Automated 3D Ultrasound-based Surveillance of Arteriovenous Fistula Maturation for Post-operative Hemodialysis Patients
Conditions: Arteriovenous Fistula, Arteriovenous Graft
Sponsor: Sonavex, Inc.

 
 
Automated Ultrasound Flow Monitoring for Maturation of 
Peripheral Arteriovenous Fistulae 
 
Stage 1: 
EchoSure Criteria Development and Early Assessment Trial 
 
Stage 2: 
EchoSure Fistula Maturation Prediction Trial 
 
 
Version: May 5, 2019 
NCT: NCT04017910 

Version: May 19, 2019 
 
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Automated Ultrasound Flow Monitoring for Maturation of 
Peripheral Arteriovenous Fistulae  
Stage 1: 
EchoSure Criteria Development and Early Assessment Trial 
Stage 2: 
EchoSure Fistula Maturation Prediction Trial 
 
Protocol Number: 
 
Clinical Investigation Plan 
Version: 
 
 
 
 
May 5, 2019 
 
 
 
 
Sonavex, Inc 
2835 O’Donnell Street 
Suite 200 
Baltimore, MD 21224 
David Narrow, CEO 
Email: dnarrow@sonvex.com 
 
  
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document and the information contained herein may not be reproduced, used, or disclosed without permission from Sonavex, Inc. 
 

Version: May 19, 2019 
 
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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 
8 
6 
Study Design  
9 
7 
Study Population  
10 
8 
Statistical Analysis  
11 
9 
Patient Enrollment and Consent  
13 
10 
Study Procedures and Methods  
14 
11 
Data Collection, Analysis, and Monitoring  
15 
12 
Ethics 
17 
13 
References 
17 
14 
Attachments 
17 
14.1 
Schematic of Study Design 
18 
14.2 
Study Schedule 
19 
14.3 
Consent Document 
20 
14.4 
Data Forms 
21 
 
 
 

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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  

Version: May 19, 2019 
 
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3.  STUDY SUMMARY 
Title:  
Automated Ultrasound Flow Monitoring for Maturation of Peripheral 
Arteriovenous Fistulae 
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 peripheral arteriovenous 
fistula creation for hemodialysis access. 
 
Stage 1: EchoMark implantation at the time of fistula creation with 
scheduled follow up for EchoSure imaging of the fistula maturation 
process. This stage will produce EchoSure criteria for early prediction of 
maturation failure.  
 
Stage 2: EchoMark implantation and imaging with EchoSure to prove 
the robustness of the fistula maturation failure criteria established in 
stage 1 and measure the effect on ultimate fistula maturation rates. 
Study Duration:  
Projected enrollment of first patient: May 2020  
Projected exit of final patient: December 2021  
Primary Objective:  
Stage 1: The primary objective of the study is to collect data to verify 
the technology’s performance in monitoring fistula maturation and 
understand the natural history of AV fistula flow physiology. 
 
Stage 2: The primary objective of the study is to assess the ability of the 
EchoMark and EchoSure system to reduce the rate of failed fistula 
maturation. 
Patient Population:  
Patients undergoing upper extremity autologous arteriovenous fistula 
creation. 
Sample Size:  
Stage 1: Up to sixty (60) patients will be enrolled.  
Stage 2: Up to sixty (60) patients will be enrolled. 
Number of Sites:  
To be determined  
Treatments: . 
Stage 1: EchoMark soft tissue marking devices will be placed and 
monitored using the EchoSure system for 24 weeks or confirmed fistula 
maturation/failure has been declared by the attending vascular surgeon, 
whichever comes first.   
 
Stage 1: EchoMark soft tissue marking devices will be placed and 
monitored using the EchoSure system for up to 52 weeks. Upon the 
decision by the attending surgeon that the fistula failure is confirmed or 
that monitoring is no longer clinically necessary patients will exit the 
study 

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Endpoints:  
Stage 1: 
• Data collection to verify accuracy 
• Data collection to understand the natural history of flow 
physiology in AV fistulas and classify fistulas that will fail 
 
Stage 2: 
Primary Performance Endpoints:   
• Rate of successful fistula maturation 
Secondary Performance Endpoints: 
• Cumulative fistula patency at the end of 1 year 
• Conduit diameter measurements 
• Volumetric flow measurements 
 

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4. INTRODUCTION, BACKGROUND AND SIGNIFICANCE 
 
Background 
Chronic kidney disease (CKD) is overwhelmingly prevalent in the United States: more than one 
in ten American adults are estimated to have CKD and it is the 9th leading cause of death 
nationally. Kidney failure, or end stage renal disease (ESRD), is the most severe form of CKD, 
and its incidence is increasing dramatically; the number of Americans with ESRD has tripled in 
the last twenty years. The incidence of kidney failure is projected to increase even more because 
of the aging American population. While the yearly incidence rates for ESRD have increased by 
about 3% for most age groups, the rate for patients over 75 has grown by 10%. The aging 
American population has substantial implications for the epidemiology of dialysis; by 2050 a 
quarter of Americans will be 65 or older. The median age at dialysis initiation is 64, and the peak 
incidence for ESRD is between 80 and 85. For comparison, by 2020 a quarter of the population 
will be 65 or older and the number of Americans 85 and older will be around twenty million. The 
incidence of ESRD is also increasing because of the growing prevalence of comorbid and 
causative conditions such as hypertension and diabetes, particularly in the elderly population.(2-
4)  
 
The health care costs associated with ESRD are substantial. In 2012, the Medicare costs for 
ESRD, excluding medication, accounted for 7.1% of the total CMS budget. (4) The most 
expensive modality of renal replacement, hemodialysis, is also the most prevalent. In 2015, 
hemodialysis cost Medicare $26.7 billion and the expenditure per patient per year was 
Inclusion Criteria  
• Age > 18 years  
• Patients presenting for upper extremity autologous arteriovenous 
fistula creation for hemodialysis access 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 variable follow up depending on the rate of fistula 
maturation as well as the follow up required by the surgeon per his or 
her standard practice.   

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$88,195.(5) The estimated cost of dialysis between 2001 and 2010 was approximately $1.1 
trillion.(4)  
 
Hemodialysis access is a conduit through which dialysis machinery may be connected to the 
patient’s circulatory system. The creation and maintenance of access constitutes a significant 
portion of dialysis costs. A fifth of all ESRD hospitalizations are attributable to access 
complications. Current clinical practice guidelines maintain that an autogenous arteriovenous 
(AV) fistula is the ideal vascular access conduit for hemodialysis (Figure 1).(6) Fistulae are 
superior to prosthetic grafts insofar as they require fewer interventions to maintain patency, have 
a far lower rate of failure and infection and a longer usable lifespan. Indwelling central venous 
catheters have the highest risk of death, infection and cardiovascular morbidity.(7) Autogenous 
AV fistulae confer a mortality benefit when used for dialysis.(1) In the United States, 63% of 
patients on dialysis use fistulae.(6)  
 
The primary limitation of AV fistulae is the high rate of failure. Between 30%-70% of fistulae 
suffer primary failure and are never used because they have failed to mature or adapt into 
suitable dialysis access.(1) This failure nearly always results in a delay in dialysis initiation and 
requires placement of a dialysis catheter in addition to another surgery for access creation. The 
financial burden of a failure to mature is accordingly substantial. Dialysis-related expenses 
incurred by patients in their first year of renal failure are 23% lower if dialysis is started in a 
mature fistula than without.(8) Techniques to maximize the rates of maturation hold substantial 
potential for cost savings. Muray-Cases et al. demonstrated that a program of pre-maturation 
ultrasonography and intervention resulted in a maturation success rate of 78% at the time of 
dialysis.(9) Notably, the study involved exclusively distal radiocephalic fistulas, a type that has a 
typical historical rate of maturation failure between 50-70%.(10) Currently, resource limitations 
enable reimbursed performance of a Duplex ultrasound if maturation is not present at six weeks. 
Ultrasound surveillance of the maturing fistula in the early postoperative period is not typically 
performed as CMS and local coverage determination criteria require clinical indications that 
cannot apply in the early postoperative period. This ‘blind period’ immediately after fistula 
creation holds substantial potential for improvement of care. 
 
Research has established that volumetric flow at six weeks after fistula creation correlates with 
flow at two weeks after creation.(11) This two-week marker has additional and substantial 
importance; two weeks postoperatively is accepted as the time at which fistula revision can be 
performed. Most revision surgeries and procedures do not disturb the primary fistula conduit. 
Taken together, these represent an opportunity to detect and treat maturation failure as early as 
two weeks postoperatively and enable a fistula to reach maturation by the expected date. 
Compared to the abovementioned 30-70% failure rate, regular early ultrasound surveillance has 
resulted in a success rate of 78%. In 2014 alone, such an improvement would result in the 
salvage of 25,000 – 70,000 fistulas.(12)  
 
A single imaging modality, ultrasonography, is able to assess volumetric flow within a fistula 
and determine anatomic factors predisposing it to maturation failure or impending late failure. 
Duplex ultrasound, however, is a resource-intensive practice that requires the dialysis patient to 
make an additional visit to an outpatient imaging laboratory and requires a trained, formally 
certified professional ultrasonographer. The examination itself requires 45 minutes to an hour. It 

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is only complete after image interpretation by a physician which can take an additional 24-48 
hours. The substantial commitment of material resources, time, and personnel make formal 
Duplex ultrasonography too costly for performance of frequent examination, despite the potential 
for economic and proven clinical and quality improvement that regular scanning holds.(9)  
 
This potential is not theoretical. Doppler ultrasound imaging has demonstrated utility in 
predicting both fistula maturity and in detecting impending fistula thrombosis.(1, 9, 11, 13-19) 
Ultrasound criteria for the prediction of  maturation failure have been established, and ultrasound 
can determine the cause of non-maturation and allow planning for surgical intervention.(1) 
Studies indicate that routine surveillance of fistulae can predict maturation and that a program of 
routine ultrasound surveillance decreases the rate of maturation failure significantly.(1, 9, 11, 16) 
A multicenter study of more than 500 upper extremity fistula creations determined that both 
fistula diameter and volumetric flow at two weeks postoperatively were significant predictors of 
successful or unsuccessful maturation at six weeks.(11)  
 
While we have described a 50% decrease in maturation failure as reasonable, at least one study 
of early postoperative ultrasound for maturation monitoring has shown results surpassing this 
figure. Muray Cases et al. used early ultrasonography to achieve a 78% maturation success rate. 
In almost all cases of incipient maturation failure, a single, correctible lesion was identified.(9) 
Remarkably, because of this early detection not a single patient initiated dialysis with a central 
venous catheter.(9) 
 
Despite the obvious benefit of ultrasonography to reduce maturation failure, regular surveillance 
imaging of dialysis access is not routinely performed in the United States. Because of the 
onerous requirements for high trained technical staff, an interpreting physician, a fully equipped 
and certified vascular laboratory and the time and effort required to undergo formal ultrasound 
examination, responsible resource utilization precludes frequent formal scanning. In fact, 
meeting Medicare criteria for medical necessity for such imaging after the maturation study at 
six weeks requires documentation of quantifiable access malfunction occurring during dialysis or 
major clinical findings such as massive upper extremity swelling. This limitation is 
understandable in light of the economic burden associated with a lengthy Duplex examination of 
hemodialysis access. Ultrasound assessment of dialysis access entails the cost of a dedicated 
vascular laboratory, an ultrasound apparatus and a qualified ultrasound technologist. A full 
examination uses color Doppler imaging, pulsed-wave spectral Doppler imaging, and B-mode 
ultrasound. The patient burden is equally involved, requiring a separate appointment on an 
additional delay at a vascular laboratory that may be distant from the patient’s dialysis center. 
The study yields a comprehensive assessment of the fistula and the potential to diagnose 
conditions ranging from aneurysmal degeneration to medial calcinosis and peripheral ischemia.  
 
Ultrasound surveillance does not require such extensive analysis to benefit maturation and 
thrombosis rates, however. A single variable – volumetric flow – has been shown effective in 
predicting both maturation and fistula thrombosis.(9, 13, 17-20) The potential for regular 
ultrasound surveillance to decrease rates of AV fistula maturation failure and thrombosis does 
not require complete examinations performed by expert ultrasonographers. This study will use a 
FDA-approved system for rapid ultrasound assessment of fistula flow during existing patient 
appointments performed by a clinic nurse, requiring minimal training and equipment. 

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Surveillance using this method, performed by a clinic nurse in the vascular clinic, will enable 
realization of that benefit in a way that significantly reduces costs and improves patient 
outcomes. 
 
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 
 
 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 an FDA-cleared 3D 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: 
• Identifying fistulae at risk for maturation failure 
• Providing key volumetric flow data to guide appropriate intervention for fistula salvage 
• Diagnosing potential issues intraoperatively prior to leaving the OR 
 
 
5.  STUDY OBJECTIVES  
 
Purpose  
Stage 1: 
The primary objective of Stage 1 of the study is to collect data to verify the  
technology’s performance in fistula monitoring. In Stage 1, EchoMark is 
implanted and monitoring is completed post-operatively. EchoSure data is  
then captured in an effort to establish normal ranges of the relevant variables in 
the context of appropriately maturing fistulae and their physiology, whis is 
currently unknown.  
 
Stage 2:  
The purpose of Stage 2 of the study is to evaluate the performance of the  
EchoMark and EchoSure (both FDA approved devices) as an ultrasound-based  
method of monitoring maturation of fistulae. The implant and ultrasound will be 
used as per IFU. The primary purpose of the study is to collect data on patient 
outcomes and assess whether or not the information generated from use of 

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EchoMark and EchoSure can decrease the fistula maturation failure rate and 
improve the patency of fistulas after up to a year. 
 
 
Performance Goals  
 
Stage 1: 
Primary Performance Endpoint:  
• Data collection to verify accuracy 
• Data collection to understand the natural history of flow physiology in 
AV fistulas and classify fistulas that will fail 
 
 
Primary Safety Endpoint: 
• Procedure freedom from Serious Adverse Events (SAEs) during the 
EchoMark implantation procedure and subsequent post-operative 
period 
 
Stage 2: 
Primary Performance Endpoint:  
• Failed fistula maturation rate 
 
 
Secondary Performance Endpoints:  
• Cumulative fistula patency at the end of 1 year 
• Volumetric flow data 
• Vessel caliber 
• Total cost of episode of care 
 
 
Primary Safety Endpoint: 
• Procedure freedom from Serious Adverse Events (SAEs) during the 
EchoMark implantation procedure and subsequent post-operative care. 
 
 
6.   STUDY DESIGN 
This is a prospective, single arm, non-randomized, multi-center observational study to record 
objective data in patients undergoing upper extremity arteriovenous fistula construction with 
autologous tissue for the purpose of eventual hemodialysis access, in whom the EchoMark 
implantable marker is placed at the site of vascular anastomosis and the EchoSure module is 
used to collect ultrasonic data. 
 
The expected duration of this study will be from May 2020 to December 2021. Patients will be 
identified and recruited by the surgeons participating in the study, who will be determined at a 
later date. Patients who have been scheduled for creation of an upper extremity autologous 
arteriovenous fistula creation 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. Participants in the study will have EchoMark devices implanted at the time of 
the surgery. Monitoring of fistulae will be performed in the postoperative period. Patients who 
wish to terminate their participation in the research will no longer receive EchoSure ultrasound 
examinations of their fistula and will revert to the standard monitoring practice of their surgeon.  

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Stage 1: 
Patients will be monitored using the EchoSure ultrasound to collect data. Data 
will be analyzed in an attempt to formulate normative ranges for relevant 
variables such that clear, objective metrics consistent with healthy versus 
pathologic fistula healing are established. 
 
Stage 2: 
Patients will be monitored via EchoSure ultrasound in addition to the standard of 
care currently followed by the surgeon. Decisions will be made by the vascular 
surgeon, using a combination of clinical data and the EchoSure data to determine 
if and when interventions need to be made to prevent failure of fistula maturation. 
We will then calculate the effect of the EchoMark and EchoSure on the rate of 
successful fistula maturation. 
 
With the implantation of any foreign material such as a radiologic marker (EchoMark), there is 
some risk of infection, inflammation or extrusion. Given the biocompatibility data collected by 
the company and the extensive prior use of the material in medicine, the probability of such risk 
is extremely low and has already been evaluated by the FDA during the approval process for 
EchoMark. There is risk that the ultrasound scan may create mild discomfort for the patient on 
the wound site. The likelihood and severity of this risk is low. If the patient begins to exhibit 
signs of infection, inflammation or extrusion, a clinical decision will be made by the team if the 
risk from the implantable device requires removal of the device. In these cases, the implantable 
device will be removed, and the patient will be monitored with conventional methods. 
 
If ultrasound scanning is found to create discomfort to patient that exceeds that of traditional 
monitoring devices such as standard ultrasonography, the patient will be offered the option of 
discontinuation of EchoSure ultrasound scans and be monitored subsequently with conventional 
methods.  
 
Despite the significant benefit of fistula surgery, there remains a significant risk of postoperative 
thrombosis, inappropriate fistula maturation, and continued reliance on prosthetic central 
vascular access for hemodialysis, all of which can cause serious morbidity and even mortality. 
By using this technology, it is possible that impending failure of fistula maturation can be 
detected early enough to salvage the fistula and prevent the impending fistula failure and 
associated morbidity. 
 
Should the patient opt out of the study, they will be monitored with the current standard of care 
within the vascular surgeon’s practice. This includes clinical observation and color Doppler 
ultrasonography per the surgeon’s standard practice.  
 
 
7.  STUDY POPULATION  
 
Number of Patients 
Stage 1:  
Up to sixty (60) patients will be enrolled and both men and women will 

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be eligible for inclusion. The estimated enrollment period is six months and 
patients will be followed until the fistula matures and is suitable for use in dialysis 
or it is ultimately considered non-salvageable by the vascular surgeon. 
 
Stage 2: 
Up to sixty (60) patients will be enrolled and both men and women will be 
eligible for inclusion. The estimated enrollment period is twelve months and 
patients will be followed until then or the decision by the attending surgeon that 
the fistula failure is confirmed, or that monitoring is no longer clinically necessary 
patients will exit the study. 
 
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 ultrasound devices are reusable and may be used in the 
operating suite, a post-operative unit such as the ICU or patient floor, or a typical outpatient 
clinic. When used intraoperatively or in the presence of breached skin, the ultrasound transducer 
should be used with a sterile probe cover. 
Inclusion Criteria  
• Age > 18 years 
• Patients presenting for upper extremity arteriovenous fistula construction with autologous 
tissue for the purpose of eventual hemodialysis access 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.   
 
This study will not target the recruitment of any potentially vulnerable subjects. If vulnerable 
subjects who are educationally or economically impaired present for fistula creation, they will 
not be given the opportunity to participate in the study. 
 
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 EchoSure ultrasound examinations of their 
fistula and their data will be removed from the study. 
 
 

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8:  STATISTICAL ANALYSIS  
Stage 1: 
We will recruit 60 patients for participation in this study who are planning to undergo elective 
construction of upper extremity autogenous hemodialysis access. The minimum sample size of 
45 was determined assuming a 50% successful fistula maturation rate (based on past studies) to 
yield sufficient power to detect a difference in maturation between this cohort and the 
intervention cohort in the next aim. It also accounts for the quantity of patient volumes needed to 
develop a 
 based on our experience with EchoSure. Lastly, this provides 
sufficient power to detect a difference in fistula maturation success based on the flow rate 
(logistic regression power estimation; α = 0.05, β = 0.8, OR 2.5 [from Pr(H0) 0.45 and Pr(H1) = 
0.65]. As a buffer, based on institutional experience with clinical research and subject attrition a 
drop-out rate of 25% has been added to yield a total of 60 patients.  
Using the EchoSure-derived conduit diameter and volumetric flow as observed values and 
Duplex-derived conduit diameter and volumetric flow as accepted values, the accuracy of 
EchoSure will be calculated. Logistic regression will be used to assess the correlation between 
successful maturation and EchoSure-derived values for flow and conduit diameter at two weeks. 
Cut points will be evaluated to establish EchoSure criteria for 
 
. Pearson’s correlation will be performed on both EchoSure-derived and Duplex-
derived values of volumetric flow and conduit diameter to determine correlation between 
EchoSure findings at two weeks and both EchoSure and Duplex findings at six weeks. 
Stage 2: 
For this portion of the study, we will recruit an additional 60 patients planning to undergo 
elective construction of upper extremity autogenous hemodialysis access. Again, the EchoMark 
fiducial marker will be inset at the time of fistula creation. The minimum sample size of 45 (60 
prior to 25% dropout factor) is powered to detect an approximate 25% reduction in all-cause 
fistula failure in the early postoperative period. A χ2 power analysis was performed with α = 
0.05, β = 0.8 and standard-of-care fistula maturation success at 50% based on institutional 
experience and prior literature which ranges from 30-70% and EchoSure early intervention 
success based on the Muray-Cases results which showed a 78% success rate achieved by a novel 
program of pre-maturation ultrasonography and early intervention. 
 

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The nominal-by-interval association coefficient, Eta, will be calculated to determine the 
correlation between successful, unassisted maturation and EchoSure-derived values for flow and 
conduit diameter at two weeks. This will be compared to the similar findings of stage 1 using 
Student’s t-testing and will validate the early maturation criteria derived from there. The 
association coefficient will be calculated to determine the correlation between successful, 
assisted maturation and EchoSure-derived values for flow and conduit diameter immediately 
following intervention. Pearson’s correlation will be performed on both EchoSure-derived and 
Duplex-derived values of volumetric flow and conduit diameter to determine correlation between 
findings immediately following intervention and those at six weeks. 
 
Using χ2 testing between the stage 1 and 2 cohorts, the benefit to maturation success of 
intervention based on early postoperative EchoSure examination will be determined. 
 
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 fistula creation 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 
(IRB), research ethics board (REB) approval, or Ethics Committee (EC) approval. Before 
starting the trial, the investigator provides the 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 

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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. If a 
patient from a vulnerable population presents for a fistula creation procedure, they will not be 
given the option to participate in the study.  
 
Study Enrollment  
Patients will be considered enrolled in the trial once informed consent has been obtained and all 
eligibility criteria confirmed.    
 
 
 
10. STUDY PROCEDURES AND METHODS  
Patients undergoing fistula creation procedures will be identified. The study will be explained to 
these patients and informed consent for participation in the study will be obtained from willing 
patients. A small, FDA-approved tissue marker will be implanted prior to closure of wounds 
following the Instructions for Use on the FDA-approved labelling. 
 
Stage 1: 
The fistula will be assessed with intermittent EchoSure examinations, sometimes 
during routine dialysis visits (maximum 3x/week) to minimize travel. This will 
conclude when the fistula has entirely matured and the patient begins 
hemodialysis via the fistula or when the vascular surgeon declares that the fistula 
has failed despite any and all salvage attempts. 
 
Stage 2: 
Similar to stage 1 but with implementation of the normative values for relevant 
variables that resulted from the data collected in stage 1, with subsequent use of 
the EchoSure flow information in the vascular surgeon’s decision making. This 
stage will also conclude when a year has passed and the fistula is functioning or 
when the vascular surgeon declares that the fistula has failed despite any and all 
salvage attempts or that monitoring is no longer clinically necessary. 
 
 

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DATA QUALITY ASSURANCE 
Case Report Forms specific to the 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.   
Only clinicians involved in the study will have access to the data. All data will be collected 
electronically through the medical record system. Access to source documents will be per 
respective EHR guidelines on computers that are encrypted and password protected. HIPAA 
compliance guidelines will be used at all time.  Human subjects will not be directly identifiable, 
but only identifiable in the study database through identifying information (Hospital, MRN). The 
study data will be saved on a HIPAA compliant secure cloud service. 
 
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.  
12:  ETHICS 
IRB approval will be sought from CPHS (Committee For the Protection of Human Subjects) for 
this study.   
An individual knowledgeable about the study, likely a listed member of the study personnel, will 
obtain consent in person from individuals involved in this study. Consent will likely be obtained 
in clinic or in the pre-operative area prior to the initiation of anesthesia. The 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. Participation will be fully optional. 

Version: May 19, 2019 
 
Page 19 of 19 
 
13:  REFERENCES 
 
14:  ATTACHMENTS 
1. Consent Document 
 
 
14.1:  CONSENT DOCUMENT 
Attached as separate document