Prospective, Randomized, Controlled, Multicenter, Post-Market Clinical Study Evaluating the Performance of HEMOBLAST Bellows Compared to FLOSEAL Hemostatic Matrix in Cardiothoracic Operations
Phase: NA
Conditions: Cardiothoracic Surgery
Sponsor: Biom'Up France SAS

 
 
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PROSPECTIVE, RANDOMIZED, CONTROLLED, MULTICENTER, POST-MARKET 
CLINICAL STUDY EVALUATING THE PERFORMANCE OF HEMOBLASTTM BELLOWS 
COMPARED TO FLOSEAL HEMOSTATIC MATRIX IN CARDIOTHORACIC OPERATIONS 
 
PROTOCOL 
 
Protocol Number 
ETC 2018-005 
Protocol Version (Date) 
Version 2.0 (15 October 2018) 
 
Sponsor Address 
Biom’up SA 
8, allée Irène Joliot Curie 
69800 Saint-Priest 
France 
 
Biom’up Medical Expert:  William Spotnitz, MD 
                                           Chief Medical Officer, Biom’up 
                                             
Sponsor Contacts 
Rachel Hoffman 
Biom’up USA, Inc. 
Vice President, Clinical Operations North America  
412 West 15th Street 
Suite 1000 
New York, NY 10011 
 
 
CONFIDENTIALITY STATEMENT: This is a confidential Biom’up document.  Acceptance of this 
document constitutes the agreement by the recipient that no unpublished information contained herein 
will be published or disclosed without prior written approval from the Sponsor or Sponsor Representative.   

 
 
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Table of Contents 
 
1 
SYNOPSIS ............................................................................................................................................ 9 
2 
INTRODUCTION ............................................................................................................................... 10 
2.1 
Purpose ........................................................................................................................................ 10 
2.2 
Device Name ............................................................................................................................... 10 
2.3 
Indication for Use ........................................................................................................................ 10 
2.4 
Study Overview ........................................................................................................................... 10 
2.4.1 
Duration of the Study........................................................................................................... 10 
2.4.2 
Number of Subjects and Sites .............................................................................................. 10 
2.5 
Sponsor Contact Information ....................................................................................................... 10 
3 
DEVICE DESCRIPTION .................................................................................................................... 11 
3.1 
Test Device Description and Indication for Use .......................................................................... 11 
3.2 
Test Device Manufacturer Details ............................................................................................... 11 
3.3 
Control Device ............................................................................................................................. 11 
4 
BACKGROUND AND RATIONALE................................................................................................ 11 
4.1 
Definition of Hemostasis ............................................................................................................. 11 
4.2 
Current Hemostatic Therapeutic Strategies ................................................................................. 12 
4.3 
Rationale ...................................................................................................................................... 12 
5 
METHODOLOGY .............................................................................................................................. 12 
5.1 
Overall Study Design ................................................................................................................... 12 
5.1.1 
Objectives ............................................................................................................................ 13 
5.2 
Primary Efficacy Endpoint .......................................................................................................... 13 
5.3 
Secondary Efficacy Endpoints ..................................................................................................... 13 
5.5          Subject Selection Criteria ......................................................................................................... 13 
5.5.1.3     Intraoperative Inclusion Criteria .......................................................................................... 14 
5.6        Point of Enrollment..................................................................................................................... 15 
5.7        Withdrawal Criteria .................................................................................................................... 15 
5.8 
Subject Compliance ..................................................................................................................... 15 
6 
STUDY PROCEDURES ..................................................................................................................... 15 
6.1 
?edule Overview .......................................................................................................................... 15 
6.2 
Preoperative Evaluations ............................................................................................................. 16 
6.2.1 
Informed Consent................................................................................................................. 16 
6.2.2 
Preoperative Eligibility ....................................................................................................... 16 
6.2.3 
Subject Identification ........................................................................................................... 16 

 
 
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6.3 
Preoperative Procedures and Evaluations .................................................................................... 17 
6.4 
Intraoperative Procedures and Evaluations.................................................................................. 17 
6.4.1 
Intraoperative Inclusion Criteria .......................................................................................... 17 
6.4.2 
Randomization and Hemostat Application .......................................................................... 18 
6.4.3 
Bleeding Severity and Hemostasis Evaluations .................................................................. 18 
6.4.4 
Other Bleeding Sites ............................................................................................................ 19 
6.4.5 
Intraoperative Data Collection ............................................................................................. 19 
6.5 
Discontinuation Procedures and Documentation ......................................................................... 20 
7 
ADVERSE EVENTS........................................................................................................................... 20 
7.1 
General ......................................................................................................................................... 20 
7.2 
Adverse Event Documentation .................................................................................................... 21 
7.3 
Reporting ..................................................................................................................................... 22 
7.4 
Regulatory Authority Reporting .................................................................................................. 23 
8 
DATA COLLECTION ........................................................................................................................ 23 
8.1 
Completion of Case Report Forms .............................................................................................. 23 
8.2 
Source Documentation ................................................................................................................. 23 
8.3 
Retention of Clinical Study Documentation ................................................................................ 23 
8.4 
Training........................................................................................................................................ 23 
9 
TERMINATION OF THE CLINICAL STUDY ................................................................................. 24 
9.1 
Subject Withdrawals and Discontinuation ................................................................................... 24 
9.2 
Early Termination of the Clinical Study ...................................................................................... 24 
10 
DATA MANAGEMENT ................................................................................................................ 24 
11 
STATISTICS ................................................................................................................................... 24 
11.1 
Overview ...................................................................................................................................... 24 
11.1.1 
Primary Endpoint ................................................................................................................. 24 
11.1.2 
Secondary Efficacy Endpoints ............................................................................................. 24 
11.1.3 
Safety Outcomes .................................................................................................................. 25 
11.1.4 
Study Success ...................................................................................................................... 25 
11.2 
General Analysis Considerations ................................................................................................. 25 
11.2.1 
Analysis Populations ........................................................................................................... 25 
11.2.2 
Handling of Missing Data .................................................................................................... 25 
11.2.3 
Subgroup Analyses .............................................................................................................. 25 
11.2.4 
Data Transformations .......................................................................................................... 25 
11.2.5 
Subject Disposition and Characteristics .............................................................................. 25 
11.2.6 
Subject Compliance ............................................................................................................. 26 

 
 
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11.2.7 
Protocol Deviations ............................................................................................................. 26 
11.3 
Analytic Methods......................................................................................................................... 26 
11.3.1 
Analysis of Primary and Secondary Efficacy Endpoints ..................................................... 26 
11.3.2 
Analysis of Safety Outcomes ............................................................................................... 26 
11.3.3 
Sample Size Justification ..................................................................................................... 27 
12 
RISK/BENEFIT ANALYSIS .......................................................................................................... 27 
12.1 
Anticipated Clinical Benefits ....................................................................................................... 27 
12.2 
Risks Associated with Participation in the Clinical Study .......................................................... 27 
12.3 
Risk/Benefit Analysis .................................................................................................................. 28 
12.4 
Conduct of Clinical Study to Reduce Risk .................................................................................. 28 
13 
REPORTS AND PUBLICATIONS ................................................................................................ 28 
13.1 
Interim Reports ............................................................................................................................ 28 
13.2 
Final Report ................................................................................................................................. 29 
13.3 
Publications.................................................................................................................................. 29 
14 
ETHICAL CONSIDERATIONS..................................................................................................... 29 
14.1 
Institutional Review Board Approval .......................................................................................... 29 
14.2 
Informed Consent and Patient Information ................................................................................. 29 
14.3 
Subject Confidentiality ................................................................................................................ 29 
14.4 
Indemnity ..................................................................................................................................... 29 
14.5 
Insurance ...................................................................................................................................... 29 
15 
COMPLIANCE ............................................................................................................................... 30 
15.1 
Overview ...................................................................................................................................... 30 
15.2 
Clinical Study Personnel Responsibilities ................................................................................... 30 
15.3 
Monitoring ................................................................................................................................... 30 
15.4 
Audits ........................................................................................................................................... 30 
15.5 
Modifications to the Protocol ...................................................................................................... 30 
16 
ABBREVIATIONS AND DEFINITIONS...................................................................................... 31 
17 
REFERENCES ................................................................................................................................ 32 
 
 
 

 
 
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Appendices 
 
Appendix A: HEMOBLAST™ Bellows Instructions for Use 
Appendix B: Sample Subject Informed Consent Form  
 
 
 
 
 

 
 
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Protocol Approval Page 
 
PROSPECTIVE, RANDOMIZED, CONTROLLED, MULTICENTER, POST-MARKET 
CLINICAL STUDY EVALUATING THE PERFORMANCE OF HEMOBLASTTM BELLOWS 
COMPARED TO FLOSEAL HEMOSTATIC MATRIX IN CARDIOTHORACIC OPERATIONS 
 
This Protocol has been read and approved by: 
 
Name 
Valérie Centis, PhD 
Title, Institution 
Chief Scientific Officer, Biom’up 
Signature 
 
 
Date (DD/MMM/YYYY) 
 
 
 
Name 
William Spotnitz, MD 
Title, Institution 
Chief Medical Officer, Biom’up 
Signature 
 
 
Date (DD/MMM/YYYY) 
 
 
 
Name 
Rachel Hoffman 
Title, Institution 
Vice President Clinical Operations North 
America, Biom’up 
Signature 
 
 
Date (DD/MMM/YYYY) 
 
 
 
Coordinating Investigators – United States 
Name 
Brian Bruckner, MD 
Title, Institution 
Surgical Director of Heart Transplant, LVAD & 
ECMO Programs, Methodist DeBakey Heart & 
Vascular Center 
Signature 
 
 
Date (DD/MMM/YYYY) 
 
 
 
Name 
Abbas Ardehali, MD 
Title, Institution 
Professor of Surgery and Medicine, UCLA School 
of Medicine, Division of Cardiothoracic Surgery; 
William E. Conner Chair in Cardiothoracic 
Transplantation; Director, UCLA Heart, Lung, 
and Heart-Lung Transplant Programs 
Signature 
 
 
Date (DD/MMM/YYYY) 
 
 

 
 
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Protocol 
 
Principal Investigator Approval Page 
 
PROSPECTIVE, RANDOMIZED, CONTROLLED, MULTICENTER, POST-MARKET 
CLINICAL STUDY EVALUATING THE PERFORMANCE OF HEMOBLASTTM BELLOWS 
COMPARED TO FLOSEAL HEMOSTATIC MATRIX IN CARDIOTHORACIC OPERATIONS 
 
I, the undersigned, have read and understood the Protocol specified above, and agree on the contents.  The 
Protocol and Clinical Trial Agreement will serve as a basis for cooperation in the clinical study. 
 
Further, I agree to conduct the clinical study in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki; guidelines of the International Conference on Harmonization (ICH) 
E6 Good Clinical Practice (GCP);21 CFR Parts 50, 54, and 56; and any other applicable national 
requirements. 
 
I am aware of my responsibilities as a Principal Investigator.  I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the study staff. 
 
Principal Investigator Name 
 
Institution 
 
 
Principal Investigator Signature 
 
Date (DD/MMM/YYYY) 
 
 
 
 
 
 

 
 
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Protocol 
 
Revision History 
 
Version Number (Date) 
Summary of Revision(s) 
Justification for Revision(s) 
Version 1.0 (04 October 
2018) 
None – new document  
Not applicable 
Version 2.0 (15 October 
2018) 
• 
Typographical edits 
• 
Update to Table 7 to include 
assignment of SPOT 
GRADE™ score immediately 
prior to hemostat application 
• 
Addition of coordinating 
investigator Abbas Ardehali 
• 
Administrative  
• 
Clarification on 
intraoperative 
procedure 
requirements 
 
 
 

 
 
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1 
SYNOPSIS 
 
Title 
Prospective, Randomized, Controlled, Multicenter, Post-Market 
Clinical Study Evaluating the Performance of HEMOBLAST™ 
Bellows Compared to FLOSEAL Hemostatic Matrix in 
Cardiothoracic Operations 
Protocol Number 
ETC 2018-005 
Purpose/Objectives 
To evaluate the performance (time to hemostasis, including device 
preparation time) of HEMOBLAST™ Bellows compared to 
FLOSEAL Hemostatic Matrix 
Indication 
HEMOBLASTTM Bellows is indicated for use in surgical 
procedures as an adjunct to hemostasis when control of minimal, 
mild, and moderate bleeding by conventional procedures is 
ineffective or impractical, except in neurosurgical, ophthalmic, 
and urological procedures. 
Study Design 
Prospective, randomized, controlled, post-market 
Number of Subjects/Sites 
A maximum of 104 subjects enrolled across a maximum of 5 
study sites.   
Preoperative Inclusion Criteria 
A subject must meet all of the following preoperative inclusion 
criteria to be enrolled into the study: 
• 
Subject is undergoing a non-emergent cardiothoracic 
surgery; and 
• 
Subject or an authorized legal representative is willing and 
able to give prior written informed consent for study 
participation. 
Preoperative Exclusion Criteria 
A subject must not meet any of the following preoperative 
exclusion criteria to be enrolled into the study: 
• 
Subject has a known sensitivity or allergy to bovine and/or 
porcine substance(s) or any other component(s) of the 
hemostatic agent; 
• 
Subject has religious or other objections to porcine or 
bovine components; and 
• 
Subject is not appropriate for inclusion in the clinical 
study, per the medical opinion of the Principal 
Investigator. 
Intraoperative Inclusion 
Criteria 
A subject must meet all of the following intraoperative inclusion 
criteria to be enrolled into the study: 
• 
Subject in whom the Investigator is able to identify a 
Target Bleeding Site (TBS) for which any applicable 
conventional means for hemostasis are ineffective or 
impractical; and 
• 
Subject has a TBS with minimal, mild, or moderate 
bleeding.1 
Assessment Schedule  
• 
Preoperative 
o Obtain consent 
o Confirm eligibility criteria 
• 
Intraoperative 
o Confirm eligibility criteria 
o Randomization 
o Performance evaluations 

 
 
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o Safety assessments 
Test Device 
HEMOBLAST™ Bellows (Biom’up, France), hereinafter referred 
to as HEMOBLAST™ 
Comparator Device 
FLOSEAL Hemostatic Matrix (Baxter Healthcare Corporation, 
Hayward, CA, USA), hereinafter referred to as FLOSEAL 
Primary Endpoint 
The primary endpoint of this study is the superiority of 
HEMOBLAST™ relative to FLOSEAL for the proportion of 
subjects reaching hemostasis within 3 minutes. 
Secondary Endpoints 
The secondary endpoint of this study is non-inferiority of 
HEMOBLAST™ relative to FLOSEAL for the proportion of 
subjects reaching hemostasis within 5 minutes. 
 
2 
INTRODUCTION 
 
2.1 
Purpose 
 
The purpose of this study is to evaluate the performance of HEMOBLAST™ compared to FLOSEAL.  
 
2.2 
Device Name 
 
HEMOBLAST™ will be used in this study. 
 
2.3 
Indication for Use 
 
HEMOBLAST™ is indicated for use in surgical procedures as an adjunct of hemostasis when control of 
minimal, mild, and moderate bleeding by conventional procedures is ineffective or impractical, except in 
neurosurgical, ophthalmic, and urological procedures. 
 
2.4 
Study Overview 
 
2.4.1 
Duration of the Study 
 
The estimated duration of the study is approximately 8 months from the time of first subject enrollment to 
the last subject enrollment.  Enrollment occurs intraoperatively after confirmation of the intraoperative 
eligibility criteria.  Subjects will undergo intraoperative performance assessments and then will be 
discontinued from the study after completion of the intraoperative visit. 
 
2.4.2 
Number of Subjects and Sites 
 
A maximum of 104 subjects will be enrolled across a maximum of 5 study sites in the United States.   
 
It is expected that approximately 20 subjects will be enrolled per site, with no more than 50% of the 
subjects being enrolled at any single site.   
 
2.5 
Sponsor Contact Information 
 
Rachel Hoffman 
Biom’up USA, Inc. 
Vice President, Clinical Operations North America  
412 West 15th Street 

 
 
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Suite 1000 
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3 
DEVICE DESCRIPTION 
 
3.1 
Test Device Description and Indication for Use  
 
HEMOBLAST™ consists of a powder composed of collagen, chondroitin sulfate, and thrombin.  The 
powder is dry, sterilized, biocompatible, and non-pyrogenic.  It is resorbed within 4 weeks.  No preparation, 
mixing or heating is required. 
 
HEMOBLAST™ is composed predominantly of highly purified porcine collagen with smaller amounts of 
bovine chondroitin sulfate and human pooled plasma derived thrombin.  Each device contains a maximum 
of 1500 IU of thrombin.  Plasma donations are from US plasma centers only.  All individual donations of 
the plasma were tested for HBsAg, anti-HIV1/-HIV2, and anti-HCV and found to be negative.  The plasma 
pools were tested and found to be non-reactive for HCV RNA, HBV DNA, and HIV1 RNA as determined 
by PCR (NAT).  The product complies with the specifications of the manufacturer and World Health 
Organization (WHO). 
 
The manufacturing procedures for HEMOBLAST™ include processing steps designed to reduce the risk 
of viral transmission. 
 
HEMOBLAST™ is approved by the United States Food and Drug Administration (FDA) for use in 
surgical procedures as an adjunct to hemostasis when control of minimal, mild, and moderate bleeding1 
by conventional procedures is ineffective or impractical, except in neurosurgical, ophthalmic, and 
urological procedures. 
 
The Instructions for Use are included as Appendix A. 
 
3.2 
Test Device Manufacturer Details 
 
The manufacturer of HEMOBLAST™ is Biom’up SA, which is located in Saint Priest, France.  Biom’up 
is ISO 13485 certified. 
 
3.3 
Control Device 
 
The control device for this study is FLOSEAL, which is distributed by Baxter Healthcare Corp. located in 
Hayward, California.  The 5 mL Full Sterile Prep kit will be utilized for this clinical study. 
 
4 
BACKGROUND AND RATIONALE 
 
4.1 
Definition of Hemostasis 
  
Despite advances in surgical techniques, excessive bleeding remains a major complication associated with 
surgery and contributes to poor clinical outcomes.2  There is no universally accepted definition of 
hemostasis.  The most current definition is the “cessation of bleeding.”3  The term comes from the Greek 
roots heme (blood) and stasis (halt).  Hemostasis can be considered as control of bleeding within the 
finely tuned balance of procoagulant, anticoagulant, fibrinolytic, and anti-fibrinolytic activities.4 
 
Hemostasis refers to the process of causing blood to form a clot (the opposite of hemostasis is 
hemorrhage).  Most of the time, this process includes the changing of blood from a fluid to a solid state.  

 
 
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Intact blood vessels are central to moderating blood’s tendency to clot.  The endothelial cells of intact 
vessels prevent blood coagulation by secretion of heparin-like molecules and thrombomodulin and 
prevent platelet aggregation by the secretion of nitric oxide and prostacyclin.  When endothelial injury 
occurs, the endothelial cells cease secretion of coagulation and aggregation inhibitors and instead secret 
von Willebrand factor and tissue thromboplastin which initiates the maintenance of hemostasis after 
injury.  Hemostasis has three major steps: vasoconstriction, formation of a platelet plug, and blood 
coagulation. 
 
4.2 
Current Hemostatic Therapeutic Strategies 
 
Hemorrhage control is vital for successful clinical outcomes after surgery.  It is essential to decrease 
postoperative morbidity and operative time, leading to potential cost savings.5, 6, 7 During surgical 
operations, it is important to maintain a fine balance between bleeding and clotting so that blood 
continues to flow to the tissues at the surgical site without excessive blood loss.  There are many tools 
used for hemorrhage control; these include preventive measures, transfusion of blood products, and 
traditional methods.2 
 
Conventional techniques for obtaining hemostasis during surgery include a variety of manual, 
mechanical, and thermal techniques.  Application of direct pressure or compression at a bleeding site is 
often the surgeon’s first choice to assist in the control of bleeding.  The placement of direct pressure over 
the injury site serves to compress vascular structures and promote localized clotting.  Direct pressure, 
while widely accepted as standard of care for the control of all levels of bleeding severity, has limited 
discourse in the surgical literature.  Other mechanical methods, including sutures, staples, and ligating 
clips, are useful if the source of bleeding is easily identifiable and able to be sealed.7 
 
Compression and other mechanical methods may not be appropriate during all surgical procedures; this 
method of controlling bleeding may not be sufficient when the source of bleeding is hard to identify, as 
for diffuse venous bleeding.8  Moreover, the mechanical methods are not applicable in some surgical 
procedures because of localization and the inaccessibility of structures.  
 
To summarize, conventional techniques show their limits in terms of bleeding control efficacy.7, 8, 9, 10, 11 
Furthermore, they may be associated with the occurrence of complications.10 
 
4.3 
Rationale 
 
Although the properties of the ideal local hemostatic agent may vary according to the surgical specialty, 
some properties are universally valued including: rapid and effective control/cessation of bleeding; ability 
to make effective contact with the bleeding surface; acceptable safety profile; and ease of preparation and 
use. 
 
According to Spotnitz et al., the ideal hemostat, sealant or adhesive must have certain performance 
characteristics (safety, efficacy, usability, cost, and approvability) that enable it to be used by surgeons.12   
Biom’up has developed and manufactured a hemostatic device, HEMOBLAST™, which is ready to use 
without any preparation required.  This post-market study will be conducted to assess time to hemostasis, 
which includes the time of device preparation. 
 
5 
METHODOLOGY 
 
5.1 
Overall Study Design 
 
This is a prospective, randomized, controlled, multicenter, post-market clinical study. 

 
 
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5.1.1 
Objectives 
 
The objective of this study is to evaluate the performance (time to hemostasis, including device 
preparation time) of HEMOBLAST™ compared to FLOSEAL. 
 
5.2 
Primary Efficacy Endpoint 
 
The primary endpoint of this study is the superiority of HEMOBLAST™ relative to FLOSEAL for the 
proportion of subjects reaching hemostasis within 3 minutes. 
 
5.3 
Secondary Efficacy Endpoints 
 
The secondary endpoint of this study is non-inferiority of HEMOBLAST™ relative to FLOSEAL for the 
proportion of subjects reaching hemostasis within 5 minutes. 
 
5.4    Additional Exploratory Outcomes 
   
The additional exploratory outcomes of this study include: 
 
• 
Number of operating room interruptions during preparation of the hemostatic device; 
• 
Proportion of HEMOBLAST™ vs. FLOSEAL subjects hemostatic at 3 minutes by baseline 
bleeding severity (minimal, mild, or moderate); and 
• 
Proportion of HEMOBLAST™ vs. FLOSEAL subjects hemostatic at 5 minutes by baseline 
bleeding severity (minimal, mild, or moderate). 
 
5.5          Subject Selection Criteria 
 
A maximum of 104 subjects undergoing non-emergent cardiothoracic surgery will be enrolled into the 
clinical study.  Subjects will need to meet all eligibility criteria to be enrolled into the study, as detailed 
below. 
 
5.5.1.1     Preoperative Inclusion Criteria 
 
A subject must meet all of the following preoperative inclusion criteria to be enrolled into the study: 
 
• 
Subject is undergoing a non-emergent cardiothoracic surgery; and 
• 
Subject or an authorized legal representative is willing and able to give prior written informed 
consent for study participation. 
 
5.5.1.2      Preoperative Exclusion Criteria 
 
A subject must not meet any of the following preoperative exclusion criteria to be enrolled into the study: 
 
• 
Subject has a known sensitivity or allergy to bovine and/or porcine substance(s) or any other 
component(s) of the hemostatic agent; 
• 
Subject has religious or other objections to porcine or bovine components; and 
• 
Subject is not appropriate for inclusion in the clinical study, per the medical opinion of the 
Investigator. 
 

 
 
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5.5.1.3     Intraoperative Inclusion Criteria 
 
A subject must meet all of the following intraoperative inclusion criteria to be enrolled into the study: 
 
• 
Subject does not have an active or suspected infection at the surgical site; 
• 
Subject in whom the Investigator is able to identify a Target Bleeding Site (TBS) for which any 
applicable conventional means for hemostasis are ineffective or impractical; and 
• 
Subject has a TBS with minimal, mild, or moderate bleeding.1 
 
Table 1.  Enrollment Based on Surface Bleeding Severity Scale (SBSS) / SPOT GRADE™ Score1 
SBSS Score 
0 
1 
2 
3 
4 
5 
Verbal 
Descriptor 
None 
Minimal 
Mild 
Moderate 
Severe; not 
immediately 
life-
threatening 
Extreme; 
immediately 
life-
threatening 
Visual 
Descriptor 
Dry 
Oozing 
Pooling 
Flowing 
Streaming 
Gushing 
Expected 
Intervention(s) 
None 
Manual 
pressure, 
cautery, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
staples, 
tissue repair 
Manual 
pressure, 
cautery, 
suture, 
staples, 
tissue repair 
Maximum 
Expected 
ACS-ATLS 
Shock Risk 
Class 
1 
1 
1 
2 
3 
4 
Eligible for 
Enrollment 
No 
Yes 
Yes 
Yes 
No 
No 
 
 
 

 
 
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5.6        Point of Enrollment 
 
All patients presenting to the Investigator for a non-emergent cardiothoracic operation are potential study 
subjects and should be screened for eligibility.  Subjects will need to meet all eligibility to be enrolled 
into the study. 
 
A subject is enrolled when he/she meets all preoperative inclusion/exclusion criteria, signs the informed 
consent form, and meets the intraoperative inclusion criteria.  The point of enrollment into the clinical 
study will occur intraoperatively.   
 
5.7        Withdrawal Criteria 
 
Subjects may withdraw from the study at any time without providing a reason.  Subjects will not be 
penalized nor lose any benefits to which they are otherwise entitled if they should choose to withdraw.  
The Investigator may also choose to withdraw the subject if he or she feels that this is in the subject’s best 
interest. 
 
Subjects who withdraw from the study before receiving the test or control hemostatic device will receive 
routine care.  No study-specific assessments will be conducted.   
 
5.8 
Subject Compliance 
 
Subject loss to follow-up is not expected, as the endpoints are collected intraoperatively and there are no 
follow-up visits after the surgical procedure.   
 
6 
STUDY PROCEDURES 
 
6.1 
Schedule Overview 
 
Table 2 details the study visits, corresponding timing, and evaluations to be performed at the visit.  
Table 3 lists the Case Report Forms (CRFs) that need to be completed at each visit.   
 
Table 2.  Study Evaluation Schedule 
Visit 
Timing 
Evaluations 
Preoperative 
Prior to surgery 
Informed consent, preoperative eligibility 
criteria confirmation 
Intraoperative 
Day of surgery 
Intraoperative inclusion criteria confirmation, 
enrollment and randomization, performance 
evaluation, and safety assessments 
 
 
 

 
 
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Table 3.  CRF Completion Schedule 
CRF 
Preoperative 
Intraoperative 
Subject Study 
Completion 
Preoperative CRF 
X 
 
 
Intraoperative CRF 
 
X 
 
Discontinuation CRF 
 
 
X 
Adverse Event CRF 
 
O 
 
Device Deficiency CRF 
 
O 
 
 
X 
Mandatory 
O 
As applicable 
 
 
6.2 
Preoperative Evaluations 
 
6.2.1 
Informed Consent 
 
Prior to performing any study specific procedures, a detailed explanation of the study procedures, 
potential discomforts, risks and benefits of participation, and alternatives will be reviewed with 
potential study subjects by a qualified member of the study team.  The informed consent process 
will follow applicable institutional and regulatory guidelines.  Subjects will be provided adequate 
time to review the informed consent document and all questions will be answered to the 
satisfaction of the subject prior to signing the informed consent.   
 
If the subject is willing to participate in the clinical study, he/she or an authorized legal 
representative must sign the informed consent form indicating that they have read and understand 
the information provided.  Each site will follow their local Institutional Review Board (IRB) and 
applicable regulatory guidelines for obtaining informed consent.  Documentation of the informed 
consent process for each subject and the original signed informed consent will be retained at the 
site and as required by applicable regulations.  A copy of the signed informed consent will be 
provided to the subject. 
 
6.2.2 
Preoperative Eligibility 
 
Once written informed consent has been obtained, the Preoperative CRF will be completed to 
document adherence to the preoperative inclusion and exclusion criteria. 
 
Where a subject fails to fulfill any element of the preoperative eligibility criteria, this will be 
documented and any signed consent form and completed preoperative inclusion/exclusion criteria 
retained.  This information will be tracked on the Screening and Enrollment Log.  The subject will 
not be advanced any further into the clinical study. 
 
6.2.3 
Subject Identification 
 

 
 
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After a subject has signed informed consent and met the preoperative inclusion and exclusion 
criteria, the subject will be allocated to the next available study number (subject ID number), which 
will be assigned. 
 
The subject ID number will consist of the site number and the subject number.  The subject number 
will be 01 for the first subject, 02 for the second subject and so on.  This subject ID number will be 
the unique identifier of the subject and included on each CRF page and all other study-specific 
documentation relating to that subject. 
 
6.3 
Preoperative Procedures and Evaluations 
 
The following data will be collected and recorded at the preoperative visit on the Preoperative CRF: 
 
• 
Demographic data 
o Age 
o Gender 
o Race and ethnicity 
• 
Physical exam  
o Height 
o Weight 
• 
Medical history 
o Disease process(es) / indication(s) for surgery 
o Concomitant illnesses 
o Preoperative anticoagulation and antiplatelet regimen, if applicable  
 
6.4 
Intraoperative Procedures and Evaluations 
 
All subjects will undergo the same intraoperative study evaluations.  Intraoperative is defined as the time 
interval from when the subject enters the surgical suite until the subject exits the surgical suite. 
 
Subjects undergoing the non-emergent cardiothoracic surgeries are eligible for enrollment into the clinical 
study.  The Investigator will perform the surgery per his or her standard procedures, including conventional 
methods of hemostasis where practical (pressure, ligature, cautery, etc.). 
 
Both test and control devices (not opened or prepared) should be available at the start of each procedure. 
 
6.4.1 
Intraoperative Inclusion Criteria 
 
A subject must then meet all of the following intraoperative inclusion criteria: 
 
• 
Subject does not have an active or suspected infection at the surgical site; 
• 
Subject in whom the Investigator is able to identify a TBS for which any applicable conventional 
means for hemostasis are ineffective or impractical; and 
• 
Subject has a TBS with minimal, mild, or moderate bleeding.1 
 
If all of these intraoperative eligibility criteria are met, then the subject is formally enrolled into the clinical 
study and randomized.  Each subject will have one TBS assessed and documented for the purposes of this 
study. 
 

 
 
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The bleeding severity of the TBS will be assessed via the SBSS/SPOT GRADE™ for intraoperative 
inclusion, which is immediately prior to enrollment.  The bleeding severity of the TBS will also be assessed 
and confirmed immediately prior to hemostat application, as bleeding severity may change between the 
time of enrollment and when the hemostat is ready to be applied.  Both bleeding severities will be recorded 
on the Intraoperative CRF.  Both bleeding severities will be presented in the analysis of the study data. 
 
If the bleeding severity at the time when the hemostat is ready to be applied is not minimal, mild, or 
moderate bleeding, then the TBS will not be treated.  If another suitable TBS is identified, the subject may 
undergo intraoperative evaluations for that TBS.  If another suitable TBS is not identified, the subject will 
be withdrawn from the clinical study.   
 
6.4.2 
Randomization and Hemostat Application 
 
Subjects will be randomized to receive HEMOBLAST™ or FLOSEAL in a 1:1 ratio: 
 
• 
52 subjects will be randomized to receive HEMOBLAST™; and 
• 
52 subjects will be randomized to receive FLOSEAL. 
 
To ensure balance through time, blocked randomization will be performed.  Random block sizes of 2, 4, or 
6 will be implemented to conceal treatment allocation.  After enrollment and randomization, the assigned 
hemostat will be used in the subject. 
 
A study-specific stopwatch will be used in the performance evaluations. 
 
After randomization, the assigned hemostat will be opened and prepared.  The study-specific stopwatch 
will be started at the time of hemostat outer packaging opening (time 00:00). 
 
The assigned hemostat will be prepared and applied to the TBS per its respective Instructions for Use (IFU).   
 
At time 03:00 (3 minutes after hemostat packaging opening), hemostasis will be assessed using the SPOT 
GRADE™.  If the TBS is hemostatic (SPOT GRADE™ score = 0), the performance evaluations are 
complete.  If the TBS is not hemostatic (SPOT GRADE™ score > 0), a re-application of the assigned 
hemostat will be performed per the respective IFU. 
 
At time 05:00 (5 minutes after hemostat packaging opening), hemostasis will be assessed using the SPOT 
GRADE™.  If the TBS is not hemostatic (SPOT GRADE™ score > 0), the Investigator may use any means 
necessary to obtain hemostasis. 
 
The study-specific stopwatch will run continuously until the 5 minute evaluation time point, except in cases 
where preparation of the hemostat is interrupted by other activities and obligations of the surgical staff.  
The study-specific stopwatch will be run by a trained and delegated study staff member.  In cases where 
the individual(s) involved in preparing the hemostat are required to perform other activities, the stopwatch 
will be paused and restarted when preparation resumes.  The number of interruptions will be recorded for 
each case. 
 
6.4.3 
Bleeding Severity and Hemostasis Evaluations 
 
Bleeding severity and hemostasis will be assessed using the SBSS / SPOT GRADE™ at each time point. 
 
A SPOT GRADE™ score of 0 is equivalent to hemostasis.  All other SPOT GRADE™ scores are 
considered failure of hemostasis.  See below in Table 6. 

 
 
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Table 6.  Bleeding Severity and Hemostasis 
SBSS Score 
0 
1 
2 
3 
4 
5 
Verbal 
Descriptor 
None 
Minimal 
Mild 
Moderate 
Severe; not 
immediately 
life-
threatening 
Extreme; 
immediately 
life-
threatening 
Visual 
Descriptor 
Dry 
Oozing 
Pooling 
Flowing 
Streaming 
Gushing 
Expected 
Intervention(s) 
None 
Manual 
pressure, 
cautery, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
adjuvant 
hemostat(s) 
Manual 
pressure, 
cautery, 
suture, 
staples, 
tissue repair 
Manual 
pressure, 
cautery, 
suture, 
staples, 
tissue repair 
Maximum 
Expected 
ACS-ATLS 
Shock Risk 
Class 
1 
1 
1 
2 
3 
4 
Hemostasis 
Yes 
No 
No 
No 
No 
No 
 
In any case where hemostasis is initially achieved but bleeding recurs prior to subject closure, the event 
will be documented.   
 
6.4.4 
Other Bleeding Sites 
 
For bleeding sites other than the TBS, the Investigator may use any means necessary to control bleeding, 
including either the test or control hemostat. No study data will be collected for other bleeding sites. 
 
6.4.5 
Intraoperative Data Collection 
 
The following data will be recorded on the Intraoperative CRF: 
 
• 
Surgical procedure(s) 
• 
Description of TBS 
o Location 
o Conventional means for hemostasis (pressure, suture, cautery, etc.) 
• 
Confirmation of intraoperative eligibility criteria 
• 
Approximate dimensions of target bleeding site 
• 
SPOT GRADE™ scores at baseline 
o Assessment of intraoperative eligibility 
o Immediately prior to hemostatic device application 
• 
SPOT GRADE™ score at 3 minutes  
• 
SPOT GRADE™ score at 5 minutes (if hemostasis is not achieved within 3 minutes) 
• 
Randomization 
o Time of randomization 
o Treatment arm 
o Device lot/batch number data 
• 
Number of incidence(s) of interruption of hemostatic device preparation 

 
 
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• 
Satisfaction on time and ease of hemostatic device preparation 
• 
Incidence of TBS re-bleeding prior to subject closure 
• 
Incidence of any device deficiencies 
• 
Incidence of any device-related adverse events 
 
Table 7 below shows a timeline of intraoperative procedures. 
 
Table 7.  Timeline for Intraoperative Procedures* 
Time Point (MM:SS) 
Study Procedures or Assessments 
Prior to 00:00 
• 
Identify Target Bleeding Site (TBS) 
• 
Assign SPOT GRADE™ score 
• 
Perform randomization  
00:00 (start stopwatch) 
• 
Open HEMOBLAST™ or FLOSEAL 
packaging and start preparation 
0X:XX 
• 
Assign SPOT GRADE™ score immediately 
prior to hemostat application 
03:00 
• 
Assign SPOT GRADE™ score 
 
If SPOT GRADE™ score = 0 
• 
Intraoperative efficacy evaluation completed 
 
If SPOT GRADE™ score is NOT 0 
• 
Re-apply HEMOBLAST™ or FLOSEAL 
05:00 
• 
Assign SPOT GRADE™ score 
 
If SPOT GRADE™ score = 0 
• 
Intraoperative efficacy evaluation completed 
 
If SPOT GRADE™ score is NOT 0 
• 
Rescue treatment 
* Assuming subject meets all intraoperative eligibility criteria 
 
6.5 
Discontinuation Procedures and Documentation 
 
Subjects will be discontinued after completion of the intraoperative visit. 
 
The Discontinuation CRF should be completed to document the reason for discontinuation: 
 
• 
Subject has completed the study;  
• 
Subject withdrawal and reason for withdrawal; or 
• 
Subject death (prior to completion of study evaluations). 
 
The date of discontinuation will also be noted on the Discontinuation CRF. 
 
7 
ADVERSE EVENTS 
 
7.1 
General 
 
An adverse event (AE) is ‘any untoward medical occurrence in a subject’.   

 
 
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A device deficiency is defined as the inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance, which may include device malfunctions, use errors and 
inadequate labeling.  
 
Only Adverse Events (AEs) possibly, probably, or definitely related to the hemostatic device (using the 
definitions below) will be recorded as part of this clinical study.  Anticipated adverse device effects are 
included in Section 12. 
 
7.2 
Adverse Event Documentation 
 
Only Adverse Events (AEs) possibly, probably, or definitely related to the hemostatic device (using the 
definitions below) will be recorded as part of this clinical study.  AEs not related to the hemostatic device 
(the AE is due to the underlying disease state or is due to concomitant medications or therapy not related 
to the use of the hemostatic device) will not be recorded as part of this clinical study. 
 
AEs will be documented by the Investigator on the appropriate source document(s) at the study site and 
also on the Adverse Event CRF.  Adverse events are to be recorded and dated according to when they are 
first observed.  The subsequent treatment(s) should also be documented.  The following will be recorded 
on the Adverse Event CRF: 
 
• 
Accepted medical term for the AE; 
• 
Description of the event; 
• 
Date of onset; 
• 
Date of resolution, if applicable; 
• 
Outcome; 
• 
Treatment(s)/action(s) taken; 
• 
Severity;  
• 
Relationship to the hemostatic device; and 
• 
Determination of reportability (see Reporting Section below). 
 
The severity of the event will be determined by the Investigator using the following definitions: 
 
• 
Mild: the symptoms are transient, barely perceptible by the subject and do not hinder normal 
activity; no treatment is usually prescribed to reduce these symptoms; 
• 
Moderate: the symptoms are sufficiently severe to provoke discomfort in the subject and 
sufficiently uncomfortable to prevent normal activity; a treatment may be required; or 
• 
Severe: the symptoms considerably modify the normal course of the subject’s activities or are 
disabling or are life-threatening; the treatment studied should be suspended; a treatment for the 
symptoms is prescribed. 
 
The relationship to the hemostatic device will be determined by the Investigator using the following 
definitions: 
 
• 
Possibly related: the AE has a reasonable temporal relationship to the use of the hemostatic 
device but alternative etiology is equally or more likely compared to the potential relationship to 
the use of the hemostatic device; 
• 
Probably related: the AE has a strong temporal relationship to the use of the hemostatic device 
and alternative etiology is less likely compared to the potential relationship to the use of the 
hemostatic device; or 

 
 
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• 
Definitely related: the AE has a strong temporal relationship to the use of the hemostatic device, 
follows a known response pattern and cannot reasonably be explained by known characteristics of 
the subject’s clinical state or other therapies. 
 
The expectedness of the AE will be determined by the Investigator as: 
 
• 
Anticipated; or 
• 
Unanticipated. 
 
Anticipated AEs are those that are identified as potential risks in the device labeling (e.g., IFU).  
Unanticipated AEs are those that are, by their nature, incidence, severity, or outcome, not identified in the 
device labeling. 
 
7.3 
Reporting 
 
A serious adverse event (SAE) is defined as an adverse event that: 
 
• 
Led to death; 
• 
Led to a serious deterioration in the health of the subject, that either resulted in a life-threatening 
illness or injury, or a permanent impairment of a body structure or a body function, or in-patient 
hospitalization or prolongation of existing hospitalization, or resulted in medical or surgical 
intervention to prevent life-threatening illness or injury or permanent impairment to a body 
structure or a body function; or 
• 
Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
 
A serious adverse device effect (SADE) is defined as an adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse event or that might have led to any of these 
consequences if suitable action had not been taken or intervention had not been made or if circumstances 
had been less opportune. 
 
An unanticipated [serious] adverse device effect (UADE/USADE) is any serious adverse effect on health 
or safety, 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 protocol; 
or any other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
All SADEs and UADEs must be reported to the Sponsor representative within 24 hours of the Investigator 
becoming aware of it.   
 
There are two methods of reporting.  The first is to complete and save the Adverse Event CRF within 24 
hours of the Investigator becoming aware of the SADE or UADE. 
 
The second method of reporting is to contact the Sponsor representative for event reporting: 
 
Telephone Number: +1 404 702 9253  
  
E-Mail: medical@biomup.com  
 
 
The Investigator should institute appropriate therapeutic and follow-up measures in accordance with good 
medical practice and record them in the subject’s source documentation and on the Adverse Event CRF.  It 

 
 
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is the responsibility of the Principal Investigator to inform the appropriate personnel as required by IRB 
policy. 
 
For SADEs and UADEs that are unresolved at the time of subject discontinuation, the Investigator will 
continue to follow the event to resolution or stabilization per standard medical care.   
 
7.4 
Regulatory Authority Reporting 
 
The study site will provide Sponsor-requested [redacted] details regarding the SADE or UADE and the 
Sponsor Regulatory Affairs Department will be notified to determine reportability per applicable 
regulations and guidelines.  Sponsor reporting to FDA will be performed per 21 CFR Part 803. 
 
8 
DATA COLLECTION 
 
8.1 
Completion of Case Report Forms 
 
Prior to enrollment of subjects at each study site, the Sponsor representative will provide the Principal 
Investigator and designated study site staff with training on electronic CRF completion procedures.  The 
Principal Investigator will be responsible for the timing, accuracy, and completeness of CRFs for each 
individual subject.  The personal data recorded on all paper and electronic documents will be regarded as 
confidential.   
 
8.2 
Source Documentation 
 
Source documents are where clinical study information for subjects are first recorded.  Data collected for 
the clinical study must be supported by source documents, and may include, but is not limited to, subject 
medical records, hospital charts, operative reports, laboratory and diagnostic test reports, and study 
worksheets.  Study worksheets should be used when other source documents do not capture study-specific 
data as part of standard of care. 
 
8.3 
Retention of Clinical Study Documentation 
 
Clinical study records will be stored in a confidential manner so as to protect the confidentiality of subject 
information.  All records related to this clinical study will be retained in appropriate study files. 
 
The Principal Investigator is responsible for retaining all copies of the records for a period of no less than 
5 years from the date on which the clinical study is completed/terminated.  In all cases, the Principal 
Investigator must contact the Sponsor prior to disposing of any records related to the clinical study.   
 
The Sponsor must approve the destruction of any study records. 
 
In addition, if the Principal Investigator moves/retires, etc., he/she should provide the Sponsor with the 
name and address of the person who will look after and be responsible for the clinical study related records. 
 
8.4 
Training 
 
Principal Investigators and study site staff will be trained on the clinical study and the specific tasks to 
which they are delegated.  Study site staff will also have documented training on Good Clinical Practice. 
 

 
 
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Further, Investigators (Principal Investigators and sub-investigators responsible for enrolling study subjects 
and applying the hemostatic devices) will have training on use of the test device, control device, and the 
SPOT GRADE™.   
 
9 
TERMINATION OF THE CLINICAL STUDY 
 
9.1 
Subject Withdrawals and Discontinuation 
 
During the course of this clinical study, subjects may elect to withdraw from study participation for any 
reason.  In addition, subjects will be withdrawn from the study for any of the following reasons: 
 
• 
TBS bleeding severity not appropriate for treatment immediately prior to hemostat application, but 
after enrollment and randomization; or 
• 
Subject death (prior to completion of study evaluations). 
 
Subjects who are withdrawn prior to receiving test or control device will be replaced. 
 
9.2 
Early Termination of the Clinical Study 
 
Both the Sponsor and Principal Investigator reserve the right to terminate the clinical study at any time.  
Should this be necessary, the procedures will be arranged on an individual site basis after review and 
consultation by both parties.  In terminating the clinical study, the Sponsor and the Principal Investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.  In case the study 
is terminated for safety reasons, this will be communicated to all participating Principal Investigators, who 
will be responsible for notifying their reviewing IRBs per IRB policy. 
 
10 
DATA MANAGEMENT 
 
All data will be housed in a validated database program.   
 
Once all the subject data has been collected, the analysis and reporting will be conducted. Any data existing 
for subjects who have not received treatment will not be used in the analysis.   
 
Any data existing for subjects who have received the test or control device, who withdraw voluntarily or 
who are withdrawn from the clinical study, will be used in the final analysis.  The inclusion of partial data 
will be documented in the final report. The final report will be the responsibility of Biom’up. 
 
11 
STATISTICS 
 
11.1 Overview 
  
11.1.1 Primary Endpoint 
 
The primary endpoint of this study is the superiority of HEMOBLAST™ relative to FLOSEAL for the 
proportion of subjects reaching hemostasis within 3 minutes. 
 
11.1.2 Secondary Efficacy Endpoints 
 
The secondary endpoint of this study is non-inferiority of HEMOBLAST™ relative to FLOSEAL for the 
proportion of subjects reaching hemostasis within 5 minutes. A margin of 10% (absolute difference) will 
be used for determining non-inferiority of HEMOBLAST™ relative to FLOSEAL.   

 
 
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11.1.3 Safety Outcomes 
 
The rate of occurrence of device malfunctions, device-related AEs, SADEs, and UADEs will be 
summarized for each treatment group. Events will be summarized by severity. 
 
11.1.4 Study Success 
 
Study success will be defined as superiority of HEMOBLAST™ relative to FLOSEAL in the proportion of 
subjects achieving hemostasis at the 3 minute assessment time point.  
 
11.2 General Analysis Considerations 
 
All statistical analyses will be performed using Power BI, SAS®, and/or R.  Unless otherwise specified, all 
continuous endpoints will be summarized using descriptive statistics, which will include the number of 
subjects (n), mean, standard deviation, median, minimum, and maximum.  All categorical endpoints will 
be summarized using frequencies and percentages.   
 
11.2.1 Analysis Populations 
 
Safety analyses will be performed on the Full Analysis Population, defined as all subjects who were 
randomized into the study and received study intervention.  Efficacy analyses will be conducted on the time 
to hemostasis (TTH) Analysis Population, defined as all subjects who were randomized, received study 
intervention, and had a TTH assessment recorded regardless of whether the measurement was censored 
(defined as the use of an additional hemostatic product or surgical rescue prior to the end of observation 
time, or failing to achieve and maintain complete hemostasis prior to the end of observation time).  Data 
summaries will be based on the intervention received, regardless of which intervention was randomly 
assigned. 
 
11.2.2 Handling of Missing Data 
 
In primary analyses, missing TTH values will not be imputed. All values censored prior to 3 minutes will 
be considered treatment failures for the purpose of the primary analysis.  For the key secondary analysis, 
all values censored prior to 5 minutes will be considered treatment failures for the purpose of the primary 
analysis.  A sensitivity analysis for the primary endpoint will consider a worst-case scenario in which all 
values censored prior to 3 minutes in the HEMOBLAST™ arm will be considered treatment failures while 
hemostasis at 3 minutes will be imputed for all values censored prior to 3 minutes on the FLOSEAL arm.   
 
11.2.3 Subgroup Analyses 
 
Analyses of performance (primary and secondary endpoints) will be presented by baseline bleeding 
severity. Additionally, the primary and secondary endpoints will be presented stratified by preoperative 
anticoagulation regimen. 
 
11.2.4 Data Transformations 
 
No transformations of data are planned. 
 
11.2.5 Subject Disposition and Characteristics 
 

 
 
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The number of subjects randomized to each treatment arm will be tabulated. Demographic variables will 
include age, sex, race, ethnicity, height, weight, and Body Mass Index (BMI).  Baseline disease 
characteristics will include indication(s) for surgery and related co-morbidities/concomitant illnesses. All 
continuous endpoints will be summarized using descriptive statistics, that will include the number of 
subjects (n), mean, standard deviation, median, minimum, and maximum.  All categorical endpoints will 
be summarized using frequencies and percentages. 
 
11.2.6 Subject Compliance 
 
Because the study device will be applied by the investigator during a single surgery, subject compliance 
with completing the study evaluations is not an issue and will not be reported.   
 
11.2.7 Protocol Deviations 
 
Eligibility criteria that were not met will be listed along with whether or not an exception was granted.  
Important protocol deviations will be summarized by treatment group.  Important protocol deviations are 
defined as: 
 
- 
Any unauthorized protocol deviations that result in a significant added risk to the study subject; 
- 
Performing study-specific activities without subject written informed consent; 
- 
Non-adherence to eligibility criteria without prior Sponsor approval; and 
- 
Non-adherence to Good Clinical Practice and/or applicable regulations; 
- 
Protocol deviations will be summarized in tables produced by the Medical Monitor or Clinical 
Research Associate. 
 
Protocol deviations will be either self-reported by the study site or identified by the Sponsor/Sponsor 
representative during site visits.  Protocol deviations will be recorded and retained in the study files. 
 
11.3   Analytic Methods  
 
11.3.1 Analysis of Primary and Secondary Efficacy Endpoints 
 
11.3.1.1 Analysis Population 
 
Efficacy analyses will be conducted on the TTH Population, defined as all subjects who were randomized, 
received study intervention, and had a TTH assessment recorded regardless of whether the measurement 
was censored.   
 
11.3.1.2 Methods of Analysis 
 
The primary efficacy endpoint is the difference in the probability of TTH at 3 minutes comparing 
HEMOBLAST™ to FLOSEAL.  Letting θ denote the true difference in the probability of hemostasis at 3 
minutes between HEMOBLAST™ to FLOSEAL, the trial will test the null hypothesis H0: θ   0 vs. the 
alternative hypothesis HA: θ > 0 using a one-sided level 0.025 Wald test. The resulting p-value based upon 
the asymptotic normal distribution and a corresponding (2-sided) 95% confidence interval for the difference 
in binomial proportions (HEMOBLAST™ minus FLOSEAL) will also be computed and reported. 
 
11.3.2 Analysis of Safety Outcomes 
 
11.3.2.1 Analysis Population 
 

 
 
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Safety analyses will be conducted on the Safety Analysis Population, defined as all subjects who were 
randomized into the study and received study intervention. 
 
11.3.2.2 Methods of Analysis 
 
Summaries of the number and percent of subjects with at least one device-related AE will be provided.  
Comparisons of the proportion of subjects experiencing SADEs and UADEs will be made between 
treatment arms. 
    
11.3.3 Sample Size Justification 
 
The sample size for the proposed study is based on: 
 
• 
Type I error α = 0.025 (one-sided); 
• 
Type II error β = 0.10; 
• 
δ = 0.30; 
• 
θHEMOBLAST™ = 0.40 at 3 minutes; and 
• 
θFLOSEAL = 0.10 at 3 minutes. 
 
Based upon the above model specification, the proposed study will require approximately N=98 patients 
(49 patients per arm).  While early discontinuation is expected to be rare, to account for potential loss of 
patients due to early discontinuation, a total of N=104 subjects (52 patients per arm) will be enrolled in 
order to ensure at least 90% power under the design assumptions while allowing for up to 5% attrition. 
   
12 
RISK/BENEFIT ANALYSIS 
 
12.1 Anticipated Clinical Benefits 
 
It is anticipated that application of a hemostatic device to a bleeding site will result in a reduced time to 
hemostasis compared to conventional methods of hemostasis (pressure, suture, or cautery).  Individual 
subjects may not directly benefit from participation in this study.  However, conducting this research 
could contribute to the overall advancement of medical and scientific knowledge and may benefit future 
patients. 
 
12.2 Risks Associated with Participation in the Clinical Study 
 
There are possible risks, complications, and discomforts associated with undergoing a cardiothoracic 
surgical procedure.  The Investigator will be responsible for discussing these risks, complications and 
discomforts with subjects along with the risks associated with anesthesia.   
 
Potential risks related to the use of hemostats similar to HEMOBLAST™ include: 
 
• 
Adhesion formation; 
• 
Allergy or anaphylaxis; 
• 
Blockage of cardiopulmonary bypass system and cell saver devices; 
• 
Compromised attachment of orthopedic implants; 
• 
Creutzfeldt-Jakob disease (CJD) agent; 
• 
Increased infection; 
• 
Nerve compression; 
• 
Thrombosis or thromboembolism; 

 
 
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• 
Transmissible Spongiform Encephalopathies (TSE); and 
• 
Viral disease transmission. 
 
Hypersensitivity of allergic/anaphylactoid reactions may occur with HEMOBLAST™.  Symptoms 
associated with allergic anaphylactic reactions include: flush, urticaria, pruritus, nausea, drop in blood 
pressure, tachycardia or bradycardia, dyspnea, severe hypotension, and anaphylactic shock. 
 
These reactions may occur in patients receiving HEMOBLAST™ for the first time or may increase with 
repetitive applications of HEMOBLAST™.  In the event of hypersensitivity reactions, discontinue 
administration of HEMOBLAST™.  Mild reactions can be managed with antihistamines.  Severe 
hypotensive reactions require immediate intervention using current principles of shock therapy. 
 
Subjects randomized to receive the control are exposed to risks associated with FLOSEAL, as described 
in the current device labeling. 
 
Participation in this clinical study also presents additional risks or inconveniences.  These may include, 
but are not limited to: 
 
• 
Additional intraoperative assessments of bleeding severity at 3 and 5 minutes. 
 
There may also be other unforeseen risks. 
 
12.3 Risk/Benefit Analysis 
 
Individual patients may experience no direct benefit from participation in the study.  However, a potential 
benefit of HEMOBLAST™ to be investigated in the study includes a higher probability of hemostasis 
within 3 minutes of device package opening, as will be tested for potential superiority.   
 
Risk mitigation steps have been taken through test device specifications; further, the test device has been 
approved by the United States Food and Drug Administration for the indication under which it will be 
used in this clinical study.  Risk mitigation steps are also implemented in the manufacture and shipment 
of the test device. 
 
The Sponsor, Medical Expert, and coordinating Investigator have determined that this clinical study is 
justified because the potential benefits outweigh the potential risks.   
 
12.4 Conduct of Clinical Study to Reduce Risk 
 
Further efforts to minimize risk in this clinical study will involve selecting investigators who are 
experienced and skilled in cardiothoracic surgery, have clinical study experience, and who are adequately 
trained on the use of the hemostatic devices and study procedures. 
 
Risks and benefits of this clinical study are included in the sample Subject Informed Consent Form, 
included as Appendix B.  Potential risks and benefits will be discussed with potential subjects during the 
informed consent process. 
 
13 
REPORTS AND PUBLICATIONS 
 
13.1 Interim Reports 
 
Interim reports will not be issued during the conduct of this clinical study.   

 
 
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13.2 Final Report 
 
The final report will be compiled by the Sponsor or designated Sponsor representative and reviewed, 
approved and signed off by the Sponsor and coordinating investigator. 
 
13.3 Publications 
 
The conduct and results of this clinical study will be documented in the final report, as mentioned above.  
Because this is a multicenter study, it is intended that the combined clinical data from all participating sites 
will be presented and/or published.  Individual investigators will not publish or present results prior to 
publication of the combined multicenter results without prior written consent from the Sponsor.  All 
publications must include the name of the Sponsor (Biom’up, France). 
 
14 
ETHICAL CONSIDERATIONS 
 
14.1 Institutional Review Board Approval 
 
Prior to the initiation of this clinical study, the Principal Investigator must submit the Protocol, informed 
consent form, and any other documents as may be required to the appropriate IRB for review and approval.  
The Principal Investigator, and any other member of the study team, must not participate in the decision-
making.  A signed and dated letter granting IRB approval must be provided to the Sponsor prior to the 
initiation of the clinical study.  A list of the members of the IRB reviewing this Protocol will be requested. 
 
14.2 Informed Consent and Patient Information 
 
The Principal Investigator or designee must explain to each subject the nature of the clinical study, including 
any risks and benefits, its purpose and procedures, and expected duration of involvement in the clinical 
study.  Each subject must be informed that participation in the clinical study is voluntary and non-
participation will not affect his/her right to the most appropriate surgical treatment or affect the 
doctor/clinician-patient relationship.  Subjects have the full right to withdraw from the clinical study at any 
time, irrespective of their initial consent. 
 
Each subject must also give their permission for representatives of the Sponsor, auditor and regulatory 
authorities to review their hospital records for purposes of source data verification. 
 
14.3 Subject Confidentiality 
 
Confidentiality of subject data will be maintained at all times.  Subject anonymity will be maintained and 
all documentation relating to a subject will be kept in a secure location.  The Sponsor, authorized Sponsor 
representatives, and regulatory bodies may have access to subject records, but identifying information will 
not be retained in the study files. 
 
14.4 Indemnity 
 
Indemnity will be documented in the Clinical Trial Agreement for each study site. 
 
14.5 Insurance 
 
The Sponsor is responsible for obtaining and maintaining clinical study insurance. 
 

 
 
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15 
COMPLIANCE 
 
15.1 Overview 
 
This clinical study will be conducted in accordance with Good Clinical Practice (GCP, ICH E6) and 21 
CFR Parts 50, 54, and 56. 
 
15.2 Clinical Study Personnel Responsibilities 
 
Prior to the initiation of this clinical study, each Principal Investigator will approve this Protocol by signing 
the signature page.  This signature confirms that the clinical study will be performed in compliance with 
the Protocol. 
 
The Sponsor shall also provide accurate, complete, and current information about any aspect of the clinical 
study as requested by reviewing IRB(s) or regulatory authorities.  Current applicable national regulations 
shall be followed. 
 
The Sponsor is also responsible for the retention of clinical study documentation per applicable regulations. 
 
15.3 Monitoring 
 
The monitor will be responsible for securing the compliance of the Principal Investigators to the signed 
agreement, the Protocol, GCP, applicable laws and regulations, and conditions of approval imposed by the 
reviewing IRBs or regulatory authorities, as specified in the study-specific Clinical Monitoring Plan. 
 
The Principal Investigator will permit the Sponsor or designated representative of the Sponsor to inspect 
all CRFs and corresponding portions of the subject’s clinic records and/or original hospital medical records, 
at regular intervals throughout the clinical study.  These inspections are for the purpose of verifying 
adherence to the Protocol and the completeness and accuracy of the data being entered on the CRFs.   
 
The planned extent of source data verification is detailed within the study-specific Clinical Monitoring 
Plan. 
 
15.4 Audits 
 
During the conduct of the clinical study, the Sponsor may appoint Quality Assurance (QA) personnel to 
provide audit of the administration and conduct of the clinical study, at the study site(s), Sponsor, and/or 
Sponsor representative(s). 
 
The relevant Regulatory Authority also has the right to conduct an audit of the clinical study.  It is the joint 
responsibility of the Sponsor and the Principal Investigator to ensure that the clinical study has been 
conducted in accordance with all government regulations. 
 
In the event that the regulatory authority desires to inspect this clinical study, the Principal Investigator will 
permit authorized inspectors to inspect all facilities and records relating to the clinical study and aid the 
Inspector to perform the audit in a timely fashion. 
 
15.5 Modifications to the Protocol 
 
Except in emergency situations, prior approval by the Sponsor is required for changes in or deviations from 
this Protocol.  This provision does not apply to those changes made to reduce discomfort or overt risks to 

 
 
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the subject.  In the event of an emergency situation, the Principal Investigator must institute any and all 
medical procedures he/she deems to be medically sound.   
16 
ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation / Term 
Definition 
ACS-ATLS 
American College of Investigators – Advanced Trauma Life 
Support® Shock Risk Class: 1 – involves up to 15% of blood 
volume; typically no change in vital signs and fluid resuscitation is 
not usually necessary.  Class 2 – involves 15-30% of total blood 
volume; patient is often tachycardic with a narrowing of the 
difference between the systolic and diastolic blood pressures; the 
body attempts to compensate with peripheral vasoconstriction; skin 
may start to look pale and be cool to the touch; volume 
resuscitation with crystalloids is all that is typically required; blood 
transfusion is not typically required.  Class 3 – involved loss of 30-
40% of circulating blood volume; patient’s blood pressure drops; 
heart rate increases, peripheral hypoperfusion worsens; fluid 
resuscitation with crystalloid and blood transfusion are usually 
necessary.  Class 4 – involves loss of > 40% of circulating blood 
volume; the limit of the body’s compensation is reached and 
aggressive resuscitation is required to prevent death. 
ADE 
Adverse Device Effect - any untoward and unintended response to 
an investigational medical device 
AE 
Adverse Event - any untoward medical occurrence in a subject 
ASA Classification 
American Society of Anesthesiologists Classification: 1 – normal 
health patient; 2 – patient with mild systemic disease; 3 – patient 
with severe systemic disease; 4 – patient with severe systemic 
disease that is constant threat to life; 5 – moribund patient who is 
not expected to survive with the operation; 6 – a declared brain-
dead patient whose organs are being removed for donor purposes 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance, which may include 
device malfunctions, use errors and inadequate labelling 
Enrollment 
For this study, the point of enrollment is intraoperatively, when the 
subject meets all intraoperative inclusion criteria 
FDA 
Food and Drug Administration  
ICF 
Informed Consent Form 
Intraoperative Time 
Time from skin open to skin closure 
IRB 
Institutional Review Board 
QA 
Quality Assurance 
SADE 
Serious Adverse Device Effect – an adverse device effect that has 
resulted in any of the consequences characteristic of a serious 
adverse event or that might have led to any of these consequences if 
suitable action had not been taken or intervention had not been 
made or if circumstances had been less opportune 
SAE 
Serious Adverse Event – an adverse event that: 
• 
Led to death 

 
 
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Led to a serious deterioration in the health of the subject, that 
either resulted in a life-threatening illness or injury, or a 
permanent impairment of a body structure or a body 
function, or in-patient hospitalization or prolongation of 
existing hospitalization, or resulted in medical or surgical 
intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body 
function. 
SBSS 
Surface Bleeding Severity Scale, also known as SPOT GRADE™ 
TBS 
Target Bleeding Site 
TTH 
Time To Hemostasis 
UADE (also USADE) 
Unanticipated [Serious] Adverse Device Effect – any serious 
adverse effect on health or safety, 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 application; or any other unanticipated serious 
problem associated with a device that relates to the rights, safety or 
welfare of subjects 
WHO 
World Health Organization 
 
17 
REFERENCES 
 
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3 Levy JH, et al.  Multidisciplinary approach to the challenge of hemostasis.  Anesth Analg 2010;110:354-364. 
4 Adams GL, et al.  The balance of thrombosis and hemorrhage in surgery.  Hematol Oncol Clin North AM 
2007;21(1):13-24. 
5 Renkens KL, et al.  A multicenter, prospective, randomized trial evaluating a new hemostatic agent for spinal 
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6 Tomizawa Y, et al.   Clinical benefits and risk analysis of topical hemostats: a review.  J Artif Organs 
2005;8(3):137-142. 
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12 Spotnitz WD.  Hemostats, sealants, and adhesives: components of the surgical toolbox.  Transfusion 2008;1502-
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