Observational Study of Outcomes After EchoMark and EchoSure-based Free Flap Monitoring
Conditions: Free Flap Transfer, Malignant Neoplasm
Sponsor: Sonavex, Inc.



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Table of Contents  
 
SECTION 
CONTENT 
PAGE 
1 
Abbreviations  
3 
2 
Primary Contacts  
4 
3 
Study Summary  
5 
4 
Introduction, Background, and Significance  
6 
5 
Study Objectives 
7 
6 
Study Design  
8 
7 
Study Population  
8 
8 
Statistical Analysis  
9 
9 
Patient Enrollment and Consent  
9 
10 
Study Procedures and Methods  
11 
12 
Data Collection, Analysis, and Monitoring  
11 
 
 
 

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1. ABBREVIATIONS   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE  
Adverse event  
CA  
Competent authority  
CE  
Conformité Européene  
CEC  
Clinical events committee  
CRF  
Case report form  
FDAAA  
Food and Drug Administration Amendments Act  
GCP  
Good clinical practices  
ID  
Identity Number  
IRB 
Institutional Review Board  
SAE  
Serious Adverse Event  
SOC  
Standard of Care  
USADE  
Unanticipated Serious Adverse Device  

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3.  STUDY SUMMARY 
 
Title:  
Observational Study of Outcomes after EchoMark and EchoSure-based 
Free Flap Monitoring 
Protocol Number:  
2019-1 
Design:  
This is a prospective, single arm, non-randomized, multi-center 
observational study to demonstrate the performance of the EchoMark 
and EchoSure devices in patients undergoing free flap surgery.     
Study Duration:  
Projected enrollment of first patient: March 2019  
Projected exit of final patient: November 2019  
Primary Objective:  
The primary objective of the study is collect data on patient outcomes in 
cases where the surgeon has chosen it as the appropriate method of 
monitoring. 
Patient Population:  
Patients undergoing free flap surgery. 
Sample Size:  
Up to four hundred (400) patients will be enrolled.  
Number of Sites:  
Up to eight (8) sites.  
Treatments:  
One or two EchoMark soft tissue marking devices will be placed and 
monitored using the EchoSure system for 72 hours.   
Endpoints:  
Primary Performance Endpoints:   
• Surgeon evaluation of improved monitoring ability and 
satisfaction 
Secondary Performance Endpoints: 
• Flap failure rate 
• Flap takeback rate 
• Flap salvage rate 
• Total cost of hospitalization 
• Time from OR departure to return to OR 
• Nurse evaluation of improved monitoring 
 
NCT Number 
03915717 

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4. INTRODUCTION, BACKGROUND AND SIGNIFICANCE 
 
Background 
In free flap surgery (microvascular tissue transfer procedures) blood flow to the skin and soft 
tissue is critical to tissue survival and wound healing. Compromised blood flow can lead to 
necrosis, wound break down, delayed wound healing, and wound infection. If blood flow to skin 
and soft tissue is not maintained, tissue death occurs. Therefore, blood flow into the tissue is of 
utmost importance in free flap surgery. Because any compromised blood flow could lead to 
tissue death if not detected early, we routinely monitor patients in hopes of detecting vascular 
compromise while reperfusion and tissue salvage remains a possibility.  
 
Currently, we rely on several methods to monitor flaps as no satisfactory solution exists. We 
inspect all flaps for color, warmth, and capillary refill. We have tried some of the existing 
monitoring devices, such as transcutaneous Doppler, implantable Doppler or near infrared 
spectroscopy. These systems each have their drawbacks, which include false positives and late 
detection of a problem. For example, current transcutaneous Doppler systems can be inaccurate 
and reflect the flow of blood through a vessel other than at the surgical site of interest. Inspection 
is subjective and can be examiner dependent. In some cases, our flaps our buried beneath the 
skin and visual inspection is not an option. For these reasons, we are interested in continuing to 
evaluate potential methods for improved flap monitoring. The Sonavex EchoMark is an FDA 
approved device that is highly echogenic to provide clear marking of the at-risk vessels such that 
the surgical site can be easily monitored. The Sonavex EchoSure is a color Doppler ultrasound 
device for monitoring blood flow. The technology provides clinicians with a clear and reliable 
assessment of blood flow into and out from the free flap to assess the viability of the tissue. We 
hypothesize that this technology could be used to detect early tissue compromise, predict tissue 
death, and potentially allow for early intervention. If this system allows detection of tissue 
compromise, it would improve wound dealing, decrease skin necrosis or flap death, and improve 
Inclusion Criteria  
• Age ≥ 18 years  
• Patients presenting for microvascular tissue transfer procedures 
where the surgeon selects EchoMark and EchoSure as an 
appropriate method of monitoring. 
• Patient is able to sign informed consent and able to participate in 
all testing associated with this clinical investigation  
• Women of childbearing potential have a negative pregnancy test  
Exclusion Criteria  
• Age <18 years old  
• Patient unable to sign informed consent  
• Patient participating in another investigational device or 
pharmacological study 
• Prisoner or patient from vulnerable populations as defined in 45 
CFR 46.   
Follow Up:  
Patients will have no follow-up responsibilities following their 
discharge from the index surgical procedure.   

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patient safety and outcomes. Of note, Doppler ultrasound has already been used to monitor flaps 
[Rosenberg JJ, Fornage BD, and Chevray PM 2006 Monitoring Buried Free Flaps: Limitations 
of the Implantable Doppler and Use of Color Duplex Sonography as a Confirmatory Test, 
Vakharia KT, Henstrom D, Lindsay R, Cunnane MB, Cheney M, and Hadlock T 2012 Color 
Doppler Ultrasound: Effective Monitoring of the Buried Free Flap in Facial Reanimation]. 
However, there is little comparative data versus other methods of monitoring. This study is 
primarily aimed at collecting data assessing the performance of Doppler ultrasound monitoring 
with EchoMark in a more quantitative way. 
 
Device Description  
 
ECHOMARK  
The EchoMark is an echogenic polymeric marker used to mark surgical sites with ultrasound. 
The device has a specially designed form factor that provides intuitive, continuous changes in its 
two-dimensional ultrasound outline when imaged from different angles and positions. EchoMark 
is produced with a manufacturing technique that enhances acoustic resonance to maximize 
brightness under ultrasound. EchoMark is composed of a bioresorbable polymer with a long 
history of use in sutures and medical devices and dissolves within 18-24 months.   
 
 
ECHOSURE  
EchoSure is a Doppler ultrasound device that automatically delivers visual and quantitative blood 
flow information, and may be utilized intraoperatively or postoperatively from the bedside by a 
nurse or other healthcare provider without the need for special sonographic training.  
 
Benefits 
EchoMark and EchoSure together enable the patient care team to collect critical blood flow 
information intraoperatively and during routine patient examinations postoperatively. The 
technology displays both a visual indication of arterial and venous blood flow in real-time and 
provides the quantitative changes in volumetric flow rate in each vessel. This information is 
critical for: 
• Detecting vascular compromise early enough for flap salvage 
• Delivering reliable information to eliminate false positives and unnecessary take-backs to 
the OR 
• Selecting optimal vessels for free flap surgery, and 
• Diagnosing potential issues intraoperatively prior to leaving the OR 
 
 
5.  STUDY OBJECTIVES  
 
Purpose  
The purpose of this study is to evaluate the performance of the EchoMark and EchoSure (both 
FDA approved devices) as an ultrasound-based method of monitoring the viability of free flaps 
and patency of at-risk vessels. The implant and ultrasound will be used per IFU. The primary 
purpose of the study is to collect data on patient outcomes in cases where the surgeon has chosen 
it as the appropriate method of monitoring. 

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Performance Goals  
 
Primary Performance Endpoint:  
• Surgeon evaluation of improved monitoring ability and satisfaction 
 
Secondary Performance Endpoints:  
• Flap failure rate 
• Flap takeback rate 
• Flap salvage rate 
• Total cost of hospitalization 
• Time from OR departure to return to OR 
• Nurse evaluation of improved monitoring 
 
Safety Goals  
 
Primary Safety Endpoint: 
• Procedure freedom from Serious Adverse Events (SAEs) during the EchoMark 
implantation procedure, hospitalization, and at discharge. 
 
 
6.   STUDY DESIGN 
This is a prospective, single arm, non-randomized, multi-center observational study to record 
subjective and objective data in patients undergoing free flap surgery where the surgeon has 
chosen to use the EchoMark and EchoSure devices for flap monitoring. 
 
 
7.  STUDY POPULATION  
 
Number of Patients 
Up to four hundred (400) patients will be enrolled and both men and women will be eligible for 
inclusion. The estimated enrollment period is nine months and patients will be followed until 
discharge from their index surgical procedure.   
 
Intended Use  
The EchoMark and EchoSure devices are intended to be used by a trained medical professional. 
The EchoMark device is intended to be a Single Use Device, used in a surgical operating suite or 
equivalent setting. The EchoSure device is reusable and may be used in the operating suite or a 
post-operative unit such as the ICU or patient floor. When used intraoperatively or in the 
presence of breached skin, the EchoSure Probe should be used with a sterile probe cover. 
Inclusion Criteria  
• Age ≥ 18 years 

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• Patients presenting for microvascular tissue transfer procedures where the surgeon has 
selected EchoMark and EchoSure as the optimal method of vascular monitoring based on 
clinical assessment and plan 
• Patient is able to sign informed consent and able to participate in all testing associated 
with this clinical investigation  
• Women of childbearing potential have a negative pregnancy test 
 
Exclusion Criteria 
• Age <18 years old 
• Patient unable to sign informed consent  
• Patient participating in another investigational device or pharmacological study  
• Prisoner or patient from vulnerable populations as defined in 45 CFR 46.   
 
PATIENT WITHDRAWAL FROM THE STUDY  
Patients are free to withdraw consent at any time.  Patients who wish to terminate their 
participation in the research will no longer receive ultrasound examinations of their free flap and 
their data will be removed from the study. 
 
 
8:  STATISTICAL ANALYSIS  
Statistical power was calculated based on determination of the number of detected thrombosis 
events needed to see a difference between EchoSure and an alternate method of flap monitoring 
(e.g., clinical examination). A one-tailed paired t-test was used to compare the dichotomous 
outcome of whether EchoSure detected a thrombotic event prior to other methods of monitoring. 
At α=0.05 and β=0.80 with a medium Cohen’s effect size of 0.5, 27 thrombotic events are 
needed for comparison. With a baseline national re-exploration rate of about 7%, an enrollment 
of 385 patients will provide sufficient sample size for the analysis. 
 
9:  PATIENT ENROLLMENT AND CONSENT   
Method of Subject Identification and Recruitment 
Patients will be identified and recruited by the surgeons participating in the study. Patients who 
have been scheduled for a free flap surgery will be identified as appropriate for study 
recruitment. The study details will be explained to identified patients and the consent process 
will begin for willing patients.   
 
Informed Consent  
Written informed consent, in accordance with applicable international standards and trial center 
regulations, shall be obtained from each subject, prior to the trial procedures. The investigator 
retains a copy of the signed informed consent document in each subject’s record, and provides a 
copy to the subject.  
 
The Investigator must obtain the written informed consent of all subjects, and must not allow any 
subject to participate in the investigation prior to obtaining governing institutional review board 

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(IRB), research ethics board (REB) approval, or Ethics Committee (EC) approval. Before 
starting the trial, the investigator provides trial Sponsor with a copy of the sample Informed 
Consent document approved by the IRB, REB, or EC with documented evidence that the IRB, 
REB, or EC approved the protocol and the informed consent. 
 
 
Process of Consent 
Patients eligible for the study will receive detailed written information on the trial, after which 
they will be asked to give written informed consent in accordance with the local clinical site’s 
Ethics Committee. Oral consent is not an acceptable substitute.  
 
Consent may only be obtained in person by a member of the study team delegated with 
consenting responsibilities.  Consent will be obtained by a member of the research team in the 
patient’s preoperative visit to clinic or in the pre-operative area prior to the initiation of 
anesthesia.  The research team will take as much time as necessary to confirm full understanding 
of the study in the consent discussion. There will be sufficient time for the patient to consider the 
study obligations and decide whether or not to participate, as study participation will not change 
clinical care and their data can be removed at any time if they choose to disenroll. Participation is 
fully optional.  
 
Study personnel should explain that even if a patient agrees to participate in the study and signs 
the ICF, the patient may not be eligible to participate if he/she fails additional eligibility criteria 
or the surgical plans changes during the procedure.  
 
Once signed, a copy of the Patient Informed Consent document and the Patient Information 
Sheet will be given to the patient. 
 
A Screening and Enrollment Log will be maintained in the on-site clinical records located at the 
study site to document select information about candidates who are enrolled in the study as well 
as those who fail to meet the entry criteria.  
 
Vulnerable Subjects 
This study will not specifically target the recruitment of any potentially vulnerable subjects. Due 
to the low risk of the study, if a patient from a vulnerable population presents for flap 
procedures, they will be given the option to participate in the study.  
 
Study Enrollment  
Patients will be considered enrolled in the Observational Study of Outcomes after EchoMark and 
EchoSure-based Free Flap Monitoring trial once informed consent has been obtained and all 
eligibility criteria confirmed.    
 
 
 
 
 
 

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The following minimum information should be recorded in the patient’s medical records: 
• The date the patient entered the trial and the patient number 
• The trial protocol number and the name of the Sponsor 
• The date that informed consent was obtained 
• Evidence that the patient meets trial eligibility requirements (e.g., medical history, trial 
procedures and/or evaluations) 
• The dates of all trial related patient visits 
• Evidence that required procedures and/or evaluations were completed 
• Documentation of specific device used, if any 
• Occurrence and status of any Adverse Events 
• The date the patient exited the trial, and a notation as to whether the patient completed the 
trial or was discontinued, including the reason for discontinuation 
 
 
DATA QUALITY ASSURANCE 
Case Report Forms specific to the Observational Study of Outcomes after EchoMark and 
EchoSure-based Free Flap Monitoring trial will be used for the collection and recording of data at 
the Investigational site. Investigators are responsible for the timely completion and storage of these 
forms.  
All CRFs will be collected by the Investigator and entered into a database. All case report forms 
received will be reviewed, tracked and filed. Prior to data entry, a pre-entry review will be 
conducted to ensure that mandatory fields have been completed. Incoming data will be reviewed 
to identify inconsistent or missing data. All hard copy forms and data files will be secured to ensure 
confidentiality. 
Investigators are to maintain all source documents, including diagnostic test reports, laboratory 
results, completed case report forms, supporting medical records and informed consent. The source 
documents will be referenced during monitoring visits to verify the information documented on 
the case report forms.   
 
PATIENT CONFIDENTIALITY 
All information concerning patients or their participation in this trial will be considered 
confidential. Only authorized Sonavex personnel and designated consultants and regulatory 
agencies will have access to these confidential files. Enrolled patients will be assigned a unique 
identifier that will be used to maintain confidentiality of each patient’s medical information. 
Patient names and other protected health information will not be captured on the case report forms.