Effect of Amplifi Vein Dilation System Treatment on Radiocephalic AVF Maturation-3
Phase: NA
Conditions: End-Stage Renal Disease Requiring Haemodialysis
Sponsor: Amplifi Vascular, Inc.

 
Clinical Protocol 
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Revision: 
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Effective Date: 
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Amplifi Vascular 
CONFIDENTIAL 
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Clinical Study Protocol 
 
Effect of AmplifiTM Vein Dilation System Treatment on 
Radiocephalic AVF Maturation-3 
 
 
 
 
Short Title: 
 
FIH-3 
 
Study Sponsor: 
Amplifi Vascular, Inc. 
3965 W 83rd Street, #300 
Prairie Village, KS 66208-5308 
 
 
Study Contact: 
Erdie De Peralta, VP Regulatory and Clinical Affairs 
Amplifi Vascular 
telephone: 978.408.0949 
email: edeperalta@amplifivascular.com 
 
 
 
 

 
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Table of Contents 
Table of Contents .......................................................................................................... 2 
List of Appendices ........................................................................................................ 5 
List of Tables ................................................................................................................. 5 
List of Abbreviations ..................................................................................................... 6 
Revision History ............................................................................................................ 7 
Protocol Signature Page ............................................................................................... 8 
Contact Information ...................................................................................................... 9 
1.0 Protocol Synopsis ................................................................................................. 10 
2.0 Introduction to Amplifi System ............................................................................ 16 
2.1 Background: End Stage Kidney Disease, Hemodialysis, and Vascular Access .......16 
2.2 Amplifi System and Intended Use ................................................................................19 
2.3 Product Rationale ..........................................................................................................21 
2.4 Proposed Indication for Use .........................................................................................22 
3.0 Prior Bench Testing and First-in-Human Clinical Study .................................... 22 
3.1 Performance and Safety Testing of Amplifi System ...................................................22 
3.2 First-In-Human Study ....................................................................................................23 
3.2.1 Device Performance Outcome ................................................................................................... 23 
3.2.2  Treatment Duration ................................................................................................................... 24 
3.2.3 Safety Outcome ......................................................................................................................... 25 
3.2.3 Summary .................................................................................................................................... 26 
4.0 Study Design ......................................................................................................... 27 
4.1 Study Objectives ...........................................................................................................27 
4.2 Study Population ...........................................................................................................27 
4.3 Study Design .................................................................................................................27 
4.4 Study Site and EC / EC ..................................................................................................28 
4.5 Primary Clinical Measures ............................................................................................28 
4.6 Inclusion and Exclusion Criteria ..................................................................................29 
6.0 Study Enrollment, Informed Consent and Subject Withdrawal ......................... 31 
6.1 Enrollment ......................................................................................................................31 
6.1.1 Informed Consent ....................................................................................................................... 31 
6.1.2 Enrollment and Study Exit .......................................................................................................... 31 
6.2 Subject Withdrawal........................................................................................................32 
7.0 Procedures and Surgeries .................................................................................... 32 
7.1 Amplifi System Placement ............................................................................................33 
7.2 Amplifi System Treatment.............................................................................................33 

 
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7.3 Amplifi System Removal ...............................................................................................33 
7.4 Study AVF Creation .......................................................................................................33 
7.5 Pump Malfunction and Stoppage .................................................................................34 
8.0 Study Assessments and Follow Up ..................................................................... 35 
8.1 Duplex Ultrasonography ...............................................................................................37 
8.1.1 Baseline Screening Ultrasonography ......................................................................................... 37 
8.1.2 Ultrasonography During Amplifi System Treatment ................................................................... 38 
8.1.3 Ultrasonography at the End of Amplifi System Treatment ......................................................... 38 
8.1.4 Ultrasonography of AVF ............................................................................................................. 38 
8.2 Demographics and Medical History .............................................................................39 
8.3 Clinical Assessments and Physical Exams .................................................................39 
8.4 Laboratory Assessments ..............................................................................................39 
8.5 Contrast Venography ....................................................................................................39 
8.5.1 Venography Prior to Amplifi System Placement ........................................................................ 39 
8.5.2 Angiography of the Inflow Catheter During Amplifi System Placement ..................................... 40 
8.5.3 Venography During Amplifi System Treatment .......................................................................... 40 
8.5.4 Angiography of the Inflow Catheter During Amplifi System Treatment ..................................... 40 
8.5.5 Venography at the End of the Amplifi System Treatment Period .............................................. 41 
8.5.6 Angiography of the Inflow Catheter at the End of the Amplifi System Treatment Period .......... 41 
8.6 Concomitant Medications .............................................................................................41 
9.0 Training .................................................................................................................. 41 
9.1 Investigator Training .....................................................................................................41 
10.0 Study Oversight, Monitoring, and Quality Control ........................................... 42 
10.1 Investigator Selection .................................................................................................42 
10.2 Site Selection ...............................................................................................................42 
10.3 Pre-Enrollment Site Visit .............................................................................................42 
10.4 Monitoring and Periodic Monitoring Visits ................................................................42 
10.5 Case Report Forms......................................................................................................43 
10.6 Maintenance of Source Documentation .....................................................................43 
10.7 Maintenance of Study Documentation and Retention of Records ...........................43 
10.8 Protocol Amendments ................................................................................................45 
10.9 Protocol Deviations and Investigator and Site Suspension and Termination .........45 
10.10 Study Termination Activities ....................................................................................46 
11.0 Ethical and Regulatory Requirements ............................................................... 46 
11.1 Ethical Requirements ..................................................................................................46 
11.2 EC and Other Regulatory Requirements ....................................................................46 
11.4 Vulnerable Populations ...............................................................................................46 
11.5 Confidentiality ..............................................................................................................46 

 
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12.0 Adverse Events and Adverse Device Effects.................................................... 46 
12.1 Definitions ....................................................................................................................47 
12.1.1 Adverse Events ........................................................................................................................ 47 
12.2.2 Device Adverse Events ............................................................................................................ 47 
12.2.3 Serious Adverse Events ........................................................................................................... 47 
12.2.4 Serious Device Adverse Effects ............................................................................................... 48 
12.2.5 Unanticipated Serious Adverse Device Effect ......................................................................... 48 
12.2.6 Potential Adverse Events and Serious Adverse Events .......................................................... 49 
12.2 Classification of Adverse Events ...............................................................................50 
12.2. Grading of AEs ........................................................................................................................... 50 
12.2.2 Relational Criteria ..................................................................................................................... 50 
12.3 Amplifi System Unplanned Stoppages, Malfunctions, and Potential Device 
Deficiencies .........................................................................................................................50 
12.10 Reporting ...................................................................................................................51 
12.10.1 Reporting of AEs .................................................................................................................... 51 
12.10.2 Reporting of ADEs ................................................................................................................. 51 
12.10.3 Reporting of SAEs .................................................................................................................. 51 
12.10.4 Reporting of SADEs ............................................................................................................... 52 
12.10.5 Reporting of USADEs ............................................................................................................ 52 
12.10.6 Reporting of Amplifi System Unplanned Stoppages and Malfunctions ................................. 52 
14.0 Data Analysis and Statistical Considerations .................................................. 53 
14.1 Study Size Calculation ................................................................................................53 
14.2 Statistical Methods ......................................................................................................53 
14.2.1 Demographic and Baseline Characteristics ............................................................................. 53 
14.2.2 Analysis of Effectiveness Measures ........................................................................................ 53 
14.2.3 Analysis of Safety Measures .................................................................................................... 54 
14.2.4 Handling of Missing Data ......................................................................................................... 54 
15.0 Study Responsibilities ........................................................................................ 54 
15.1 Sponsor Responsibilities ............................................................................................54 
15.2 Investigator Responsibilities ......................................................................................55 
15.3 Site Personnel Responsibilities ..................................................................................57 
15.4 Site Responsibilities ....................................................................................................58 
15.5 Independent Safety Board (ISB) and Medical Monitor (MM) Responsibilities .........59 
16.0 Risks and Benefits .............................................................................................. 59 
16.1 Background .................................................................................................................59 
16.2 Review of Literature ....................................................................................................60 
16.3 Benefit Analysis ...........................................................................................................60 
16.4 Risk/Benefit Analysis ..................................................................................................61 
16.5 Risk Mitigation .............................................................................................................61 
17.0 Miscellaneous ...................................................................................................... 61 
17.1 Publication Policy ........................................................................................................61 

 
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18.0 References ........................................................................................................... 62 
Appendix 1: Definitions .............................................................................................. 64 
Appendix 2: Literature Review for Safety ................................................................. 70 
 
List of Appendices 
Appendix 1: 
Definitions 
Appendix 2: 
Literature Review 
List of Tables 
Table 1: Performance and Safety Testing .................................................................................22 
Table 2: Adverse Events for FIH1 and FIH2 ..............................................................................25 
Table 3: Study Assessments and Actions .................................................................................35 
Table 4: Time Windows for Study Assessments ........................................................................36 
Table 5: Publications Relevant to Safety and Effectiveness - Catheters ....................................70 
Table 6: Publications Relevant to Safety and Effectiveness – Extracorporeal Blood Pumps .....73 
List of Figures 
Figure 1: Example of a Distal Forearm Radiocephalic AVF .......................................................17 
Figure 2: Human Fistula Maturation Study Data ........................................................................18 
Figure 3: Histogram reproduced from Dageforde, et al ..............................................................19 
Figure 4: Amplifi System in Place During Treatment .................................................................20 
Figure 5: Cephalic Vein Diameter Measurements in FIH1 (left) and FIH2 (right) .......................24 
Figure 6: Blood Flow Measurements in FIH1 (left) and FIH2 (right) ...........................................24 
Figure 7: FIH2 Treatment Duration ............................................................................................25 
 
 

 
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List of Abbreviations 
ACT  ................. Activated Clotting Time 
ADE .................. Adverse Device Effect 
AE ..................... Adverse Event 
AVF ................... Arteriovenous Fistula 
AVG .................. Arteriovenous Graft 
CBC .................. Complete Blood Count 
CKD .................. Chronic Kidney Disease 
CRF  ................. Case Report Form 
CSA .................. Clinical Study Agreement 
ECMO ............... Extracorporeal Membrane Oxygenation 
EDC .................. Electronic Data Capture 
eNOS ................ Endothelial Nitric Oxide Synthase 
ESRD ................ End Stage Kidney Disease 
FIH .................... First-in-Human 
FDA .................. US Food and Drug Administration 
FMEA ................ Failure Mode and Effect Analysis 
GCP .................. Good Clinical Practice 
GUI ................... Graphical User Interface 
ICF .................... Informed Consent Form 
IFU .................... Instructions For Use 
EC ..................... Independent Ethics Committee 
KDOQI .............. Kidney Disease Outcomes Quality Initiative 
LDH .................. Lactate Dehydrogenase 
PICC ................. Peripherally Inserted Central Catheter 
pSLOT .............. Piggyback Straight-Line On-Lay Technique 
RPM .................. Revolutions Per Minute 
SADE ................ Serious Adverse Device Effect 
SAE .................. Serious Adverse Event 
USADE ............. Unanticipated Serious Adverse Device Effect 
VNH .................. Venous Neointimal Hyperplasia 
WSS ................. Wall Shear Stress 
 
 

 
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Revision History 
Revision 
Date 
Description of Changes 
Originator 
A 
01/24/2023 
Initial Release 
E. De Peralta 
B 
12/19/2023 
Updated study design for nonrandomized 
inpatient cohort 
E. De Peralta 
C 
01/28/25 
Updated study design for reduced treatment 
duration; change in vein diameter inclusion 
criteria to 1.7 mm-3.3 mm; update on criteria for 
AVF creation; additional safety outcome 
measures; clarification on Definition of terms; 
change the Title from Amplifi-1 to FIH-3; Identified 
CRO and Investigation Site; overall update for 
consistency 
E. De Peralta 
D 
02/06/25 
Clarification on the outcome measures to 
categorize some safety outcome measures into 
technical performance measures. Also, added 
definition of treatment/device success in the 
Definition of Terms section. 
E. De Peralta 
 
 

 
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Protocol Signature Page 
I, the undersigned Investigator(s), have read and understood the terms of the Protocol. 
I agree to perform and conduct the Study as described in the Protocol and in 
accordance with the ICH/GCP Guidelines and 21 CFR 812. 
 
 
 
  Principal Investigator’s Signature 
Date 
 
 
 
  Co-investigator’s Signature 
Date 
 
 
 
  Co-investigator’s Signature 
Date 
 
 
 
  Co-investigator’s Signature 
Date 
 
 
 
  Sponsor’s Signature 
Date 
 
 
 

 
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Contact Information 
 
The sponsor of this Clinical Study is as follows: 
 
 
Sponsor Information 
Erdie De Peralta 
 
 
Amplifi Vascular, Inc. 
3965 W 83rd Street, #300 
Prairie Village, KS 66208-5308 
978-408-0949  
 
 
 
 
 
edeperalta@amplifivascular.com 
  
 
Data Management:   
MMC Medical International Services 430 Forest Ave.  
 
 
 
 
 
Laguna Beach, CA 92651 
 
Investigational Site   
Sanatorio Italiano El Dorado 284 Casa Zanotti 
 
 
 
 
Asuncion, Paraguay 1849 
 
 
 
 
 

 
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1.0 Protocol Synopsis 
INVESTIGATIONAL DEVICE 
AmplifiTM Vein Dilation System (“Amplifi System”) 
STUDY TITLE 
Effect of AmplifiTM Vein Dilation System Treatment on 
Radiocephalic AVF Maturation- (FIH3) 
STUDY DESCRIPTION 
Prospective, nonrandomized, single-arm, open-label clinical 
study (the “Study”) in patients with end-stage renal disease 
(ESRD) receiving maintenance hemodialysis using a catheter for 
vascular access (“Subjects”). Patients who are indicated for 
creation of a forearm radiocephalic AVF based on an 
Investigator’s standard practice and who have a forearm cephalic 
vein diameter of ≥ 1.7 mm and ≤ 3.2 mm at the proposed Study 
AVF creation site will be enrolled in the study. 
 
The Subjects will be treated in an inpatient (hospital) setting and 
will receive Amplifi System treatment and undergo subsequent 
AVF creation (a “Study AVF”) immediately after treatment. Amplifi 
System removal immediately followed by AVF creation will be 
performed when Subject had:  
• Amplifi treatment for ≥ 48 hours duration and that 
cephalic vein is suitable for AVF creation determined by 
physician (e.g., vein diameter ≥ 3.3 mm as defined in 
Dageforde17 as Quartile 3 and baseline diameter increased 
≥ 50%); or  
• Amplifi treatment could be extended up to 60 hours (± 
12hrs) if the cephalic vein was not determined to be 
adequate by the investigator.  
 
Data will be collected at screening, baseline, during Amplifi 
System implantation, during Amplifi System treatment, during 
Amplifi System removal and AVF creation, and follow-up patient 
visits at 1, 2 and 6 weeks after AVF creation. 
OBJECTIVES 
The Amplifi System will be assessed and analyzed for 
effectiveness to demonstrate similar outcome from the earlier 
First-in-Human Studies with shorter treatment duration. Safety 
analysis will be performed to confirm that major adverse events 
will be in an acceptable range. 
INDICATIONS FOR USE 
The Amplifi Vein Dilation System is a temporary, ambulatory, 
extracorporeal blood pump system designed to dilate upper 
extremity veins in patients with a forearm cephalic vein diameter 
of > 1.7 mm and < 3.2 mm prior to forearm arteriovenous fistula 
creation to increase vein diameter and improve forearm 
arteriovenous fistula maturation. 

 
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BACKGROUND  
Arteriovenous fistula (AVF) is the preferred form of vascular 
access for hemodialysis. AVF use has demonstrated lower rates 
of associated morbidity, mortality, contributing to lower overall cost 
of care1,4. Forearm AVF is widely viewed as the preferred location. 
The National Kidney Foundation recommends a distal to proximal 
approach to AVF creation citing ease of creation, low complication 
rates, and preservation of more proximal access options, yet only 
32% of hemodialysis patients in the US use a forearm AVF for 
vascular access2-4 and more than 80% of forearm AVFs fail to 
mature within 6 weeks of creation, with many abandoned prior to 
routine use4-7.  
 
In studies performed to evaluate likelihood of AVF maturation, 
initial vein diameter was identified as one of the strongest 
predictors of AVF maturation success11-13. In the HFM study14, 
92% of forearm AVFs failed to mature 2 weeks (84% @ 6 weeks) 
after AVF creation based on KDQOI criteria. The HFM study 
suggested that the probability of AVF maturation increases with 
increasing initial vein diameter at AVF creation. 
 
A retrospective study of 158 subjects undergoing brachiobasilic or 
brachiocephalic AVF showed increased minimum vein diameter 
was associated with an increased likelihood of fistula maturation 
and secondary patency15. In this study, the authors reported that 
hazard ratios (HRs) indicate that for each 1.0-mm increase in 
Minimum Vein Diameter MVD, there was approximately a 45% 
reduction in the risk for failure of maturation (HR, 0.555; P = .005) 
and a 36% reduction in the risk of fistula failure (HR, 0.639; P = 
.001). The authors stated that vein diameter is the only clinical or 
demographic factor associated with both AVF maturation and 
long-term patency in their study. 
 
In a first-in-human (FIH) clinical study with a total of n=10 
Subjects, Amplifi Vascular, Inc. (“Sponsor”) demonstrated that 
treatment with the Amplifi System increased the diameter of the 
mid forearm cephalic vein by an average of 150% prior to AVF 
creation, and that AVFs created with treated forearm cephalic 
veins matured rapidly and demonstrated high maturation rates. 
PRODUCT RATIONALE 
The Amplifi System is designed to deliver continuous, non-
pulsatile, venous blood to upper extremity veins to stimulate vein 
wall remodeling and persistent dilation. The Amplifi System 
capable of increasing vein diameter  prior to fistula creation  would 
increase the prevalence of forearm AVFs in patients who are not 
suitable to receive AVF due to small vein diameter. The Amplifi 
system would also improve AVF maturation through AVF creation 
with larger veins that mature rapidly, reduce catheter contact time 
and prolong AVF patency.  

 
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PATIENT POPULATION 
Patients with end-stage renal disease (ESRD) and are currently 
receiving maintenance hemodialysis via a tunneled, cuffed 
hemodialysis catheter indicated for forearm radiocephalic AVF 
creation based on an Investigator’s standard practice and have a 
wrist or distal forearm cephalic vein diameter of  ≥ 1.7 mm and ≤ 
3.2 mm at the proposed Study AVF creation.  
EFFECTIVENESS 
MEASURES 
Percent change in cephalic vein diameter and blood flow in 
the middle third of the arm as measured by ultrasonography 
[Timeframe: from baseline, during Amplifi System treatment 
(minimum daily), and prior to Amplifi System removal and AVF 
creation] 
 
Mean vein diameter of the cephalic vein and blood flow of 
brachial artery in the middle third of the forearm as measured by 
ultrasonography [Timeframe: 1, 2and 6 weeks post AVF creation] 
 
Forearm AVF maturation success at 2 and 6 weeks post-AVF 
creation  [Timeframe: 2, 6 WK post AVF creation] 
 
Percentage of subjects who experience an increase in the 
cephalic vein diameter of ≥2.7 mm from their baseline 
measurement, or an increase of >1 mm from baseline, 
following treatment with the Amplifi System. [Timeframe: prior 
to removal of the Amplifi System and creation of the AVF]. 
SAFETY MEASURES 
Rate of Occurrence of Major Device-Related Adverse Events 
defined as: [Timeframe: from device implantation and up to 30 
days from device removal and AVF creation] 
• 
Amplifi System-related death; 
• 
Amplifi System-related major bleeding, major 
pneumothorax, major air embolism, major thrombosis, 
major thromboembolism, major hemolysis, or major 
thrombocytopenia; localized infection 
• 
Amplifi System-related re-hospitalization or prolonged 
hospitalization; 
• 
Amplifi System-related major surgery or major 
interventional procedure; or 
• 
any Amplifi System-related complication determined to be 
an Amplifi System-related major complication by both an 
Investigator and the Medical Monitor.  

 
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Rate of Occurrence of Cannulation-related Complications 
[Timeframe: from AVF creation through end of follow-up period] 
 
 
 
EXPLORATORY 
TECHNICAL 
PERFORMANCE 
MEASURES 
 
Rate of Occurrence of Amplifi System Treatment Failure 
[Timeframe: from device implantation through less than required 
minimum treatment hours of duration (e.g., 48 hours] 
 
Rate of Occurrence of Amplifi System component 
replacement [Timeframe: from device implantation through 
device removal and AVF creation] 
 
Rate of Occurrence of Pump Stoppages and Device 
Malfunction [Timeframe: from device implantation through device 
removal and AVF creation] 
 
NUMBER OF SUBJECTS 
Up to n=10 Subjects, all Treatment Subjects 
STUDY DURATION 
All Subjects will be followed for 1, 2 and 6-weeks post AVF 
creation or to a censoring event (including return of kidney 
function, kidney transplant, death, loss to follow-up, or Study end) 
whichever occurs first. 
INCLUSION CRITERIA 
1. Age ≥ 18 years 
2. Indicated for wrist or distal forearm radiocephalic AVF creation 
based on Investigator’s standard practice  
3. ESRD currently receiving maintenance hemodialysis via a 
tunneled, cuffed hemodialysis catheter 
4. Baseline wrist or distal forearm cephalic vein diameter of > 1.7 
mm and < 3.2 mm at the proposed Study AVF creation site, 
wherein the wrist or forearm cephalic vein at the proposed 
Study AVF creation site is suitable for Amplifi Distal Outflow 
Catheter placement and Amplifi System treatment, including: 

 
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1. > 1.7 mm to < 3.2 mm diameter of the wrist or forearm 
cephalic vein at the proposed Study AVF creation 
2. patency and continuity of blood flow from the proposed 
Study AVF creation site centrally to the upper arm at 
the elbow through to at least one or more of: 1) the 
upper arm cephalic vein; 2) the median cubital vein to 
the upper arm basilic system; or 3) the perforator vein to 
the deep venous system; and 
3. no occlusion or stenosis > 50% along the course of the 
forearm cephalic vein and at least one upper arm 
venous outflow up to the subclavian vein, as 
determined by duplex ultrasonography 
5. Estimated forearm hemodialysis needle cannulation zone 
length > 18 cm after creation of the proposed Study AVF   
6. At least one patent internal jugular vein suitable for Amplifi 
Inflow Catheter insertion 
7. Subject has voluntarily signed written informed consent  
EXCLUSION CRITERIA 
 
1. Known allergy to Amplifi System components (polyurethane, 
nitinol), iodinated contrast agents, heparin, or apixaban 
2. Known or suspected active infection at the proposed time of 
Amplifi System placement 
3. Known bleeding diathesis, including from uncorrected 
coagulopathy  
4. Known thrombophilia, requiring treatment 
5. Hb <10 gm/dL 
6. Platelet level < 100,000 /mm3 
7. Need for continued treatment with anti-platelet agents or other 
anticoagulants (other than apixaban) during the Amplifi 
System treatment period 
8. Known history of patent foramen ovale > 2 mm 
9. History of recent intracranial or gastrointestinal bleeding 
10. Documented recent central venous or right atrial thrombus 
11. Known presence or recent history of intracranial or 
gastrointestinal bleeding or presence of underlying conditions 
that would predispose to intracranial or internal bleeding. 
12. History of ipsilateral central venous occlusion, stenosis > 50%, 
angioplasty, or stent placement 
13. Pregnancy, lactation, or plans to become pregnant during the 
Study 

 
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14. Unwillingness or inability to comply with procedures specified 
in the Protocol, or difficulty or inability to return for follow-up 
visits as specified by the Protocol 
15. Participation in any other investigational drug or medical 
device study that has not completed primary endpoint 
evaluation or clinically interferes with the endpoints from the 
Study, or planned future participation in such studies prior to 
the completion of the Study 
STUDY FOLLOW-UP 
INTERVALS 
• 
Screening 
• 
Baseline 
• 
Amplifi System placement 
• 
Amplifi System treatment 
• 
Amplifi System removal and creation of Study AVF  
• 
Discharge after Amplifi System removal and creation of Study 
AVF 
• 
1, 2 and 6 weeks after creation of Study AVF 
STATISTICAL 
CONSIDERATION 
General descriptive statistics will be used for the analysis of data 
 
 

 
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2.0 Introduction to Amplifi System 
2.1 Background: End Stage Kidney Disease, Hemodialysis, and 
Vascular Access  
 
Kidney function is essential to sustain life. Patients with end-stage kidney disease (ESRD) have 
an irreversible loss of kidney function and need some form of kidney replacement therapy for 
survival. The preferred form of kidney replacement therapy is kidney transplantation; however, 
the availability of transplant organs is limited. Hemodialysis remains the most prevalent kidney 
replacement therapy in the US1 and worldwide.  
 
There are more than 550,000 patients in the US on hemodialysis1, a population projected to 
surpass one million by 20302. During hemodialysis, blood is removed from a patient’s body, 
filtered through a synthetic dialyzer membrane, and returned to the body. Prior to initiating 
hemodialysis, physicians must create a vascular access site to provide access to a patient’s 
circulatory system for blood removal and return. The main types of vascular access sites, 
includes each requiring a surgery or interventional procedure for site creation: 
• 
Hemodialysis catheter 
• 
Arteriovenous graft (AVG) 
• 
Arteriovenous fistula (AVF) 
 
An AVF is the preferred type of access and is created by directly connecting an artery to a vein. 
AVFs are usually created surgically, but percutaneous AVFs are an option for some patients. 
Common locations for AVF placement include the wrist/forearm, and upper arm. The radial and 
brachial arteries and the cephalic and basilic veins are most often used to make AVFs. After 
creation, the inflow arteries and outflow veins of AVFs are subjected to marked changes in 
hemodynamic stress that induce dilation and increases in blood flow, a process known as 
“maturation”.  
 
There are several widely recognized thresholds for AVF outflow vein diameter and blood flow 
that are required to enable routine needle cannulation and to ensure adequate delivery of blood 
to a hemodialysis machine and back to the patient for hemodialysis treatments. AVF maturation 
usually requires several weeks and may take several months to a year, often resulting in long 
catheter contact times for patients and increasing their risk of catheter-related blood stream 
infections, which can lead to sepsis and death. A depiction of a distal forearm radiocephalic AVF 
is shown in  Figure 1 , with needle cannulation of the outflow vein to remove and return blood 
for hemodialysis.   
 

 
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Figure 1: Example of a Distal Forearm Radiocephalic AVF 
 
Survival of hemodialysis patients is directly related to adequacy of their hemodialysis which in 
turn, is dependent on the availability and function of their vascular access. Vascular access 
failure is common, resulting in interruptions in hemodialysis care and leading to more than two 
million surgeries and interventional procedures each year in the US alone, with an estimated 
$2.8 billion in annual Medicare costs3. Vascular access complications are also common, often 
resulting in hospitalization and contributing to the high mortality rates seen in the ESRD 
population.  
 
Patients using an AVF for hemodialysis have lower rates of morbidity, mortality, and the overall 
cost of care4 when compared with other forms of vascular access for hemodialysis. The National 
Kidney Foundation recommends a distal to proximal approach to AVF creation for preservation 
of more proximal access options for later use . However, prevalence of wrist and forearm AVFs 
is low, especially in the US. Many ESRD patients are unsuitable for AVF surgery 5,6 (especially 
in the forearm) primarily due to inadequate vein diameter. For those patients that are suitable, 
maturation failure rates are high, up to 84% at 6 weeks in some studies6-9.  The high rate of 
maturation failure of forearm AVFs has led to a practice of creating upper arm AVF as an earlier 
option for many patients10-12. 
 
In studies performed to evaluate likelihood of AVF maturation, initial vein diameter was identified 
as one of the strongest predictors of AVF maturation13-15. These findings were corroborated by 
the Hemodialysis Fistula Maturation Study conducted by the National Institute of Diabetes and 
Digestive and Kidney Diseases of the National Institute of Health which showed the probability 
of AVF maturation increases with increasing initial vein diameter and blood flow16. As shown 
below, Figure 2 from the Hemodialysis Fistula Maturation Study shows the estimated probability 
that patients will meet KDOQI anatomic and physiologic AVF maturation criteria based on 1-day 
(dashed curves) and 2-week (solid curves) AVF outflow vein diameter and blood flow. Shown 
are the predicted probabilities that AVF maturation will be reached at 6 weeks for different 1-day 
(dashed curves) or 2-week (solid curves) outflow vein diameters (horizontal axis) and AVF blood 
flow with the black, blue, and red curves representing AVF blood flows of 250, 500, and 1000 
mL/min, respectively. The curves were fit by using logistic regression with cubic splines for both 

 
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AVF blood flow and outflow vein diameters. As shown, larger AVF outflow vein diameter and 
higher initial AVF blood flow are positively correlated with a greater probability of achieving AVF 
maturation.  
 
 
Figure 2: Human Fistula Maturation Study Data 
 
A retrospective study of 158 subjects undergoing brachiobasilic or brachiocephalic AVF showed 
increased minimum vein diameter was associated with decreased risk of failure to mature, 
which is synonymous with an increased likelihood of fistula maturation and secondary 
patency17. The authors assigned 25th, 50th, and 75th percentile rank values to statistically 
define minimum vein diameter (MVD) quartiles to the population. As reported by the authors, 
each patient’s MVD was classified as being within the first, second, third, or fourth quartile. 
Univariate Kaplan-Meier survival analysis with log-rank tests was used to determine whether 
preoperative MVD quartile was associated with AVF maturation and long-term patency. 
 
The results indicated that vein diameter data were normally distributed with a mean of 3.4 ± 1.1 
mm (see Figure 3). MVD quartiles were defined as:  
• 
Quartile 1: < 2.7 mm  
• 
Quartile 2: 2.7 to 3.2 mm 
• 
Quartile 3: 3.3 to 4.1 mm 
• 
Quartile 4: > 4.1 mm 
 

 
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Figure 3: Histogram reproduced from Dageforde, et al 
 
The Kaplan-Meier estimates of fistula maturation were reported as 63%, 79%, 90%, and 90% 
for the quartiles.  
 
The authors report that hazard ratios (HRs) indicate that for each 1.0-mm increase in MVD, 
there was approximately a 45% reduction in the risk for failure of maturation (HR, 0.555; P = 
.005) and a 36% reduction in the risk of fistula failure (HR, 0.639; P = .001). Quartile 3 had 
significantly greater likelihood of fistula maturation than Quartile 1 (P = 0.028), with Quartile 3 
and Quartile 4 both having fistula maturation of 90%. The authors stated that vein diameter is 
the only clinical or demographic factor associated with both AVF maturation and long-term 
patency in their study. 
 
2.2 Amplifi System and Intended Use 
 
The Amplifi System is designed to rapidly dilate and remodel upper extremity veins prior to AVF 
creation by delivering continuous, non-pulsatile venous blood flow to upper extremity veins and 
providing sustained increases in vein wall shear stress (WSS) during the  treatment period.  
 
The Amplifi System comprises of the following main components:  
• 
an extracorporeal blood pump with an integrated cable (“Pump”) to pump blood; 
• 
a catheter to convey blood from the central venous circulation to the Pump (“Inflow 
Catheter”) 
• 
a catheter assembly to convey blood from the Pump to upper extremity veins) 
(comprising a “Proximal Outflow Catheter” joined to a “Distal Outflow Catheter”); 

 
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• 
two access ports to enable flushing of the Amplifi System and the injection of 
radiographic contrast (“Access Ports”); 
• 
a blood flow sensor with an integrated cable (“Blood Flow Sensor”); and 
• 
a controller (“Controller”) to provide power to the Pump and control Pump function.  
  
A complete version of the Amplifi System on a patient is shown in Figure 4 with the front flap of 
the Patient Vest open. Patients can carry the Controller from place-to-place, allowing them to 
carry on with activities of daily living during treatment while in the hospital.  
 
Figure 4: Amplifi System in Place During Treatment 
 
The Amplifi System is designed for placement by trained physicians using standard 
percutaneous, minimally invasive techniques. The Inflow Catheter tip is inserted into an internal 
jugular vein and advanced under fluoroscopic guidance to the right atrium. The proximal portion 
of the Inflow Catheter is tunneled under the skin of the chest for a short distance to provide 
resistance to infection using a custom Inflow Catheter Tunneler provided with the Inflow 
Catheter. The proximal end of the Inflow Catheter can be trimmed to the appropriate length and 

 
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attached to the Inflow Access Port via a quick-connect (“Screw Lock”) fitting. The Distal Outflow 
Catheter tip is inserted into a vein in the upper extremity, with a taper to facilitate easy vein 
insertion. The Distal Outflow Catheter is joined to the Proximal Outflow Catheter using a 
connector (“Inline Connector”) and Screw Lock fittings. The proximal end of the Proximal 
Outflow Catheter can be trimmed to the appropriate length and attached to the Outflow Access 
Port via a Screw Lock fitting. During placement of the Amplifi System, the Pump is connected to 
the Controller via the integrated Pump cable. A control algorithm in the Controller automatically 
increases the speed of the Pump to maintain an elevated WSS in the cephalic vein as the 
treatment progresses and the cephalic vein dilates. During placement of the Amplifi System, the 
Blood Flow Sensor is connected to the Pump via the integrated Blood Flow Sensor cable. 
 
Additional details of the Amplifi System can be found in the Investigator’s Brochure. 
2.3 Product Rationale  
 
KDOQI guidelines suggest wrist and distal forearm AVF is the best first option for vascular 
access, if a patient is expected to need hemodialysis for at least a year. However, the 
prevalence of  forearm AVF is low in the US and the failure of forearm AVFs to mature often 
results in patients using hemodialysis catheters, AVGs, and upper arm AVF. 
 
The Amplifi System dilates veins by persistently increasing WSS in treated veins and inducing 
vein wall remodeling through the well understood process of flow-mediated dilation where rapid 
blood flow results in elevated WSS and nitric oxide (eNOS) release from endothelial cells, 
leading to vascular smooth muscle cell relaxation. If rapid blood flow is sustained for a period of 
days to weeks, there is remodeling of the vein wall that is characterized by elastin and collagen 
fragmentation, endothelial and smooth muscle cell proliferation, and a persistent increase in 
diameter18.   
The use of the Amplifi System to dilate veins prior to AVF creation could provide the following 
benefits for patients: 
• 
Rapid, robust, and reliable vein dilation – due to the controlled delivery of high 
flow, non-pulsatile venous blood to the treated vein, and better control of WSS 
during the vein maturation period when compared with conventional AVF 
creation. 
• 
Improved suitability for AVF creation – enabling AVF creation in patients who 
are not suitable to receive an AVF due to small vein diameter, especially in the 
forearm. 
• 
Improved AVF maturation – through AVF creation with larger veins, which has 
been shown to correlate with improved AVF maturation, and also from high WSS 
in the AVF inflow artery after connection to a large, low resistance, Amplifi 
System-treated vein, which could stimulate faster and greater outward 
remodeling of the AVF inflow artery and result in higher AVF blood flows. 
• 
Reduced time to AVF maturation and reduced catheter contact time – by 
creating AVFs with large veins that mature rapidly and allow for early catheter 
removal.  
• 
Prolonged AVF patency – by creating AVFs with higher blood flows (that are 
resistant to thrombosis) and larger outflow veins (that are more resistant to 

 
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stenosis formation). 
• 
Early identification and treatment or exclusion of vein segments with pre-
existing disease – by identifying vein segments with hypertrophic valves or 
fibrosis that do not dilate in response to elevated WSS and treating them with 
angioplasty immediately prior to AVF creation or excluding them from the AVF 
circuit. This could provide an opportunity to address pre-existing outflow vein 
problems that would have otherwise gone undetected at the time of AVF creation 
and could impair AVF maturation. 
2.4 Proposed Indication for Use  
The Amplifi Vein Dilation System is a temporary, ambulatory, extracorporeal blood pump system 
designed to dilate upper extremity veins in patients with a wrist or forearm cephalic vein 
diameter of > 1.7 and < 3.2 mm prior to wrist or forearm arteriovenous fistula creation to 
improve wrist or forearm arteriovenous fistula maturation. 
3.0 Prior Bench Testing and First-in-Human Clinical Study 
3.1 Performance and Safety Testing of Amplifi System 
Verification and validation testing for the Amplifi System was conducted to ensure design 
outputs meet defined design inputs. A high-level summary of Sponsor’s testing for the Amplifi 
System is presented in Table 1: Performance and Safety Testing. 
 
Table 1: Performance and Safety Testing 
Item 
Evidence/Meets Standard 
Pass/Fail 
Design Validation 
First-in-human (10 subjects) – Vein diameter increased by over 
100%; no serious adverse events 
Pass 
Biocompatibility 
ISO 10993-1:2018 Biological evaluation of medical devices — 
Part 1: Evaluation and testing within a risk management 
process 
Pass 
ETO Sterilization 
ISO 11135:2014 and A1:2018 Sterilization of health care 
products – Ethylene oxide - Requirements for the development, 
validation, and routine control of a sterilization process for 
medical devices 
Pass 
ISO 10993-7:2008/AMD 1:2019 Biological evaluation of 
medical devices – Part 7: Ethylene oxide sterilization residuals  
Pass 
ISO 11138-1:2017 Sterilization of health care products - 
Biological indicators - Part 1: General requirements 
Pass 
Packaging  
ASTM D4169 Standard Practice for Performance Testing of 
Shipping Containers and Systems 
Pass 
Catheter Design 
ISO 10555-1:2013 Intravascular catheters - Sterile and single-
Pass 

 
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Verification 
use intravascular catheters - Part 1: General requirements 
+AMENDMENT 1 (2017) 
Electrical Safety 
IEC/ISO 60601-1:2005 Ed3+C1; C2; A1 Medical Electrical 
Equipment – Part 1: General Requirements for Basic Safety 
and Essential Performance 
Pass 
Software 
Verification 
IEC 62304:2006 Ed.1 +A1 Medical Device Software - Software 
Life Cycle Processes 
Pass 
Labeling  
ISO 15233-1:2021 Medical devices - Symbols to be used 
information to be supplied by the manufacturer- Part 1: General 
requirements 
Applied 
ISO 18242:2016 Cardiovascular implants and extracorporeal 
systems — Centrifugal blood pumps 
Applied 
3.2 First-In-Human Study 
A prospective, nonrandomized, single arm First-in-Human (FIH) clinical study was performed at 
the Sanatoria Italiano Hospital in Asuncion, Paraguay in 2021-2022 under the direction of 
Principal Investigator Adrian Ebner, MD. The study sponsor for this research was Artio Medical, 
Inc., which later transitioned to Amplifi Vascular, Inc. A total of n=10 subjects underwent 
inpatient treatment with the Amplifi System followed by AVF creation with treated veins. AVF 
maturation was assessed by duplex ultrasound 2 and 6-weeks after AVF creation. 
 
Treatment of the first cohort (FIH1; n = 5) was concluded in Q2 2021 with a mean treatment 
time of 8.6 days. All FIH1 subjects had successful AVF creation with treated veins and 4 out of 5 
AVFs matured (based on KDOQI criteria). Treatment of the second cohort (FIH2; n = 5) was 
concluded in Q3 2022 with a mean treatment time of 6.3 days. All FIH2 subjects had successful 
AVF creation with treated veins and all AVFs were mature at 2 weeks after AVF creation (based 
on KDOQI criteria).  
 
3.2.1 Device Performance Outcome 
 
For both FIH1 and FIH2 the primary performance endpoint was the percent change in the 
treated cephalic vein diameter from baseline to the end of Amplifi System treatment. As shown 
in Figure 5, the cephalic vein diameter increased by 105% in FIH1 subjects and 150% in FIH2 
subjects during the treatment period. As shown in Figure 6, mean imputed cephalic vein blood 
flow (as measured in the Proximal Outflow Catheter) increased 186% for FIH1 and 134% for 
FIH2 during the treatment period.  
 
AVFs were successfully created with treated veins in all FIH1 and FIH2 subjects. As shown in 
Figure 5, for FIH1 subjects, mean AVF outflow vein diameter increased to 6.3 mm and mean 
AVF blood flow (imputed from brachial artery blood flow in some FIH1 subjects) increased to 
851 mL/min six weeks after AVF creation (Figure 6). As shown in Figure 5 and Figure 6, for 
FIH2 subjects, mean AVF outflow vein diameter increased to 7.0 mm and mean AVF blood flow 
(imputed from brachial artery blood flow in all FIH2 subjects) increased to 1,153 mL/min six 

 
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weeks after AVF creation. There were no Amplifi System related or procedure-related serious 
adverse events.  
 
   
 
 
Figure 5: Cephalic Vein Diameter Measurements in FIH1 (left) and FIH2 (right) 
 
 
 
Figure 6: Blood Flow Measurements in FIH1 (left) and FIH2 (right) 
 
3.2.2  Treatment Duration 
After 
Radio/Brachiocephalic  
After 
Radio/Brachiocephalic  

 
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In the FIH2, vein diameter experienced rapid dilation, started to level off  at 48 hours, and 
remained constant up to 120 hours of treatment duration as shown in Figure 7. 
Immediate dilation of the vein (as early as less than 24 hours of therapy) is indicative 
treatment effect in the early stage of vein dilation. With controlled increase of non-pulsatile 
flow, vein dilation plateaus at around 48-72 hours indicative of vein remodeling with 
sustained effect up to 120 hours. Based on this data, the proposed treatment duration for 
Amplifi treatment requires a minimum of 60 hours (± 12 hours) of treatment to ensure that 
optimal vein dilation through remodeling is achieved. The recommended treatment 
duration of 60 hours (± 12 hours) is based on the data that vein dilation remained constant 
as shown in the plot. 
 
 
Figure 7: FIH2 Treatment Duration 
3.2.3 Safety Outcome 
The primary safety endpoint was freedom from the composite of death, re-hospitalization, 
bacteremia, Amplifi System-related or AVF-related infection, thromboembolic events, or 
major bleeding from Amplifi System placement to six weeks after AVF creation. There 
were no serious adverse events (SAEs), deaths, re-hospitalizations, Amplifi System-
related or AVF-related infections, major bleeding, or thromboembolic events from Amplifi 
System placement to six weeks after AVF creation. Table 2 outlines all adverse events 
that occurred in the FIH study. Notably, although none of the events were considered 
more than mild, a minor pump design modification was incorporated to reduce the need 
for pump replacement. 
 
Table 2: Adverse Events for FIH1 and FIH2 
Subject 
Adverse Event 
Severity 
Relation to 
Amplifi 
System 
Relation to 
Procedure 
SAE or 
UADE 
01 
Pulmonary air embolism 
Mild 
Not related 
Definite 
No 

 
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03 
Blood oozing at catheter 
insertion site 
Mild 
Definite 
Definite 
No 
Pump unable to achieve 
desired speed; Pump replaced 
Mild 
Definite 
Possibly 
No 
04 
Pump unable to achieve 
desired speed and low blood 
flow alarm; Pump replaced 
Mild 
Definite 
Possibly 
No 
05 
Low blood flow alarm; Pump 
replaced 
Mild 
Definite 
Possibly 
No 
07 
Decreasing Pump speed and 
blood flow with increasing 
current; Pump replaced 
Mild 
Definite 
Possibly 
No 
08 
Decreasing Pump speed and 
blood flow with increasing 
current; Pump replaced  
Mild 
Definite 
Possibly 
No 
Decreasing Pump speed and 
blood flow with increasing 
current; Pump replaced 
Mild 
Definite 
Possibly 
No 
Decreasing Pump speed and 
blood flow with increasing 
current; Pump replaced 
Mild 
Definite 
Possibly 
No 
 
3.2.3 Summary  
The FIH Study met its primary performance endpoint. Cephalic vein diameter increased by 
>100% in all ten Subjects during treatment, with a mean increase of 105% for the FIH1 cohort 
and 150% for the FIH2 cohort. 7 of 10 FIH subjects had successful radiocephalic AVF creation 
and 3 of 10 Subjects had successful brachiocephalic AVF creation. In FIH2, the starting forearm 
cephalic vein diameters were 1.7, 1.9, 1.9, 2.2, and 2.4 mm, all below the widely recognized 
suitability threshold of 2.5 mm for AVF creation, suggesting the Amplifi System could be used to 
increase forearm AVF suitability in patients with small forearm veins. All five FIH2 subjects had 
fully mature forearm AVFs two weeks after creation, with a mean AVF outflow vein diameter of 
7.0 mm and an imputed AVF blood flow of 1153 mL/min, a remarkable result considering that all 
five FIH2 subjects had pre-treatment forearm cephalic vein diameters < 2.5 mm and forearm 
AVFs.  
 
There were no serious adverse events, deaths, re-hospitalizations, bacteremia, major Amplifi 
System-related, or AVF-related infection, thromboembolic events, or major bleeding from Amplifi 
System placement to six weeks after AVF creation. 
 
In some FIH subjects, replacement of the Pump portion of the Amplifi System was required to 
complete treatment. Subsequent analysis of replaced Pumps determined lower bearing gaps 

 
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were out of specification (low) in Pumps that were replaced, likely resulting in reduced washing 
under the impeller and thrombus formation in the lower bearing gap. Upon completion of the FIH 
study, an updated assembly process was developed, implemented, tested, and verified. 
Analysis has confirmed that the lower bearing gap for all Pumps built with the updated 
manufacturing process have been within specification to date.  
 
The FIH study demonstrated that treatment of upper extremity veins with the Amplifi System 
prior to AVF creation was feasible and safe, and the treatment resulted in large increases in 
cephalic vein diameters. AVFs made with treated veins matured quickly and fully. These highly 
promising results support using the Amplifi System to increase AVF suitability (especially 
forearm AVF), improve maturation, and reduce time to maturation.  
 
The data on the treatment duration from the FIH2 study was used to design the FIH3 study to 
further optimize the treatment duration of the Amplifi System and further confirm safe use of the 
device.   
 
4.0 Study Design  
This nonrandomized study is designed to confirm the safety and effectiveness of using the 
Amplifi System for dilating upper extremity veins prior to surgical AVF creation as observed 
during the FIH study. The working hypothesis for the study is that the cephalic vein in 
hemodialysis   patients can be treated safely with the Amplifi System and the treatment will 
result in dilation of the cephalic vein, and the treated and dilated cephalic vein can be used to 
make an AVF and improve AVF maturation. 
4.1 Study Objectives 
The Amplifi System will be assessed and analyzed for effectiveness to demonstrate similar 
outcome from the earlier First-in-Human Studies with shorter treatment duration. Safety analysis 
will be performed to confirm that major complications will be in an acceptable range. 
4.2 Study Population 
Subjects who have ESRD and are currently receiving maintenance hemodialysis via a tunneled, 
cuffed hemodialysis catheter (“Subjects”) will be enrolled in a prospective, nonrandomized, 
multicenter, open label clinical study designed to evaluate the safety and effectiveness of the 
Amplifi System as specified in this protocol (“Protocol”).  
4.3 Study Design  
The Study is a prospective, nonrandomized, single-arm, open-label clinical study evaluating the 
use of the Amplifi System. 
 
Up to ten (10) Subjects with a forearm or upper arm cephalic vein with a diameter ≥ 1.7 mm 
and ≤ 3.2 mm, and radial artery diameter ≥ 2.0 mm who have ESRD and are receiving 
maintenance hemodialysis using a catheter for vascular access. The Subjects will be treated in 
an inpatient (hospital) setting and will receive Amplifi System treatment and undergo 
subsequent AVF creation (a “Study AVF”) immediately after treatment. Amplifi System removal 

 
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immediately followed by AVF creation will be performed when Subject had:  
• Amplifi treatment for ≥ 48 hours duration and physician determined that cephalic vein is 
suitable for AVF creation determined by physician (e.g., vein diameter ≥ 3.3 mm as 
defined in Dageforde17 as Quartile 3 and baseline diameter increased ≥ 50%); or  
• Amplifi treatment could be extended up to 60 hours (± 12hrs) if the cephalic vein was 
not determined to be adequate by the investigator.  
 
After the Amplifi System treatment period, the device will be removed completely and an AVF 
will be made using the treated cephalic vein. After AVF creation, Subjects will be discharged 
from the hospital with outpatient follow up visits 1, 2 and 6-weeks after AVF creation. 
 
4.4 Study Site and EC / EC 
 
Subjects will be enrolled at Sanatorio Italiano, Asuncion, Paraguay Investigation Site.  
  
4.5 Primary Clinical Measures 
 
Effectiveness Measures 
 
o Percent change in cephalic vein diameter and blood flow in the middle third 
of the arm as measured by ultrasonography [Timeframe: from baseline, during 
Amplifi System treatment (daily), and prior to Amplifi System removal and AVF 
creation] 
 
o Mean vein diameter of cephalic vein and blood flow of brachial artery in the 
middle third of the forearm as measured by ultrasonography [Timeframe: 1, 2and 
6 weeks post AVF creation] 
 
o Forearm AVF maturation success at 1, 2, 6 weeks post-AVF creation 
[Timeframe: 1, 2, 6-WK post AVF creation] 
 
o Percentage of subjects who experience an increase in the cephalic vein 
diameter of ≥2.7 mm from their baseline measurement, or an increase of >1 
mm from baseline, following treatment with the Amplifi System. [Timeframe: 
prior to removal of the Amplifi System and creation of the AVF]. 
 
 
Safety Measures 
 
• 
Rate of Occurrence of Major Device-Related Adverse Events (MDRAE)* 
defined as: [Timeframe: from device implantation and up to 30 days from device 
removal and AVF creation] 
• 
Amplifi System-related death; 
• 
Amplifi System-related major bleeding, major pneumothorax, major air 

 
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embolism, major thrombosis, major thromboembolism, major hemolysis, 
or major thrombocytopenia; local infection 
• 
Amplifi System-related re-hospitalization or prolonged hospitalization; 
• 
Amplifi System-related major surgery or major interventional procedure; 
or 
• 
any Amplifi System-related complication determined to be an Amplifi 
System-related major complication by both an Investigator and the 
Medical Monitor.  
 
*Detailed definition of Major Device-Related Adverse Events is described in Attachment 
1: Definitions 
 
• 
Rate of Occurrence of Cannulation-related Complications [Timeframe: from 
AVF creation through end of follow-up period] 
 
 
Exploratory Technical Performance Measures 
 
• 
Rate of Occurrence of Amplifi System component replacement [Timeframe: 
from device implantation through device removal and AVF creation] 
 
 
• 
Rate of Occurrence of Amplifi System treatment failure [Timeframe: from 
device implantation through less than required minimum treatment hours of 
duration (e.g., 48 hours)  
 
*Detailed definition of Treatment Failure is described in Attachment 1: Definitions 
 
Rate of Occurrence of pump stoppages and device malfunction [Timeframe: 
from device implantation through device removal 
4.6 Inclusion and Exclusion Criteria 
 
Inclusion Criteria 
• 
Age ≥ 18 years 
• 
Indicated for wrist or distal forearm radiocephalic AVF creation based on 
Investigator’s standard practice  
• 
ESRD currently receiving maintenance hemodialysis via a tunneled, cuffed 
hemodialysis catheter 
• 
Baseline wrist or distal forearm cephalic vein diameter of > 1.7 mm and < 3.2 mm 
at the proposed Study AVF creation site, wherein the wrist or forearm cephalic 
vein at the proposed Study AVF creation site is suitable for Amplifi Distal Outflow 
Catheter placement and Amplifi System treatment, including: 

 
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o > 1.7 mm to < 3.2 mm diameter of the wrist or forearm cephalic vein at 
the proposed Study AVF creation site; 
o patency and continuity of blood flow from the proposed Study AVF 
creation site centrally to the upper arm at the elbow through at least one 
or more of: 1) the upper arm cephalic vein; 2) the median cubital vein to 
the upper arm basilic system; or 3) the perforator vein to the deep venous 
system; and 
o no occlusion or stenosis > 50% along the course of the forearm cephalic 
vein and at least one upper arm venous outflow up to the subclavian vein, 
as determined by duplex ultrasonography 
• 
Estimated forearm hemodialysis needle cannulation zone length > 18 cm after 
creation of the proposed Study AVF   
• 
At least one patent internal jugular vein suitable for Amplifi Inflow Catheter 
insertion 
• 
Subject has voluntarily signed written informed consent 
 
Exclusion Criteria 
1) Known allergy to Amplifi System components (polyurethane, nitinol), 
iodinated contrast agents, heparin, or apixaban 
2) Known or suspected active infection at the proposed time of Amplifi 
System placement 
3) Known bleeding diathesis, including from uncorrected coagulopathy  
4) Known thrombophilia, requiring treatment 
5) Hb <10 gm/dL 
6) Platelet level < 100,000 /mm3 
7) Need for continued treatment with anti-platelet agents or other 
anticoagulants (other than apixaban) during the Amplifi System treatment 
period 
8) Known history of patent foramen ovale > 2 mm 
9) History of recent intracranial or gastrointestinal bleeding 
10) Documented recent central venous or right atrial thrombus 
11) Known presence or recent history of intracranial or gastrointestinal 
bleeding or presence of underlying conditions that would predispose to 
intracranial or internal bleeding. Documented recent central venous or 
right atrial thrombus 
12) History of recent ipsilateral central venous occlusion, stenosis > 50%, 
angioplasty, or stent placement 
13) Pregnancy, lactation, or plans to become pregnant during the Study 

 
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14) Unwillingness or inability to comply with procedures specified in the 
Protocol, or difficulty or inability to return for follow-up visits as specified 
by the Protocol 
15) Participation in any other investigational drug or medical device study that 
has not completed primary endpoint evaluation or clinically interferes with 
the endpoints from the Study, or planned future participation in such 
studies prior to the completion of the Study 
 
6.0 Study Enrollment, Informed Consent and Subject 
Withdrawal 
6.1 Enrollment  
6.1.1 Informed Consent 
Informed Consent is a process that is initiated prior to an individual agreeing to participate in a 
study and continuing throughout the individual’s study participation. Investigators or designated 
research staff will obtain a patient’s informed consent before any study procedures or data 
collection are performed. 
 
Patient or Legal Authorized Representative (LAR) will receive a concise and focused 
presentation of key information about the clinical trial, verbally and with a written consent form. 
The key information about the study will be organized and presented in lay terminology and 
language that facilitates an understanding of why one might or might not want to participate. 
Informed Consent form(s) (ICF) will be EC-approved, and patients will be asked to read and 
review the consent form. Patient (or LAR) must sign the ICF prior to starting any study 
procedures being done specifically for this trial. Once signed, a copy of the ICF will be given to 
the patient for their records. The original form shall be maintained in the patient’s medical 
records at the site. Patient who signed informed can refuse to participate and can withdraw at 
any time without concern for further treatment. 
 
If new information becomes known to the Sponsor that may affect the risks and benefits of a 
Subject’s participation in the Study, Investigators will revise the informed consent and ICF as 
necessary and re-consented Subjects. Revisions to the ICF will be approved by Sponsor and 
ECs prior to re-consenting Subjects. Sites will keep the original signed ICFs for each Subject, 
including any updated ICFs, on file and available for inspection by Sponsor or its designees.  
 
6.1.2 Enrollment and Study Exit  
After signing informed consent, potential Subjects will be screened against inclusion and 
exclusion criteria for entry into the Study as close to the scheduled Amplifi System placement 
time as possible. If all inclusion criteria and no exclusion criteria are met, the patient can be 
enrolled into the Study as a Subject.  
Subjects will undergo screening duplex ultrasonography prior to enrollment and the results will 
be documented on the appropriate CRF. The protocol for the baseline screening duplex 

 
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ultrasonography is summarized in the FIH3 Duplex Ultrasonography Protocol. A complete 
blood count (CBC) will be evaluated at baseline and will be used to assess eligibility for the 
study. 
A patient is considered enrolled in the Study (and a Subject) after all the following criteria 
are met: 
• 
patient has provided informed consent; 
• 
Investigator has determined that the patient continues to meet all the inclusion criteria 
and none of the exclusion criteria; and 
• 
an attempt has been made to treat the patient with the Amplifi System by inserting at 
least a portion of the Inflow Catheter or Distal Outflow Catheter into the patient’s body. 
 
Each subject enrolled in the study will be assigned a unique identification number (see Section 
11.5). Subjects who receive any amount of Amplifi System treatment and had AVF creation will 
be followed at 1,2 and 6 weeks after Study AVF creation and will then exit the Study. Subjects 
who receive any amount of Amplifi System treatment but did not have AVF creation will be 
followed up to 30 days after Amplifi System removal. Patients in which no portion of the Inflow 
Catheter or Distal Outflow Catheter was inserted into the body will be considered screening 
failures and will not be considered enrolled as Subjects. There will be no data entry or follow-up 
for these patients.   
For all consented patients, adverse events shall be collected, and the patient followed until they 
have resolved, have a stable level of sequelae or, in the Investigator’s opinion, are no longer 
clinically relevant, or study exit (whichever comes first) for safety. 
6.2 Subject Withdrawal 
Subjects retain the right to withdraw from the Study at any time if they wish to do so, without any 
consequences. Should a Subject elect to withdraw from the Study, the Investigator or Site 
Personnel will record the reason for withdrawal in source documentation and on the appropriate 
CRF. In addition, the Investigator may discontinue the Subject from the study due to any of the 
following situations: 
 
• 
Serious Adverse Event (SAE); or 
• 
any other reason determined by the Investigator to be in the best interest of 
the subject. 
Subjects with an ongoing AE at the time of withdrawal should be followed on study 
until the clinical event has been resolved or is stable if possible. 
7.0 Procedures and Surgeries 
The Amplifi System placement, operation, and removal will be done in a hospital’s interventional 
suite or operating room. All subjects will be treated in an inpatient hospital setting. Subjects will 
be discharged only after Amplifi System removal with or without AVF creation. 
 
Investigators, and other Site Personnel involved in placing, operating, monitoring, interacting 

 
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with, or removing the Amplifi System, including during Study-related procedures or surgeries, 
will review the Amplifi System IFU and Operator’s Manual prior to these activities and will refer 
to the Amplifi System IFU during these activities, as needed. 
 
Please refer to Amplifi System IFU and Operator’s Manual for the use and operation of the 
Amplifi System. 
 
7.1 Amplifi System Placement 
Prior to placing the Amplifi System, Investigators will review the Amplifi System IFU and 
Protocol for instructions on how to place the Amplifi System and will refer to the Amplifi System 
IFU during the placement procedure, as needed. 
 
The Inflow Catheter will not be placed in fully occluded internal jugular veins, even after 
recanalization. The Inflow Catheter will not be placed in other veins such as the external jugular, 
subclavian, and femoral veins.  
7.2 Amplifi System Treatment 
Prior to treating Subjects with the Amplifi System, Investigators will review the Amplifi System 
IFU and Protocol, and will refer to the Amplifi System IFU, Operator’s Manual and Protocol 
during treatment, as needed.  
 
If, during the Amplifi System treatment period, a Subject has an Amplifi System-related major 
hemolysis event, the Investigator will discontinue Amplifi System treatment, provide treatment 
for the hemolysis, and create an AVF with the treated cephalic vein as soon as possible, if 
clinically indicated. Subject(s) will continue their post AVF follow-up, if applicable.  
 
If, during Amplifi System treatment period, a Subject has experienced pump early stoppage, 
malfunction or deficiencies prior to the scheduled end of treatment, please refer to Section 7.5 
Pump Malfunction and Stoppage. 
7.3 Amplifi System Removal 
Prior to removing the Amplifi System, Investigators will review the Amplifi System IFU, 
Operator’s Manual and Protocol for instructions on how to remove the Amplifi System and will 
refer to the Amplifi System IFU during the removal procedure, as needed. 
 
If a suspected thrombus is present in the Amplifi System after removal, high-resolution color 
photographs will be obtained of all blood-contacting components of the Amplifi System such that 
any thrombus present is clearly seen and documented. The Pump will be opened, the impeller 
removed, and photographs taken of the top bottom of the impeller and the blood contacting 
surfaces of the top and bottom housing.  
7.4 Study AVF Creation 
Although Study AVF creation in the distal forearm using an anastomosis surgical technique of 
“artery side to vein end” is encouraged, Investigators will create a Study AVF for each Subject at 

 
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the location and using a technique they believe is best for each Subject. 
The Protocol specifies that Investigators should create Study AVFs at the location pre-identified 
by the Investigator prior to enrollment. If, after Amplifi System treatment, in the Investigator’s 
clinical judgment, creation of a Study AVF at the pre-planned location is not in the best interest 
of the Subject, the Investigator should create an AVF at a location that, in the Investigator’s 
clinical judgment, is in the best interest of the Subject, if possible. If, after Amplifi System 
treatment, in the Investigator’s clinical judgment, creation of an AVF is not in the best interest of 
the Subject, the Investigator should create a vascular access that, in the Investigator’s clinical 
judgment, is in the best interest of the Subject, if possible.  
 
* If, at any time during Amplifi System treatment, in the Investigator’s clinical judgment, creation 
of a Study AVF is in the best interest of the Subject, the Investigator should create an AVF.  
** 
 
If the pump stops prior to the schedule end of treatment duration, please refer to Section 7.5 
Pump Malfunction and Stoppage. 
7.5 Pump Malfunction and Stoppage 
If a Pump experiences a deficiency or malfunction and stops prior to the scheduled end of 
treatment (e.g., < 48 hours of treatment) and cannot be re-started: 
• 
The patient may be scheduled for Blood Pump replacement or possible AVF creation, if 
clinically indicated as determined by the Investigator 
• 
To reduce the risk of thrombus formation, the patient should continue to take apixaban 
anticoagulant until advised by physician to discontinue 
• 
The Amplifi System should be removed as specified in the Instruction For Use (IFU); the 
Blood Pump, Inflow Catheter, and Outflow Catheters should not be flushed; and no 
angiography should be performed using the Access Ports. 
• 
An ultrasound examination of the treated upper extremity will be performed to determine 
the amount of thrombus formation in the veins of the treated arm documented in eCRF, 
if any, as described in 8.1.2 Ultrasonography During Amplifi System Treatment. 
o If thrombus is present in the treated cephalic vein and the Investigator believes 
the thrombus can be removed during AVF creation, then the Investigator should 
proceed to AVF creation, if clinically indicated. Any thrombus in the cephalic vein 
should be managed appropriately prior to AVF creation (e.g., using a method 
such as mechanical thrombectomy). 
o  High resolution color photographs will be obtained of all blood-contacting 
components of the Amplifi System such that any thrombus present is clearly 
seen and documented. An investigation of the pump will be conducted per the 
Sponsor’s Device Return Investigation procedure.   
• 
A venogram of the treated upper extremity, central veins, and right atrium will be 
performed by the Investigator during Amplifi System removal, as described in Section 
8.5 Contrast Venography. 
 

 
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All Amplifi System unplanned stoppages, including Pump stoppages, that occur and are 
observed during the Study shall be documented by the Investigator and other Site Personnel 
by submitting a completed CRF in the Study EDC System as described in Section 12.3 
Amplifi System Unplanned Stoppages, Malfunctions, and Potential Device Deficiencies 
and reporting as described in Section 12.10.6 Reporting of Amplifi System Unplanned 
Stoppages and Malfunctions and data analysis will be conducted as described in Section 
14.2.2 Analysis of Effectiveness Measures.  
8.0 Study Assessments and Follow Up 
The total duration of Subject participation in the nonrandomized cohort will be up to 6 weeks 
after AVF creation. Table 3 summarizes Study assessments and actions and Table 4 
summarizes the assessment window. 
 
Table 3: Study Assessments and Actions 
Assessment or Action 
Screening 
Day 0 - Amplifi System Placement  
Day 1 – 3 - Amplifi System Treatment 
 Amplifi System Removal and Study 
AVF Creation 
Week 1,2 and Week 6 after Study 
AVF Creation 
Duplex Ultrasonography 
X 
X 
X 
X 
X 
Inclusion and Exclusion Criteria 
X 
 
 
 
 
Informed Consent and HIPAA Authorization 
X 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
Clinical Assessment, Physical Exam 
X 
X 
X 
X 
X 
Laboratory Testing - Chemistry, Hematology  
X 
X 
X 
X 
 
Laboratory Testing – ACT 
 
X2 
 
X2 
 
Laboratory Testing – PFH, LDH, and CBC  
X 
X 
X3 
X 
X 
Amplifi System Blood Flow Measurement  
(From Recorded Amplifi System Data) 
 
X 
X 
X 
 

 
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B-Mode Ultrasonography During Amplifi System Treatment 
(by Investigator) 
 
X 
X3 
 
 
Contrast Venography (by Investigator)  
 
X 
X1 
X 
 
Concomitant Medications 
 
X 
X 
X 
X 
Adverse Event Logging 
 
X 
X 
X 
X 
Determination of Study AVF Maturation (Y/N) 
 
 
 
 
X 
Documentation of unplanned stoppages, malfunction and 
deficiencies  
 
X 
X 
X 
 
Documentation of Study AVF Thrombosis Events, 
Interventional Procedures, and Surgeries 
 
 
 
 
X 
Documentation of Access-Related Thrombosis Events, 
Interventional Procedures, and Surgeries (all types of access) 
 
 
 
 
X 
1. For Subjects that experience a prolonged Pump stoppage only 
2. ACT measurements during Amplifi System placement and AVF creation per Amplifi System IFU 
3. Daily testing 
 
Table 4: Time Windows for Study Assessments 
Assessment 
Time Window1 
Baseline Screening Ultrasonography 
<14 days prior to planned Amplifi System placement 
Inclusion and Exclusion Criteria, 
Demographics and Medical History, and 
Informed Consent and HIPAA Authorization 
<14 days prior to planned Amplifi System placement 
Baseline Clinical Assessment and Physical 
Exam 
<14 days prior to planned Amplifi System placement 
Baseline Laboratory Testing 
<14 days prior to planned Amplifi System placement 
Daily Ultrasonography During Amplifi System 
Treatment 
Within 12-hour period of each day2 
Daily Clinical Assessment and Physical Exam 
during Amplifi System Treatment 
Within 12-hour period of each day 
Daily Laboratory Testing During Amplifi 
System Treatment 
Within 12-hour period of each day 
Documentation of unplanned stoppages, 
malfunction, and deficiencies 
Within 48-hour period of the time of event 
Ultrasonography at the End of Amplifi System 
Treatment 
<4 hours prior to the planned end of treatment 
Contrast Venography 
During Amplifi System placement 

 
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Assessment 
Time Window1 
During Amplifi System removal and Study AVF 
creation surgery  
Laboratory Testing after Study AVF Creation 
±7 days 
Clinical Assessment and Physical Exam after 
Study AVF Creation 
±7 days  
Study AVF Ultrasonography 
+7 days for two (2) week ultrasonography 
+2 weeks for six (6) week ultrasonography 
Determination of Study AVF Maturation 
+7 days for two (2) week ultrasonography 
+2 weeks for six (6) week ultrasonography 
Documentation of Study AVF Thrombosis 
Events, Interventional Procedures, and 
Surgeries 
±7 days at 2 weeks 
±2 weeks at 6 weeks 
Documentation of Vascular Access-Related 
Thrombosis Events, Interventional 
Procedures, Surgeries (all types of access)3  
±7 days at 2 weeks 
±2 weeks at 6 weeks 
Documentation of Hemodialysis Vascular 
Access-Related Hospitalizations (all types of 
access)4 
±7 days at 2 weeks 
±2 weeks at 6 weeks 
Adverse Event Logging 
Within 24-hour period of each day during Amplifi 
System treatment 
±7 days at 2 weeks 
±2 weeks at 6 weeks 
1. Unless otherwise specified, times are measured from Study AVF creation date 
2. Required 
3. Does not include Study AVF 
4. Includes Study AVF 
 
8.1 Duplex Ultrasonography 
8.1.1 Baseline Screening Ultrasonography 
As shown in Table 3, Subjects will undergo screening duplex ultrasonography prior to 
enrollment and the results will be documented on the appropriate CRF. The protocol for the 
baseline screening duplex ultrasonography is summarized in FIH3 Duplex Ultrasonography 
Protocol. The patency, diameter, and blood flow of the veins of both upper extremities will be 
assessed, including the cephalic, basilic, median cubital, and perforator veins, to provide 
Investigators information to help them determine patient eligibility for the Study, choose potential 
locations for insertion of the Distal Outflow Catheter, and choose a planned location for Study 
AVF creation. The patency, diameter, and blood flow of the arteries of both upper extremities 
will be assessed, including the radial artery, to provide Investigators information to help them 

 
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determine patient eligibility for the Study, and to choose a planned location for Study AVF 
creation. The patency, diameter, and blood flow of both internal jugular veins will be also 
assessed to provide Investigators information to help them choose potential locations for 
insertion of the Inflow Catheter, if needed. 
Vein diameters will be measured in both the vertical and horizontal vessel dimension and artery 
diameters will be measured in the vertical dimension only, and reported in fraction of millimeters 
using digital calipers. A tourniquet will be applied at the proximal portion of the upper arm during 
assessment of upper extremity vein diameters. No tourniquet will be used during assessment of 
vein blood flow, and artery diameter and blood flow.  
8.1.2 Ultrasonography During Amplifi System Treatment 
Subjects will have limited ultrasonography at least daily to assess the patency and diameter of 
the cephalic vein in the middle third of the forearm. The protocol for ultrasonography during 
Amplifi System treatment is summarized in FIH3 Duplex Ultrasonography Protocol. 
 
Vein diameters will be measured in both the vertical and horizontal vessel dimension. Amplifi 
System treatment will continue during this ultrasound examination and tourniquet will be 
placed. At the time of the first measurement post AVF creation, a mark will be made on the skin 
at the location of the first measurement using a permanent marker, and this mark will be used to 
make subsequent measurements. 
 
Subjects that experience a prolonged Pump stoppage will have a duplex ultrasound 
examination of the treated upper extremity to evaluate patency of the upper extremity arm veins 
and identify any signs of injury, stenosis, occlusion, aneurysm formation, or intraluminal 
thrombus using the protocol for ultrasonography at the end of Amplifi System treatment, as 
summarized in FIH3 Duplex Ultrasonography Protocol, Sonographers will identify and record 
the location and extent of intraluminal thrombus present in the treated upper extremity after a 
prolonged Pump stoppage, if any, on the appropriate CRF. If no thrombus is identified, that will 
also be recorded on the CRF. 
8.1.3 Ultrasonography at the End of Amplifi System Treatment 
Subjects will have duplex ultrasonography at the end of the Amplifi System treatment period 
prior to Study AVF creation. The protocol for the ultrasonography after Amplifi System 
Treatment is summarized in FIH3 Duplex Ultrasonography Protocol. The patency, diameter, 
and blood flow of the veins of both upper extremities will be assessed at the same locations as 
the baseline screening duplex ultrasound examination.  
 
Vein diameters will be measured in both the vertical and horizontal vessel dimension. Amplifi 
System treatment will continue during this ultrasound examination and tourniquet will be 
placed on the treated arm.  
8.1.4 Ultrasonography of AVF 
Subjects will have duplex ultrasonography of the Study AVF at 1, 2 and 6 weeks after Study 
AVF creation. The protocol for Study AVF duplex ultrasonography is summarized in FIH3 
Duplex Ultrasonography Protocol. The patency, diameter, and blood flow of the arteries and 
veins of the upper extremity with the Study AVF will be assessed at the same locations as the 

 
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baseline screening duplex ultrasound examination. Vein diameters will be measured in both the 
vertical and horizontal vessel dimension and artery diameters will be measured in the vertical 
dimension only. No tourniquet will be placed.  
8.2 Demographics and Medical History 
All Subjects will have demographics and a medical history recorded in the Study EDC System.  
8.3 Clinical Assessments and Physical Exams 
Clinical assessments and physical exams, including vital signs and temperature, will be 
performed at screening, day 1 (prior to Amplifi System placement), and at the end of the Amplifi 
System treatment period. Assessments will be recorded in the Study EDC System.  
8.4 Laboratory Assessments 
• 
A routine chemistry panel will be evaluated at baseline, at day 1 prior to Amplifi System 
placement, and at the end of Amplifi System treatment.  
• 
A complete blood count (CBC) will be evaluated at baseline, on day 1 prior to Amplifi 
System placement, daily during the Amplifi System treatment period, at the end of 
Amplifi System treatment after Amplifi System removal, and 1, 2 weeks and 6 weeks 
after Study AVF creation. The baseline CBC results will be used to assess eligibility, the 
daily testing during the Amplifi System treatment period and the testing 1, 2 weeks and 6 
weeks after Study AVF creation will be used to assess for hemolysis and anemia.   
• 
PFH and LDH will be evaluated at baseline, on day 1 prior to Amplifi System placement, 
daily during the Amplifi System treatment period, at the end of Amplifi System treatment 
period after Amplifi System removal, and 1, 2 weeks and 6 weeks after Study AVF 
creation to assess for hemolysis.   
• 
ACT will be evaluated during Amplifi System placement and removal, as per the Amplifi 
IFU, and during AVF creation, as per Standard of Care.  
8.5 Contrast Venography 
The protocols for contrast venography are summarized in the FIH3 Contrast Venography 
Protocol. The Investigator performing each fluoroscopic, venographic, or angiographic study 
will document the findings on the appropriate CRF. 
8.5.1 Venography Prior to Amplifi System Placement 
Contrast venography of the upper extremity, ipsilateral central veins, superior vena cava, and 
right atrium using an IV catheter will be performed for all Subjects prior to insertion of the Inflow 
Catheter or Distal Outflow Catheter evaluate patency of the cephalic vein, the draining veins of 
the upper arm, the ipsilateral central veins, the superior vena cava, and the right atrium. 
Evaluating the veins of the arm by ultrasound is generally preferred to contrast venography. 
Ultrasound is generally inadequate in identifying subtle stenotic issues and flow pattern in the 
normal low flow state. It is also not adequate to visualize the central veins and right atrium, so 
contrast venography is needed to evaluate the patency of the central veins and right atrium prior 
to Amplifi System placement. If ultrasound is not available, or if the information obtained from an 

 
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ultrasound examination is incomplete or uncertain, then contrast venography may also be used 
to evaluate upper extremity vein patency and flow.  
Preferably, contrast venography should be performed through a standard IV catheter prior to 
placement of the Distal Outflow Catheter. If contrast venography cannot be performed through a 
standard IV catheter, or if the information obtained from this venography is incomplete or 
uncertain, then contrast venography may be performed through a Distal Outflow Catheter.  
Preferably, contrast venography should be performed prior to starting the Amplifi System Pump. 
If contrast venography cannot be performed prior to starting the Pump, or if the information 
obtained from this venography is incomplete or uncertain, then contrast venography may be 
performed after starting the Pump.    
Contrast venography will not be used to make vein diameter measurements due to variability in 
the volume and rate of contrast injections. Contrast venography will not be used to identify signs 
of vein injury, stenosis, or occlusion during Amplifi System placement due to the potential to 
induce vasospasm during vein access and contrast injection and cause false positive results. 
8.5.2 Angiography of the Inflow Catheter During Amplifi System 
Placement  
Contrast angiography of the right atrium after insertion and positioning of the Inflow Catheter will 
be performed for all Subjects during Amplifi System placement to identify Inflow Catheter tip 
location and to evaluate for right atrial thrombus.     
If contrast angiography of the Inflow Catheter and the right atrium cannot be performed prior to 
starting the Amplifi System Pump, or if the information obtained from this venography is 
incomplete or uncertain, then contrast venography of the Inflow Catheter and the right atrium 
may be performed after starting the Pump.     
8.5.3 Venography During Amplifi System Treatment  
Contrast venography of the upper extremity, ipsilateral central veins, superior vena cava, and 
right atrium will be performed for Subjects that experience prolonged Pump stoppage to: 
1) evaluate patency of the cephalic vein, the draining veins of the upper arm, the ipsilateral 
central veins, the superior vena cava, and the right atrium; 
2) identify any signs of injury, stenosis, occlusion, aneurysm formation, or intraluminal 
thrombus formation in the cephalic vein, the draining veins of the upper arm, the 
ipsilateral central veins, and the right atrium;  
3) evaluate flow in the forearm cephalic vein, and to and through the draining veins of the 
upper arm and central veins to the right atrium. 
Investigators will identify and record the location and extent of intraluminal thrombus present in 
the treated upper extremity, ipsilateral central veins, superior vena cava, and right atrium after a 
prolonged Pump stoppage, if any, on the appropriate CRF. If no thrombus is identified, that will 
also be recorded on the CRF. 
Contrast venography of the upper extremity, ipsilateral central veins, superior vena cava, and 
right atrium may optionally be performed during Amplifi System treatment for Subjects that 
experience other problems or potential problems, as clinically indicated. 
8.5.4 Angiography of the Inflow Catheter During Amplifi System Treatment 

 
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Contrast angiography of the right atrium using the Inflow Catheter will not be performed for 
Subjects that experience a prolonged Pump stoppage.   
Contrast venography of the right atrium may optionally be performed during Amplifi System 
treatment Subjects that experience other problems or potential problems, as clinically indicated. 
8.5.5 Venography at the End of the Amplifi System Treatment Period 
Contrast venography of the upper extremity, ipsilateral central veins, superior vena cava, and 
right atrium will be performed at the end of the Amplifi System treatment period, and will be 
used to: 
1) evaluate patency of the cephalic vein, the draining veins of the upper arm, the ipsilateral 
central veins, the superior vena cava, and the right atrium; 
2) identify any signs of injury, stenosis, occlusion, aneurysm formation, or intraluminal 
thrombus formation in the cephalic vein, the draining veins of the upper arm, the 
ipsilateral central veins, and the right atrium;  
3) evaluate flow in the forearm cephalic vein and to and through the draining veins of the 
upper arm and central veins to the right atrium. 
Contrast venography will not be used to make vein diameter measurements due to variability in 
the volume and rate of contrast injections. At the end of the Amplifi System treatment period the 
potential for vasospasm is reduced and therefore contrast venography may be used to identify 
signs of vein injury, stenosis, or occlusion if the Outflow Access Port is used to make contrast 
injections and venography is performed with the Pump running. 
8.5.6 Angiography of the Inflow Catheter at the End of the Amplifi System 
Treatment Period 
Contrast angiography of the right atrium at the end of the Amplifi System treatment period will 
be performed for all Subjects to identify Inflow Catheter tip location and to evaluate for right 
atrial thrombus or signs of right atrial injury.    
8.6 Concomitant Medications 
All concomitant medications the Subject is prescribed during the Study Period will be recorded 
in the Study EDC System.  
9.0 Training 
9.1 Investigator Training 
All Investigators and Site Personnel will undergo training by the Sponsor or its designee on the 
design, function, storage, placement, use, operation, maintenance, care, cleaning, monitoring, 
interaction with, removal, and disposal of the Amplifi System and its components. Only trained 
Site Personnel will be allowed to place, use, monitor, interact with, or remove the Amplifi 
System and perform Study-related procedures or surgeries. The Amplifi System Instructions for 
Use (IFU) will be provided to educate and assist Investigators and other appropriate Site 
Personnel on the proper placement, operation, monitoring, care, maintenance, and removal of 
the Amplifi System. 

 
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10.0 Study Oversight, Monitoring, and Quality Control 
10.1 Investigator Selection 
Prior to the initiation of the Study, Sponsor will evaluate potential Investigators through a formal 
review process prior to selecting Investigators for the Study to ensure patient safety and 
optimize patient outcomes. Investigators will be selected based on: 
• 
qualifications, training, skill, experience, and education;  
• 
perceived commitment to ethics and confidentiality, and 
• 
expected adherence to the Protocol.  
Sponsor will maintain an updated list of Investigators.  
10.2 Site Selection 
Prior to the initiation of the Study, Sponsor will evaluate Sites through a formal review process 
prior to selecting Sites for the Study. Sites will be selected based on: 
• 
experience with the care of patients with ESRD undergoing AVF creation;  
• 
availability of adequate resources at the Site to conduct the Study in accordance with the 
Protocol, including the availability of adequate personnel, facilities, equipment, and other 
research infrastructure to perform the tests, examinations, procedures, surgeries, and 
interventions specified in the Protocol; 
• 
personnel with experience conducting clinical studies; and 
• 
ability to enroll Subjects in a timely manner. 
Sponsor will maintain an updated list of Sites.  
10.3 Pre-Enrollment Site Visit 
Sponsor will conduct a Site initiation visit prior to Subject enrollment. During the Site initiation 
visit, Sponsor or its designees will confirm and document that each Investigator and Site and all 
Site Personnel understands and accepts their Study responsibilities, as specified in Section 15. 
If an Investigator attends a Study-specific Investigator meeting where Sponsor accepts and 
document this understanding, this Investigator meeting may take the place of a Site initiation 
visit.  
10.4 Monitoring and Periodic Monitoring Visits 
Sponsor and its designees will monitor the Study to ensure Investigators, Sites, and Site 
Personnel are meeting their Study responsibilities, as specified in Section 15.0 Study 
Responsibilities.  
Details related to Site monitoring will be documented in the Sponsor’s Study-specific monitoring 
plan. Ongoing communication with Investigators and Site Personnel related to Site monitoring 
will be performed through written correspondence and telephone conversations.    
After the Study has been initiated, Sponsor and its designees will perform additional periodic 
Site monitoring visits to assess Study progress, perform Amplifi System storage and 

 
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accountability reviews, assess the adequacy of records, and to ensure adherence to the 
Protocol. Monitoring visits will be conducted in accordance with applicable local, regional, and 
national regulations, the Study-specific monitoring plan, and Sponsor’s procedures. A summary 
of monitoring visits, including documentation of completed previous action items, new or 
outstanding action items, and significant findings will be provided to the Investigator.  
In addition to periodic Site monitoring visits, Sponsor may perform remote monitoring to ensure 
data is submitted in a timely manner. The Site, Investigators and Site Personnel will, upon 
request, provide to the Sponsor the necessary Study documents and records necessary for a 
complete review of the work related to the Study at the Site by Investigators and Site Personnel. 
These records include, but are not limited to, access to Amplifi System storage and 
accountability logs and records, CRFs and original source documents and records such as 
ICFs, clinical charts, examination reports, procedure or operative reports, test results and 
radiology reports.  
To meet its responsibility for monitoring the Study to ensure the Protocol is being appropriately 
followed, Sponsor and its designee’s clinical, regulatory, engineering, and research personnel 
may be present at Study-related Subject examinations, tests, procedures, interventions, and 
surgeries. Sponsor may contract with a contract research organization to help Sponsor meet its 
responsibilities for monitoring the Study. 
10.5 Case Report Forms 
Appropriate Site Personnel will be trained on the Study EDC System and database and will 
receive a unique username and password. Sponsor may grant or restrict the right of all Site 
Personnel to access the Study EDC System and database throughout the duration of the Study 
in its sole and absolute discretion. Investigators will ensure that Study observations and findings 
are recorded correctly and completely in CRFs. Data submitted during of the Study will be 
reviewed by the Sponsor or its designees for accuracy and completion. Source documents will 
be available for access by the Sponsor to review for monitoring of data accuracy and validity of 
all data recorded on CRFs. 
10.6 Maintenance of Source Documentation 
Original documentation supporting data recorded on CRFs and eCRFs will be maintained at 
Sites, including clinical charts, medical records, laboratory reports, test results, physician 
referral or consultation letters, and radiology and pathology reports. During Site monitoring 
visits, Sponsor and its designees may review source documents to ensure the accuracy and 
validity of data recorded on the CRFs, including eCRFs. Sponsor and its designees will maintain 
confidentiality of Subject source documents.  
10.7 Maintenance of Study Documentation and Retention of 
Records 
Sites will maintain adequate and accurate Study documents, records, and data generated by 
the Sites during the Study, including electronic and hard copies of documents, with such 
documents, records, and data subject to inspection by Sponsor and its designees, and local, 
regional, and national regulatory bodies. Investigators will also maintain Study documents and 
records in accordance with their local EC requirements, regulations of local, regional, and 

 
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national regulatory bodies and agencies, the CSA, and the Protocol. At a minimum, the 
following Study documents will be maintained by each Site: 
• Protocol and amendments, including current Protocol; 
• current Amplifi System IFU; 
• local EC approval(s); 
• local EC correspondence; 
• current, local EC-approved ICF(s) including translation certification, if applicable; 
• current local EC membership roster(s);  
• CSA and amendments, including current CSA; 
• Investigator agreement(s), including current Investigator agreement; 
• updated Investigator curriculum vitae(s); 
• confidentiality agreement(s), if separate from CSAs; 
• updated financial disclosures; 
• Site Personnel Signature and Delegation of Responsibilities Log; 
• current ICF form and signed ICFs; 
• source documentation, including Subject clinical charts, medical records, laboratory 
records, test results, and radiology and pathology reports; 
• current laboratory certification(s) and normals, if applicable; 
• Sponsor correspondence;  
• documentation of Investigator and Site Personnel training; 
• Monitoring Visit Log; and 
• Amplifi System storage and accountability logs and records. 
Investigators will maintain adequate and accurate Study documents, records, and data, 
including source documents, of all observations and data Investigators generate during the 
Study, including electronic and hard copy documents, with such documents, records, data, and 
source documents subject to inspection by Sponsor and its designees, and local, regional, and 
national regulatory bodies. Investigators will also maintain Study documents and records in 
accordance with their local EC requirements, regulations of local, regional, and national 
regulatory bodies and agencies, the CSA, and the Protocol. At a minimum, the following Study 
documents will be maintained by each Investigator: 
• Protocol and amendments; 
• Investigator agreement(s); 
• Investigator curriculum vitae(s); 
• Amplifi System IFU; 
• Amplifi System labeling 
• Signed ICFs 
• CRFs; 
• all Study-related correspondence;  
• observations and data generated by Investigator during the Study; and 
• other documents pertaining to the conduct of the Study. 

 
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Investigator shall not dispose of any records relevant to the Study without written permission 
from Sponsor and until providing an opportunity for Sponsor to collect such records.  
10.8 Protocol Amendments  
Significant changes to the Protocol during the Study will be made by formal protocol 
amendment. Sponsor will collect information on the appropriateness and completeness of the 
Protocol from Investigators and Site Personnel and update the Protocol, as needed, to ensure 
Subject safety and the integrity of Study data. Sponsor will provide proposed Protocol 
amendments to Central EC for review and approval. 
10.9 Protocol Deviations and Investigator and Site Suspension and 
Termination  
Investigators, Sites, and Site Personnel will conduct the Study in accordance with the Protocol. 
All deviations from the Protocol will be reported to the Sponsor by Investigators and Site 
Personnel by submitting a Protocol deviation through the Study EDC System. Sites and Site 
Personnel will notify their local EC of Protocol deviations in accordance with the Central EC 
requirements. 
If Investigators commit serious or repeated Protocol deviations that may affect the safety of 
Subjects or the integrity of Study data, or if an Investigator is not complying with the 
Investigator’s Agreement, applicable local, regional, and national regulatory requirements, or 
any other conditions imposed by the EC or the Sponsor, Sponsor will recommend corrective 
action, including providing additional training to Investigators. Investigators will notify the EC of 
any corrective action, as required by the EC and the Sponsor. If there is an inadequate 
response or action from the Investigator, Sponsor will suspend shipment of Amplifi System 
components to the Site until an appropriate response or action is obtained. If serious or 
repeated deviations from the Protocol by an Investigator continue to occur, even after corrective 
action recommendations and apparently adequate responses and actions, or if Sponsor 
determines that there is an unacceptable risk to Subject safety if an Investigator were to 
continue to enroll Subjects or participate in the Study, Sponsor may terminate an Investigator’s 
participation in the Study. After termination of the Investigator’s participation, Sponsor may seek 
another Investigator at the Site or terminate the Study at the Site. In such cases, Sponsor will 
notify the EC, appropriate regulatory authorities, and other participating Sites, as required by 
local, regional, and national regulations and the Sponsor.  
If Sites and Site Personnel commit serious or repeated Protocol deviations that may affect the 
safety of Subjects or the integrity of Study data, or if a Site or Site Personnel are not complying 
with the Investigator’s Agreement, applicable local, regional, and national regulatory 
requirements, or any other conditions imposed by their local EC or the Sponsor, Sponsor will 
recommend corrective action, including providing additional training to Site Personnel. The Site 
and Site Personnel will notify their local EC of any corrective action, as required by their local 
EC and the Sponsor. If there is an inadequate response or action from the Site, Sponsor will 
suspend shipment of Amplifi System components to the Site until an appropriate response or 
action is obtained. If serious or repeated deviations from the Protocol by a Site continue to 
occur, even after corrective action recommendations and apparently adequate responses and 
actions, or if Sponsor determines that there is an unacceptable risk to Subject safety if a Site 
were to continue to enroll Subjects or participate in the Study, Sponsor may terminate the Study 

 
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at the Site. In such cases, Sponsor will notify their local EC, appropriate regulatory authorities, 
and other participating Sites, as required by local, regional, and national regulations and the 
Sponsor.  
10.10 Study Termination Activities 
A Study termination Site visit will be performed prior to Study termination to ensure all Study 
data has been transmitted to Sponsor by Site. The following Study termination activities will be 
performed prior to completion of the Study at a Site in accordance with Sponsor’s procedures:  
• ensure that all required CRF and eCRFs have been completed and submitted; 
• ensure final disposition of Amplifi Systems and components; 
• confirm with Investigators and Sites their obligation to retain Study records in accordance 
with their local EC requirements; and 
• prepare a final Study report and submit to the Sponsor and the Central EC. 
11.0 Ethical and Regulatory Requirements  
11.1 Ethical Requirements 
This study will be conducted in accordance with Good Clinical Practices (GCP), an international 
ethical and scientific quality standard for designing, conducting, recording and reporting clinical 
studies that involved human subjects. 
11.2 EC and Other Regulatory Requirements 
Approval of the EC, as well as any other required regulatory body or agency will be obtained 
prior to initiation of the Study at any Site. Copies of all submissions to, and correspondence with 
EC (including approvals) and other regulatory bodies or agencies (if any) will be sent to Sponsor 
and maintained on file at the Site.  
11.4 Vulnerable Populations 
No patients from vulnerable populations will be recruited for the Study. 
11.5 Confidentiality 
No individually identifiable or confidential patient or Subject data collected as part of the Study 
will be released publicly by Sponsor. Unique Study identification codes will be assigned to all 
Subjects. Sites will use Subject’s Study identification codes on all Study-related materials. 
Subject identifiable data will be de-identified by the Site prior to submission to Sponsor. 
12.0 Adverse Events and Adverse Device Effects 
All Subjects participating in this study will be assessed for adverse events from the point of 
enrollment through the follow-up period. Assessments will be performed by the site Principal 
Investigator. An Independent Safety Board shall monitor the overall safe conduct of the study. 
The ISB will also make recommendations for or against trial continuation, if required. All serious 
adverse events (see the definition of serious adverse event, below) occurring after the point of 

 
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enrollment through study participation must be reported accordingly. 
12.1 Definitions 
12.1.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical sign or abnormal lab finding in a Subject, regardless of whether the 
AE was related to the Amplifi System or Study. Stable, chronic, pre-existing conditions will not 
be categorized as AEs. However, worsening of these conditions occurring during the Study 
Period may be categorized as AEs.  
Investigators will categorize AEs or suspected AEs as unrelated, possibly related, probably 
related, or definitely related to the Amplifi System using the relational criteria summarized in 
Section 12.2 Classification of Adverse Events.   
Investigators will document all AEs and suspected AEs occurring during the Study Period on the 
appropriate CRF regardless of whether the AE or suspected AE was related to the Amplifi 
System or Study. Documentation of the AE or suspected AE will include the characterization of 
the likelihood the AE was related to the Amplifi System. 
Investigators will follow all AEs or suspected AEs until they have resolved, have a stable level of 
sequelae or, in the Investigator’s opinion, are no longer clinically relevant. 
 
12.2.2 Device Adverse Events  
For AEs or suspected AEs that are categorized by an Investigator as definitely, possibly, or 
probably related to the Amplifi System, the Medical Monitor will adjudicate whether the AE or 
suspected AE is an ADE.  
Investigators will review all reports of Amplifi System deficiencies, malfunctions, or unplanned 
stoppages and determine if an AE occurred during the reported event. If an Investigator 
determines that an AE or possible AE occurred, they will document the AE or possible AE on 
the appropriate CRF. The Investigator will also document, in their opinion, the likelihood the AE 
or possible AE was related to the Amplifi System using the relational criteria summarized in 
Section 12.2 Classification of Adverse Events.  
Mild-moderate hand, wrist, arm, neck, or face swelling that resolves within 7 days after the end 
of the Amplifi System treatment period will not be categorized as an AE.   
Investigators will follow all ADEs or suspected ADEs until they have resolved, have a stable 
level of sequelae or, in the Investigator’s opinion, are no longer clinically relevant. 
12.2.3 Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence, unintended 
disease or injury, or untoward clinical sign or abnormal lab finding in a Subject, that:  
• 
causes death;  
• 
causes a life-threatening illness or injury; 
• 
results in permanent disability; 
• 
requires the need for hospitalization or prolongs a hospitalization; 

 
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• 
requires intervention to prevent a life-threatening illness or injury, or permanent 
disability; or 
• 
is determined to be an SAE by both an Investigator and the Medical Monitor, 
regardless of whether the occurrence, disease, injury, or untoward clinical sign was related to 
the Amplifi System or the Study. 
Note:  planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
Investigators will categorize all SAEs or suspected SAEs as unrelated, possibly related, 
probably related, or definitely related to the Amplifi System using the relational criteria 
summarized in Section 12.2 Classification of Adverse Events.   
Investigators will document all SAEs or suspected SAEs occurring during the Study Period on 
the appropriate CRF regardless of whether the SAE or suspected SAE was related to the 
Amplifi System or Study. Documentation of the SAE or suspected SAE will include the 
characterization of the likelihood the SAE or suspected SAE was related to the Amplifi System. 
Mild-moderate hand, wrist, arm, neck, or face swelling that resolves within 7 days after the end 
of the Amplifi System treatment period will not be categorized as an SAE.   
Investigators will follow all ASEs or suspected SAEs until they have resolved, have a stable 
level of sequelae, or, in the Investigator’s opinion, are no longer clinically relevant. 
12.2.4 Serious Device Adverse Effects 
For SAEs or suspected SAEs that are categorized by an Investigator as definitely, possibly, or 
probably related to the Amplifi System, the Medical Monitor will adjudicate whether the SAE or 
suspected SAEs is a SADE.  
Investigators will review all reports of Amplifi System deficiencies, malfunctions, or unplanned 
stoppages and determine if an SAE or suspected SAE occurred. If an Investigator determines 
that an SAE or suspected SAE occurred, they will document the SAE or suspected SAE on the 
appropriate CRF. The Investigator will also document, in their opinion, the likelihood the SAE 
was related to the Amplifi System using the relational criteria summarized in Section 12.2 
Classification of Adverse Events and the Medical Monitor will adjudicate with PI whether the 
SAE or suspected SAE is a SADE. 
Investigators will follow all SADEs and suspected SADEs until they have resolved, have a stable 
level of sequelae, or, in the Investigator’s opinion, are no longer clinically relevant. 
12.2.5 Unanticipated Serious Adverse Device Effect  
An unanticipated serious adverse device effect (USADE) is a SADE which, by its nature, 
incidence, severity, or outcome, has not been identified or fully identified during the Amplifi 
System risk analysis process and is not included or fully included in the Amplifi System risk 
analysis documents as a potential SADE.  
For SAEs or suspected SAEs that are categorized by an Investigator as possibly, probably, or 
definitely related to the Amplifi System, Investigators will characterize whether the SAE or 
suspected SAE is definitely not, possibly, probably, or definitely a SADE. Investigators will 
document the characterization on the appropriate CRF. The Investigator’s characterization of 
these events in the appropriate CRF(s) along with hospital source records will be reviewed and 
adjudicated by to the Medical Monitor. 

 
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Investigators will follow all USADEs and suspected USADEs until they have resolved, have a 
stable level of sequelae, or, in the Investigator’s opinion, are no longer clinically relevant. 
12.2.6 Potential Adverse Events and Serious Adverse Events 
AEs and SAEs that may occur during the placement, operation, use, or removal of the Amplifi 
System, or the subsequent creation and use of an AVF made with a vein treated with the Amplifi 
System have been identified during the Amplifi System risk analysis process, included in the 
Amplifi System risk analysis documents, and are summarized here: 
• 
death; 
• 
vascular injury; 
• 
bleeding; 
• 
pneumothorax; 
• 
air embolism; 
• 
vascular thrombosis; 
• 
thromboembolism; 
• 
hemolysis; 
• 
anemia; 
• 
thrombocytopenia; 
• 
Inflow Catheter and Distal Outflow Catheter dislodgement; 
• 
Amplifi System component fracture or laceration; 
• 
Inflow Catheter and Distal Outflow Catheter tunnel or skin exit site infection; 
• 
Amplifi System thrombosis; 
• 
Amplifi System component failure or replacement; 
• 
unplanned re-hospitalization or prolonged hospitalization;  
• 
unplanned surgery or interventional procedure;  
• 
AVF bleeding or thrombosis; 
• 
AVF infection; 
• 
ipsilateral vascular access steal syndrome after creation of an AVF; 
• 
AVF aneurysm or pseudoaneurysm formation;  
• 
allergic reaction; and 
• 
drug toxicity. 
AEs and SAEs that may occur during the placement, operation, use, or removal of the Amplifi 
System, or the subsequent creation and use of an AVF made with a vein treated with the Amplifi 
System may be related to: 
• 
testing required prior to Amplifi System treatment;  
• 
the Amplifi System placement procedure; 
• 
the operation and use of the Amplifi System; 
• 
procedures where the Amplifi System is evaluated, such as venography; 
• 
the Amplifi System removal procedure; 
• 
surgery to create a Study AVF; and 

 
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• 
cannulation of a Study AVF. 
AEs and SAEs that may occur during the placement, operation, use, or removal of the Amplifi 
System, or the subsequent creation and use of an AVF made with a vein treated with the Amplifi 
System may or may not be related to the Amplifi System, based on the relational criteria 
summarized in Section 12.2 Classification of Adverse Events. 
12.2 Classification of Adverse Events 
12.2. Grading of AEs 
Investigators will grade adverse events using the following scale. 
• 
Mild: easily tolerated 
• 
Moderate: sufficiently discomforting to interfere with daily activities 
• 
Severe: prevents normal daily activities 
12.2.2 Relational Criteria 
Investigators will document their opinion of the likelihood of the relationship of 
all adverse events to the Amplifi System using the criteria summarized below: 
• 
Unrelated: a temporal relationship between the adverse event and the 
placement, use, or removal of the Amplifi System is not clear, or there 
is evidence of potential alternative causes for the adverse event such 
as concurrent medication or illness 
• 
Possibly related: a temporal relationship between the adverse event 
and the placement, use, or removal of the Amplifi System is not clear 
and potential alternative causes for the adverse event such as 
concurrent medication or illness are possible 
• 
Probably related: a temporal relationship between the adverse event 
and the placement, use, or removal of the Amplifi System is clear and 
potential alternative causes for the adverse event such as concurrent 
medication or illness are possible but unlikely 
• 
Definitely related: a temporal relationship between the adverse event 
and the placement, use, or removal of the Amplifi System is clear and 
no potential alternative causes for the adverse event such as 
concurrent medication or illness are possible 
12.3 Amplifi System Unplanned Stoppages, Malfunctions, and 
Potential Device Deficiencies 
All Amplifi System unplanned stoppages, including Pump stoppages, that occur and are 
observed during the Study, whether they are associated with an AE, ADE, SAE, SADE, or 
USADE, shall be documented by the Investigator and other Site Personnel by submitting a 
completed CRF in the Study EDC System. 
All Amplifi System malfunctions and deficiencies that are related to the identity, quality, 
durability, reliability, safety, or performance of the Amplifi System that occur and are observed 
during the Study, whether they are associated with an AE, ADE, SAE, SADE, or USADE, shall 

 
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be documented by the Investigator and other Site Personnel by submitting a completed CRF in 
the Study EDC System.  The Medical Monitor shall adjudicate device relatedness in 
accordance with protocol definitions.  
12.10 Reporting  
12.10.1 Reporting of AEs 
Investigators will report AEs or suspected AEs to Sponsor as soon as possible after 
learning of the event by submitting a completed CRF through the Study EDC System. 
Investigators will report AEs or suspected AEs to Sponsor regardless of whether they 
are related to the Amplifi System or Study.  
Investigators will characterize AEs or suspected AEs as unrelated, possibly related, 
probably related, or definitely related to the Amplifi System on the AE CRF, using the 
relational criteria summarized in Section 12.2 Classification of Adverse Events.   
Investigators will report AEs or suspected AEs to the Central ECEC, in accordance 
with the Central ECEC requirements.  
12.10.2 Reporting of ADEs 
The Medical Monitor will report ADE adjudication decisions to the Investigator and 
Sponsor or Sponsor delegate in accordance with the charter.  
Investigators will report ADEs to the Central EC in accordance with the Central EC 
requirements.  
12.10.3 Reporting of SAEs 
Investigators will report SAEs or suspected SAEs to the Sponsor (or Sponsor 
delegate) as soon as possible, preferably within 24 hours, but no later than two (2) 
working days of the Investigator or Site Personnel becoming aware of an SAE or 
suspected SAE, by: 
• calling Sponsor; 
• emailing Sponsor; 
• submitting a completed CRF through the Study EDC System, including 
documentation of the call and email to Sponsor or Sponsor delegate; 
Investigators will report SAEs or suspected SAEs regardless of whether they are 
related to the Amplifi System or Study.   
After notifying Sponsor or (Sponsor delegate) and Medical Monitor of an SAE or 
suspected SAE, Investigators will provide a written report of the SAE or suspected 
SAE to Sponsor within five (5) working days of the SAE or suspected SAE through 
the Study EDC System. Investigators will also transmit the written report to the 
Medical Monitor in accordance with the charter.   
Investigators will report SAEs or suspected SAEs that, in their opinion, possibly 
related, probably related, or definitely related to the Amplifi System to the Medical 
Monitor for adjudication as SADEs through the Study EDC System, using the 
relational criteria summarized in Section 12.3.  
Investigators will report SAEs or suspected SAEs to the Central EC, in accordance 

 
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with their local EC requirements. Sponsor will report all SAEs and communicate 
relevant SAE information to the appropriate regulatory agencies and bodies in 
accordance with relevant local, regional, and national regulatory requirements. 
12.10.4 Reporting of SADEs 
The Medical Monitor will report SADE adjudication decisions to the Investigator and 
Sponsor or Sponsor delegate in accordance with the charter.  
The Medical Monitor will report SADEs to the Central EC in accordance with EC 
requirements.  
Sponsor will report all SADEs and communicate relevant SADE information to the 
appropriate regulatory agencies and bodies in accordance with relevant local, 
regional, and national regulatory requirements.  
12.10.5 Reporting of USADEs 
Investigators will report SAEs or suspected SAEs that are characterized by the Investigator as 
possibly, probably, or definitely related to the Amplifi System, and also characterized as 
possibly, probably, or definitely a SADE, to Sponsor (or Sponsor delegate) as soon as possible, 
preferably within 24 hours, but no later than two (2) working days after Investigator or other Site 
Personnel becoming aware of a USADE or suspected USADE, by: 
• calling Sponsor; 
• emailing Sponsor; 
• submitting a completed CRF through the Study EDC System, including 
documentation of the call and email to Sponsor; and 
 
After reporting a USADE or suspected USADE to Sponsor, Investigators will provide a written 
report about the USADE or suspected USADE to Sponsor within five (5) working days after 
Investigator or other Site Personnel becoming aware of the USADE or suspected USADE.   
With Sponsor communication, Investigators will also report USADEs or suspected 
USADEs to the Central EC, in accordance with the EC requirements.  
Sponsor will report all USADEs and communicate relevant USADE information to the 
appropriate regulatory agencies and bodies in accordance with relevant local, 
regional, and national regulatory requirements. 
12.10.6 Reporting of Amplifi System Unplanned Stoppages and 
Malfunctions 
Investigators will report all Amplifi System unplanned stoppages or malfunctions (including 
component malfunctions) on the appropriate CRF and to Sponsor as soon as possible, 
preferably within 48 hours, but no later than three (3) working days after Investigator or other 
Site Personnel becoming aware, by: 
• calling Sponsor; 
• emailing Sponsor; and 
• submitting a completed CRF through the Study EDC System, including 
documentation of the call and email to Sponsor. 

 
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After notifying Sponsor (or Sponsor delegate) and Medical Monitor of an Amplifi 
System unplanned stoppage or malfunction, Investigators will provide a written 
report of the Amplifi System unplanned stoppage or malfunction to Sponsor and 
Medical Monitor within five (5) working days of the unplanned stoppage or 
malfunction through the Study EDC System.  
Investigators will also report all Amplifi System unplanned stoppages and 
malfunctions to the Centrall EC in accordance with the EC requirements.  
Sponsor will report all Amplifi System unplanned stoppages and malfunctions to the 
appropriate regulatory agencies and bodies in accordance with relevant local, 
regional, and national regulatory requirements. 
14.0 Data Analysis and Statistical Considerations 
14.1 Study Size Calculation 
This study is not powered for a specific outcome, given the small number of Subjects in the 
study. Rather, the goal of this study is to collect additional data on multiple effectiveness and 
safety measures as described in Section 4.1 Study Objectives.  
 
The effectiveness measure of the Study is to determine percent change in cephalic vein 
diameter from baseline examination (pre-treatment ultrasound) to end treatment (immediately 
prior to Amplifi System removal and AVF creation, with Amplifi System running at final speed). 
The Sponsor reviewed results of Amplifi System treatment during the First-in-Human Study and 
determined that up to ten (10)  Inpatient Subjects would be sufficient to evaluate the safety and 
effectiveness of the Amplifi System.  
 
14.2 Statistical Methods 
14.2.1 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively using the number of 
available observations (n), means, standard deviations, medians, minimum, and maximum 
values for continuous variables, and frequencies and percentages for categorical variables. 
14.2.2 Analysis of Effectiveness Measures 
In general, descriptive statistics will be provided. Categorical variables will be summarized using 
frequencies and percentages of     Subjects in each category. Continuous variables will be 
summarized using descriptive statistics and 95% confidence intervals for means will be 
computed where appropriate. Statistical modeling will be used to identify potential predictors of 
treatment success as well as safety events and effectiveness. 
 
A subgroup analysis will be performed for patients who received  Amplifi System treatment but 
have Amplifi System stoppage and AVF creation prior to the specified treatment duration. 
Patients who received Amplifi treatment at the specified treatment duration (e.g., completed the 
maximum treatment duration (i.e., 72 hours) without having an AVF created will be reported, 

 
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along with the reasons for not having one (e.g., inadequate vein diameter, other factors). 
14.2.3 Analysis of Safety Measures 
All safety data for the Subjects will be summarized descriptively and the number of AEs, ADEs, 
SAEs, and SADEs will be reported as a single group. The AEs, ADEs, SAEs, and SADEs will be 
grouped by type, and the number and percentage of Subjects experiencing each type will be 
reported as a single group. An assessment of the severity and causative relation to Amplifi 
System placement, treatment, and removal, and Study AVF creation and use for each AE, ADE, 
SAE, and SADE will be reported.  
 14.2.4 Handling of Missing Data  
Every effort will be undertaken to ascertain completeness of data collection and limit premature 
discontinuations. All analyses will utilize only actual Subject data which is collected, and no 
imputation of missing data will be performed. However, partial dates in medication and adverse 
events may be imputed. The imputation principles will be described in the Statistical Analysis 
Plan. 
15.0 Study Responsibilities 
15.1 Sponsor Responsibilities 
The Sponsor is responsible for: 
• 
manufacturing, packaging, and sterilizing Amplifi System components; 
• 
preparing the Protocol and updating the Protocol, as needed, by providing 
proposed Protocol amendments to Investigators for submission to their local 
ECs for review and approval; 
• 
selecting Investigators and Sites; 
• 
maintaining an updated list of Investigators and Sites; 
• 
selecting consultants for the Study; 
• 
establishing regulatory standards consistent with local, regional, and national 
governmental regulations for Sites; 
• 
providing financial support to Investigators and Sites, along with 
product liability and no-fault clinical study insurance; 
• 
conducting Site initiation visits prior to Subject enrollment; 
• 
providing Investigators with a signed Clinical Study Agreement (CSA), 
Investigator’s Brochure, Protocol, all necessary CRFs, and all other 
Study-related documents necessary to conduct the Study; 
• 
providing the Amplifi System, including all components necessary for Amplifi System 
placement, operation, use, and removal, to the Sites; 
• 
providing Study-related accessory devices and materials necessary for Amplifi System 
placement, operation, use, and removal to the Sites for those Study-related accessory 
devices that are not reasonably available at the Site or the responsibility of the 
Investigator or Site to obtain or provide; 
• 
providing instructions and training to Investigators and other Site Personnel 

 
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involved in the Study on the proper placement, operation, use, care, and 
removal of the Amplifi System (including all components), and other Study-
related accessory devices, either directly or through consultants; 
• 
providing revisions to the ICF to Investigators, as needed; 
• 
maintaining a Clinical Study Master File;  
• 
granting or restricting the right of Site Personnel to access the Study EDC System 
along with Data Manager and database; 
• 
providing Study monitoring and performing or overseeing all aspects of data quality 
assurance, including data collection, data auditing and monitoring at Sites, either 
directly or through consultants; 
• 
reviewing data submitted by Investigators and Sites for accuracy and completion, and 
reviewing source documents to ensure accuracy and validity of all data recorded on 
CRFs, as needed; 
• 
performing Site monitoring, either directly or through consultants;  
• 
recommend corrective actions if serious or repeated deviations from the Protocol by a 
Site occur, or if a Site is not complying with the Investigator’s Agreement, applicable 
local, regional, and national regulatory requirements, or any other conditions imposed 
by the local EC or the Sponsor; 
• 
terminate an Investigator or Site’s participation in the Study if serious or repeated 
deviations from the Protocol by an Investigator continue to occur, even after corrective 
action recommendations and apparently adequate responses and actions, or if Sponsor 
determines that there is an unacceptable risk to Subject safety if an Investigator were to 
continue to enroll Subjects or participate in the Study;  
• 
reviewing all reports of known or suspected AEs, SAEs, SADEs, and USADEs;  
• 
reviewing all reports of known or suspected Amplifi System deficiencies, malfunctions, 
and unplanned stoppages;  
• 
communicating information and reporting all SAEs, SADEs, and USADEs to the 
appropriate regulatory agencies and bodies in accordance with relevant local, regional, 
and national regulatory requirements;  
• 
completing the Interim Analysis;  
• 
completing the Final Analysis; and 
• 
performing Study termination visits prior to Study termination; and 
• 
reviewing all publications and presentations related to the Study. 
15.2 Investigator Responsibilities 
The Investigator is responsible for: 
• 
providing Sponsor with current curriculum vitae; 
• 
signing the Protocol and the Investigator’s Agreement in the appropriate locations; 
• 
receiving adequate training on the design, function, storage, placement, use, operation, 
maintenance, care, cleaning, monitoring, interaction with, removal, and disposal of the 
Amplifi System and its components before enrolling Subjects;  
• 
understanding the Protocol, carrying out the Study in accordance with the Protocol, and 

 
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ensuring the Protocol is being properly followed during the Study; 
• 
obtaining local EC approval of the Study before enrolling Subjects; 
• 
keeping the Sponsor informed of all their local EC actions concerning the Study;  
• 
determining if a patient meets all the inclusion criteria and none of the exclusion criteria 
prior to enrollment; 
• 
obtaining informed consent from Subjects; 
• 
updating and revising the ICF and re-consenting Subjects, as necessary; 
• 
determining if patients are indicated for creation of a wrist or distal forearm 
radiocephalic AVF based on their standard practice, prior to enrolling patients as 
Subjects; 
• 
determining if a Subject’s internal jugular vein is suitable for Amplifi Inflow Catheter 
insertion; 
• 
establishing an Amplifi System treatment time for each Subject prior to initiating 
treatment; 
• 
ensuring Site Personnel carrying out Study activities have appropriate experience and 
training; 
• 
performing all tests, assessments, procedures, interventions, and surgeries that are 
specified in the Protocol to be performed by Investigator, including: 
o placing of the Amplifi System; 
o initiating Amplifi System treatment; 
o obtaining contrast venography during Amplifi System placement, evaluation, and 
removal procedures; 
o obtaining outflow vein measurements using B-mode ultrasonography during 
Amplifi System treatment, as needed; 
o removing the Amplifi System; and 
o creating the Study AVF, 
o overseeing the performance of other tests, assessments, procedures, and 
surgeries specified in the Protocol or needed by Subjects; 
• 
providing patient care for Subjects in accordance with the requirements and guidelines 
of Sites, federal, state, and local regulatory bodies and agencies, and reasonable 
standards of care; 
• 
providing or overseeing instruction and training on the monitoring and care of the 
Amplifi System to Subjects and their homecare providers, as needed; 
• 
ensuring that Study observations and findings are recorded correctly and completely in 
CRFs; 
• 
maintaining accurate, complete, and current Study documents as specified in Section 
10.7 and ensuring the information recorded and submitted to the Sponsor is 
representative of the Subject’s record and other supporting documentation;  
• 
providing Sponsor with the Study documents and records necessary for a complete 
review of the work related to the Study at the Site by Investigator; 
• 
meeting all Study reporting obligations, including: 
o reporting actual or suspected Amplifi System deficiencies, malfunctions, or 

 
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unplanned stoppages to Sponsor, as specified in Section 12.10 Reporting;  
o reporting actual or suspected AEs, SAEs, SADEs, and USADEs to Sponsor, as 
specified in Section 12.10 Reporting and submitting accurate, complete, and 
timely adverse event reports to Sponsor; and  
o submitting all other reports to the Sponsor that are required, 
• 
grading adverse events using the scale summarized in Section 12.2 Classification of 
Adverse Events; 
• 
determining whether, in the opinion of the Investigator, an adverse event is related to 
the Amplifi System or Study procedures or surgeries using the criteria summarized in 
Section 12.2 Classification of Adverse Events; 
• 
determining whether, in the opinion of the Investigator, an Amplifi System-related 
complication is an Amplifi System-related major complication; 
• 
following all known and suspected AEs, ADEs, SADEs, and USADEs until they have 
resolved, have a stable level of sequelae, or, in the Investigator’s opinion, are no longer 
clinically relevant; 
• 
understanding and accepting the obligations of continuing review by their local EC while 
conducting the Study, including notifying their local EC of any changes to the Protocol 
per their local EC requirements, and submitting required reports to their local EC; 
• 
reporting deviations from the Protocol to the Sponsor, as specified in Section 10.9 
Protocol Deviations and Investigator and Site Suspension and Termination; 
• 
notifying their local EC of Protocol deviations in accordance with their local EC 
requirements; 
• 
reporting known and suspected AEs, SAEs, SADEs, and USADEs to their local EC in 
accordance with their local EC requirements; 
• 
understanding and complying with all applicable local, regional, and national regulatory 
requirements while conducting the Study; 
• 
communicating SAE, SADE, and USADE information and reporting all SAEs, SADEs, 
and USADEs to the appropriate regulatory agencies and bodies in accordance with 
relevant local, regional, and national regulatory requirements; 
• 
recording the reason for withdrawal in source documentation and on the appropriate 
CRF for Subjects that withdraw from the Study;  
• 
understanding the requirements for Amplifi System device and component 
accountability; 
• 
returning all unused Amplifi System components to Sponsor at the end of the Study or 
at the end of the participation of a Site in the Study; 
• 
submitting a Study summary to the Sponsor and their local EC promptly after the 
completion of the Study or at the end of the participation of a Site in the Study;  
• 
providing data for publications and presentations related to the study, as needed by 
Sponsor and other Investigators; and 
• 
reviewing all publications and presentations related to the study, as needed by Sponsor 
and other Investigators. 
15.3 Site Personnel Responsibilities 

 
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Site Personnel are responsible for: 
• 
understanding the Protocol, carrying out the Study in accordance with the Protocol, and 
ensuring the Protocol is being properly followed during the Study; 
• 
receiving adequate training on the design, function, storage, placement, use, operation, 
maintenance, care, cleaning, monitoring, interaction with, removal, and disposal of the 
Amplifi System and its components before participating in the care of Subjects; 
• 
reviewing the Amplifi System IFU prior to participating in the storage, placement, use, 
operation, maintenance, care, cleaning, monitoring, interaction with, removal, and 
disposal of the Amplifi System and its components; 
• 
providing instruction and training on the monitoring and care of the Amplifi System to 
Subjects and their homecare providers, as needed. 
• 
meeting all Study reporting obligations, including: 
o reporting deviations from the Protocol to the Sponsor, as specified in Section 
10.9 Protocol Deviations and Investigator and Site Suspension and 
Termination; 
o reporting actual or suspected SAEs, SADEs, and USADEs to Investigators, as 
specified in Section 12.10 Reporting; 
o reporting actual or suspected Amplifi System deficiencies, malfunctions, or 
unplanned stoppages to Investigators, as specified in Section 12.10 Reporting; 
and 
o submitting all other reports to the Sponsor that are required; and 
• 
providing Study documents and records necessary for a complete review of the work 
related to the Study at the Site to Sponsor. 
15.4 Site Responsibilities 
Sites are responsible for: 
• 
providing and maintaining adequate resources to the Investigator at the Site to conduct 
the Study in accordance with the Protocol; 
• 
ensuring Site Personnel carrying out Study activities have appropriate experience and 
training;  
• 
maintaining copies of all submissions to, and correspondence with, local ECs (including 
approvals) and other regulatory bodies or agencies (if any) on file at the Site; 
• 
making Site available for a Site initiation visit prior to Subject enrollment; 
• 
keeping Amplifi System components used in the Study stored in a secure area separate 
from other medical devices in a location with restricted access that is accessible only by 
authorized Site Personnel and maintain associated Amplifi System storage and 
accountability logs and records; 
• 
using a Subject’s Study identification codes on all Study-related materials and de-
identifying data prior to submission to Sponsor. 
• 
providing Subjects treated with the Amplifi System with 24 hours per day, 7 days per 
week access for consultation with an Investigator or trained Site Personnel to answer 
questions from Subjects and their caregivers related to the Amplifi System, assist 
Subjects in responding to Amplifi System alarms and for other unanticipated events or 

 
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Subject concerns, and assisting in the scheduling of care for Subjects; 
• 
maintaining Study documents and original documentation supporting the data recorded 
on CRFs at the Sites;   
• 
keeping original and updated signed ICFs for each Subject on file and available for 
inspection by Sponsor or its designees;  
• 
retaining Study records in accordance with their local EC requirements;  
• 
notifying their local ECs of Protocol deviations in accordance with their local EC 
requirements; and 
• 
upon request, providing to the Sponsor the necessary Study documents and records for 
a thorough review of the work related to the Study at the Site.  
15.5 Independent Safety Board (ISB) and Medical Monitor (MM) 
Responsibilities 
The ISB shall consist of a minimum of 3 physicians who are experts in the fields of nephrology, 
vascular access surgery, and diagnostic and interventional radiology, who are not participating 
in the study, and who do not have any investment with the study Sponsor. Membership will be 
restricted to individuals who have no significant conflict of interest (COI) as described in the COI 
section. One member of the ISB shall serve as the Chair and one member shall serve as the 
Medical Monitor with an adjudication role but no voting role. 
16.0 Risks and Benefits 
16.1 Background 
The Amplifi System has not been authorized for commercial distribution in the US by the FDA 
nor has it been authorized for commercial distribution by any other regulatory agency. Bench, 
laboratory, and animal testing has been performed on the Amplifi System in studies and a first-
in-human clinical study has been completed, as summarized in this Protocol and in the Amplifi 
System Investigator’s Brochure. 
 
A risk analysis has been conducted. The risks associated with the placement, operation, use, 
and removal of the Amplifi System have been identified by performing a Failure Mode and Effect 
Analysis (FMEA) and Risk Analysis, as a risk/benefit assessment. Risks have been proven, 
minimized, or eliminated through appropriate design control, confirmed by bench, laboratory, 
and animal testing, and a first-in-human clinical study. 
 
The Amplifi System shares many similarities with extracorporeal blood pump systems and 
catheters that convey blood from patients to pumps and to return blood from pumps to patients, 
including devices for hemodialysis (including home hemodialysis), extracorporeal membrane 
oxygenation (ECMO), extracorporeal circulatory support, including the following similarities: 
• 
Amplifi System catheters, hemodialysis catheters, ECMO catheters, and extracorporeal 
circulatory support catheters are designed for insertion into an internal jugular vein with 
tip placement in the superior vena cava or right atrium; 
• 
Amplifi System catheters, hemodialysis catheters, ECMO catheters, and extracorporeal 

 
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circulatory support catheters are designed to connect to extracorporeal blood pumps; 
• 
the Amplifi System pump and catheters and some hemodialysis pumps and catheters, 
ECMO pumps and catheters; and extracorporeal circulatory support pumps and 
catheters are designed to remove and return patient’s blood at similar flow rates; 
• 
Amplifi System catheters, hemodialysis catheters, and ECMO catheters are intended for 
chronic use, with hemodialysis catheters routinely used for many months and even years 
in some cases; and 
• 
Patients and caregivers can be trained to perform Amplifi System and hemodialysis 
treatment in an inpatient setting. 
 
The risk profile of the Amplifi System is similar or lower than hemodialysis blood pumps and 
catheters (including those for home use), and ECMO and extracorporeal circulatory support 
pumps and catheters.   
16.2 Review of Literature 
Sponsor reviewed the published safety data associated with hemodialysis blood pumps and 
catheters, ECMO blood pumps and catheters, and circulatory support blood pumps and 
catheters. The review of this data is summarized in Attachment 2: Literature Review for 
Safety. The potential safety events reported in these devices used in a similar patient 
population described in Attachment 2: Literature Review for Safety are comparable to 
the potential safety events identified in the risk analysis for the Amplifi System. 
16.3 Benefit Analysis 
Enlarging the cephalic vein in hemodialysis patients prior to forearm radiocephalic AVF through 
Amplifi System treatment has the potential to: 
• 
improve suitability for forearm AVF creation; 
• 
increase the rate of forearm AVF maturation; 
• 
reduce the time required for forearm AVF maturation and use; 
• 
identify pre-existing disease and potentially problematic side branches in veins of the 
upper extremity prior to AVF creation; 
• 
reduce catheter contact time and catheter-related bloodstream infections; 
• 
provide for easier AVF cannulation; 
• 
provide higher hemodialysis session blood flows, which could allow for shorter 
hemodialysis sessions and more efficient hemodialysis 
• 
reduce complications and hospitalization rates related to vascular access; 
• 
reduce the number of procedures and surgeries needed to regain or maintain vascular 
access; 
• 
increase wrist and distal forearm radiocephalic AVF prevalence; 
• 
reduce the overall cost of care; and 
• 
reduce mortality risk. 

 
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The risk benefit ratio for using the Amplifi System in the Study has been deemed appropriate for 
an Investigational Device Exempt clinical study and the risk to Subjects has been appropriately 
mitigated to protect their safety. 
16.4 Risk/Benefit Analysis 
The risks associated with the placement, operation, use, and removal of the Amplifi System 
have been identified, confirmed by bench, laboratory, and animal testing and a first-in-human 
clinical study, are well understood, and have been eliminated or minimized through appropriate 
design control. Based on bench, laboratory, and animal testing of the Amplifi System, and 
results of a first-in-human clinical study, the potential benefits to Subjects from creation of a 
distal forearm radiocephalic AVF with an enlarged cephalic vein that matures rapidly and fully is 
clear and balances the risk. A literature review shows the risk/benefit profile for Subjects 
receiving Amplifi System treatment in the Study is similar to patients currently receiving 
treatment with widely used blood pump systems, including home hemodialysis, ECMO, and 
extracorporeal circulatory devices, providing additional support for the assessment that the 
risk/benefit profile for the use of the Amplifi System in the Study is acceptable. 
16.5 Risk Mitigation 
The Study has been designed to protect the safety and well-being of all Subjects. During the 
Study, potential risks will be controlled and mitigated through extensive training of Investigators 
and other Site Personnel, compliance with the Protocol, monitoring of Subjects during the 
Amplifi System treatment period, and ensuring the availability of additional treatment and 
support measures for Subjects, as needed.  
17.0 Miscellaneous 
17.1 Publication Policy 
The first publication or presentation of the clinical results of the Study shall be made as a joint, 
multi-center publication or presentation by the Investigators at Sites that enrolled Subjects and 
contributed data and analyses, participated in the review of the data, and contributed to the 
preparation of the publication or presentation. All publications and presentations of the clinical 
results of the Study will be reviewed by all Investigators and approved by the Sponsor, and in 
accordance with the Site-specific CSAs. 
 
 

 
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18.0 References 
1. 2020 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. 
National Institutes of Health, National Institute of Diabetes and Digestive and Kidney 
Diseases, Bethesda, MD, 2020. 
2. McCullough KP, Morgenstern H, Saran R, Herman WH and Robinson BM. Projecting ESRD 
Incidence and Prevalence in the United States through 2030. Journal of the American 
Society of Nephrology 2019; 30:127-35, https://doi.org/10.1681/asn.2018050531 
3. Thamer M, Lee TC, Wasse H, Glickman MH, Qian J, Gottlieb D, Toner S and Pflederer TA. 
Medicare Costs Associated with Arteriovenous Fistulas Among US Hemodialysis Patients. 
American Journal of Kidney Diseases 2018; 72:10-8, 
https://doi.org/10.1053/j.ajkd.2018.01.034 
4. Drew DA, Lok CE, Cohen JT, Wagner M, Tangri N, Weiner DE: Vascular access choice in 
incident hemodialysis patients: a decision analysis. J Am Soc Nephrol, 26: 183-191, 2015 
10.1681/ASN.201311123 
5. Mendes RR, Farber MA, Marston WA, Dinwiddie LC, Keagy BA, Burnham SJ: Prediction of 
wrist arteriovenous fistula maturation with preoperative vein mapping with ultrasonography. 
J Vasc Surg, 36: 460-463, 2002 10.1067/mva.2002.126544 
6. Pirozzi N, Mancianti N, Scrivano J, Fazzari L, Pirozzi R, Tozzi M. Monitoring the Patient 
Following Radio-Cephalic Arteriovenous Fistula Creatioin: Current Perspectives. Vasc 
Health and Risk Management 2021:17, 111-121 
7. Li H, Jen S, Ramayya T, Gregory Bowers H, Rotem E. Unanticipated Late Maturation of an 
Arteriovenous Fistula after Creation of Separate Graft Access. Quant Imaging Med Surg, 
2018;8(4):444-446 
8. Tordoir JHM, Zonnebeld N, Van Loom MM, Gallieni M, Hollenbeck M. Surgical and 
Endovascular Intervention for Dialysis Access Maturation Failure During and After 
Arteriovenous Fistula Surgery: Review of the Evidence. Eur J Vasc Endovas Surg, 
2018;55:240-248 
9. Wilmink T, Hollingworth L, Powers S, Allen C, Dasgupta I. Natural History of Common 
Autologous Arteriovenous Fistulae: Consequences for Planning of Dialysis Access. Eur J 
Vasc Endovasc Surg, 2016;51:134-140 
10. Pisoni RL, Zepel L, Fluck R, Lok CE, Kawanishi H, Süleymanlar G, et al.: International 
Differences in the Location and Use of Arteriovenous Accesses Created for Hemodialysis: 
Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). American 
Journal of Kidney Diseases, 71: 469-478, 2018 https://doi.org/10.1053/j.ajkd.2017.09.012 
11. Tan T-W, Farber A: Brachial-Basilic Autogenous Access. Seminars in Vascular Surgery, 24: 
63-71, 2011 10.1053/j.semvascsurg.2011.05.004 
12. Al-Jaishi AA, Oliver MJ, Thomas SM, Lok CE, Zhang JC, Garg AX, et al.: Patency Rates of 
the Arteriovenous Fistula for Hemodialysis: A Systematic Review and Meta-analysis. 
American Journal of Kidney Diseases, 63: 464-478, 2014 10.1053/j.ajkd.2013.08.023 
13. Feldman HI, Joffe M, Rosas SE, Burns JE, Knauss J, Brayman K: Predictors of successful 
arteriovenous fistula maturation. Am J Kidney Dis, 42: 1000-1012, 2003 
10.1016/j.ajkd.2003.07.003 

 
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14. Browne LD, Bashar K, Griffin P, Kavanagh EG, Walsh SR, Walsh MT: The Role of Shear 
Stress in Arteriovenous Fistula Maturation and Failure: A Systematic Review. PloS one, 10: 
e0145795, 2015 10.1371/journal.pone.0145795 
15. Bashar K, Clarke – Moloney M, Burke PE, Kavanagh EG, Walsh SR: The role of venous 
diameter in predicting arteriovenous fistula maturation: When not to expect an AVF to 
mature according to pre-operative vein diameter measurements? A best evidence topic. 
International Journal of Surgery, 15: 95-99, 2015 10.1016/j.ijsu.2015.01.035 
16. Robbin ML, Greene T, Cheung AK, Allon M, Berceli SA, Kaufman JS, et al.: Arteriovenous 
Fistula Development in the First 6 Weeks after Creation. Radiology, 279: 620-629, 2016 
10.1148/radiol.2015150385 
17. Dageforde, LA, Harms, KA, Feurer, ID and Shaffer, D. Increased minimum vein diameter on 
preoperative mapping with duplex ultrasound is associated with arteriovenous fistula 
maturation and secondary patency. J Vasc Surg 2015; 61:170-6. 
18. Achneck HE, Sileshi B, Li M, Partington EJ, Peterson DA, Lawson JH: Surgical aspects and 
biological considerations of arteriovenous fistula placement. Semin Dial, 23: 25-33, 2010 
10.1111/j.1525-139X.2009.00651. 
 
 

 
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Appendix 1: Definitions 
 
• 
Abandonment of Study AVF is defined as the discontinuation of the clinical use of Study 
AVF because it is no longer functional and considered not to be salvageable, including the 
discontinuation of the clinical use of Study AVF because it can no longer be used for 
prescribed hemodialysis, because it is unable to provide adequate blood flow, or because it 
is deemed unsafe for the patient, and the associated problem(s) cannot be corrected by 
any medical, procedural, or surgical intervention.  
• 
Amplifi System and AVF local infection is defined as: 1) the presence of purulent discharge 
from the Inflow Catheter skin exit site, the Distal Outflow Catheter skin exit site, or the 
Study AVF skin incision; or 2) the presence of serous discharge from the Inflow Catheter 
skin exit site, the Distal Outflow Catheter skin exit site, or the Study AVF skin incision with 
erythema, induration, or tenderness and a positive culture of the serous discharge. 
• 
Amplifi System component replacement is defined as the replacement of one or more 
components of the Amplifi System during the Amplifi System treatment period, not 
including replacement or addition of Access Port caps, suture anchoring tools, a Patient 
Vest, or Patient Vest components. 
• 
Amplifi System-related major complication is defined as: 
o Amplifi System-related death; 
o Amplifi System-related major bleeding, major pneumothorax, major air embolism, 
major thrombosis, major thromboembolism, major hemolysis, or major 
thrombocytopenia; local infection 
o Amplifi System-related re-hospitalization or prolonged hospitalization; 
o Amplifi System-related major surgery or major interventional procedure; or 
o any Amplifi System-related complication determined to be an Amplifi System-related 
major complication by both an Investigator and the CEC.  
• 
Amplifi System-related major bleeding is defined as: 
o overt bleeding plus a drop in hemoglobin of 3 to 5 g/dL wherein the hemoglobin drop 
is related to the bleeding;  
o transfusion for overt bleeding;  
o bleeding requiring an interventional procedure or surgery for control (not including the 
placement or removal of skin sutures or pressure dressings);  
o the administration of intravenous vasoactive agents for overt bleeding; or  
o probable or definite fatal bleeding. 
• 
Amplifi System-related major pneumothorax is defined as the introduction of air in the 
cavity between the lungs and the chest wall during the placement, operation, use, or 
removal of the Amplifi System that is not due to a cause other than the placement, 
operation, use, or removal of the Amplifi System, wherein the pneumothorax is 
documented by imaging and a chest tube is placed. 
• 
Amplifi System-related major air embolism is defined as the entry of air into the vascular 

 
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system during the placement, operation, use, or removal of the Amplifi System that is not 
due to a cause other than the placement, operation, use, or removal of the Amplifi System; 
wherein the air embolism is documented by imaging and: 
o results in air embolism-related hypotension, arrhythmia, hemodynamic instability, 
paradoxical embolization, myocardial infarction, stroke, mesenteric ischemia, or 
death;  
o requires a procedure or surgery to remove the air that forms after air embolism; or 
o requires a thrombectomy procedure or surgery, thrombolytic therapy, or long-term 
anticoagulation to remove thrombus that forms after air embolism. 
• 
Amplifi System-related major thrombosis is defined as the formation of thrombus in an 
artery, vein, or the right atrium due to the placement, operation, use, or removal of the 
Amplifi System, wherein the thrombosis is documented by imaging and the Subject 
requires a thrombectomy procedure or surgery, thrombolytic therapy, or long-term 
anticoagulation; not inclusive of a thrombectomy procedure or surgery that occurs during 
the creation of the Subject AVF.  
• 
Amplifi System-related major thromboembolism is defined as thromboembolism in the 
arterial or venous system due to the placement, operation, use, or removal of the Amplifi 
System, wherein the thromboembolism is documented by imaging and the Subject requires 
a thrombectomy procedure or surgery, thrombolytic therapy, or long-term anticoagulation; 
not inclusive of a thrombectomy procedure or surgery that occurs during the creation of the 
Subject AVF.  
• 
Amplifi System-related major hemolysis is defined as hemolysis documented by laboratory 
testing during the Amplifi System treatment period that is not due to a cause other than the 
placement, operation, use, or removal of the Amplifi System, and requires blood 
transfusion and/or results in thrombotic events, multiple organ failure and mortality. 
• 
Amplifi System-related major thrombocytopenia is defined as a platelet level of < 51,000 
per microliter during the Amplifi System treatment period that is not due to a cause other 
than the placement, operation, use, and removal of the Amplifi System, and requires 
transfusion. 
• 
Amplifi System-related re-hospitalization is defined as an admission to a hospital due to an 
Amplifi System-related complication, not inclusive of a visit to an emergency room, clinic, or 
outpatient facility that does not result in admission to a hospital. 
• 
Amplifi System-related prolonged hospitalization is defined as a prolongation of a hospital 
admission due to an Amplifi System-related complication. 
• 
Amplifi System-related major surgery is defined as an open surgery involving an incision 
and the cutting of the body to address a life-threatening adverse event, to prevent disability, 
or to treat or prevent permanent impairment or damage to a vital body structure or function 
due to an Amplifi System-related complication; not inclusive of the placement of pressure 
dressings, the placement or removal of skin sutures, the creation of an AVF or AVG, or the 
placement or removal of a hemodialysis catheter. 
• 
Amplifi System-related major interventional procedure is defined as an interventional 
procedure to address a life-threatening adverse event, to prevent disability, or to treat or 
prevent permanent impairment or damage to a vital body structure or function due to an 

 
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Amplifi System-related complication and the loss or damage to sites for dialysis access or 
the need to convert an AV fistula to an AV graft or hemodialysis catheter; not inclusive of 
the placement of pressure dressings, the placement or removal of skin sutures, the 
creation of an AVF or AVG, or the placement or removal of a hemodialysis catheter. 
• 
Amplifi System-related complication is defined as any untoward medical occurrence, 
unintended disease or injury, or untoward clinical sign or abnormal lab finding related to the 
placement, use, operation, or removal of the Amplifi System; not inclusive of mild-moderate 
hand, wrist, arm, neck, or face swelling that resolves within 7 days after the end of the 
Amplifi System treatment period.  
• 
Amplifi System treatment period is defined as starting when a needle is used to access the 
internal jugular vein or cephalic vein at the start of Amplifi System placement and ending 
when the Inflow Catheter and Distal Outflow Catheter have been completely removed and 
any related incisions have been closed. 
• 
Aneurysm of Study AVF is defined as expansion of the intimal, medial, and adventitial 
layers of the wall of a segment of outflow vein of a Study AVF in the region between the 
Study AVF anastomosis and the axilla that requires treatment through an interventional 
procedure or surgery. 
• 
Anti-platelet agent is defined as a pharmaceutical that is approved for use to decrease 
platelet aggregation and inhibit thrombus formation.  
• 
AVF circuit is defined as the region starting with the origin of the inflow artery and 
continuing to the junction of the superior or inferior vena cava and the right atrium.  
• 
AVF creation is defined as the making of an opening between the lumen an artery and vein 
for the purpose of creating a vascular access for hemodialysis, inclusive of interventional 
and surgical methods. 
• 
AVF-related intervention is defined as an interventional procedure or surgery after the 
creation of an AVF to evaluate an AVF, promote maturation of an AVF, achieve or maintain 
patency of an AVF, or reduce AVF blood flow, including thrombectomy, pharmacologic 
thrombolysis, angioplasty and stenting of an inflow artery, outflow vein, or ipsilateral central 
vein, embolization or surgical ligation of an AVF tributary vein, surgical revision of an AVF 
anastomosis, the cutting, removal or otherwise rendering of a valve in an AVF outflow vein 
incompetent, resection of a segment of outflow vein, unplanned superficialization of a 
segment of outflow vein, and surgical or interventional treatment of ipsilateral arterial steal.  
• 
AVF maturation is defined as an AVF having a mid or distal forearm outflow vein diameter 
> 6 mm and blood flow > 500 mL/min, both as measured by ultrasound, with AVF blood 
flow imputed from distal brachial artery blood flow.  
• 
AVF thrombosis is defined as the formation of thrombus in a component of the AVF circuit, 
inclusive of occlusive and non-occlusive thrombus. 
• 
Bleeding diathesis is defined as an unusual susceptibility to bleeding, including due to 
hypocoagulability. 
• 
Central venous and right atrial thrombus is defined as intraluminal thrombus in the axillary, 
subclavian, brachiocephalic, femoral, external iliac, internal iliac, common iliac, or internal 
jugular veins, the superior or inferior vena cava or the right atrium, inclusive of occlusive 
and non-occlusive thrombus.  

 
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• 
Central venous angioplasty is defined as an interventional procedure or surgery to enlarge 
the lumen of the axillary, subclavian, or brachiocephalic veins, or the superior vena cava. 
• 
Central venous occlusion is defined as the complete blockage of the axillary, subclavian, or 
brachiocephalic veins, or the superior vena cava. 
• 
Central venous stenosis > 50% is defined as a > 50% narrowing of the lumen of an axillary, 
subclavian, or brachiocephalic vein, or the superior vena cava, wherein a normal segment 
of vein adjacent to the narrowed segment is used as a reference vessel for making the 
determination and the maximum observed diameter reduction is used, inclusive of 
measurements made with ultrasound imaging, venography, or MRI. 
• 
Central venous stent placement is defined as an interventional procedure or surgery 
wherein a metal tube is permanently placed in the lumen of the axillary, subclavian, or 
brachiocephalic veins, or the superior vena cava for the purpose of keeping the vessel 
open. 
• 
Coagulopathy is defined as a derangement of hemostasis resulting in either excessive 
bleeding or clotting.  
• 
Gastrointestinal bleeding is defined any form of hemorrhage or bleeding that occurs in the 
gastrointestinal tract from the mouth to the anus.  
• 
Hemodialysis catheter placement is defined as the placement of a new hemodialysis 
catheter, including the replacement of an existing hemodialysis catheter with a new 
catheter, and not inclusive of the repositioning of a catheter where the same catheter 
remains in the Subject before and after the procedure. 
• 
Hemodialysis catheter-related bloodstream infection is defined as the growth of the same 
organism from a hemodialysis catheter and a peripheral venipuncture (or a suitable 
surrogate such as a hemodialysis blood line) in a patient with clinical signs of a 
bloodstream infection and no alternative source of bloodstream infection other than the 
hemodialysis catheter.  
• 
Indicated for forearm radiocephalic AVF creation based on an Investigator’s standard 
practice is defined as: 
o indicated for wrist or distal forearm radiocephalic AVF creation based on an 
Investigator’s standard practice; 
o a wrist or distal forearm cephalic vein diameter of > 1.75 mm and < 3.2 mm at the 
proposed AVF creation site; 
o a forearm cephalic vein demonstrating patency and continuity of blood flow from the 
proposed AVF creation site to and through the upper arm through at least one of:  
 
the upper arm cephalic vein;  
 
the median cubital vein to the upper arm cephalic or basilic vein; or  
 
the perforator vein to the deep venous system  
with no occlusion or stenosis > 50% along the course of the proposed AVF outflow 
from the proposed AVF creation site to and through the upper arm to the axilla, as 
determined by duplex ultrasonography; and 
o a wrist or distal forearm radial artery diameter of ≥ 2.0 mm at the proposed AVF 

 
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creation site. 
• 
Internal jugular vein suitable for Amplifi Inflow Catheter insertion is defined as a widely 
patent internal jugular vein without thrombus and with a lumen diameter > 8.5 mm (during 
Valsalva) that does not contain any catheter or intravascular implant and is deemed to be 
suitable for Inflow Catheter insertion by the Investigator. 
• 
Intervention-free AVF maturation is defined as AVF maturation (as defined above) in the 
absence of any interventional procedure, surgery, or medical treatment to promote 
maturation of the AVF.  
• 
Interventional procedure, surgery, or medical treatment to promote maturation of the AVF 
of Study AVF is defined as an interventional procedure, surgery, or a medical treatment 
intended to: 
o increase the diameter of a segment of an artery or vein in Study AVF circuit or 
increase Study AVF blood flow, including by angioplasty or stent placement, cutting, 
removing, or otherwise rendering a venous valve incompetent, resecting of a 
segment of outflow vein, and surgical revision of the Study AVF anastomosis;  
o remove thrombus from the lumen of the artery or vein in Study AVF circuit; and 
o reduce the flow of blood in Study AVF tributaries including by embolization or surgical 
ligation;  
and excluding planned superficialization of a segment of Study AVF outflow vein for the 
purpose of enabling easier cannulation.  
• 
Interventional procedure, surgery, or medical treatment to achieve or maintain functional 
patency of Study AVF is defined as an interventional procedure, surgery, or a medical 
treatment intended to: 
o increase the diameter of a segment of artery or vein in Study AVF circuit or increase 
Study AVF blood flow, including by angioplasty or stent placement; 
o cut, remove, or otherwise render a venous valve incompetent; 
o surgically revise the Study AVF anastomosis; 
o remove thrombus from the lumen of the artery or vein in Study AVF circuit;  
o resect a segment of Study AVF outflow vein; and 
o reduce the flow of blood in Study AVF tributaries including by embolization or surgical 
ligation;  
inclusive of interventional procedures, surgeries, and medical treatments intended to 
promote maturation of Study AVF; and 
exclusive of planned superficialization of a segment of Study AVF outflow vein for the 
purpose of enabling easier cannulation.  
• 
Intracranial bleeding is defined as any bleeding within the intracranial vault, including 
bleeding in the brain parenchyma and meningeal spaces. 
• 
Pseudoaneurysm of Study AVF is defined as a locally contained hematoma of a Study AVF 
outflow vein with persistent blood flow in the hematoma and a neck between the hematoma 
and the Study AVF outflow vein that does not close spontaneously that is located between 
the Study AVF anastomosis and the axilla that requires treatment with an interventional 

 
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procedure or surgery, inclusive of percutaneous injection of an agent intended to induce 
thrombosis. 
• 
Site Personnel is defined as persons employed by the Site, other than Investigators, that 
are involved in the storage, placement, use, operation, maintenance, care, cleaning, 
monitoring, interaction with, removal, and disposal of the Amplifi System and its 
components. 
• 
Thrombophilia is defined as a clinical tendency to thrombosis or molecular abnormalities of 
hemostasis that predispose to thrombosis.  
• 
Treatment Failure is defined as “a subject will be classified as a treatment failure if they do 
not achieve the minimum required Amplifi treatment duration of 48 hours. This classification 
applies regardless of whether the subject has an arteriovenous fistula (AVF) created or 
not.” 
• 
Device technical success is defined as successful operation of the Amplifi system 
throughout the treatment period (from device implantation through device removal and 
AVF creation) without unplanned pump stoppages or device malfunctions that require 
intervention or prevent completion of the intended 48-hour treatment duration. 
• 
Treatment success is achieved when the Amplifi system operates without unplanned 
pump stoppages or device malfunctions, allowing for the full 48-hour treatment duration, 
and results in successful creation of an arteriovenous fistula (AVF) or meets the 
predefined clinical objectives as specified in the study protocol. 
• 
Vascular access for hemodialysis is defined as an AVF, AVG, or hemodialysis catheter. 
• 
Vascular access-related hospitalization is defined as admission to a hospital for treatment 
of a vascular access or a vascular access-related complication, not inclusive of a visit to an 
emergency room, clinic, or outpatient facility that does not result in admission to a hospital. 
• 
Vascular access steal syndrome is defined as one or more signs or symptoms of ipsilateral 
hand ischemia that requires treatment with an interventional procedure or a surgery. 
• 
Wrist or distal forearm radiocephalic AVF is defined as an AVF made with the radial artery 
and the cephalic vein, wherein the anastomosis is made in the hand, wrist, or distal 
forearm. 
 
 

 
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Appendix 2: Literature Review for Safety 
 
Table 5: Publications Relevant to Safety and Effectiveness - Catheters 
Publication 
Overview 
Safety Data 
Amy Leung, et al. The 
Incidence of Peripheral 
Catheter-related infection in 
surgical patients. Thrombosis: 
2016(1):1-6 
A prospective 
observational study 
determines the incidence 
of peripheral catheter-
related thrombosis in 
surgical patients. N=54 
surgery patients with high 
risk of venous thrombus 
studied with ultrasound 
before placement and at 
discharge. Catheters were 
in place between 2-5 
days. 
9.2% rate of superficial vein thrombus formation – 
all asymptomatic 
1.8% rate of deep vein thrombus formation – all 
asymptomatic 
No pulmonary embolism identified 
this (study) confirmed the asymptomatic nature of 
peripheral catheter-related thrombosis.”  
 
Chick, et al. Significance of 
Echocardiographically 
Detected Central Venous 
Catheter Tip-Associated 
thrombi. J Vasc Interv Radiol 
2016; 27:1872–1877 
 
 Review of significance, 
management, and 
outcomes of central 
venous catheter (CVC) 
tip-associated thrombi 
incidentally detected on 
echocardiography. 
Echocardiogram data of 
n=170 were screened and 
n=49 patients with CVC-
tip associated thrombi 
were selected. 
29% had catheter-associated thrombus formation 
“In this sample with CVC tip–associated thrombi but 
without PFO or other intracardiac shunts, no 
embolic or other complications were detected, 
regardless of anticoagulation status. These data 
suggest a benign course for such thrombi and that 
anticoagulation, catheter removal, thrombectomy, 
and thrombolysis may be unnecessary when 
catheter tip–associated thrombi are incidentally 
detected on echocardiography.” 
Miller, et al “Hemodialysis 
Tunneled Catheter 
Noninfectious Complications” 
Canadian Journal of Kidney 
Health and Disease; Volume 
3: 1–10: 2016 sagepub.com/ 
Review publication on 
behalf of the Canadian 
Society of Nephrology 
Vascular Access Work 
Group (VAWG) 
Noninfectious hemodialysis catheter 
complications include catheter dysfunction, 
catheter-related thrombus, and central vein 
stenosis. Catheter-related thrombus is a less 
common but serious complication of catheters, 
requiring catheter removal and systemic 
anticoagulation. 
Bream, et al “Update on 
Insertion and Complications 
of Central Venous Catheters 
for Hemodialysis”, Semin 
Intervent Radiol 2016;33:31–
38 
Review publication of 
collaboration with the 
Accreditation Council for 
Continuing Medical 
Education (ACCME) and 
Tufts University School of 
Medicine (TUSM) 
Acute central venous catheter complications and 
frequency include the following. 

 
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Publication 
Overview 
Safety Data 
 
Long-term central venous catheter complications 
include: infections (overall the rate of catheter-
related bacteremia (CRB) are 1.6 – 5.5 
episodes/1,000 catheter days; catheter 
malfunction; thrombosis; catheter tip malposition; 
and central vein stenosis. 
Patel, et al “Central Line 
Catheters and Associated 
Complications: A Review” 
(May 22, 2019) Central Line 
Catheters and Associated 
Complications: A Review. 
Cureus 11(5): e4717. DOI 
10.7759/cureus.4717 
Joint Review Publication of 
Kaiser Permanente and 
the Marshall University 
School of Medicine 
Acute complications of central venous catheters 
include: arrhythmia; vascular injury (arterial or 
venous); bleeding hematoma; pneumothorax; air 
embolism; and chylothorax. Long-term 
complications of central venous catheters: 
infection (80 - 189 episodes per 100,000 patient 
years); and device dysfunction, including fibrin 
sheath, catheter fracture, venous thrombosis, 
venous stenosis, or infection. 
Hyder, et al “Complications 
Associated with Permanent 
Internal Jugular Hemodialysis 
Catheter: A 
Retrospective Study” (April 
22, 2019) Cureus 11(4): 
e4521. DOI 
10.7759/cureus.4521 
Single center experience 
of n = 212 hemodialysis 
patients. 
Complications were documented in 24% of 
patients with internal jugular vein hemodialysis 
catheters.19 patients had acute complications, 
including: failed puncture (5.1%); cannulation of 
wrong vessel (0.9%); hematoma (1.9%); and 
hemothorax (0.9%).  
39 patients had long-term complications, 
including: infection (12.3%); venous thrombosis 
(2.8%); catheter thrombosis (2.4%); and 
pneumothorax (0.9%). 
Javeri, et al “Indian Society of 
Critical Care Medicine 
Position Statement for 
Central Venous 
Catheterization and 
Management 2020” Indian J 
Crit Care Med. 2020 Jan; 
24(Suppl 1): S6–S30. 
Clinical practice guidelines 
developed by Indian 
Society of Critical Care 
Medicine 
Infection: The clinical practice guidelines include 
specific recommendations to mitigate infection 
risks. A systematic review and meta-analysis of 
79 studies found that strict adherence to CRBSI 
(catheter related bloodstream infections) 
prevention activities reduced its incidence 
significantly from median 6.4/1000 catheter- days 
(IQR 3·8 – 10.9) to 2.5/1000 catheter-days (1.4 – 
4.8) (IRR 0.44, 95% CI 0.39 – 0.50, p < 0·0001; I 
= 89%). 
Mechanical Complications: The clinical practice 
guidelines include specific recommendations to 

 
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Publication 
Overview 
Safety Data 
mitigate risk of mechanical complications 
including pneumothorax, hemothorax, arterial 
puncture, hematoma formation, and malposition 
of central venous catheter. 
Shafique, et al “Hemodialysis 
Internal Jugular Vein Versus 
Subclavian Vein Catheters: 
Complications, Patients’ 
Comfort, Tolerance and Cost-
Effectiveness” Pak J Med Sci. 
2019;35(1):124- 128. 
Single-center experience 
of n = 66 hemodialysis 
patients with internal 
jugular vein and subclavian 
vein catheters 
 
Cavallazzi, et al. “Central 
Venous Access Sites for the 
Prevention of Venous 
Thrombosis, Stenosis and 
Infection (Review)” Cochrane 
Database of Systematic 
Reviews 2012, Issue 3. Art. 
No.: CD004084.DOI: 10.1002 
/14651858.CD004084.pub3. 
 
Systematic literature 
review comparing internal 
jugular vein and subclavian 
vein: catheter-related 
infection rates; thrombotic 
complications; immediate 
mechanical complications; 
and late mechanical 
complications. 
 
Ravani, et al, “Associations 
between Hemodialysis 
Access Type and Clinical 
Outcomes: A Systematic 
Review” J Am Soc Nephrol. 
2013 Feb 28; 24(3): 465– 
Systematic literature 
review comparing patient 
outcomes from 67 articles 
published 
1985 - 2011 reporting data 
on n = 363 vascular 
Catheter versus AVF: Patients using catheters 
had an increased risk of all-cause mortality (risk 
ratio [RR] = 1.53, 95% confidence interval [95% 
CI] = 1.41 – 1.67), fatal (RR = 2.12, 95% 
CI=1.79–2.52) and nonfatal (RR = 4.66, 95% 
CI=2.63 – 8.26) infection, major cardiovascular 
event (RR = 1.38, 95% CI = 1.24 – 1.54), and 

 
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Publication 
Overview 
Safety Data 
473. 
access type comparisons 
in 586,337 participants. 
hospitalization rates (RR = 1.68, 95% CI=1.33–
2.12) compared with patients using AVFs. 
Catheter versus AVG: Patients using catheters 
had increased risk of all-cause mortality (RR = 
1.38, 95% CI=1.25–1.52), fatal (RR=1.49, 95% 
CI=1.15 – 1.93) 
and nonfatal (RR = 2.78, 95% CI = 1.80 – 4.29) 
infection, cardiovascular event (RR = 1.26, 95% 
CI = 
1.11 – 1.43), and hospitalization (RR = 1.51, 
95% CI = 1.30 – 1.75) compared with patients 
using AVGs. 
Leib, et al “Central Line”, 
NCBI Bookshelf. A service of 
the National Library of 
Medicine, National Institutes 
of Health. StatPearls 
[Internet]. Treasure Island 
(FL): StatPearls Publishing; 
2020 Jan 
Review paper evaluating 
central venous catheters 
Complications associated with central venous 
catheters include pneumothorax; pericardial 
effusion and tamponade; bleeding; arterial 
puncture with an expanding hematoma; infection; 
thrombosis; injury to the nerves; losing guidewire 
inside the vein; air embolism; and arrythmias 
 
Table 6: Publications Relevant to Safety and Effectiveness – Extracorporeal Blood 
Pumps 
Publication 
Overview 
Safety Data 
Thomas, et al. 
“Bleeding and Thrombotic 
Complications in the Use of 
Extracorporeal Membrane 
Oxygenation 
Semin Thromb Hemost. 
2018 Feb;44(1):20-29. doi: 
10.1055/s-0037-1606179. 
Epub 2017 Sep 12. 
Section of Pediatric 
Critical Care Medicine, 
Department of Pediatrics, 
Baylor College of 
Medicine, Texas 
Children's Hospital, 
Houston, Texas. 
Division of Transfusion 
Medicine and 
Coagulation, Department 
of Pathology and 
Immunology, Baylor 
College of Medicine, 
Texas Children's Hospital, 
Houston, Texas. 
Extracorporeal membrane oxygenation (ECMO) 
has been used for >40 years to support lung and 
heart failure; however, bleeding and thrombosis 
remain serious complications. The known 
etiologies of bleeding include heparin effect or 
overdose, coagulopathy, thrombocytopenia, 
platelet dysfunction, acquired von Willebrand 
syndrome, and hyperfibrinolysis. Bleeding sites 
may include cannula insertion sites, recent 
surgical incisions, vascular access sites, lung, 
gastrointestinal tract, mouth, nose, thoracic 
cavity, abdominal cavity, and brain. Massive 
bleeding in the brain, the most feared bleeding 
complication, can be rapidly fatal because it 
occurs in a rigid closed space, is difficult to drain, 
and cannot be stopped with direct pressure to 
the bleeding site. Pulmonary hemorrhage may 
cause irreversible lung damage. Management 
should be swift and precise to prevent fatal 

 
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Publication 
Overview 
Safety Data 
bleeding. In contrast, etiologies of thrombosis 
include high fibrinogen and factor VIII levels, 
heparin resistance, and platelet activation. 
Achieving the optimal anticoagulation balance to 
prevent bleeding and thrombosis in ECMO 
patients is extremely complex. Experts in 
hemostasis should be a part of an institutional 
ECMO team and continuously available for 
immediate management. 
 
Sniderman J, Monagle P, 
Annich GM, MacLaren G. 
“Hematologic concerns in 
extracorporeal membrane 
oxygenation.” Res Pract 
Thromb Haemost. 2020 
May 15;4(4):455-468. doi: 
10.1002/rth2.12346. 
PMID: 32548547; PMCID: 
PMC7292669. 
Review by International 
Society of Thrombosis 
and Haemostasis (ISTH) 
to consider ‘State of the 
Art’ in ECMOs and 
considerations for 
choosing outcome 
measures. 
Pre-existing risks to patients for hematologic 
events may be exacerbated by the ECMO. Blood 
exposure to artificial surfaces results in 
fibrinogen, albumin, and other proteins coating 
the artificial surface, platelet activation, and 
inflammation. This may be dampened by a 
heparin-bonded biomimetic surface which 
reduces cellular activation and inflammation, but 
systemic anticoagulation is still required.  
The degree of thrombocytopenia is related to the 
patient’s illness rather than the duration of 
ECMO treatment. The artificial cannulation 
surface and the shear stress may contribute to 
platelet activation and reduced platelet bonding, 
along with other factors, leading to thrombosis 
and bleeding. 
Across multiple pediatric and adult studies, 
severe hemolysis occurs at a rate of 2-20%. 
Hemolysis is associated with increased rates of 
endothelial failure, kidney failure, thrombotic 
events, transfusions, and mortality.  
Meta-analysis reports venovenous ECMO 
hemorrhage rates of 19% with pre-existing 
respiratory distress syndrome and central 
cannulation being 2 highly contributing factors. 
All ECMO configurations carry high risk of 
infections between 13-40%. 
Strunina S, Hozman J, 
Ostadal P. “The peripheral 
cannulas in extracorporeal 
life support.” Biomed Tech 
(Berl). 2019 Apr 
24;64(2):127-133. doi: 
Review  
Faculty of Biomedical 
Engineering, Czech 
Technical University in 
Prague, Nám. Sítná 3105, 
272 01Kladno, Czech 
Republic. 
When peripheral (rather than central) cannula 
ECMOs are used, bleeding, thrombosis and 
hemolysis are the most common complications. 
The peripheral ECMO cannulas provide greater 
versatility for cannulation techniques and strive 
for smaller incisions. Heparin-coated surfaces 
result in reduced complement and inflammatory 

 
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Publication 
Overview 
Safety Data 
10.1515/bmt-2017-0107. 
PMID: 29648990. 
 
Cardiovascular Center, 
Na Homolce Hospital, 
Roentgenova 2/37, 15030 
Prague, Czech Republic. 
 
activation due to its anti-inflammatory properties. 
Nevertheless, heparin causes the development 
of osteopenia and thrombocytopenia [16], [28]. 
Heparin-coated surfaces can release cytokines, 
which exert a damaging effect on the lungs [29]. 
Furthermore, heparin-based coatings can leach 
into the blood and result in the exposure of the 
blood to extremely high heparin doses (>50 
U/kg) [30]. This can cause excessive bleeding 
and can be lethal. 
The dimensions of the cannula can also play a 
role in adverse events, and they should be 
optimized for the patient. High pressure flow can 
become turbulent and may damage red blood 
cells. In addition, it can cause microbubbles and 
induce air emboli. While smaller cannulas reduce 
bleeding complications, the risk of vascular 
damage, ischemia, and obstruction of the 
arteries, it is balanced with using the largest 
possible to maximize blood flow. 
 
Bleeding is the most frequent complication in 
ECMO therapy. A meta-analysis of 20 studies 
reported an estimated rate of 41% with the 
femoral cannula insertion site being the most 
frequent source. 
 
Ischemia is the 2nd most frequent complication 
of using cannulas. The most concerning is the 
lower extremity ischemia with VA ECMO at 10-
20%. 
 
Hemolysis is reported to have an incidence of 5-
18%, mostly induced by shear stress when using 
high flow velocity through small cannulas; 
consequently, renal insufficiency or multiple 
organ failure can occur.  
Besser MW.  
“Post-operative of 
bleeding, haemolysis and 
coagulation in mechanical 
circulatory support 
patients.” Ann Transl Med. 
2020 Jul;8(13):832. doi: 
Review by 
Department of 
Haematology, 
Addenbrooke's Hospital, 
Cambridge, UK 
Shear force, during ECMO use, can compress 
blood by deforming the red blood cells and at a 
molecular level, changing the shape of its 
platelets. Higher viscosity flow disrupts 
marginalization of platelets, and a pre-existing 
thrombocytopenia becomes more symptomatic. 

 
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10.21037/atm-20-405. 
PMID: 32793677; PMCID: 
PMC7396228. 
Vezzani A, Manca T, 
Vercelli A, Braghieri A, 
Magnacavallo A. 
“Ultrasonography as a 
guide during vascular 
access procedures and in 
the diagnosis of 
complications.” J 
Ultrasound. 2013 Oct 
29;16(4):161-70. doi: 
10.1007/s40477-013-0046-
5. PMID: 24432170; 
PMCID: PMC3846948. 
Review to support 
clinician ultrasound use. 
Terapia Intensiva 
Cardiochirurgica, 
Dipartimento Cardio Nefro 
Polmonare, Azienda 
Ospedaliero, Universitaria 
di Parma, Parma, Italy. 
 
U.O.C. di Pronto 
Soccorso/OBI/Medicina 
D'Urgenza, Ospedale G. 
Da Saliceto, 29100 
Piacenza, Italy. 
 
Ultrasound guidance used during catheterization 
of peripheral veins and for peripheral insertion of 
central venous catheters increases the 
catheterization success rate and reduces 
complications such as catheter-related infections 
and venous thrombosis. Ultrasound can also 
access basilic and cephalic veins deeper in the 
arm that cannot be identified by palpitation. 
Ultrasound is not indicated for routine 
catheterization of peripheral veins, but when 
access is expected to be complicated, it can 
reduce complications. 
Insertion of a central venous catheter (CVC) still 
carries the risk of improper placement and 
mechanical complications. For this reason, a 
chest X-ray is advisable to verify the position of 
the catheter tip and exclude the possibility of 
iatrogenic pneumothorax. The presence of the 
catheter tip in the right atrium is reported in 8–
47 % of cases; even in expert hands, placement 
error rates range from 6 to 14 %. FDA 
recommends the tip of CVC should be placed in 
the SVC, along the axis of the vessel so as not to 
slide into the right atrium. Post-procedural 
pneumothorax occurs in 0.1-0.2% of CVCs 
inserted into the internal jugular vein. Ultrasound 
should be used especially with advanced age or 
complex disease. 
 
Abruzzo A, Gorantla V, 
Thomas SE.  
“Venous thromboembolic 
events in the setting of 
extracorporeal membrane 
oxygenation support in 
adults: A systematic 
review.” Thromb Res. 
2022 Apr;212:58-71. doi: 
10.1016/j.thromres.2022.0
2.015. Epub 2022 Feb 23. 
PMID: 35219933. 
Systemic Review of 30 
records including n=2049 
Department of Anatomical 
Sciences, St. George's 
University School of 
Medicine, Grenada. 
Department of Internal 
Medicine, University of 
Maryland Medical Center 
MTC, Baltimore, USA. 
Electronic address: 
sneha.thomas@umm.edu. 
ECMO-supported patients not only experienced 
high rates of venous thrombosis (VT) and VTE, 
ECMO was also a positive predictor for VTE. VT 
and VTE were prevalent in 41.6% of 63 patients 
on ECMO for ARDS or organ failure with no prior 
history of thrombosis. There is a positive 
correlation between incidence of VTE or VT and 
the length of time patients were supported by 
ECMO. The longer the patients relied on ECMO 
therapy, the likelihood of inducing an 
inflammatory response or undergoing blood 
clotting factor modification was significantly 

 
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Safety Data 
 
 
increased. Patients on ECMO therapy for 
prolonged periods of time, advanced age, and 
those who had developed an infection during 
treatment are at an increased risk of developing 
DVT upon weaning. Follow up should be done 
after ECMO therapy.  
Low circuit flow, insufficient volume, pump 
speed, blood flow velocity, kinks, or obstruction 
in flow, malpositioning, large size of ECMO 
cannulas, sheer stress and multitude of other 
factors that activate platelet and coagulation 
cascade may be contributing to this increased 
risk of cannula associated DVT and VTE in 
general. Platelet count less than 100 G/L during 
ECMO had lower DVT risk. 
Gross-Hardt S, 
Hesselmann F, Arens J, 
Steinseifer U, Vercaemst L, 
Windisch W, Brodie D, 
Karagiannidis C.  
“Low-flow assessment of 
current ECMO/ECCO2R 
rotary blood pumps and 
the potential effect on 
hemocompatibility.” Crit 
Care. 2019 Nov 
6;23(1):348. doi: 
10.1186/s13054-019-
2622-3. PMID: 31694688; 
PMCID: 
Department of 
Cardiovascular 
Engineering, Medical 
Faculty, Institute of 
Applied Medical 
Engineering, Helmholtz 
Institute, RWTH Aachen 
University, Aachen, 
Germany. 
Department of Perfusion, 
University Hospital 
Gasthuisberg, Leuven, 
Belgium. 
Center for Acute 
Respiratory Failure, 
Columbia University 
College of Physicians and 
Surgeons/New 
The role of blood pumps in contributing to 
adverse effects at the lower blood flow rates 
used during ECCO2R is significant. Current 
rotary blood pumps should be used with caution 
if operated at blood flow rates below 2 L/min, 
because of significant and high recirculation, 
shear stress, and hemolysis.