the 4 events of special 
interest were abdominal abscess, wound infections, postprocedural hemorrhage, and 
wound dehiscence.
The proportions of SAEs/SADEs were similar between treatment groups, with 12.7% of 
subjects in the CELSTAT group reporting SAEs/SADEs and 11.1% of subjects in the 
Surgicel group reporting SAEs/SADEs. The Surgicel group had 1 SAE/SADE (liver 
abscess, moderate intensity) considered by the investigator to be related to study 
treatment. No related SAEs/SADEs were reported in the CELSTAT group. In each 
group, 1 fatal AE/ADE occurred, neither of which was related to study treatment. 
The results of the pilot study demonstrated the safety and effectiveness of CELSTAT as a 
treatment option to achieve hemostasis in subjects undergoing intraabdominal, pelvic, or 
open cardiac surgery. The present study (3584-001) will test CELSTAT versus Surgicel 
in a larger population of 258 subjects scheduled for cardiothoracic, general and vascular 
surgery.
7.3.3 Choice of Surgicel as Comparator
Surgicel was chosen as comparator, as it is the standard among comparable marketed 
devices. Surgicel has been an approved medical device since 1960 (N12159, approval
date 14 Oct 1960) in the United States. It has a long history of safety and effectiveness. 
The study device will only be used after primary surgical hemostasis has been achieved. 
Only bleeding sites appropriate for use of an OC device will be chosen. Therefore, no 
additional comparators are necessary.

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7.3.4 Types of Surgery
Feasibility data show that OC/Surgicel is frequently used during general, vascular, 
gynecological, and oncological surgeries. A pilot clinical study of CELSTAT 
(Study 621101), conducted to provide sound relevant experience for planning the current 
study, supported cardiothoracic and general surgery. Therefore, general and vascular 
surgeries were chosen for this protocol. Excluded from this study are neurological, 
ophthalmological, urological, and gynecological surgery (except for gynecological 
surgery in postmenopausal women or surgery that results in removal of childbearing 
potential).
Minimally invasive surgery, as a distinct technique within each of the surgery types 
featured in this protocol, will not be allowed due to a potential significant bias resulting 
from, among others, differences in subject profile, technical demands, pre-and 
postoperative conduct, level of trauma and hemostasis achievement compared to the open 
surgery.
7.3.5 Primary Effectiveness Endpoint
TTH is the most meaningful criterion to assess the effectiveness of a hemostatic device. 
Timepoints were selected based on adequacy of demonstrating effectiveness of 
CELSTAT. In 3 nonclinical studies (Studies 53075, 52483, and 54201, summarized in 
the CELSTAT IB), the TTH after CELSTAT application was compared to commercially 
available hemostatic strip products (BloodSTOP or Surgicel Original); in all 3 studies, 
CELSTAT showed a statistically significantly shorter TTH than the comparator products. 
Other clinical studies use TTH between 3 minutes and 10 minutes after application of the 
device. A TTH of 5 minutes, which is supported by the pilot study, is a good compromise 
and applicable for all surgery types.
7.3.6 Statistical Considerations
Subgroup analyses in the pilot study showed that the surgery type seems to have high 
potential to influence the effectiveness results. Randomization will be stratified by 
surgery type in this study to control this effect. The sample size estimation is based on the 
assumption that the proportion of achieved hemostasis for the primary endpoint is 
% 
for CELSTAT and 
% for Surgicel.
The non-inferiority margin is defined as 10%. While the pilot study identified different 
rates of hemostasis at 5 minutes across surgery types, and surgery type had a high 
potential to influence effectiveness, a non-inferiority margin of 10% is still regarded as 

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appropriate, as the small-scaled pilot study may not provide adequate information 
allowing for a consistent judgement.
7.3.7 Relevant Literature and Data
Absorbable hemostatic adjuncts based on OC were first introduced into the market in the 
1940s2,3 and devices based on oxidized regenerated cellulose were launched in 1960.4 OC
offers superior handling characteristics when compared with gelatin foams. The knitted 
tissue strips can be cut to fit any size. The device does not stick to instruments and can 
easily be held firmly against the bleeding tissue until hemostasis is achieved.5 The device 
forms a lattice-like structure that traps platelets and contributes to clot formation by 
expanding and absorbing up to several times its own weight.6 Although the time to 
absorption of OC is thought to range from 2 to 6 weeks, depending on the amount used,7
there are reports describing histologic evidence of OC fibers several years after cardiac 
surgery.8,9,10
Complications like allergic reactions, infections, granulomas and interference with bone 
healing have been noticed only rarely after the application of topical hemostatics.11
Complications with the use of OC devices may arise from local swelling or possible 
inflammatory reactions.12 Swelling of Surgicel in the proximity of the spinal cord or optic 
nerve has been linked to paralysis or nerve damage13,14 and it is therefore recommended 
to remove Surgicel after use in confined areas. Additionally, foreign body reactions have 
been reported after the use of OC devices.15
7.4 Anticipated Benefits and Risks of the Investigational Device and Clinical 
Investigation
Benefits
The use of CELSTAT as an adjunct to hemostasis offers the following benefits:

CELSTAT is intended to serve as an adjunctive treatment to hemostasis similar to 
other OC devices. It offers a wide application range within the surgical area with 
currently only brisk (major) arterial bleeding as contraindication

CELSTAT is a biodegradable material that can be left in situ, if used in 
accordance with instructions and general site practice, thus reducing the risk of 
recurrent bleeding, traumatization of the subject and disruption of the healing 
process

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
Based on former and current animal data, CELSTAT is expected to be well
tolerated. To date, no undesirable effects such as allergic reactions at the 
application site have been reported for CELSTAT

CELSTAT is easy to use and requires no specific preparations before application. 
Based on its ease of use, effective hemostasis, and comparably low costs, 
CELSTAT may reduce the overall costs for therapy
Risks
Potential risks associated with the use of either CELSTAT or Surgicel include the 
following:

Foreign body reaction

Inflammatory reaction (including adhesive disease)

Infection

Rebleeding at the treated site (with or without removal of the device after 
acheivement of hemostasis

Hematoma/seroma

Thromboembolic hazards (blood clots)

Compression-related problems (eg, stenosis, nerve damage, or sequelae related to 
decreased blood flow)
The study inclusion and exclusion criteria (see Section 10), and the study-specified 
device application procedures (see Section 9.8.1.3), have been developed to minimize the 
magnitude of these risks, while still allowing the study objectives to be met.
Conclusions
Considering that it is not planned to include surgery types with the highest of the 
associated risks and that the study device application procedures are designed to further 
mitigate these risks, and the previously noted potential benefits, the study is considered to 
be medically justified.
7.5 Compliance Statement
This study will be conducted in accordance with this CIP, the Declaration of Helsinki (as 
currently amended), Title 21 of the United States Code of Federal Regulations Parts 50, 
54, 56, and 812, the International Conference on Harmonisation Guideline for Good 

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Clinical Practice (GCP) E6 (Apr 1996), GCP as laid down in ISO Norm 14155:2011, the 
European Union Medical Devices Directive 93/42/EEC as amended by Directive 
2007/47/EC, MEDDEV 2.7/3 and MEDDEV 2.7/4 Guidelines on Medical Devices, and 
applicable national and local regulatory requirements.
8. OBJECTIVES OF THE CLINICAL INVESTIGATION
8.1 Primary Objective
The primary objective of the study is to assess the hemostatic effectiveness of CELSTAT
in comparison to Surgicel, based on the achievement of hemostasis within 5 minutes after 
the start of treatment application (for a detailed definition see Section 9.4.1.1).
8.2 Secondary Objectives
The secondary objectives of the study are:

To evaluate additional hemostatic effectiveness parameters of CELSTAT in 
comparison to Surgicel (for detailed definition, see Section 9.4.2.1)

To evaluate the safety of CELSTAT (see Section 9.4.2.2)
9. STUDY DESIGN
9.1 Brief Summary
This is a prospective, randomized, controlled, single-blind pivotal trial of CELSTAT as 
an adjunct to hemostasis for the treatment of mild to moderate bleeding in subjects 
undergoing cardiothoracic, general and vascular surgery. The study is to evaluate the 
effectiveness and safety of CELSTAT vs active control in 258 subjects. It will be
conducted at approximately 26 sites in the United States (20) and Europe (6).
9.2 Overall Study Design
This is a prospective, randomized, positive-controlled, subject-blinded, multicenter study.
Surgicel was chosen as comparator, as it is the standard among comparable marketed 
devices.
A total of 258 subjects scheduled for cardiothoracic, general and vascular surgery are 
planned to be randomized, at a 1:1 ratio to CELSTAT or Surgicel, in the study. Patients
will be evaluated for eligibility at screening (Visit 1; in- or outpatient setting) within
14 days prior to the planned surgery. Final inclusion of subjects depends on the 
fulfillment of the intraoperative eligibility criterion. On the day of surgery (Visit 2; 

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Day 1), inclusion and exclusion criteria will be verified pre- and intraoperatively. The 
surgeon will be kept blinded to treatment assignment until after the TBS is selected.
The bleeding scale developed for use in the study in determining TBS inclusion 
suitability and response to study treatment is presented in the following table (Table 2).
Table 2. Bleeding Severity Scale
Grade
Visual Presentation
Anatomical 
Appearance
Qualitative 
Description
Visually Estimated 
Rate of Blood Loss 
(mL/min)
0
No bleeding
No bleeding
No bleeding
≤1.0
1
Ooze or intermittent 
flow
Capillary-like 
bleeding
Mild
>1.0-5.0
2
Continuous flow
Venule- and 
arteriolar-like 
bleeding
Moderate
>5.0-10.0
3
Controllable spurting 
and/or overwhelming 
flow
Non-central venous-
or non-arterial-like 
bleeding
Severe
>10.0-50.0
4
Unidentified or 
inaccessible spurting 
or gush
Central arterial- or
venous-like bleeding
Life threateninga
>50.0
a Systemic resuscitation is required (eg, volume expanders, vasopressors, blood products).
Administration of the device is detailed in Section 9.8.1.3. Effectiveness and safety of the 
device will be assessed as described in Section 12.
Postoperative follow-up visits are scheduled for hospital discharge (or at Day 8 [1] if the 
subject remains hospitalized for more than 1 week postsurgically; Visit 3); Day 31 (5)
(Visit 4); Day 61 (10) (Visit 5); and Day 91 (10) (Visit 6; end of study).
AEs and device related complications will be recorded from enrollment (time of signing 
of the informed consent form [ICF]) until the subject has completed participation in the 
study. Concomitant medication will be recorded from enrollment through the end of 
study participation. Safety laboratory assessments including coagulation parameters will 
be assessed at specified time points and the subject’s vital signs will be monitored. 
Intraoperative complications and intra- as well as postoperative rebleeding events will be 
documented.
An overview of the study design is presented in Supplement 21.1. 

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9.3 Duration of Study Period(s) and Subject Participation
The planned overall duration of the study is approximately 14 months from study 
initiation (ie, first subject’s enrollment) to study completion (ie, last subject’s last visit). 
The recruitment period is expected to be approximately 10 months.
The subject participation period is approximately 15 weeks from screening to subject 
completion (ie, last study visit), unless prematurely discontinued.
9.4 Outcome Measures
9.4.1 Primary Outcome Measures
9.4.1.1 Effectiveness
The primary effectiveness outcome measure is the proportion of subjects with hemostasis
achieved at the TBS at 5 minutes after the start of application of the study device.
Hemostasis is defined as Grade 0 bleeding (no bleeding; see Table 2 in Section 9.2) at the 
TBS after application of the randomized treatment, with no subsequent rebleeding at the 
TBS through surgical closure and no additional hemostatic treatment of another type after 
application of the randomized treatment.
9.4.1.2 Safety
The primary safety outcome measure is postoperative rebleeding from the TBS requiring 
surgical re-exploration during the subject’s study participation.
9.4.2 Secondary Outcome Measures
9.4.2.1 Effectiveness

TTH at the TBS within the 10-minute assessment period

Proportions of subjects with hemostasis achieved at the TBS at 3, 7 and 
10 minutes after the start of application of the study device

Intraoperative rebleeding from the TBS after occurrence of  hemostasis
9.4.2.2 Safety

Occurrence of AEs/ADEs during the subject’s study participation

Clinical laboratory parameters

Vital signs

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9.5 Factors Influencing the Outcome
Surgery type (cardiothoracic, general and vascular) and bleeding severity (mild, 
moderate) may potentially influence hemostatic effectiveness. Therefore, these factors 
will be considered in the analysis.
9.6 Randomization and Blinding
9.6.1 Randomization
Subjects will be randomly assigned to CELSTAT or Surgicel at a ratio of 1:1.
Randomization will be stratified by study center and surgery types (cardiothoracic, 
general, vascular surgery). It is aimed to achieve a similar distribution of the 3 surgery 
types in the randomized study population. This will be controlled via an interactive Web-
response system (IWRS), 
 
USA), using dynamic allocation. Within 
, a capping strategy will be 
used to ensure equal allocation of randomized subjects across surgical types. On the day 
of surgery, upon confirmation of preoperative eligibility criteria, a member of the site 
study staff other than the surgeon will obtain a treatment assignment (CELSTAT or
Surgicel) from the IWRS. To keep the surgeon blinded until an eligible TBS has been 
identified for study treatment, adequate amounts of each study product (CELSTAT and 
Surgicel) will be taken into the operating room for potential use of one of them as the 
study treatment.
Immediately after the subject’s intraoperative eligibility for study treatment has been 
confirmed (ie, an eligible TBS with Grade 1 or 2 bleeding has been identified), the 
assigned treatment will be revealed to the surgeon and the assigned device will be applied
to the TBS. Following surgery, the treatment assignment and the actual treatment applied 
will be entered in the electronic case report form (eCRF) for the subject.
If the subject’s eligibility is not confirmed pre- or intraoperatively, the subject’s operation 
will be performed according to hospital standards. The study site designee will enter the 
date and reason(s) for the subject’s exclusion in the eCRF.
9.6.2 Blinding
This will be a single-blinded study. The subjects undergoing scheduled surgery will be 
blinded. In addition, the surgeon performing the surgery will remain blinded until an 
eligible TBS has been identified for study treatment (see Section 9.6.1). Otherwise, 
investigators, surgery personnel, site study personnel, CRO personnel and sponsor 
personnel will not be blinded.

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9.7 Suspension or Premature Termination of the Clinical Investigation 
This study will be terminated if 1 or more of the following criteria are met:

The incidence of device-related AEs/ADEs signals a potential health hazard

New scientific data on the investigational device do not justify a continuation of 
the clinical study

Serious or persistent non-adherence to the protocol, GCP, and/or applicable 
regulatory requirements by an investigator site may lead to a stop of recruitment 
and closure at this specific site

The study is stopped by the sponsor for any reason
The clinical investigation may be terminated at an individual study site if no subjects are 
recruited within 6 months after site initiation, as well as in case of GCP non-compliance.
Subject follow-up after premature termination of the clinical investigation will include all 
procedures scheduled for the post-operation follow-up visits on Day 8 (±1)/discharge, 
Day 31 (5), Day 61 (10), and Day 91 (10)/End of Study (Supplement 21.2).
9.8 Investigational Device(s) and Comparator(s)
9.8.1 Description and Administration of Treatment
9.8.1.1 Description of the Investigational Device - CELSTAT
CELSTAT is a medical device intended for use adjunctively in surgical procedures to 
assist in the control of capillary, venous and small arterial hemorrhage when ligation or 
other conventional methods of control are impractical or ineffective. It is a gamma-
sterilized absorbable hemostat in a flat (matrix/OC) form based on OC. It has a textile 
structure and the raw material for manufacturing of CELSTAT is natural cotton. The 
cotton is oxidized in the gaseous phase by nitrogen dioxide. This reaction results 
primarily in the conversion of hydroxyl groups to carboxylic acid groups, making the 
material soluble at physiological conditions. Cellulosic acid within the device causes 
localized denaturation of blood proteins. The device does not contain substances derived 
from natural rubber latex, and is both polyvinyl chloride-free and diethylhexyl phthalate-
free.
The manufacturer and supplier of CELSTAT is 
 
, Czech Republic. The manufacturer takes all necessary measures to ensure that 
the investigational device corresponds to the manufacturing and sterilization 
documentation.

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CELSTAT is provided sterilized (gamma irradiated), endotoxin-free with the following 
physical properties:

Composition: OC (100%)

Weight: 90 to 120 g/m2

Nitrogen content: ≤0.5%

Quantity of carboxyl groups: 16% - 24%

Loss on drying: ≤15%
For this study, CELSTAT sheets with the dimension 5×7.5 cm will be provided. Each 
sheet will be packed in a sterile pouch. Ten sterile pouches (each containing 1 CELSTAT
sheet) will be included in each box of CELSTAT.
CELSTAT should be stored in a dry area protected from light between 2ºC and 30ºC. 
CELSTAT’s shelf-life is 3 years after sterilization in original packaging.
9.8.1.2 Description of Comparator Device – Surgicel
Surgicel  is a commercially available hemostatic device manufactured by Johnson and 
Johnson's Ethicon subsidiary. Surgicel is an absorbable knitted fabric prepared by the 
controlled oxidation of regenerated cellulose (polyanhydroglucuronic acid).
Surgicel is used adjunctively in a variety of surgical procedures to assist in the control of 
capillary, venous, and small arterial bleeding when conventional methods of control are 
impractical or ineffective.
Surgicel is white with a pale yellow cast and has a faint, caramel-like aroma. It is strong 
and can be sutured or cut without fraying. After Surgicel has been saturated with blood, it 
swells into a brownish or black gelatinous mass.
For this study, Surgicel Original will be supplied to the investigator sites in the 
configuration as prepared for final use by the manufacturer: knitted fabric sheets of 
5.1×7.6 cm Surgicel Original (for United States investigator sites) or 5.0×7.5 cm
Tabotamp (for European investigator sites). Each sheet will be packed in a sterile pouch
containing an inner sterile envelope that houses the sheet. Twelve or 24 sheets and 
1 Instructions for Use insert will be included in each box of the product.
Surgicel should be stored at controlled room temperature (Surgicel at 15° to 30°C /
Tabotamp at 15° to 25°C). Surgicel’s shelf life is 3 years.

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9.8.1.3 Administration of the Study Device
In case more than 1 bleeding site is identified after conventional hemostasis, the first site 
appearing adequate according to the study eligibility criteria will be considered the TBS 
for hemostatic effectiveness and safety assessments. Additional bleeding sites are to be 
treated according to the hospital’s standard of care, but not using either the CELSTAT or 
Surgicel that was supplied for study use, or any CELSTAT or Surgicel product otherwise 
available at the site. These bleeding sites will not be assessed for efficacy as part of the 
study.
Sterile technique should be observed in removing the study device from its sterile 
container. Once removed, the device is applied directly to the dried TBS. The nuber and 
size of layers required depends on the nature and intensity of the bleeding to be stopped. 
No upper limit is stipulated. The surgeon may obtain different sheet sizes by cutting the 
provided sheets with dry scissors. Only as much (length/width/numbers of layers) 
CELSTAT or Surgicel is to be used as is necessary to achieve hemostasis. The study 
device should not be wrapped too tightly when used as a wrap during vascular surgery.
The device is to be laid on the TBS and held firmly in place against the TBS for at least 
30 seconds. The way the product is held in place is at the discretion of the surgeon 
depending on the nature of the TBS and should be similar for both products. The device 
should not be used for packing or wadding, unless it is to be removed after hemostasis is 
achieved.
The achievement or lack of hemostasis following treatment application to the TBS will 
be recorded at different time points during the first 10 minutes after the start of device 
application, as described in Section 12.2. If hemostasis appears to be achieved early, but 
rebleeding occurs during the 10-minute assessment period, more of the randomized 
product may be applied and the hemostasis assessment will continue.
During the 10-minute observation period all efforts should be made to achieve hemostasis
at the TBS only by using the randomized study treatment.
Prior to surgical closure, any parts of the device not soaked with blood are to be carefully 
cut off to promote absorption and minimize the possibility of foreign body reaction.
Both CELSTAT and Surgicel are considered absorbable hemostats (based on preclinical 
data, absorption of CELSTAT is expected to take no more than 30 days). For study safety 
assesment purposes, both devices should be left in situ after hemostasis has been 
achieved, unless the investigator believes that the subject’s safety would be jeopardized,

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or if the product is ineffective. However, no more than 5 CELSTAT sheets or 
14 Surgicel sheets are to remain in situ at surgical closure in a given subject (see 
Section 9.8.2). If some or all of the applied sheets are removed, the removal of the 
device(s) must be recorded on the eCRF, along with the rationale for removal.
Any rebleeding from the TBS after the 10-minute assessment period following treatment 
application is to be recorded as an AE, and is to be treated according to standard of care
as determined by the surgeon. Should the investigator think that only OC is indicated, the 
randomized study device should be used if possible. However, no more than 
5 CELSTAT sheets or 14 Surgicel sheets are to remain in situ at surgical closure in a 
given subject.
9.8.2 Number of Investigational Devices and Justification
No more than 5 CELSTAT sheets are to remain in situ at surgical closure in a given 
subject. The results of a toxicological evaluation of CELSTAT demonstrated that no risk 
of adverse effects caused by extractable substances is anticipated when up to 5 of the 
5.0 x 7.5 cm sheets are applied per adult patient (ie, approximately 1 sheet per 14 kg 
[31 lb] body weight). This corresponds to an amount of 43 mg of CELSTAT per kg body 
weight (eg, 5 sheets for a 70 kg [154 lb] adult).
In order to allow an adequate safety comparison between the test and control products, no 
more than 14 Surgicel sheets are to remain in situ at surgical closure in a given 
subject. This provides an approximately equivalent maximum mass of Surgicel, which 
has a lower density than CELSTAT, that can be allowed to be left in situ.
9.8.3 Justification for Use of Comparator(s)
Surgicel was chosen as active comparator, as it is considered standard among comparable 
marketed devices.
9.9 Investigational Device Accountability
The investigator will ensure that the investigational device and the comparator are stored 
as specified in the CIP and that the storage area is secured, with access limited to 
authorized study personnel, as described in the Clinical Study Agreement. A temperature 
log will be completed on a daily basis, in order to ensure maintenance of the correct 
storage temperature. In addition, the investigator will maintain records that the 
investigational device and comparator were received, including the date received, device 
identity code, date of manufacture or expiration date, number of devices received and 
their disposition. The investigational device and comparator must be dispensed only at 

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the study site. Records will be maintained that include the subject identification code 
(SIC) (see Section 11.2), application date, and number of devices used. All unused boxes 
and pouches of investigational device will be disposed of in accordance with the 
sponsor’s instructions and all applicable laws and regulations after study 
completion/termination.
9.10 Source Data
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 following: 

Paper or electronic hospital records 

Paper or electronic medical records 

Hospital discharge summaries

Study-specific source document templates, if used

Treatment care records

Nursing care records

Anesthesia reports

Signed and dated central laboratory reports indicating clinical relevancy

Clinical and office charts

Laboratory notes, memoranda

Pharmacy dispensing records

Copies or transcriptions certified after verification as being accurate copies

Subject files and records kept at the pharmacy/ at the laboratories involved in the 
clinical study.
For additional information on study documentation and eCRFs refer to Section 17.2.
10. SUBJECTS
A total of 258 subjects (129 subjects per treatment group) will be randomized (see sample 
size calculation in Section 13.1). This is expected to be achieved in an enrollment period 

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of 10 months. The number of subjects should be approximately equally distributed 
among the 26 planned sites.
The following inclusion and exclusion criteria define the population.
10.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
Preoperative
1.
Male or female subjects, 18 years or older at the time of signing the ICF (female 
subjects of childbearing potential must present with a negative serum pregnancy 
test, and must agree to employ adequate birth control measures [restricted to 
abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed 
hormonal products] for the duration of their participation in the study)
2.
Subject is undergoing planned (non-emergency) cardiothoracic, general or 
vascular surgery
3.
Subject is willing and able to comply with the requirements of the CIP
Intraoperative
Bleeding scale Grade 1 or 2 (mild or moderate; see Table 2) soft tissue, vascular or 
parenchymal bleeding present at the TBS after standard conventional surgical 
hemostatic methods (eg, ligature, suture, compression, cautery) prove to be ineffective 
or impractical
10.2 Exclusion Criteria 
Subjects who meet ANY of the following criteria are not eligible for this study:
Preoperative
1. Subject needs emergency surgery
2. Subject will undergo renal transplantation, or minimally invasive/laparoscopic
surgery
3. Subject will undergo neurological or ophthalmological surgery
4. Subject will undergo urological or gynecological surgery (except for 
gynecological surgery in a postmenopausal subject or that results in removal of 
childbearing potential [eg, hysterectomy or other permanent sterilization 
procedure])

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5. Subject has known congenital coagulation disorder (eg, hemophilia)
6. Subject has known hypersensitivity to any ingredient of the investigational device
7. Subject has a clinically significant medical condition (eg, concomitant illness, 
psychiatric disorder, drug/alcohol abuse), that, in the investigator’s opinion, could 
adversely affect the safety of the subject and/or compliance with the study 
procedures
8. Subject has participated in another clinical study involving an investigational 
product within 30 days prior to enrollment, or is scheduled to participate in 
another clinical study involving an investigational product during their 
participation in this study
9. Subject is a family member or employee of the investigator
10. Subject is pregnant or lactating at the time of enrollment, or becomes pregnant 
prior to the planned surgery
Intraoperative:
1. Occurrence of any surgical complication that requires resuscitation or deviation 
from the planned surgical procedure prior to identification of a TBS
2. Disseminated intravascular coagulopathy
3. Application of any topical hemostatic product to the TBS prior to application of 
the study treatment
4. TBS is within an inflamed or actively infected field
5. TBS is in, around, or in close proximity to foramina in bone, area of bony 
confinement or the spinal cord
6. Bleeding scale Grade 3 or 4 (severe or life-threatening; see Table 2) bleeding at 
the TBS
7. TBS is a non-treated hemorrhage from a visible capillary, vein or small artery,
where ligation or other conventional means are likely to be effective
10.3 Criteria and Procedures for Subject Withdrawal or Discontinuation
Any subject 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 

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recorded on the end-of-study eCRF. The data collected on withdrawn subjects will be 
used in the analysis and included in the clinical investigation report.
Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by 
subject without notice or action). Additionally, the investigator and the sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
For subjects who terminate the clinical investigation prematurely after treatment 
exposure, a final examination including all Day 8 (±1)/discharge, Day 31 (±5), or Day 61
(10)/end-of-study follow-up assessments, depending on the time of withdrawal, should 
be performed, if possible. If a subject cannot come to a final examination, the investigator 
should try to clarify the reason and timepoint for discontinuation/drop out and document 
this in the source document used at the site. In case of drop out due to an 
SAE/SADE/UADE/AE of special interest, the event has to be documented sufficiently in 
the SAER form and the investigator has to report the SAE/SADE/UADE/AE of special 
interest to the CRO within 24 hours (see Section 12.3.2.4).
11. PROCEDURES
11.1 Informed Consent and Enrollment
Any subject who provides informed consent (ie, signs and dates the ICF, see Section 
16.3) is considered enrolled in the study. Any subject who meets the inclusion criteria 
(including the intraoperative inclusion criterion) and does not fulfill the exclusion criteria 
is considered eligible for randomization. Screening failures are subjects who provide 
informed consent, but do not meet the eligibility criteria for treatment.
11.2 Subject Identification Code
The following series of numbers will comprise the SIC: 3584-001-SSS-EEEE

3584-001: CIP identifier

SSS: 3-digit study site number

EEEE: 4-digit enrolment number, reflecting the order of signing the ICF
For example, the third subject who signs an ICF at study site 02 will be identified as 
Subject 3584-001-002-0003.
All subject-related study documents (eg, eCRFs, clinical documentation, sample 
containers, device accountability logs) will be identified with the SIC. 

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11.3 Screening and Study Visits
All screening data will be collected and reported in eCRFs, regardless of screening 
outcome. In case a subject provided informed consent, was assigned an SIC, was 
screened and is eligible, but the operation could not be performed within 14 days, the 
End-of-Study eCRF will be completed indicating that the subject was not randomized and 
treated. In such a case, re-screening is allowed. If the subject is re-screened, a new ICF,
new SIC, and new eCRF are required for the subject. The eCRF for the original SIC will 
be retained.
The study flow chart is illustrated in Supplement 21.1. An overview on the procedures to 
be performed at each study visit, including screening, can be found in Supplement 21.2.
11.4 Medications and Non-Drug Therapies
The following medications may be discontinued prior to the surgery according to the 
local standard of care:

Anti-platelet agents

Anti-coagulant therapy (oral or intravenous) and thrombolytic agents

Non-steroidal anti-inflammatory drugs
Selective serotonin re-uptake inhibitors (SSRIs) may increase the risk of bleeding 
events.16 Discontinuing an SSRI prior to the scheduled surgery should, therefore, be 
considered.
However, if antiplatelet agents or anticoagulant therapy cannot be discontinued prior to 
surgery due to medical reasons, these drugs must be documented as concomitant 
medication.
Homeopathic medications should generally be avoided because of the lack of information 
on safety and efficacy or possible effects on coagulation.
11.5 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has completed all study visits in accordance
with the CIP (with or without deviations).
Reasons for discontinuation will be reported on the end-of-study eCRF, including: screen 
failure, completion, premature discontinuation, and, if applicable, the reason for 
premature discontinuation (AE, discontinuation by subject [eg, lost to follow-up, defined 

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as 3 documented unsuccessful attempts to contact the subject, or dropout), physician 
decision, study terminated by sponsor, or other reason [to be specified by the 
investigator]). Regardless of the reason, all data available for the subject up to the time of 
discontinuation will be recorded on the appropriate eCRF and will be used in the analysis 
and included in the clinical study report. Refer to Section 10.3 for reasons for premature 
discontinuation or withdrawal.
Every effort will be made to have prematurely discontinuing subjects complete the 
procedures/assessments scheduled for the end-of-study visit (Visit 6). The assessment 
results shall be recorded on the end-of-study (Visit 6) eCRF, and not as an unscheduled 
visit. If a subject prematurely terminates participation in the study during or immediately 
after a scheduled visit and does not return for an additional premature termination visit, 
the data from their last scheduled visit will remain as recorded (ie, no data from that visit 
will be repeated on or transferred to the Visit 6 eCRF).
In the event of subject discontinuation due to an AE/ADE, 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 CRO, and the details 
of the outcome may be reported to the appropriate regulatory authorities by the CRO.
11.6 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures are needed to monitor subject compliance.
12. ASSESSMENT OF OUTCOMES
12.1 Medical, Medication and Non-Drug Therapy History
At screening, the subject’s medical history (including surgery; disease or condition 
severity [mild, moderate, or severe as defined in Section 12.3.2.2]; and start and end 
dates) will be described for the following body systems, if known: eyes, ears, nose, and 
throat; respiratory; cardiovascular; gastrointestinal; musculoskeletal; neurological; 
endocrine; hematopoietic/lymphatic; dermatological; and genitourinary. Subject 
demographics will also be entered in the eCRF.
All medications taken and non-drug therapies received from enrollment through the end 
of study participation will be recorded on the concomitant medications and non-drug 
therapies eCRFs.

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For the purpose of this study, standard routine perioperative medication/treatment and 
anesthesia in relation to the surgical intervention (except anticoagulation and reversal) do 
not have to be recorded as concomitant medication.
12.2 Assessment of Effectiveness
For statistical analysis, the observation period includes the 10 minutes after start of
application of the study device to the TBS.
The surgeon (who will be trained on the Bleeding Severity Scale [see Table 2] prior to 
study participation) will perform all intraoperative hemostasis assessments of the TBS, 
including identifying the TBS.
The severity of bleeding (Grade 1 or 2; see Table 2) at the TBS at the time of its 
identification (and prior to start of study device application) will be recorded.
A stop watch will be started at the start of device application. After application, the 
device is to be held firmly in place for at least 30 seconds. The occurrence and time of 
occurrence (or absence) of hemostasis (ie, Grade 0 bleeding; see Table 2) at the TBS will 
be recorded after the start of device application. Recurrence of bleeding, time of 
recurrence, and subsequent time of hemostasis will also be recorded, if applicable.
If hemostasis appears to be achieved early, but rebleeding occurs during the 10-minute 
assessment period, more of the randomized product may be applied and the hemostasis 
assessment will continue. TTH is defined as the time from the start of application of the 
study device until the first timepoint at which hemostasis at the TBS was observed and 
after which no rebleeding from the TBS occurred during the 10-minute observation 
period (subsequent intraoperative rebleeding will be considered a treatment failure).
In addition, any intraoperative rebleeding from the TBS after the initial 10-minute 
assessment period and prior to surgical closure will be recorded.

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Treatment failure is defined as any of the following:

Hemostasis not being achieved within 10 minutes

Occurrence of bleeding complications during the 10-minute hemostasis 
assessment period requiring hemostatic measures other than application of the 
randomized study treatment

Intraoperative rebleeding after the 10-minute hemostasis assessment period that is 
treated with the randomized study treatment or with any other hemostatic 
measures
The responsible study personnel will also record the following surgical, TBS, device 
administration, and hemostasis/rebleeding information during the peri- and intraoperative 
periods:

Date of surgery

Time of start and end of surgery (first skin incision/last skin suture)

Surgery type (cardiothoracic, general, vascular)

Indication for surgery and surgical procedure performed

Anatomical location of TBS

Tissue type (soft tissue, parenchymal or vascular)

Type of conventional hemostatic measures at the TBS before randomization

Time of completion of conventional hemostatic methods at TBS

Identity ( CELSTAT or Surgicel) and lot number of the applied study product

Number of sheets of the study product applied to the TBS

Number of sheets of the study product left in situ at surgical closure

Reason, if study product removed prior to surgical closure

Use of additional hemostatic treatment (yes/no) other than the study product at the 
TBS (ie, if hemostasis was not obtained during the 10-minute observation period, 
or if hemostasis was achieved but intraoperative rebleeding occurred); time of use 
(ie, number of minutes after clock start or after the 10 minute observation period), 
and type of additional hemostatic treatment

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
Use of anticoagulation and reversal during surgery, including:

Whether any anticoagulation was used (yes/no)

Anticoagulant used, start and end times of administration and dose 
administered for each dose administered

Reversal agent used (if any), start and end times of administration and dose 
administered for each dose administered

Whether cardiopulmonary bypass was used (yes/no) and, if yes, start and end 
times of bypass

Timepoint(s) of intraoperative rebleeding, if any, at the TBS after the 10-minute
observation period (to also be documented as an AE [see Section 12.3.2.4])

Intraoperative complications including death (to be documented as AEs)
12.3 Assessment of Safety
12.3.1 Postoperative Rebleeding
The occurrence of any postoperative rebleeding from the TBS requiring surgical
re-exploration during the remainder of the subject’s participation in the study will be 
recorded in the eCRF and will also be documented as an AE.
12.3.2 Adverse Events, Adverse Device Effects and Device Deficiencies
12.3.2.1 Definitions
12.3.2.1.1 Adverse Event
An AE (also refers to adverse experience) is defined as any untoward medical 
occurrence, unintended disease or injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device. This definition includes events related to the 
investigational medical device or the comparator, as well as events related to the 
procedures involved. However, for users or other persons, this definition is restricted to 
events related to investigational medical devices.
AEs occurring after application of the study device are to be specified as treatment-
emergent AEs.
Certain events that do not necessarily meet the definition of AEs, regardless of causal 
association with the investigational device(s), will still be recorded because they may be 

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reportable to regulatory authorities according to AE reporting regulations. These include 
the following:

Exposure to a device during pregnancy

Inadvertent or accidental exposure

Unexpected therapeutic or clinical benefit from the medical device

Application errors (ie, incorrect use of product)
12.3.2.1.2 Serious Adverse Event/ Serious Injury 
An SAE/SI is an AE that:

Leads to death

Leads to serious deterioration in the health of the subject, that either results in:
A life-threatening illness or injury (NOTE: “Life-threatening” in the definition 
of “serious” refers to an AE in which the subject was at risk of death at the 
time of the event or reaction; it does not refer to an event or reaction which 
hypothetically might have caused death had it been more severe), or
A permanent impairment of a body structure or a body function, or
In-patient or prolonged hospitalization (NOTE: Planned hospitalization for a 
pre-existing condition, or a procedure required by the CIP without serious 
deterioration in health, is not considered an SAE), or
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function

Leads to fetal distress, fetal death or a congenital abnormality or birth defect

Is a medically important event that may not be immediately life-threatening or 
require hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definitions 
above. Examples of such events are:
Rebleeding requiring surgical revision
Wound infection requiring surgical re-exploration

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Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in
hospitalization
12.3.2.1.3 Nonserious Adverse Event
A nonserious AE is an AE that does not meet the criteria of an SAE.
12.3.2.1.4 Unexpected Adverse Event
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the reference safety 
information (eg, IB, Instructions for Use). “Unexpected” also refers to the AEs that are 
mentioned in the IB as occurring with a class of devices or as anticipated from the 
properties of the device, but are not specifically mentioned as occurring with the 
particular device under investigation.
For the purposes of this investigation, each unexpected AE experienced by a subject 
treated with the study device will be recorded on the AE eCRF.
12.3.2.1.5 Adverse Device Effect
An ADE is an AE related to the use of an investigational medical device. ADEs include 
AEs resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational medical 
device. ADEs also include any event resulting from use error or from intentional misuse 
of the investigational medical device.
12.3.2.1.6 Serious Adverse Device Effect
A SADE is an ADE that has resulted in any of the consequences characteristic of an 
SAE.
12.3.2.1.7 Unanticipated (Unexpected) Serious Adverse Device Effect
An unanticipated SADE is any SADE on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan/application/instructions for use, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
An anticipated serious ADE is an effect which by its nature, incidence, severity, or 
outcome has been identified in the IB, risk analysis report, or Instructions for Use.

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In case an ADE or AE has been reported with other products of the same class but not 
with the investigational device, this ADE or AE shall be considered unanticipated/
unexpected for the investigational device.
12.3.2.1.8 Adverse Events of Special Interest
In this study, AEs of special interest are defined as any of the following events (Medical 
Dictionary for Regulatory Activities [MedDRA] preferred terms shown in parentheses):

Postoperative rebleeding (post procedural hemorrhage) from the TBS during the 
subject’s participation in the study

Signs of local inflammation, adhesions or encapsulation (post procedural 
inflammation, postoperative adhesion, encapsulation reaction) at the device 
application site

Local infection (post procedural infection, postoperative abscess) at the TBS 

Hematoma (post procedural hematoma) at the TBS

Foreign body reactions (foreign body reaction), and allergic reactions 
(hypersensitivity) to the device, both systemic or local

Thromboembolic events (postoperative thrombosis, deep vein thrombosis 
postoperative), especially in a vascular surgery case
AEs of special interest will be reported to the CRO’s Safety Department on the SAER 
form (see Section 2). However, AEs of special interest should not be considered serious 
unless they meet SAE criteria (see Section 12.3.2.1.2). Nonserious AEs of special interest 
are to be reported to the authorities or committees concerned according to the procedures 
and timelines applicable for nonserious AEs. Serious AEs of special interest are to be 
reported according to the procedures and timelines applicable for SAEs (see Section 2).
12.3.2.1.9 Device Deficiency
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. 
All device deficiencies related to the identity, quality, durability, reliability, safety, or 
performance of an investigational medical device shall be documented on the appropriate 
forms throughout the clinical investigation (see also Section 12.3.2.10 for documentation 
and reporting of device deficiencies that did not lead to an AE, ie, non-medical 
complaints).

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Device deficiencies that did not lead to an AE but might have led to a SADE if either 
suitable action had not been taken, intervention had not been made, or circumstances had 
been less fortunate, must be reported as specified in Section 2.
12.3.2.2 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description as follows:

Mild
The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level
The AE resolves spontaneously or may require minimal therapeutic 
intervention

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention
The AE produces no sequelae

Severe
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern
The AE produces sequelae, which require (prolonged) therapeutic intervention
12.3.2.3 Causality
Causality is a determination of whether there is a reasonable possibility that the 
investigational device is etiologically related to/associated with the AE. Causality 
assessment includes, eg, assessment of temporal relationships, dechallenge/rechallenge 
information, association (or lack of association) with underlying disease, presence (or 
absence) of a more likely cause, and physiological plausibility. For each AE assessed as 
not related or unlikely related, the investigator shall provide an alternative etiology. For 
each AE, the investigator will assess the causal relationship between the investigational 
device 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)

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Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the investigational device (ie, does not follow a 
reasonable temporal relationship to the administration of investigational 
device or has a much more likely alternative etiology) 

Unlikely related (either one or both circumstances are met)
Has little or no temporal relationship to the investigational device 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of the 
investigational device
An alternative etiology is equally or less likely compared to the potential 
relationship to the investigational device

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of an 
investigational device, which may include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a sensitivity test (eg, skin test)
o
Toxic level of one or more components of the investigational device, as 
evidenced by measurement of concentration in the blood or other bodily 
fluid
Another etiology is unlikely or significantly less likely
12.3.2.4 Assessment of Adverse Events
Each AE occurring after the subject signs the ICF until study completion or premature
discontinuation from the study (except for specified forseeable events; see 
Section 12.3.2.7) will be described on the AE eCRF (ie, 1 AE per form) using the 
medical diagnosis (preferred), or, if no diagnosis could be established at the time of 
reporting the AE, a symptom or sign, in standard medical terminology in order to avoid 
the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 12.3.2.1.1). Each AE will be evaluated by the investigator for:

Seriousness as defined in Section 12.3.2.1.2

Severity as defined in Section 12.3.2.2

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
Causal relationship to investigational device exposure as defined in 
Section 12.3.2.3
For each AE, the outcome (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal) and action taken (ie, 
dose increased, dose not changed, dose reduced, device interrupted, device withdrawn, 
not applicable, or unknown) will also be recorded on the AE eCRF. Recovering/resolving 
AEs will be followed until resolution, until medically stabilized, or for 30 days after the 
subject’s study completion/termination visit, whichever comes first. Only outcome-
related follow-up information received after the subject’s study completion/termination 
visit will be recorded in the AE eCRF.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the SAER form within 24 hours after becoming 
aware of the SAE (see Section 12.3.2.4).
AE and laboratory safety data will be monitored by an independent DSMB on a regular 
basis. Further information on the DSMB is presented in Section 16.4.
12.3.2.5 Expedited Adverse Event Reporting
All SAEs/SADEs/UADEs occurring during the course of the study will be reported to the 
CRO within 24 hours of becoming aware of the event.
AEs of special interest (see Section 12.3.2.1.8) will also be captured on the SAER form 
and reported to the CRO; however, they will only be considered serious if they meet the 
SAE criteria (see Section 12.3.2.1.2). Within 24 hours of becoming aware of the event, 
the study site will send the completed SAER form to the CRO by e-mail or fax.
As required, the CRO will report SAEs, SADEs, and UADEs to the competent 
authorities, manufacturers, central reviewing IRBs/IECs/REBs, and investigative sites 
according to country-specific reporting timelines. Reporting to the competent authorities 
will be performed by the sponsor (Baxter) for CELSTAT.
Nonserious AEs of special interest are to be reported to the authorities or 
IRBs/IECs/REBs concerned according to the procedures and timelines applicable for 
nonserious AEs. Serious AEs of special interest are to be reported according to the 
procedures and timelines applicable for SAEs (see Section 2).

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12.3.2.6 Pre-existing Diseases
Pre-existing diseases that are present before entry into the study as described in the 
medical history, and that manifest with the same severity, frequency, or duration after 
investigational device exposure, will not be recorded as AEs. However, when there is an 
increase in the severity, duration, or frequency of a pre-existing disease, the event must 
be described on the AE eCRF.
12.3.2.7 Foreseeable Adverse Events
A foreseeable AE is defined as an AE inherent to the surgical procedure that is expected 
to occur in all subjects. Each of the following events experienced after device exposure 
will not be considered an AE, will not be captured in the eCRF and thus, will not be
included in the analysis of AEs (unless their severity and/or duration exceeds the 
clinically expected range):

Postoperative nausea

Postoperative vomiting

Postoperative sleep disturbances

Postoperative tiredness/fatigue

Postoperative pain at the surgery site

Back/neck/shoulder pain related to lying on the operating table

Postoperative constipation
12.3.2.8 Urgent Safety Measures
The investigator is to take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. This does not need prior 
authorization from the sponsor. In the event(s) of an apparent immediate hazard to the 
subject, the investigator will notify the CRO immediately by phone and confirm 
notification to the CRO in writing as soon as possible, but within 1 calendar day after the 
change is implemented. The CRO will also ensure the responsible ethics committee and 
competent authorities are notified of the urgent measures taken in such cases according to 
local regulations.
12.3.2.9 Untoward Medical Occurrences Not Considered Adverse Events
Each serious untoward medical occurrence experienced before the first investigational 
device exposure (eg, from the time of signed informed consent up to, but not including,
the first investigational device exposure) will be described on the SAER form and will be 

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entered into the eCRF. However, these events will not be considered as SAEs and will 
not be included in the analysis of SAEs.
Each nonserious untoward medical occurrence experienced by a subject before the first 
investigational device exposure will be recorded on the AE eCRF; these events will not 
be considered as AEs and will not be included in the analysis of AEs.
For the purposes of this study, preplanned elective procedures and hospitalizations for 
such procedures, before and after device exposure will not be considered AEs (unless the 
condition for which the procedure was planned has worsened since baseline) and thus, 
not included in the analysis of AEs. Such preplanned procedures must be recorded at 
screening.
12.3.2.10 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 did not 
result in an AE. NMCs include but are not limited to the following:

Device malfunctions, which are defined as failure of the device to meet its 
performance specifications or otherwise to perform as intended

Missing components

Damage to the product or unit carton

A mislabeled product (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 will be documented on an NMC form. If an investigational device fails to 
perform in the expected manner, the CRO will be notified within one (1) business day. If 
requested, defective devices will be returned to the sponsor for inspection and analysis 
according to specified procedures.
For reporting of device deficiencies that did not lead to an AE, but could have led to an
SADE, refer to Section 12.3.2.1.8 and Section 2.
12.3.3 Physical Examinations
At screening and each of the postsurgical study visits, a physical examination will be 
performed on the following body systems (being described as normal or abnormal): 
general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, 

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abdomen, extremities and joints, lymph nodes, skin, and neurological system. At 
screening, if an abnormal condition is detected, the condition will be described on the 
medical history eCRF. At subsequent study visits, if a new abnormality or a worsened 
pre-existing abnormality is detected, the condition will be reported as an AE on the AE 
eCRF. If the abnormality was not deemed an AE because it was due to a preexisting 
disease (described in Section 12.3.2.6), is not clinically significant, is a symptom of a 
new/worsened condition already recorded as an AE, or due to another issue, the 
investigator will record the justification on the source record.
12.3.4 Clinical Laboratory Parameters
12.3.4.1 Hematology, Clinical Chemistry and Coagulation
The hematology panel will consist of complete blood count [hemoglobin, hematocrit, 
erythrocytes (ie, red blood cell count), and leukocytes (ie, white blood cell count)] with 
differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. 
The clinical chemistry panel will consist of sodium, potassium, calcium, chloride, 
bicarbonate, protein, albumin, alanine aminotransferase, bilirubin, alkaline phosphatase, 
blood urea nitrogen, creatinine, and glucose.
The coagulation panel will consist of prothrombin time, activated partial thromboplastin 
time and, where applicable, international normalized ratio.
Blood samples will be drawn for assessment of hematology and clinical chemistry 
parameters at screening (Visit 1) and at each of the postsurgical study visits (Visits 3 
through 6). A central laboratory will be used. Blood samples will be handled and stored 
according to the instructions provided by the central laboratory. The laboratory reports 
provided by the central laboratory will be reviewed, signed and dated by the investigator 
and attached to the source documents.
Screening laboratory samples (for hematology, clinical chemistry, coagulation and serum 
pregnancy test) must be taken within 7 days prior to surgery.
12.3.4.2 Other Laboratory Tests
A serum pregnancy test for females of childbearing potential will be performed at 
screening to confirm that the subject is not pregnant (preoperative exclusion criterion 9; 
see Section 10.2). The serum pregnancy test will be performed by the central laboratory. 
An additional urine pregnancy test will be performed preoperatively on the day of 

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surgery if the serum pregnancy test was performed >7 days prior to the planned surgery. 
The urine pregnancy test will be performed by the investigator site.
12.3.4.3 Assessment of Laboratory Values
The investigator’s assessment of each abnormal laboratory value is to be recorded on the 
eCRF. For each abnormal laboratory value, the investigator will determine whether the 
value is considered clinically significant. For clinically significant values, the investigator 
will consider whether or not to report an AE (see definition in Section 12.3.2.1.1). If yes, 
the sign, symptom, or medical diagnosis will be recorded on the AE eCRF. If the 
abnormal value was not deemed clinically significant, the investigator will indicate on the 
eCRF the reason (ie, lab error, due to pre-existing disease [described in 
Section 12.3.2.6]), symptom of a new/worsened condition already recorded as an AE, or 
due to another issue that will be specified). Additional tests and other evaluations 
required to establish the significance or etiology of an abnormal result, 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.
Clinically significant abnormal deviations of laboratory parameters (ie, values suggesting 
an unknown disease and requiring further clinical evaluation) revealed at the screening 
visit are not considered to be AEs.
12.3.5 Vital Signs
Vital signs will include body temperature (°C or °F; otic, oral or axillary method), 
respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood 
pressure (mmHg). Height (in or cm) and weight (lb or kg) will also be collected.
Vital signs will be measured at screening and at all postsurgical study follow-up visits
(height will only be collected at screening).
Vital sign values are to be recorded on the eCRF. For each vital sign value recorded 
postoperatively, the investigator will determine whether the value is considered an AE 
(see definition in Section 12.3.2.1.1). If assessed as an AE, the medical diagnosis 
(preferably), symptom, or sign, will be recorded on the AE eCRF. If the abnormal value 
was not deemed an AE, the investigator will indicate the reason on the source record
(ie, error, due to a pre-existing disease [described in Section 12.3.2.6], not clinically 
significant, a symptom of a new/worsened condition already recorded as an AE, or due to 
another issue that will be specified). Additional tests and other evaluations required to 
establish the significance or etiology of an abnormal result, or to monitor the course of an 

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AE should be obtained when clinically indicated. Any abnormal value that persists 
should be followed at the discretion of the investigator.
13. STATISTICAL CONSIDERATIONS
13.1 Sample Size and Power Calculations
The study is designed to show non-inferiority of CELSTAT compared to Surgicel based 
on the primary effectiveness endpoint, ie, the proportion of subjects achieving hemostasis 
within 5 minutes of the start of application of study treatment, which is maintained until 
surgical closure. These proportions are assumed to be 
% for CELSTAT and 
% for 
Surgicel (based on the experience from the pilot study, Study 621101 [see Section 7.3.2]
and considering some buffer in the proportions). Using a non-inferiority margin of 10% 
(the largest clinically acceptable difference), a 1-sided Type 1 error rate () of 2.5%, and 
a statistical power (1-) of 80%, the sample size estimation results in 121 evaluable 
subjects per treatment group. The estimation of the sample size was performed using 
 (
, NC).
The primary analysis will be performed on the per-protocol analysis set (PPS). Assuming 
that the PPS is 5% less than the total number of randomized subjects and adjusting 
slightly upward to allow for equal numbers of subjects of the 3 surgery types, 
129 subjects per treatment group have to be randomized.
13.2 Datasets and Analysis Cohorts
Two types of analyses of effectiveness are planned: analysis of the full analysis set (FAS) 
and of the PPS. 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 are randomized. Subjects will 
be analyzed as randomized.
Per-protocol analysis set: The PPS is defined as a subset of the FAS. Subjects will be 
excluded from the PPS if they:

Do not meet all inclusion/exclusion criteria

Are randomized but not treated according to the randomization scheme

Violate other major study procedures that may influence the study results
Safety analysis set: The safety analysis set will consist of all subjects who are treated 
with CELSTAT or Surgicel. Subjects will be analyzed as treated.

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13.3 Handling of Missing, Unused, and Spurious Data
Only subjects for whom data are available will be included in the statistical analysis. 
Missing values will be neither replaced nor estimated in the primary analysis. A 
sensitivity analysis, in which all missing data will be considered as treatment failures will 
be performed for the FAS to assess the influence of missing data on the primary efficacy 
results. In addition, a worst-case analysis will also be performed, in which any subjects in 
the CELSTAT treatment group with missing primary efficacy data will be categorized as 
treatment failures, and any subjects in the Surgicel treatment group with missing primary 
efficacy data will be categorized as treatment successes.
13.4 Methods of Analysis
13.4.1 Primary Outcome Measures
The primary efficacy analysis will be carried out on the PPS. The analysis using the FAS
will be used as a supportive analysis.
The primary efficacy parameter is defined as follows: The primary endpoint is set to 
success if hemostasis is achieved at 5 minutes after the treatment application and is 
maintained until surgical closure. If hemostasis is not achieved at 5 minutes, if additional 
hemostatic treatment other than study device is required, or if intraoperative rebleeding 
occurs, the primary endpoint will be set to “treatment failure”.
The primary effectiveness endpoint will be investigated by a 2-sided test for 
non-inferiority using the confidence-interval (CI) approach to compare the CELSTAT 
group to the Surgicel group. 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 (CELSTAT 
group - Surgicel group) is greater than -10% in the final analysis, CELSTAT will be 
declared non-inferior to Surgicel.

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The specific hypotheses of the risk difference to be tested are as follows:
H0: PCELSTAT - PSurgicel ≤-δ
H1: PCELSTAT - PSurgicel > -δ
where 
PCELSTAT = the proportion (%) of subjects achieving hemostasis by 5 minutes in the 
CELSTAT group,
PSurgicel = the proportion (%) of subjects achieving hemostasis by 5 minutes in the 
Surgicel group, and
δ = the non-inferiority margin of 10%.
Additionally, if the lower bound of the 2-sided 95% CI is larger than zero, superiority of 
CELSTAT versus Surgicel will be claimed.
The null hypothesis will be tested against the alternative using logistic regression, taking 
into account the following covariates: study center, surgery type (cardiothoracic, general
or vascular) and initial bleeding severity (mild or moderate).
The primary safety analysis, of the difference in proportion of subjects rebleeding from 
the TBS requiring surgical re-exploration during the subject’s study participation, will be 
performed using the same logistic regression model described for the primary efficacy 
endpoint.
13.4.2 Secondary Outcome Measures 
The logistic regression model used for the primary analysis will also be performed for the 
following secondary endpoints:

The difference in proportion of subjects having achieved hemostasis at 3 minutes 
and which is maintained until surgical closure

The difference in proportion of subjects having achieved hemostasis at 7 minutes 
and which is maintained until surgical closure

The difference in proportion of subjects having achieved hemostasis at 10 minutes 
and which is maintained until surgical closure

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
The difference in proportion of subjects with intraoperative rebleeding from the 
TBS after achievement of hemostasis
The TTH will be presented by Kaplan-Meier curves. In addition, a log-rank test will be 
performed to assess the difference between the distributions of TTH for CELSTAT and 
Surgicel.
AEs that occurred during or after treatment application will be presented in summary 
tables. Summary tables shall indicate the number of subjects who experienced AEs. In 
addition, tables will be prepared to list each AE, the number of subjects in each treatment 
group who experienced an AE at least once, and the rate of subjects with AEs. AEs 
grouped by MedDRA system organ class and preferred term will be presented by severity 
grade (mild, moderate, severe) and relatedness to treatment (“possibly related” or 
“probably related” AEs will be considered “related”; “unlikely related” or “not related” 
AEs will be considered “not related”).
All AEs for each subject, including the same event on several occasions, will be listed, 
giving both MedDRA preferred term and the original term used by the investigator, 
system organ class, severity grade, seriousness, relation to the treatment, onset date, and 
stop date.
AEs that occurred before the start of treatment application will be listed separately.
Clinical laboratory parameters and vital signs will be summarized by visit and treatment 
group. Shift tables will be generated for laboratory parameters.
13.5 Interim Analysis
No interim analysis is planned for the study.
14. ACCESS TO SOURCE DATA
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 CRO and sponsor, review by the IRBs/IECs/REBs, 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 CRO of this contact, 
cooperate with the authority, provide the CRO with copies of all documents received 
from the authority, and allow the CRO to comment on any responses, as described in the 
Clinical Study Agreement.

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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the CIP (which has been approved/given favorable 
opinion by the IRBs/IECs/REBs), GCP, 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 CRO. The term “investigator” as used in this CIP as 
well as in other study documents, refers to the investigator or authorized study personnel 
that the investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
Where required by national regulations and/or the responsible IRB/IEC/REB, the 
investigator will submit written progress reports of the study’s status to the CRO and/or
the reviewing IRB/IEC/REB and/or a final report to the CRO and/or the reviewing 
IRB/IEC/REB.
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the CIP, the investigational status of the investigational device, and 
his/her regulatory responsibilities as an investigator. Training may be provided at an 
investigator’s meeting, 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 CRO.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the CIP, standard operating procedures, other written 
instructions/agreements, GCP, and applicable regulatory guidelines/requirements. The 
investigator will permit the study monitor to visit the study site at appropriate intervals. 
Monitoring processes specific to the study will be described in the clinical monitoring 
plan.
15.4 Auditing
The CRO and sponsor may conduct audits to evaluate study conduct and compliance with 
the CIP, standard operating procedures, other written instructions/agreements, GCP, and 
applicable regulatory guidelines/requirements. The investigator will permit auditors to 

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visit the study site, as described in the Clinical Study Agreement. Auditing processes 
specific to the clinical investigation will be described in the auditing plan.
15.5 Noncompliance with the Clinical Investigation Plan
The investigator may deviate from the CIP to eliminate an apparent immediate hazard to 
the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the CRO immediately by phone and confirm notification to the 
CRO in writing as soon as possible, but within one (1) calendar day after the change is 
implemented. The investigator will also notify the responsible IRB/IEC/REB of the 
urgent measures taken in such cases according to local regulations (see also 
Section 12.3.2.8).
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
CIP, the CRO may terminate the investigator’s participation. The CRO will notify the 
IRB/IEC/REB and applicable regulatory authorities of any investigator termination.
15.6 Laboratory Standardization
Not applicable; a central laboratory will be used for all clinical laboratory tests.
16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of subjects into this study, the CIP, ICF, any promotional 
material/advertisements, and any other written information to be provided to the subjects 
will be reviewed and approved/given favorable opinion by the IRB/IEC/REB and 
applicable regulatory authorities. The IB will be provided for review. The 
IRB/IEC/REB’s composition or a statement that the IRB/IEC/REB’s composition meets 
applicable regulatory criteria will be documented. The study will commence only upon 
the CRO’s receipt of approval/favorable opinion from the IRB/IEC/REB and, if required, 
upon the CRO’s notification of applicable regulatory authority(ies) approval, as described 
in the Clinical Study Agreement.
If the CIP or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the IRB/IEC/REB
and applicable regulatory authorities, where applicable. The CIP amendment will only be 

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implemented upon the CRO’s receipt of approval and, if required, upon the CRO’s
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose subjects for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All subjects and/or their legally authorized representative must sign an ICF before 
entering into the study according to applicable regulatory requirements and GCP. Before 
use, the ICF will be approved by the IRB/IEC/REB 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 GCP 
and applicable regulatory requirements. Subjects or their legally authorized 
representative(s) will be allowed sufficient time to consider participation in the study. By 
signing the ICF, subjects or their legally authorized representative(s) 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 CRO will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with investigational device exposure. 
The informed consent will be updated, if necessary. This new information and/or revised 
ICF, that have been approved by the applicable IRB/IEC/REB and regulatory authorities, 
where applicable, will be provided by the investigator to the subjects who consented to 
participate in the study.
16.4 Data Safety Monitoring Board
This study will be monitored by an independent unblinded DSMB. The DSMB will be 
composed of 4 members, 3 of whom are recognized experts in the field of surgery, 
clinical care and research, and the fourth of whom is a biostatistician. The DSMB 
surgeons will have expertise in the areas of cardiothoracic, general and vascular 
surgeries, and will not be involved in enrolling or treating study subjects.
The DSMB will review the safety data (AEs and laboratory test results) from the study 
after approximately one-third and two-thirds of the subjects have been treated, and will 
have the discretion to recommend stopping the trial due to safety concerns. The DSMB 
will monitor ongoing safety data for evidence of postsurgical adhesion formation, wound 
infection, fistula formation, and persistent bleeding at the TBS.

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Details of the composition of and procedures used by the DSMB will be presented in a 
formal DSMB charter issued prior to the start of study enrollment.
17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 Study Documentation and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include medical records, records detailing 
the progress of the study for each subject, signed ICFs, device/drug disposition records, 
correspondence with the IRB/IEC/REB and the study monitor/CRO, enrollment and 
screening information, eCRFs, SAERs, laboratory reports, and data clarifications 
requested by the CRO.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to study documentation must be performed as follows: 1) the first entry will 
be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data.
Only authorized study site personnel will record or change data on the eCRFs. Changes 
to an eCRF will require documentation of the reason for each change. An identical 
(electronic/paper) version of the complete set of eCRFs for each subject will remain in 
the investigator file at the study site in accordance with the data retention policy (see 
Section 17.4).
The handling of data by the CRO, including data quality assurance, will comply with 
regulatory guidelines (eg, ISO 14155, GCP) and the standard operating procedures of the 
CRO. Data management and control processes specific to the study will be described in 
the data management plan.
17.3 Extent of Source Data Verification
Site monitors will follow the instructions given in the monitoring plan for source data 
verification. In this study, 100% source data verification will be performed for all 

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enrolled subjects. The investigator will ensure that the site monitor has access to all 
source documents for the enrolled subjects.
17.4 Document and Data Retention
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements, site requirements, and the document 
and data retention policy as described in the Clinical Study Agreement.
18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the Clinical Study 
Agreement.
The insurance will be provided for each subject in the clinical investigation. Clinical 
trials insurance is product liability coverage designed to respond to claims brought by 
study subjects, or their families, for bodily injury.
19. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN
The investigator or CRO should not implement any deviation from, or changes of, the 
CIP without mutual agreement, prior review and documented approval from the 
IRB/IEC/REB of a respective amendment. The only exceptions are where necessary to 
eliminate an immediate hazard to study subjects, or when the changes involve only 
logistical or administrative aspects of the study (eg, change in monitor(s), change of 
telephone number(s)).
The party initiating an amendment must confirm it clearly in writing and it must be 
signed and dated by the same persons who have signed the original CIP. CIP
amendments will be submitted to the appropriate IRBs/IEC/REBs and competent 
authorities as required.
20. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement.

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21. SUPPLEMENTS
21.1 Study Flow Chart
Visit Number (Study Day)
Visit Type/Assessments
Visit 1 (Day-14 to -1)
Screening visit
Assessment of inclusion and exclusion criteria
Visit 2 (Day 1)
Randomization and treatment visit (day of surgery)
Preoperative: Confirmation of preoperative inclusion/randomization 
criteria; randomization
Intraoperative: Identification of eligible target bleeding site; treatment 
application; assessment of hemostatic effectiveness and safety
Visit 3 (hospital discharge or 
Day 8 [1] if hospitalized 
longer than 1 week)
Hospital discharge visit
Assessment of postoperative rebleeding and safety
Visit 4 (Day 31 [5])
Follow-up visit
Assessment of postoperative rebleeding and safety
Visit 5 (Day 61 [±10])
Follow-up visit
Assessment of postoperative rebleeding and safety
Visit 6 (Day 91 [±10] or at 
premature discontinuation)
End-of-study visit
Assessment of postoperative rebleeding and safety

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21.2 Schedule of Study Procedures and Assessments
Visit 1
Screening
Day -14 to -1
Visit 2
Randomization/Surgery
Day 1
Visit 3
Discharge
≤Day 8 (±1)a
Visit 4
Follow-up
Day 31 (±5)
Visit 5
Follow-up
Day 61 (±10)
Visit 6
End of Study
Day 91 (±10)
Informed consent
X
Inclusion/exclusion
X
Xb
Demographic characteristics
X
Medical history
X
Concomitant medication
Xc
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Hematology and clinical 
chemistry testsd
Xe
X
X
X
X
Pregnancy testf
X
X
Randomization
X
Study device application
X
Hemostasis assessmentsg
X
Additional intraoperative 
assessmentsg
X
Postoperative rebleeding
X
X
X
X
X
Adverse events
X
X
X
X
X
X
aTo be performed on the day of discharge from the hospital; or on Day 8 (±1) should the subject remain in the hospital for more than a week postsurgically.
bReview of preoperative and assessment of intraoperative eligibility criteria.
cMedication will be recorded from enrollment (signing of informed consnet form) through the end of study participation.
dHematology: prothrombin time, activated partial thromboplastin time, international normalized ratio (when applicable), hemoglobin, hematocrit, erythrocytes, leukocytes 
with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. Clinical chemistry: sodium, potassium, calcium, chloride, bicarbonate, 
protein, albumin, alanine aminotransferase, bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose.
eScreening samples (for hematology, clinical chemistry and serum pregnancy test) to be taken within 7 days prior to surgery.
fSerum pregnancy test at screening; urine pregnancy test at Day 1 (prior to surgery) if serum pregnancy test >7 days prior to Day 1.
gSee Section 12.2 for details.

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22. REFERENCES
1.
Tomizawa Y. Clinical benefits and risk analysis of topical hemostats: a review. 
J Artif Organs. 2005; 8:137–142
2.
Frantz VK. Absorbable Cotton, Paper and Gauze: Oxidized Cellulose. Ann 
Surg. 1943 Jul; 118(1): 116–126
3.
Frantz VK, Clarke HT, Lattes R. Hemostasis with Absorbable Gauze (Oxidized 
Cellulose). Ann Surg. 1944 Aug; 120(2): 181–198
4.
Lebendiger A, Gitlitz GF, Hurwitt GS, Lord GH, Henderson J. Laboratory and 
clinical evaluation of a new absorbable hemostatic material prepared from 
oxidized regenerated cellulose. Surg Forum 1960; 10: 440-443
5.
Achneck HE, Sileshi B, Jamiolkowski RM, Albala DM, Shapiro ML, Lawson 
JH. A Comprehensive Review of Topical Hemostatic Agents: Efficacy and 
Recommendations for Use. Ann Surg 2010 Feb; 251 (2): 217-228
6.
Tomizawa Y. Clinical benefits and risk analysis of topical hemostats: a review. 
J Artif Organs. 2005; 8:137–142
7.
Frantz VK. Absorbable Cotton, Paper and Gauze: Oxidized Cellulose. Ann 
Surg. 1943 Jul; 118(1): 116–126
8.
Ibrahim MF, Aps C, Young CP. A foreign body reaction to Surgicel mimicking 
an abscess following cardiac surgery. Eur J Cardiothorac Surg. 2002 Sep; 
22(3):489–490; author reply 490
9.
Tomizawa Y, Endo M, Kitamura M, et al. Coronary artery bypass graft stenosis 
suspected to be due to hemostatic agents: a case report. Kyobu Geka. 1991 Aug; 
44(3):764–766
10.
Igari T, Iwaya F, Abe T, et al. A case of foreign body granuloma after aortic 
valve replacement. Kyobu Geka. 1990 Jul; 43(7):550 –552
11.
Schonauer C, Tessitore E, Barbagallo G et al. The use of local agents: bone 
wax, gelatin, collagen, oxidized cellulose. Eur Spine J 2004 October; 13 (Suppl 
I): 589-596
12.
Tomizawa Y. Clinical benefits and risk analysis of topical hemostats: a review. 
J Artif Organs. 2005; 8:137–142
13.
Brodbelt AR, Miles JB, Foy PM et al. Intraspinal oxidised cellulose (Surgicel) 
causing delayed paraplegia after thoracotomy-a report of three cases. Ann R 
Coll Surg Engl 2002 Mar; 84(2):97-9
14.
Banerjee T, Goldschmidt K. ‘Surgiceloma’ manifested as cauda equina 
syndrome. South Med J. 1998 May; 91(5):481-483
15.
Seyednejad H, Imani M, Jamieson T et al. Topical haemostatic agents, British 
Journal of Surgery 2008 Oct; 95(10): 1197-1225.
16.
Lexapro [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2014.

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INVESTIGATOR ACKNOWLEDGEMENT
CELSTAT
A Prospective, Randomized, Controlled Study to Evaluate the Effectiveness and 
Safety of CELSTAT as an Adjunct to Hemostasis for Tissue Bleeding in 
Cardiothoracic, General and Vascular Surgery
INVESTIGATION PLAN IDENTIFIER: 3584-001
By signing below, the investigator acknowledges that he/she has read, understands and 
agrees to this clinical investigation plan. He/she will comply with the requirements for 
obtaining informed consent from all study subjects prior to initiating any investigation-
specific procedures, obtaining written initial and ongoing IRB/IEC/REB (s) investigation 
plan review and approval, understands and abides by the requirements for maintenance of 
source documentation, and provides assurance that this study will be conducted according 
to all requirements as defined in this clinical investigation plan, Clinical Study 
Agreement, GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator