A Phase 3, Randomized, Multicenter, Single-blind, Controlled Study Evaluating Arteriovenous Fistula Outcomes With and Without a Perivascular Sirolimus-Eluting Collagen Implant
Phase: PHASE3
Conditions: Complication of Renal Dialysis, End Stage Renal Disease, End Stage Kidney Disease, ESRD, Chronic Kidney Failure, Complication of Hemodialysis, Vascular Access Complication, Arteriovenous Fistula
Sponsor: Vascular Therapies, Inc.

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
1 
1. 
TITLE PAGE 
A PHASE 3, RANDOMIZED, MULTICENTER, SINGLE-BLIND 
CONTROLLED STUDY EVALUATING ARTERIOVENOUS 
FISTULA OUTCOMES WITH AND WITHOUT A 
PERIVASCULAR SIROLIMUS-ELUTING COLLAGEN 
IMPLANT 
(THE ACCESS TRIAL) 
 
Protocol No.: 
VT-304 
Investigational Product: 
Sirolimus-eluting Collagen Implant 
Sponsor: 
Vascular Therapies, Inc. 
105 Union Avenue 
Cresskill, NJ 07626 
Medical Monitor: 
Maria DeVita, MD 
CRO: 
CTI Clinical Trial and Consulting Services, Inc. 
Author: 
Sriram Iyer, MD, FACC, FSCAI 
Date of Version: 
22-Jan-2018 
Version: 
Version 5.3 
 
 
CONFIDENTIAL 
The information provided in this document is strictly confidential and is intended solely for the guidance of the clinical 
investigation. Reproduction or disclosure of this document to parties not associated with the clinical investigation or its use for 
any other purposes without the written consent of the sponsor is not permitted. 
 
Property of Vascular Therapies, Inc. 
 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
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2. 
SYNOPSIS 
Name of Sponsor: 
Vascular Therapies, Inc. 
Name of Investigational Product: 
Sirolimus-eluting Collagen Implant (SeCI) 
Name of Active Ingredient: 
Sirolimus 
Title of Study: 
A Phase 3, Randomized, Multicenter, Single-blind, Controlled Study evaluating Arteriovenous fistula 
outcomes with and without a Perivascular Sirolimus-eluting Collagen Implant (The ACCESS Trial) 
Study center(s): 
Approximately 20 centers in the United States will participate in this study. 
Studied period (years): 
Estimated date first patient enrolled: 01 Nov 2015 
Estimated date last patient completed: 30 Jun 2019 
Phase of 
development: 
3 
Study Objectives and Hypothesis: 
The objective of this study is to evaluate efficacy and safety outcomes following use of the 
Sirolimus-eluting Collagen Implant in subjects undergoing surgical creation of an AV fistula for vascular 
access (index procedure). Following successful creation of the AV fistula, the cohort randomized to the 
treatment group will receive the SeCI; the control group will not receive an implant. The primary study 
hypothesis is that the proportion of subjects that meet requirements for fistula suitability for dialysis, six 
months following the index procedure, will be higher in the treatment group in comparison to the control 
group. 
Methodology: 
This is a randomized, single blind, multicenter study designed to evaluate the efficacy and safety of the 
SeCI in subjects who are on hemodialysis or are preparing for hemodialysis and are undergoing surgery 
for creation of a new AV fistula. Subjects will be randomized 1:1 to the treatment group or control group. 
Subjects randomized to the treatment group will receive the investigational product; subjects randomized 
to the control group will undergo AV fistula surgery without implantation of the investigational product. 
Randomization will be stratified by surgeon and fistula location (radiocephalic or brachiocephalic); at 
least 80% of the randomized subjects will receive a radiocephalic fistula and at most 20% of the subjects 
will receive a brachiocephalic fistula. The randomization scheme will be monitored and controlled via the 
IVR/IWR system.  
The first subject enrolled by each participating surgeon will be a “run-in subject”, not part of the 
randomized subject set. “Run-in subjects” will undergo surgery for the creation of an AV fistula and 
receive the SeCI. This is to familiarize the investigators with the SeCI implant procedure. Enrolled 
subjects will be followed for a period of one year from the time of their index procedure. 
Number of patients (planned): 
Planned enrollment is approximately 240 subjects. Approximately 220 subjects are planned to be 
randomized in equal proportions to treatment and control to yield approximately 200 evaluable subjects. 
The randomized cohort will include a minimum of 100 evaluable subjects who are on hemodialysis at the 

Protocol No. VT-304 
 
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The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
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time of the index procedure. 
In addition to the 220 randomized subjects, approximately 20 run-in subjects will be enrolled. 
Diagnosis and main criteria for inclusion: 
Subjects of either gender, at least 18 years of age and undergoing a planned creation of a single-stage 
radiocephalic or brachiocephalic, end-to-side fistula are eligible to participate in this study. All subjects 
must meet inclusion/exclusion criteria prior to enrollment in the study. 
Inclusion Criteria: 
Subjects must meet ALL of the following inclusion criteria to be enrolled in the study: 
1. Age of at least 18 years 
2. Provide written informed consent using a form that is approved by the Institutional Review Board 
(IRB) 
3. Currently on hemodialysis for ≤12 months or expected to initiate hemodialysis within approximately 
6 months of the creation of the AV fistula. 
4. Life expectancy of at least one year  
5. Vascular anatomy suitable for creation of the AV fistula, determined by pre-procedure duplex 
ultrasound (target artery ≥2 mm, target vein ≥2.5 mm, and vein depth ≤5 mm in the cannulation 
segment, the latter approximately 10 cm in length) 
6. Successful creation of a single-stage radiocephalic or brachiocephalic end-to-side fistula 
7. Willing to comply with the specified follow-up evaluations 
Exclusion Criteria: 
Subjects will be excluded if ANY of the following exclusion criteria apply: 
1. Pregnant, breastfeeding, or plans to be pregnant during the course of the study 
2. Prior AV access created on the limb where the fistula surgery is planned 
3. History of steal syndrome from a previous hemodialysis vascular access requiring intervention or 
access abandonment 
4. ST-elevation MI or cerebrovascular accident within 30 days of the index procedure 
5. Known hypersensitivity to the following: sirolimus, beef or bovine collagen 
6. Hypotension with systolic blood pressures <100 mm Hg at the time of screening 
7. Receiving anticoagulant therapy for non-cardiac indications 
8. Currently on immunosuppressive medication(s) 
9. Known or suspected active infection at the time of the AV fistula surgery 
10. Known to be HIV positive 
11. Presence of a medical condition, which, in the Investigator’s opinion, may interfere with the subject’s 
optimal participation in the study (e.g., malignancy or undergoing chemotherapy or radiation 
treatments) 
12. Known advanced liver disease with decompensated cirrhosis, jaundice, ascites or bleeding varices 
13. Prisoner, mentally incompetent, and/or current alcohol or drug abuser 
14. Currently participating in another investigational study 
Investigational product, dosage and mode of administration: 
• 
Test Product: Sirolimus-eluting Collagen Implant (SeCI) 
• 
Dose: Each implanted product will consist of two component membranes, an anastomosis component 
(AF) and a venous component (VF). The 3 cm2 anastomosis component will contain a nominal 
sirolimus dose of 225 μg. The venous component (selection based on the diameter and the length of 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
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the exposed vein) will contain a nominal sirolimus dose of 225 μg (3 cm2), 300 μg (4 cm2), 337.5 μg 
(4.5 cm2), or 450 μg (6 cm2). Depending on the combined size of the two implanted membranes, the 
resulting nominal sirolimus dose will be 450 μg (total implant planar area = 6 cm2), 525 μg (total 
implant planar area = 7 cm2), 562.5μg (total implant planar area = 7.5 cm2), or 675 μg (total implant 
planar area = 9 cm2). 
• 
Mode of Administration: Perivascular implant 
Duration of treatment: 
Single-use, intra-operative implant. 
Reference therapy, dosage and mode of administration:  
No reference therapy will be employed in this study. Subjects randomized to the control group will 
undergo surgery for creation of an AV fistula without the SeCI.  
Criteria for Evaluation: 
Efficacy: 
The primary endpoint of the study is Fistula Suitability for Dialysis at 6 months (FSD6) defined as a 
composite of: 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be determined 
by the ability to use the fistula for dialysis using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min for at least two-thirds of the dialysis sessions performed 
during a 30 day suitability ascertainment period that will commence on day 150. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not initiate 
hemodialysis by day 150, suitability for dialysis will be determined by a vascular ultrasound 
performed at the 6 month follow up visit. Suitability for dialysis will be defined as a fistula 
with an access vein diameter (AVD) of ≥6 mm (internal diameter) and an access blood flow 
of ≥500 mL/min. 
Secondary Endpoints 
1. Fistula Suitability for Dialysis at 12 months defined as a composite of: 
a. For subjects who are on hemodialysis by day 330, suitability for dialysis will be determined 
by the ability to use the fistula for dialysis using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min for at least two-thirds of the dialysis sessions performed 
during a 30 day suitability ascertainment period that will commence on day 330. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not initiate 
hemodialysis by day 330, suitability for dialysis will be determined by a vascular ultrasound 
performed at the 12 month follow up visit. Suitability for dialysis will be defined as a fistula 
with an access vein diameter (AVD) of ≥6 mm (internal diameter) and an access blood flow 
of ≥500 mL/min. 
2. Fistula Maturation by Day 90 defined as a composite of: 
a. For subjects who are on hemodialysis by day 90: 
− Three consecutive dialysis sessions using 2-needles with a mean dialysis machine blood 
pump speed of ≥300 mL/min, the first of these three dialysis sessions completed on or 
before 90 days from the time of creation of the AV fistula, or 
− Two-needle dialysis on or before 90 days, with no further use of the catheter prior to 
achieving three consecutive dialysis sessions using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min. 
b. For subjects who do not initiate hemodialysis by day 90, fistula access vein diameter (AVD) 
of ≥6 mm (internal diameter) and an access blood flow of ≥500 mL/min determined by a 

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vascular ultrasound performed at the 3-month follow up visit. 
3. Secondary Patency, defined as the interval from the time of access placement until access 
abandonment. 
4. Re-intervention Rate, defined as the total number of vascular access interventions performed during 
study participation to maintain or re-establish patency of the index fistula, as well as interventions to 
assist fistula maturation divided by the total subject participation time in the study. 
Tertiary Endpoints 
1. Time To First Dialysis (TTFD) defined as the time from fistula creation to the time when the fistula 
can support three consecutive dialysis sessions using 2-needles with a mean dialysis machine blood 
pump speed of ≥300 mL/min. TTFD will be evaluated in subjects who are on hemodialysis at the 
time of study enrollment or initiate hemodialysis within 28 days of the index procedure. 
2. Fistula Suitability for Dialysis at 6 months with preserved primary patency defined as a composite of: 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be determined 
by the ability to use the fistula for dialysis using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min for at least two-thirds of the dialysis sessions performed 
during a 30 day suitability ascertainment period that will commence on day 150 
b. For subjects who are not on hemodialysis on day of enrollment and who do not initiate 
hemodialysis by day 150, suitability for dialysis will be determined by a vascular ultrasound 
performed at the 6 month follow up visit. Suitability for dialysis will be defined as a fistula 
with an access vein diameter (AVD) of ≥6 mm (internal diameter) and an access blood flow 
of ≥500 mL/min 
3. Fistula Suitability for Dialysis at 12 months with preserved primary patency 
4. Primary Patency, defined as the interval from the time of fistula creation until the first occurrence of 
fistula thrombosis or an intervention performed to restore/maintain patency. 
Safety: 
Safety evaluations will be based on treatment emergent adverse events (TEAEs) up to the 2 month visit 
and vascular access events reported during study participation. Treatment emergent is defined as any 
adverse event that emerges after the subject is enrolled (run-in and randomized) in the study. The run-in 
subjects’ adverse events will be included in the safety evaluation. Vascular access events include access 
dysfunction, thrombosis, access-related hand ischemia, infiltration requiring a rest period, fistula-related 
bleeding, infection, problems with wound healing, aneurysm, pseudoaneurysm, and all interventional 
procedures performed on the study fistula. During follow-up, up to the 2 month visit, all AEs and 
concomitant medications will be recorded. After the 2 month visit, the following will be reported and 
recorded: vascular access events, concomitant medications and therapies associated with vascular access, 
serious adverse events (SAEs) and AEs reported during an SAE. 
An independent Data and Safety Monitoring Board (DSMB) will periodically review safety data. 
Data Analysis and Statistical methods: 
The data will be summarized in tables by treatment group, and will list the mean, standard deviation, 
median, minimum, maximum, and number of subjects in a group for continuous data; count and 
percentage for categorical data; and median, 25th and 75th percentiles, relative risk and 95% confidence 
intervals for time-to-event data. Data will be listed for each subject. Statistical analyses will be performed 
and data appendices will be created using SAS.  
The efficacy analysis will be conducted on the full analysis set. The full analysis set will consist of all 
randomized subjects who received vascular access surgery (NOTE: The run-in patient at each site will 
be excluded from the full analysis set but will be included in the safety set). The primary efficacy 
endpoint is Fistula Suitability for Dialysis at 6 months (FSD6) This endpoint will be analyzed using 
logistic regression with factors for treatment and stratum. The treatment effect will be tested at overall 

Protocol No. VT-304 
 
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The ACCESS Trial 
 
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alpha=0.05, 2-sided, to compare the proportions of patients between treatments. 
Time to event secondary endpoints will be analyzed via stratified log rank test. Binary endpoints will be 
compared between treatments via the same logistic regression model as for the primary endpoint. 
Continuous secondary endpoints will be compared via analysis of covariance for a model including 
treatment, strata, and baseline covariate if measured at baseline, or non-parametric rank tests if normality 
or homogeneity assumptions appear substantially violated. Endpoints will be tested for statistically 
significant difference between treatments, each at alpha=0.05, 2-sided. 
Summary statistics for demographics and important baseline parameters will be provided by treatment 
group and for all subjects combined. TEAE’s and SAE’s will be summarized by counts and proportions 
by treatment for each body system organ class and by preferred term within class. 
Power and Sample Size Considerations 
All power calculations are via EAST® 6.4.  Assuming the TRUE underlying FSD6 rates are 45% for 
control and 76% for treatment (based on Phase 2 data), the sample size of N=200 patients contributing to 
the analysis has >99% power to yield a statistically significant (alpha=0.05 2-sided) difference between 
treatments.  Allowing for uncertainty in the Phase 2 data, if the TRUE underlying FSD6 rates are 45% 
and 65%, N=200 has approximately 82% power. 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
5. 
INTRODUCTION ......................................................................................................16 
5.1. 
Background .................................................................................................................16 
5.2. 
Unmet Clinical Need ..................................................................................................17 
5.3. 
Rationale for Evaluating the Sirolimus-eluting Collagen Implant .............................17 
5.4. 
Rationale for the Study Endpoints ..............................................................................18 
5.5. 
Summary .....................................................................................................................21 
6. 
STUDY ENDPOINTS AND OBJECTIVE ................................................................22 
6.1. 
Primary Endpoint ........................................................................................................22 
6.2. 
Secondary Endpoints ..................................................................................................23 
6.3. 
Tertiary Endpoints ......................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design ..................................................................................................24 
7.2. 
Schedule of Events .....................................................................................................25 
7.3. 
Subject Visits ..............................................................................................................28 
7.3.1. 
Baseline (-45 days) .....................................................................................................28 
7.3.2. 
Index Procedure (0 day) ..............................................................................................29 
7.3.3. 
1 Week Visit (+7±2 days) ...........................................................................................29 
7.3.4. 
2 Week Visit (+15±2 days) .........................................................................................30 
7.3.5. 
3 Week Visit (+21±2 days) .........................................................................................31 
7.3.6. 
4 Week Visit (+28±2 days) .........................................................................................32 
7.3.7. 
5 Week Visit (+35±2 days) .........................................................................................32 
7.3.8. 
6 Week Visit (+42±2 days) .........................................................................................33 
7.3.9. 
2 Month Visit (+60±4 days) .......................................................................................34 
7.3.10. 
3 Month Visit (+90±4 days) .......................................................................................35 
7.3.11. 
6 Month Visit (+180±15 days) ...................................................................................35 

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7.3.12. 
9 Month Visit (+270±15 days) ...................................................................................36 
7.3.13. 
End of Study Visit (+360±15 days) ............................................................................37 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................38 
8.1. 
Inclusion Criteria ........................................................................................................38 
8.2. 
Exclusion Criteria .......................................................................................................38 
8.3. 
Withdrawal or Discontinuation ...................................................................................39 
9. 
TREATMENT OF SUBJECTS ..................................................................................40 
9.1. 
Description of Investigational Product .......................................................................40 
9.2. 
Subject Enrollment .....................................................................................................41 
9.2.1. 
Index Procedure ..........................................................................................................41 
9.2.2. 
Treatment Assignment ................................................................................................42 
9.2.2.1. 
Run-in Subjects ...........................................................................................................42 
9.2.2.2. 
Randomization ............................................................................................................42 
9.2.3. 
Blinding/Unblinding ...................................................................................................43 
9.3. 
Packaging and Labeling ..............................................................................................44 
9.4. 
Storage Conditions ......................................................................................................44 
9.5. 
Accountability .............................................................................................................44 
9.6. 
Return and Destruction ...............................................................................................44 
9.7. 
Concomitant Medications ...........................................................................................45 
9.7.1. 
Prohibited Concomitant Medication ...........................................................................45 
9.8. 
Treatment Compliance ................................................................................................45 
10. 
ASSESSMENT OF EFFICACY ................................................................................45 
10.1. 
Primary Endpoint ........................................................................................................45 
10.2. 
Secondary Endpoints ..................................................................................................46 
10.2.1. 
Fistula Suitability for Dialysis at 12 months ..............................................................46 
10.2.2. 
Fistula Maturation by Day 90 .....................................................................................46 
10.2.3. 
Secondary Patency ......................................................................................................47 
10.2.4. 
Re-intervention Rate ...................................................................................................47 
10.3. 
Tertiary Endpoints ......................................................................................................47 
10.3.1. 
Time To First Dialysis (TTFD) ..................................................................................47 
10.3.2. 
Fistula Suitability for Dialysis at 6 months with preserved primary patency .............48 
10.3.3. 
Fistula Suitability for Dialysis at 12 months with preserved primary patency ...........48 
10.3.4. 
Primary Patency ..........................................................................................................49 

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10.4. 
Additional Definitions ................................................................................................49 
10.4.1. 
Mean Dialysis Machine Blood Flow ..........................................................................49 
10.4.2. 
Fistula Abandonment ..................................................................................................49 
10.4.3. 
Censored Events .........................................................................................................50 
11. 
ASSESSMENT OF SAFETY .....................................................................................50 
12. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................51 
12.1. 
Adverse Event Definition ...........................................................................................51 
12.2. 
Collection and Recording of Adverse Events .............................................................51 
12.2.1. 
Collection of Adverse Events .....................................................................................51 
12.2.2. 
Recording of Adverse Events .....................................................................................52 
12.2.3. 
Pregnancy and Pregnancy Outcome ...........................................................................54 
12.3. 
Serious Adverse Events ..............................................................................................55 
12.3.1. 
Serious Adverse Event Definition ..............................................................................55 
12.3.2. 
Collection, Recording and Reporting of Serious Adverse Events ..............................56 
12.3.2.1. 
SAE Reporting by the Investigator .............................................................................56 
12.3.2.2. 
Expedited Reporting by Sponsor ................................................................................56 
12.4. 
Follow-up of Adverse Events and Serious Adverse Events .......................................56 
12.4.1. 
Follow-up of Adverse Events with Onset during the Study .......................................56 
12.4.2. 
Collection of Serious Adverse Events with Onset after Last Study Visit ..................57 
12.4.3. 
Tissue Explant and Histology .....................................................................................57 
12.5. 
Data and Safety Monitoring Board .............................................................................57 
13. 
STATISTICS ..............................................................................................................57 
13.1. 
Statistical Analysis Plan .............................................................................................57 
13.2. 
Determination of Sample Size ....................................................................................57 
13.3. 
Data Analysis Considerations .....................................................................................58 
13.3.1. 
Analysis Sets ...............................................................................................................58 
13.3.1.1. 
Full Analysis Set .........................................................................................................58 
13.3.1.2. 
Safety Set ....................................................................................................................58 
13.3.2. 
Key Endpoints ............................................................................................................58 
13.3.3. 
Main Analysis .............................................................................................................58 
13.3.4. 
Secondary Efficacy Endpoints ....................................................................................59 
13.3.5. 
Safety Analysis ...........................................................................................................59 
13.3.5.1. 
Adverse Events ...........................................................................................................59 

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13.3.5.2. 
Baseline Variables and Concomitant Medications .....................................................59 
13.3.6. 
Exploratory Analyses ..................................................................................................60 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................60 
14.1. 
Study Monitoring ........................................................................................................60 
14.2. 
Audits and Inspections ................................................................................................61 
14.3. 
Confidentiality of Subject Data ..................................................................................61 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
15.1. 
Protocol Amendments ................................................................................................61 
15.2. 
Deviations from the Protocol ......................................................................................61 
15.3. 
Premature Study Termination .....................................................................................62 
16. 
ETHICS ......................................................................................................................62 
16.1. 
Ethical Conduct of the Study ......................................................................................62 
16.2. 
Ethics Review .............................................................................................................62 
16.3. 
Written Informed Consent ..........................................................................................63 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................63 
17.1. 
Direct Access to Source Data/Documents ..................................................................63 
17.2. 
Retention of Records ..................................................................................................64 
18. 
REPORTING AND PUBLICATION .........................................................................65 
18.1. 
Clinical Study Report .................................................................................................65 
18.2. 
Confidentiality and Ownership of Study Data ............................................................65 
18.3. 
Publications and Public Disclosure ............................................................................65 
18.3.1. 
Publication Policy .......................................................................................................65 
18.3.2. 
Public Disclosure Policy .............................................................................................65 
19. 
REFERENCES ...........................................................................................................67 
APPENDIX A. INFORMED CONSENT FORM TEMPLATE .................................................71 
APPENDIX B. KIDNEY DISEASE QUALITY OF LIFE-SHORT FORM SURVEY ............83 
APPENDIX C. INSTRUCTIONS FOR USE .............................................................................84 
 
LIST OF TABLES 
Table 1: 
Study Team Contact Information .................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 3: 
Summary of Absolute Risks Associated with Vascular Access Types 
(Catheter vs. Fistula) ...................................................................................................18 

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Table 4: Estimated Annual Number of CLABSIs by Health-care Setting and Year .....................19 
Table 5: 
Cumulative AV Fistula Survival Based on Number of Interventions 
Required for Fistula Suitability for Dialysis ...............................................................21 
Table 6: 
Relevance of Study Endpoints ....................................................................................22 
Table 7: 
Schedule of Events .....................................................................................................26 
Table 8: 
Description of the Component Membranes ................................................................40 
Table 9: 
Product Matrix and Nominal Sirolimus Dosages .......................................................41 
 
LIST OF FIGURES 
Figure 1: 
Dysfunctional AV Fistula ...........................................................................................16 
Figure 2: 
Survival curves for Hemodialysis-CVC (short-dashed line), Hemodialysis-
AV fistula/AV graft (long-dashed line), and Peritoneal Dialysis (solid line) ............19 
Figure 3: 
Intervention-free Access Survival after Angioplasty .................................................20 
Figure 4: 
Product Implantation Scheme .....................................................................................40 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialized terms are used in this study protocol. 
 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist 
Term 
Explanation 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
AF 
Anastomotic component of the Sirolimus-eluting Collagen Implant 
ASA 
Acetylsalicylic acid, Aspirin 
AV 
Arteriovenous 
CFD 
Complication Free Days 
CFR 
Code of Federal Regulations 
CKD 
Chronic Kidney Disease 
CRO 
Contract Research Organization 
DAC 
Dialysis Access Consortium 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ESRD 
End Stage Renal Disease 
FSD6 
Fistula Suitability for Dialysis 
GCP 
Good Clinical Practice 
HEENT 
Head, Eyes, Ears, Nose and Throat 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IVR System 
Interactive Voice Response System 
IWR System 
Interactive Web Response System 
KDQOL-SF 
Kidney Disease and Quality of Life Short Form survey 
MI 
Myocardial infarction 
PI 
Principal Investigator 
P.O. 
Per OS (oral administration) 

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Abbreviation or Specialist 
Term 
Explanation 
RRT 
Renal Replacement Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SeCI 
Sirolimus-eluting Collagen Implant 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial Master File 
TTFD 
Time to First Dialysis 
USRDS 
United States Renal Data System 
VF 
Venous Component of the Sirolimus-eluting Collagen Implant 
 

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5. 
INTRODUCTION 
5.1. 
Background 
Hemodialysis represents the most common form of renal replacement therapy for patients with 
End-Stage Renal Disease (ESRD). Since successful hemodialysis requires a repeated, reliable 
and durable access to the circulation, a functional vascular access is a lifeline for this patient 
population and a critical and actionable determinant of mortality and morbidity. 
A mature AV fistula is the preferred vascular access for hemodialysis because compared to the 
alternatives of AV grafts and catheters, an AV fistula has substantially lower thrombosis and 
infection rates, as well as decreased health care related expenditures. These advantages are 
reflected in clinical practice guidelines and also explain the rationale underlying the Centers for 
Medicare and Medicaid Services’ “Fistula First Initiative”. 
Unfortunately, in contemporary practice, on average, approximately 50% of AV fistulae never 
develop to the point of being suitable for hemodialysis, and those that do, often take up to five 
months or more to mature [1-6]. Fistula maturation is the process of dilatation and thickening of 
the anastomosed blood vessels – a consequence of changes in pressure and blood flow. Although 
dilatation and wall thickening have to occur in both artery and vein, venous dilatation is the 
clinically more apparent process in fistula maturation and ultimately determines fistula suitability 
for dialysis. The most common finding related to AV fistula maturation failure is 
juxta-anastomotic segment (JAS) stenosis, starting at or around the anastomosis and extending 
for a variable distance along the outflow vein (Figure 1) [7-14]. 
In 2007, Roy Chaudhury and colleagues published results from histological, morphometric, and 
immuno-histochemical analysis of tissue samples obtained from stenotic venous segments from 
patients with early AV fistula failure [10]. They showed significant luminal stenosis, primarily as 
a result of eccentric neointimal hyperplasia, a manifestation of the blood vessel tissue response to 
injury and healing. A recent prospective randomized study [7] reported that a flow limiting 
stenosis located at and around the juxta-anastomotic segment was responsible for failure to 
mature in ~ 50% of the cases. 
Figure 1: 
Dysfunctional AV Fistula 
 

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The etiology of neointimal hyperplasia is likely multifactorial and includes trauma, vascular 
manipulation related to surgery, as well as altered shear stress, i.e., exposing the low-flow, 
low-pressure venous conduit to high arterial pressures and flow [9,11,13].  
Vascular access continues to be the weakest link in maintenance hemodialysis, with access 
complications being the leading cause for hospitalization among ESRD patients. Of particular 
concern are hospitalizations for infection in the hemodialysis population, which have increased 
43% since 1993 [15].  
 
5.2. 
Unmet Clinical Need 
The lack of a therapeutic solution to correct the problem of fistula non-maturation defines a 
huge, well-recognized, unmet clinical need since in the absence of a functional fistula, patients 
dialyze with a catheter. All the stakeholders involved in the care of the patient with ESRD are 
aligned and in agreement that there is an urgent need to find a solution to the problem. 
Specifically what is needed is: 
1. A reduction in time to fistula maturation as well as an increase in the proportion of 
fistulae that mature and become suitable for cannulation for first dialysis. The sooner the 
newly constructed fistula is functionally ready to support dialysis, the less the 
dependence on catheters. 
2. Ensuring that the fistula maintains functionality without need for supplementary 
interventions. Currently, supplementary interventions are performed with the intent of 
assisting the fistula to become suitable for dialysis and/or maintain functional patency. 
These additional interventions have variable levels of success in the short term but 
negatively impact long term durability [16-18]. 
The status quo will continue until such time a therapeutic solution to the problem of fistula 
non-maturation and reduced suitability for dialysis becomes available. The investigational 
product that is being tested in the clinical trial seeks to provide this solution and bridge this 
unmet need.  
 
5.3. 
Rationale for Evaluating the Sirolimus-eluting Collagen Implant 
Sirolimus (Rapamycin), marketed under the trade name Rapamune® for the prevention of organ 
rejection in patients with a kidney transplant, has shown clinically useful anti-restenotic 
properties in coronary arteries [19-22]. Sirolimus has a unique dual mechanism of action 
involving both anti-inflammatory and cytostatic anti-proliferative effects resulting from 
inhibition of a signal transduction kinase, the mammalian target of rapamycin (mTOR) [23]. 
When delivered locally to the vascular wall from a stent platform, sirolimus suppresses 
neointimal hyperplasia. This therapeutic effect has translated into a clinically meaningful 
reduction in the incidence of in-stent restenosis [24-28].  
Local perivascular delivery of sirolimus using the Sirolimus-eluting Collagen Implant (SeCI) at 
the time of AV fistula creation is expected to inhibit neointimal proliferation at the local 

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treatment sites thereby reducing the risk of a flow limiting stenosis. In turn, this is expected to 
improve fistula maturation and suitability for dialysis with preserved primary patency.  
 
5.4. 
Rationale for the Study Endpoints 
In the United States, over 80% of all ESRD patients initiate dialysis with a catheter and 
approximately 50% are still utilizing a catheter after 90 days [15]; hence, the sooner the newly 
constructed fistula is functionally ready to support dialysis, the less the dependence on catheters. 
The single largest vascular access related contributor to mortality and morbidity is related to 
catheter use. Catheter complications result from lower dialysis dose, missed/shorter dialysis 
sessions, central vein stenosis and occlusions (which besides contributing to highly morbid 
situations like superior vena cava syndrome, prevent creation of an access on the ipsilateral side) 
and most importantly from infections and septicemia.  
In 2013, Ravani and colleagues reported the results of a meta-analysis of 67 cohort studies 
comprising 586,337 participants [29]. The primary outcome of the analysis was all cause 
mortality; secondary outcomes included fatal and non-fatal cardiovascular events, fatal and non-
fatal infections and all cause hospitalizations. The relative risks (catheter vs. AV fistula) for these 
various metrics are shown in Table 3. 
Table 3: 
Summary of Absolute Risks Associated with Vascular Access Types 
(Catheter vs. Fistula) 
Cause (Number of Patients) 
RR (95% CI) 
All cause mortality (N=411,068) 
1.53 (1.41-1.67) 
Fatal infections (N=229,824) 
2.12 (1.79-2.52) 
Non Fatal Infections (N=14,947) 
4.66 (2.63-8.26) 
Cardiovascular Events (N=232,236) 
1.38 (1.24-1.54) 
Hospital Admissions (N=54,660) 
1.68 (1.33-2.12) 
In a registry-based, observational, cohort study, Perl et al. compared the outcomes of 40,526 
incident dialysis patients who were registered between 2001 and 2008 to those of 7,412 
peritoneal dialysis patients. One year mortality was similar for the 6,663 patients on 
hemodialysis using an AV fistula or graft but was 80% higher for the 24,437 hemodialysis 
patients dialyzing with a catheter (adjusted HR, 1.8; 95% confidence intervals [CI], 1.6 to 1.9) 
Figure 2 [30].  

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Figure 2: 
Survival curves for Hemodialysis-CVC (short-dashed line), Hemodialysis-AV 
fistula/AV graft (long-dashed line), and Peritoneal Dialysis (solid line) 
 
Survival curves demonstrate higher 1-year mortality in HD-CVC patients. (A) Unadjusted. (B) Adjusted on the basis 
of a stratified Cox proportional Hazards model stratified by HD-CVC, PD, and HD-AVF/AVG and adjusted for age, 
race, gender, era of dialysis initiation, end-stage renal disease comorbidity index, primary renal diagnosis, serum 
albumin, eGFR, province of treatment, and late referral. 
Central line–associated blood stream infections (CLABSIs) are an important subset of 
health-care associated infections, and affect approximately 5% of patients hospitalized in the 
United States each year. In an effort to focus on the growing problem of CLABSIs within the 
hemodialysis patient population, the CDC published national estimates of the number of 
CLABSIs among patients in intensive-care units (ICUs), inpatient wards and outpatient 
hemodialysis facilities for calendar years 2008 and 2009 (Table 4) [31]. 
Table 4: Estimated Annual Number of CLABSIs by Health-care Setting and Year 
Health-care Setting 
Year 
No. of Infections (Upper and Lower 
Bound of Sensitivity Analysis) 
Intensive-care units 
2001 
2009 
43,000 (27,000–67,000) 
18,000 (12,000–28,000) 
Inpatient wards 
2009 
23,000 (15,000–37,000) 
Outpatient hemodialysisa 
2008 
37,000 (23,000–57,000) 
a Case definitions approximate current definition of CLABSI according to the National Healthcare Safety Network 

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This CDC report from 2011 highlighted the following: 
1. Whereas in 2001, the number one cause of CLABSI in the United States was a patient in 
the ICU, this was no longer the case eight years later. In 2009, an estimated 25,000 fewer 
CLABSIs occurred among patients in ICUs in comparison to 2001 (a 58% reduction).  
2. The reported mortality risk from CLABSIs is 12-25%; hence, these reductions represent 
an estimated savings of 3,000–6,000 lives and reduction in health-care costs of 
$414 million in ICUs in 2009 alone [32]. 
3. Today in the United States, the majority of CLABSIs are occurring outside of ICUs, 
many outside of hospitals altogether, especially in outpatient dialysis clinics. 
4. The substantial number of estimated CLABSIs among hemodialysis patients (more than 
40,000/year) emphasizes another important prevention priority because these infections 
are a major cause of hospital admissions and mortality [33]. 
Delays and failures of the fistula becoming suitable for dialysis prolongs catheter dependence 
and increases the unfavorable downstream consequences of catheter use [29,34-36]. 
Preserving fistula functionality at 6 and 12 months addresses the issue of fistula durability, the 
primary goal of vascular access creation. At the present time, if follow up clinical evaluations, 
often supported by duplex ultrasound studies, suggests fistula non-maturation or fistula 
dysfunction is a result of a flow limiting stenosis, a supplementary intervention is performed – 
most often a balloon angioplasty to dilate and treat anastomotic and/or venous segment stenosis 
[37,38]. Hence, these supplementary interventions are performed with the intent of assisting the 
fistula to become suitable for dialysis and/or maintain functional patency. Although in the short 
term, in a variable proportion of fistulae these additional intervention(s) are successful in their 
intent [16], in the longer term, these additional procedures negatively impact durability 
(Figure 3; Table 5) [17,18]. The most plausible explanation for this reduced durability is that the 
vascular trauma related to the interventional procedure itself fuels an aggressive neointimal 
response resulting in recurrent stenosis [17]. 
Figure 3: 
Intervention-free Access Survival after Angioplasty 
 
 Analysis was restricted to the first angioplasty for each patient. P=0.36 by log-rank test for the comparison 
between the 2 survival curves [18]. 

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Table 5: 
Cumulative AV Fistula Survival Based on Number of Interventions Required 
for Fistula Suitability for Dialysis 
No of Interventions required for Fistula 
Suitability for Dialysis Æ 
Zero 
Interventions 
One Intervention 
Two or More 
Interventions 
Cumulative AV Fistula Survival at 1-yeara 
92% 
78% 
68% 
Number of Interventions per Year after AV 
fistula Cannulation 
0.76±0.10 
1.37±0.31 
3.51±2.20 
a Cumulative access survival as measured from access cannulation to permanent failure. 
 
It is important to emphasize that supplementary interventions are performed in response to a 
clinical need signaling either lack of fistula maturation or fistula dysfunction. Hence, as long as a 
therapeutic solution to this unmet clinical need is unavailable (the negative connotations of 
additional procedures notwithstanding), the clinical relevance of these supplementary 
interventions cannot be diminished. Conversely, the therapeutic solution to address the problem 
of fistula non-maturation being evaluated in the clinical trial is expected to reduce or eliminate 
the need for supplementary interventions. Maintaining patency without the need for additional 
interventions manifests as preserved primary patency and is one clinical measure of the effect of 
the study drug. Reducing or altogether eliminating the need for supplementary interventions is 
very beneficial to patients (by providing freedom from procedure related pain and morbidity and 
avoiding interruption of dialysis schedules), to the fistula (by preserving its durability) and to 
dialysis providers and payors. 
 
5.5. 
Summary 
Providing a functional AV fistula by shortening time to first dialysis and ensuring its durability, 
i.e., ensuring suitability of the fistula for dialysis at later time points is vital for ESRD patients on 
dialysis. The current standard of care is unable to provide a solution to the problem of fistula 
non-maturation, setting the stage for a huge, well acknowledged unmet clinical need. Stated 
differently, fistula maturation is the most critical event in the natural history of an AV fistula and 
maximizing the proportion of fistula that become suitable for cannulation for first dialysis and 
remain useful for dialysis (i.e., maintain functionality) continues to be high priority goals in 
vascular access. Fistula suitability for dialysis should occur not only without assistance of 
supplementary procedures, it should also occur early - typically within 6 weeks of surgical fistula 
creation. The timing is important since a functional fistula triggers end of catheter dependence 
reducing the risk of catheter related complications, which are substantial.  
The clinical importance and rationale of the study endpoints are summarized in Table 6. 
 
 

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Table 6: 
Relevance of Study Endpoints 
Metric 
Implication 
Comment 
Reducing time to first dialysis using 
the fistula 
Fistula maturationa
, signaling 
functionality is a critical event 
Reduces catheter dependence 
Catheter use for hemodialysis 
increases mortality and morbidity 
Maintaining a higher proportion of 
fistulae suitable for dialysis at 6 
months 
Addresses durability of the mature 
functional fistula 
Approximately 50% of all AV 
fistulae are not suitable for 
hemodialysis 
Fistula with and without preserved 
primary patency 
Supplementary interventions impact 
fistula durability 
Patient morbidity 
Multiple interventions 
Adequacy of dialysis 
Health care costs 
a Lack of a solution to the problem of fistula non-maturation defines the unmet clinical need 
 
6. 
STUDY ENDPOINTS AND OBJECTIVE 
The objective of this study is to evaluate efficacy and safety outcomes following use of the 
Sirolimus-eluting Collagen Implant in subjects undergoing surgical creation of an AV fistula for 
vascular access (index procedure). Following successful creation of the AV fistula, the cohort 
randomized to the treatment group will receive the SeCI; the control group will not receive an 
implant.  
The primary study hypothesis is that the proportion of subjects that meet fistula suitability for 
dialysis six months following the index procedure, will be higher in the treatment group in 
comparison to the control group. 
 
6.1. 
Primary Endpoint 
The primary endpoint of the study is Fistula Suitability for Dialysis at 6 months (FSD6) 
defined as a composite of: 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 150. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 150, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 6 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 

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6.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
1. Fistula Suitability for Dialysis at 12 months defined as a composite of: 
a. For subjects who are on hemodialysis by day 330, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 330. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 330, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 12 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 
2. Fistula Maturation by Day 90 defined as defined as a composite of: 
a. For subjects who are on hemodialysis by day 90: 
− Three consecutive dialysis sessions using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min, the first of these three dialysis sessions 
completed on or before 90 days from the time of creation of the AV fistula, or 
− Two-needle dialysis on or before 90 days with no further use of the catheter prior 
to achieving three consecutive dialysis sessions using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min. 
b. For subjects who do not initiate hemodialysis by day 90, fistula access vein diameter 
(AVD) of ≥6 mm (internal diameter) and an access blood flow of ≥500 mL/min 
determined by a vascular ultrasound performed at the 3-month follow up visit. 
3. Secondary Patency, defined as the interval from the time of access placement until access 
abandonment. 
4. Re-intervention Rate, defined as the total number of vascular access interventions 
performed during study participation to maintain or re-establish patency of the index 
fistula, as well as interventions to assist fistula maturation divided by the total subject 
participation time in the study. 
 
6.3. 
Tertiary Endpoints 
The tertiary endpoints of the study are: 
1. Time To First Dialysis (TTFD) defined as the time from fistula creation to the time when 
the fistula can support three consecutive dialysis sessions using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min. TTFD will be evaluated in subjects who 

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are on dialysis at the time of study enrollment or initiate dialysis within 28 days of the index 
procedure. 
2. Fistula Suitability for Dialysis at 6 months with preserved primary patency defined as a 
composite of: 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 150 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 150, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 6 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min 
3. Fistula Suitability for Dialysis at 12 months with preserved primary patency 
4. Primary Patency, defined as the interval from the time of fistula creation until the first 
occurrence of fistula thrombosis or an intervention performed to restore/maintain 
patency. 
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, multicenter, randomized, single blind, controlled, adaptive study designed to 
evaluate the efficacy and safety of the use of the Sirolimus-eluting Collagen Implant (SeCI) in 
subjects who are on hemodialysis or are preparing for hemodialysis and are undergoing surgical 
creation of an AV fistula in comparison to subjects who do not receive the implant.  
Subjects of either gender, who are at least 18 years of age, undergoing hemodialysis or are 
expected to initiate hemodialysis within 6 months of study enrollment, and require a new 
single-stage radiocephalic or brachiocephalic end-to-side fistula will be eligible to participate in 
this study. It is expected that all subjects will be enrolled across approximately 20 sites and each 
enrolled subject will be followed for one year from the time of fistula creation. 
Subjects who meet eligibility criteria and undergo successful AV fistula creation will be eligible 
for enrollment. The study plans to enroll approximately 240 subjects. Of these, the first subject 
enrolled by a participating surgeon will be a run-in subject; run-in subjects will not be part of the 
randomized set; all run-in subjects will receive the SeCI. The intent of enrolling run-in subjects 
in the clinical study is to familiarize the investigators with the implant procedure. Approximately 
220 subjects will be randomized in a 1:1 ratio using permuted block randomization stratified by 
surgeon and fistula location (radiocephalic or brachiocephalic) to yield approximately 200 
evaluable subjects. The randomized cohort will include a minimum of 100 evaluable subjects 
who are on hemodialysis at the time of the index procedure. 

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Subjects who are on hemodialysis at the time of enrollment will undergo evaluations to 
determine fistula suitability for cannulation starting no earlier than day 28 post index procedure; 
the frequency of assessments for cannulation suitability will be at the discretion of the 
investigator and/or designee. The decision to proceed with first cannulation will be made by the 
investigator based on clinical assessment of the fistula. In addition, subjects who have not 
initiated hemodialysis by: 
• Day 90 post index procedure, and the index fistula has not been abandoned, a 
vascular ultrasound will be performed at the 3 month follow up visit, 
• Day 150 post index procedure, and the index fistula has not been abandoned, a 
vascular ultrasound will be performed at the 6 month follow up visit, and 
• Day 330 post index procedure, and the index fistula has not been abandoned, a 
vascular ultrasound will be performed at the 12 month follow up visit. 
An intervention to assist fistula maturation is not permitted in the study prior to 42 days 
following the index procedure. However, an intervention, if deemed necessary, is permitted 
upon diagnosis of one or more of the following events: 
1. Access thrombosis 
2. Access-related hand ischemia 
3. High output cardiac failure 
4. Access infiltration or AV fistula-related bleeding 
5. Access-related infection/wound complication 
6. Aneurysm and pseudoaneurysm 
All enrolled subjects will be followed for a period of one year from the time of their index 
procedure. 
 
7.2. 
Schedule of Events 
A schedule of events/assessments is provided Table 7.

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Table 7: 
Schedule of Events 
 
Baseline 
Index 
Proc. 
1W 
Visita 
2W 
Visit 
3W 
Visita 
4W 
Visit 
5W 
Visita 
6W 
Visit 
2M Visit 
3M Visit 
6M Visit 
9M Visit 
End of 
Study 
Visit 
 
-45d 
0d 
+7±2d 
+15±2d 
+21±2d 
+28±2d 
+35±2d 
+42±2d 
+60±4d 
+90±4d 
+180 
±15d 
+270 
±15d 
+360 
±15d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessmentsd 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Dialysis adequacy 
datae 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Pregnancy testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Access planning 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Index procedure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Access assessmentg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
examinationh 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Cannulation 
assessmenti 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vascular 
ultrasound 
 
 
 
 
 
 
 
 
 
Xj 
Xk 
 
Xl 

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Baseline 
Index 
Proc. 
1W 
Visita 
2W 
Visit 
3W 
Visita 
4W 
Visit 
5W 
Visita 
6W 
Visit 
2M Visit 
3M Visit 
6M Visit 
9M Visit 
End of 
Study 
Visit 
 
-45d 
0d 
+7±2d 
+15±2d 
+21±2d 
+28±2d 
+35±2d 
+42±2d 
+60±4d 
+90±4d 
+180 
±15d 
+270 
±15d 
+360 
±15d 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
Xm 
Xm 
Concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
Xm 
Xm 
KDQOL Survey 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
a This visit is applicable to subjects who are undergoing hemodialysis at the time of the visit. 
b Medical history should include the subject’s vascular access history (prior AV accesses and catheters) including number of interventions (e.g., number of 
angioplasties, thrombectomies, etc.) over the previous 6months. 
c For subjects on hemodialysis, vital sign values will be obtained from the dialysis session records. 
d Laboratory values will be obtained from the local medical records; the assays will not be performed centrally and should be the most recent available relative to 
the visit. 
e Dialysis adequacy data should be collected for subjects undergoing hemodialysis at the time of the scheduled visit. 
f A pregnancy test should be performed within 7 days prior to the index procedure for women with childbearing potential. 
g Access assessment to document fistula patency and fistula development status. Evaluations include thrill and bruit assessment, arm elevation test, and 
augmentation test. Access assessments should be performed by delegated dialysis unit personnel. 
h Clinical exam to document wound healing, any local problems such as infection, wound dehiscence, unexpected amount of arm swelling, etc., and evaluation 
for presence of steal syndrome (e.g. pain in digits, discoloration, cold fingers, blue fingers, etc.). 
i For subjects on hemodialysis at the time of enrollment or subjects who initiate dialysis within 28 days of index procedure, cannulation assessment will start no 
earlier than 28 days post index procedure with subsequent assessments occurring at discretion of the investigator and/or designee. The decision to proceed with 
first cannulation will be based on the investigator’s clinical assessment. 
j For subjects who do not initiate hemodialysis by Day 90 and the index fistula has not been abandoned, a duplex ultrasound must be performed at the 3 month 
follow up visit. 
k For subjects whose index fistula is not in use for hemodialysis on day 150 and the index fistula has not been abandoned, a duplex ultrasound must be performed 
at the 6 month follow up visit. 
l For subjects whose index fistula is not in use for hemodialysis on day 330 and the index fistula has not been abandoned, a duplex ultrasound must be performed 
at the 12 month follow up visit. 
m Record adverse events and concomitant medications that are associated with or occurred during an SAE or vascular access events. See sections 9.7 and 12. 
 

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7.3. 
Subject Visits 
7.3.1. 
Baseline (-45 days) 
Screening assessments must occur within 45 days of the index procedure. Assessments can be 
performed at any time within the 45 day window unless otherwise indicated below. 
Once informed consent has been obtained, a subject will be screened for study participation. The 
original signed Subject Information and Informed Consent Form (ICF) must be maintained in the 
subject’s source document, with a copy provided to the subject (see Section 16.3). 
The following evaluations must be performed: 
• Inclusion/exclusion criteria (see Section 8) 
• Demographic data (age, gender, race, and ethnicity) 
• Medical and medication history. Information on relevant previous and concomitant 
illnesses, or any clinically significant signs or symptoms discovered as a result of 
screening procedures will be recorded as medical history. Particular emphasis should 
be given to etiology of renal failure and co-morbidities like diabetes, hypertension, 
coronary artery disease, peripheral vascular disease, cerebrovascular disease, 
congestive heart failure, dyslipidemia, tobacco and alcohol use, allergies, and 
bleeding history. Medical history should also include the subject’s vascular access 
history including number of interventions (e.g., number of angioplasties, 
thrombectomies, etc.) over the previous 6 months. 
• Vital signs (temperature, heart rate, blood pressure), body weight, and height. Note: If 
the subject is undergoing hemodialysis, these values should be obtained, post-
dialysis, from the most recent hemodialysis session in relation to the scheduled visit. 
All abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• General physical exam 
• Local laboratory assessments 
• Dialysis adequacy data, if the subject is undergoing hemodialysis 
• Pregnancy test for women with childbearing potential (non-childbearing potential is 
defined as not having had a menstrual period for 1 year or surgically sterilized). The 
pregnancy test must be performed within 7 days prior to the index procedure. 
• Access planning procedures. Duplex ultrasound of the index limb for vascular 
mapping to determine diameter and depth of the target outflow vein and diameter of 
the target artery. In subjects with a history of or current use of a catheter ipsilateral to 
the side where the AV fistula is planned or a pacemaker has been placed in the 
ipsilateral central vein, a venogram is strongly recommended as part of access 
planning. This approach is consistent with current standard of care. 
Note: Access planning procedures may be performed/repeated on the day of index 
procedure to verify individual measurements. 

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• Kidney Disease and Quality of Life – Short Form (KDQOL-SF) survey (see 
Appendix B) 
 
7.3.2. 
Index Procedure (0 day) 
The following evaluations must be performed prior to enrollment: 
• Vital signs (temperature, heart rate, and blood pressure); pre-surgical 
• Confirmation of successful AV fistula creation. Successful creation is defined as a 
patent fistula with satisfactory hemostasis. Successful creation will be determined by 
the presence of a palpable thrill and any one of the following: 
− a satisfactory auditory signal using a handheld Doppler, or 
− visual augmentation of the juxta-anastomotic segment following application of a 
proximal tourniquet, or, 
− verification of fistula patency using duplex ultrasound 
• Should the AV fistula creation procedure fail, the subject will be considered a 
screen failure and will not be enrolled. 
Subjects designated as run-in patients will receive the SeCI. Randomization is accomplished 
using the IVR/IWR System. See Section 9.2 for further details. 
The following activities must be performed following enrollment and prior to discharge: 
• Pre-discharge access assessment (presence of a thrill and bruit) of the AV fistula to 
document fistula patency 
• Assessment of AEs following completion of the index procedure 
• Update of concomitant medications 
In subjects undergoing hemodialysis at the time of enrollment, the following assessment must be 
performed at the first dialysis session following subject enrollment: 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
 
7.3.3. 
1 Week Visit (+7±2 days) 
This visit is applicable to subjects who are undergoing hemodialysis at the time of the visit. The 
following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. These 
values should be obtained, post-dialysis, from the most recent hemodialysis session in 
relation to the scheduled visit. All abnormal vital sign values must be evaluated by 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
30 
the investigator for clinical significance in relation to the subject’s underlying 
condition. 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update concomitant medications 
 
7.3.4. 
2 Week Visit (+15±2 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Note: If the 
subject is undergoing hemodialysis, these values should be obtained, post-dialysis, 
from the most recent hemodialysis session in relation to the scheduled visit. Any 
abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• Clinical examination of the surgical wound to document wound healing, any local 
problems such as infection, wound dehiscence, unexpected amount of arm swelling, 
etc., and evaluation for presence of steal syndrome (e.g. pain in digits, discoloration, 
cold fingers, blue fingers, etc.). 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Symptoms spontaneously reported by the subject 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
31 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update concomitant medications 
 
7.3.5. 
3 Week Visit (+21±2 days) 
This visit is applicable to subjects who are undergoing hemodialysis at the time of the visit. The 
following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. These 
values should be obtained, post-dialysis, from the most recent hemodialysis session in 
relation to the scheduled visit. All abnormal vital sign values must be evaluated by 
the investigator for clinical significance in relation to the subject’s underlying 
condition. 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update concomitant medications 
 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
32 
7.3.6. 
4 Week Visit (+28±2 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Note: If the 
subject is undergoing hemodialysis, these values should be obtained, post-dialysis, 
from the most recent hemodialysis session in relation to the scheduled visit. All 
abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• Clinical examination of the surgical wound to document wound healing, any local 
problems such as infection, wound dehiscence, unexpected amount of arm swelling, 
etc., and evaluation for presence of steal syndrome (e.g. pain in digits, discoloration, 
cold fingers, blue fingers, etc.). 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• KDQOL-SF survey (see Appendix B). 
• Cannulation assessment if the subject is undergoing hemodialysis (see Section 10.1). 
The first evaluation to determine fistula suitability for cannulation will start no earlier 
than 28 days from the time of index procedure. The investigator and/or designee will 
determine the frequency of subsequent assessments for cannulation suitability. The 
decision for first cannulation will be based on the investigator’s clinical assessment of 
the fistula. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update of concomitant medications 
 
7.3.7. 
5 Week Visit (+35±2 days) 
This visit is applicable to subjects who are undergoing hemodialysis at the time of the visit. The 
following evaluations must be performed: 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
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Confidential 
 
33 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. These 
values should be obtained, post-dialysis, from the most recent hemodialysis session in 
relation to the scheduled visit. All abnormal vital sign values must be evaluated by 
the investigator for clinical significance in relation to the subject’s underlying 
condition. 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update concomitant medications 
 
7.3.8. 
6 Week Visit (+42±2 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. 
Note: If the subject is undergoing hemodialysis, these values should be obtained, 
post-dialysis, from the most recent hemodialysis session in relation to the scheduled 
visit. All abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• Clinical examination of the surgical wound to document wound healing, any local 
problems such as infection, wound dehiscence, unexpected amount of arm swelling, 
etc., and evaluation for presence of steal syndrome (e.g. pain in digits, discoloration, 
cold fingers, blue fingers, etc.). 
• Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and augmentation 
test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
34 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update concomitant medications 
 
7.3.9. 
2 Month Visit (+60±4 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. These 
values should be obtained, post-dialysis, from the most recent hemodialysis session in 
relation to the scheduled visit. All abnormal vital sign values must be evaluated by 
the investigator for clinical significance in relation to the subject’s underlying 
condition. 
• For subjects whose index fistula is not in use for hemodialysis at the 2 month visit 
and the index fistula has not been abandoned, access assessment to document fistula 
patency and fistula development status. Evaluations include thrill and bruit 
assessment, arm elevation test, and augmentation test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments must include: 
− Symptoms spontaneously reported by the subject 
− Any examination findings and test results determined by the investigator to be a 
clinically significant change or abnormality 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, lab abnormalities, etc.) 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
• Update of concomitant medications 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
35 
• Laboratory assessments. All abnormal laboratory values must be evaluated by the 
investigator for clinical significance in relation to the subject’s underlying condition 
• Dialysis adequacy data, if the subject is undergoing hemodialysis 
 
7.3.10. 
3 Month Visit (+90±4 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Note: If the 
subject is undergoing hemodialysis, these values should be obtained, post-dialysis, 
from the most recent hemodialysis session in relation to the scheduled visit. All 
abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• For subjects whose index fistula is not in use for hemodialysis at the 3 month visit 
and the index fistula has not been abandoned 
− Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and 
augmentation test. 
Note: Access assessments should be performed by delegated personnel. 
− A duplex ultrasound must be performed. The ultrasound report should include the 
cephalic vein diameter and include fistula flow measurements 
• KDQOL-SF survey (see Appendix B) 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, etc.) 
• Update of concomitant medications (See Section 9.7) 
 
7.3.11. 
6 Month Visit (+180±15 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Note: If the 
subject is undergoing hemodialysis, these values should be obtained, post-dialysis, 
from the most recent hemodialysis session in relation to the scheduled visit. All 
abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
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36 
• For subjects whose index fistula is not in use for hemodialysis on day 150 and the 
index fistula has not been abandoned 
− Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and 
augmentation test. 
− A duplex ultrasound must be performed. The ultrasound report should include the 
cephalic vein diameter and include fistula flow measurements 
• KDQOL-SF survey (see Appendix B) 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, etc.) 
• Update of concomitant medications (See Section 9.7) 
• Laboratory assessments. All abnormal laboratory values must be evaluated by the 
investigator for clinical significance in relation to the subject’s underlying condition. 
• Dialysis adequacy data, if the subject is undergoing hemodialysis 
 
7.3.12. 
9 Month Visit (+270±15 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Note: If the 
subject is undergoing hemodialysis, these values should be obtained, post-dialysis, 
from the most recent hemodialysis session in relation to the scheduled visit. All 
abnormal vital sign values must be evaluated by the investigator for clinical 
significance in relation to the subject’s underlying condition. 
• For subjects whose index fistula is not in use for hemodialysis at the 9 month visit 
and the index fistula has not been abandoned, access assessment to document fistula 
patency and fistula development status. Evaluations include thrill and bruit 
assessment, arm elevation test, and augmentation test. 
Note: Access assessments should be performed by delegated personnel. 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
37 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, etc.) 
• Update of concomitant medications (See Section 9.7) 
 
7.3.13. 
End of Study Visit (+360±15 days) 
The following evaluations must be performed: 
• Vital signs (temperature, heart rate, and blood pressure) and body weight. Vital signs 
should be obtained at the time of the general physical exam. All abnormal vital sign 
values must be evaluated by the investigator for clinical significance in relation to the 
subject’s underlying condition. 
• For subjects whose index fistula is not in use for hemodialysis on day 330 and the 
index fistula has not been abandoned 
− Access assessment to document fistula patency and fistula development status. 
Evaluations include thrill and bruit assessment, arm elevation test, and 
augmentation test. 
− A duplex ultrasound must be performed. The ultrasound report should include the 
cephalic vein diameter include fistula flow measurements 
• KDQOL-SF survey (see Appendix B) 
• General physical exam 
• Adverse event assessments (see Section 12.2). AE assessments include: 
− Vascular access related AEs and interventions (e.g., angioplasty, percutaneous 
thrombectomy, surgical revision, surgical thrombectomy, declotting, 
administration of lytics, etc.) since last visit 
− Introduction/creation of a new, alternate access (catheter, AV fistula, or AV graft) 
since last visit 
− Other information relating to the subject’s health becoming known to the 
investigator (e.g., hospitalization, etc.) 
• Update of concomitant medications (See Section 9.7) 
• Laboratory assessments. All abnormal laboratory values must be evaluated by the 
investigator for clinical significance in relation to the subject’s underlying condition. 
• Dialysis adequacy data, if the subject is undergoing hemodialysis 
 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
38 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects at least 18 years age, of either gender undergoing a planned creation of an upper 
extremity AV fistula, without known contraindications for use of sirolimus or collagen are 
eligible to participate in this study. All subjects are to be screened for study participation 
according to the inclusion and exclusion criteria described below. Every effort will be made to 
establish a subject’s eligibility prior to enrollment. Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be eligible to participate in the study. 
 
8.1. 
Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria to be enrolled in the study: 
1. Age of at least 18 years 
2. Provide written informed consent using a form that is approved by the Institutional 
Review Board (IRB) 
3. Currently on hemodialysis for ≤12 months or expected to initiate hemodialysis within 
approximately 6 months of the creation of the AV fistula. 
4. Life expectancy of at least one year  
5. Vascular anatomy suitable for creation of the AV fistula, determined by pre-procedure 
duplex ultrasound (target artery ≥2 mm, target vein ≥2.5 mm, and vein depth ≤5 mm in 
the cannulation segment, the latter approximately 10 cm in length) 
6. Successful creation of a single-stage radiocephalic or brachiocephalic end-to-side fistula 
7. Willing to comply with the specified follow-up evaluations 
 
8.2. 
Exclusion Criteria 
Subjects will be excluded if ANY of the following exclusion criteria apply: 
1. Pregnant, breastfeeding, or plans to be pregnant during the course of the study 
2. Prior AV access created on the limb where the fistula surgery is planned 
3. History of steal syndrome from a previous hemodialysis vascular access requiring 
intervention or access abandonment 
4. ST-elevation MI or cerebrovascular accident within 30 days of the index procedure 
5. Known hypersensitivity to the following: sirolimus, beef or bovine collagen 
6. Hypotension with systolic blood pressures <100 mm Hg at the time of screening 
7. Receiving anticoagulant therapy for non-cardiac indications 
8. Currently on immunosuppressive medication(s) 
9. Known or suspected active infection at the time of the AV fistula surgery 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
Ver. 5.3 | 22-Jan-2018 
Confidential 
 
39 
10. Known to be HIV positive 
11. Presence of a medical condition, which, in the Investigator’s opinion, may interfere with 
the subject’s optimal participation in the study (e.g., malignancy or undergoing 
chemotherapy or radiation treatments) 
12. Known advanced liver disease with decompensated cirrhosis, jaundice, ascites or 
bleeding varices 
13. Prisoner, mentally incompetent, and/or current alcohol or drug abuser 
14. Currently participating in another investigational study 
 
8.3. 
Withdrawal or Discontinuation 
Following randomization, neither the sponsor nor the investigator should discontinue any subject 
from the study. However, subjects may be discontinued from the clinical study for any of the 
following reasons: 
• Withdrawal of consent by the subject; or 
• Lost to follow-up  
Although each subject is expected to remain in this study for the duration of follow-up, all 
subjects have the right to withdraw at any point during the study without prejudice. Withdrawal 
of consent for follow-up should be accompanied by documentation of the reason for withdrawal. 
Withdrawal of consent for follow-up visits should be distinguished from withdrawal of consent 
for non-patient contact follow-up, e.g., medical records checks. Preferably the subject should 
withdraw consent in writing and, if the subject or the subject’s representative refuses or is 
physically unavailable, the site should document and sign the reason for the subject’s failure to 
withdraw consent in writing. The investigator and/or designee will, if at all possible, complete all 
End of Study evaluations on subjects who withdraw from the study. If a subject chooses to 
withdraw from the study because of an adverse event, the subject should be explicitly asked 
about the contribution of possible adverse events to their decision to withdraw consent; any 
adverse event information elicited along with the principal specific event and any related test 
results must be captured in the source document and eCRF. Subjects who discontinue 
participation in the study due to an adverse event experienced during study conduct will, at 
minimum, be followed until resolution or until stabilization. 
If a subject is lost to follow-up, the investigator and/or designee will make at least 3 phone 
attempts to reach the subject. If the phone attempts are unsuccessful, the site will mail a certified 
letter to the subject’s last known address requesting they return for evaluation. If a subject dies 
during the course of the study, they will not be considered withdrawn from the study, but rather 
no further follow-up will be required. The reason for withdrawal or discontinuation will be 
documented in the subject’s source document and eCRF. 
 

Protocol No. VT-304 
 
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The ACCESS Trial 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Investigational Product 
The Sirolimus-eluting Collagen Implant is a sterile, bioabsorbable implant comprised of 
sirolimus at a nominal drug density of 75 μg per cm2 of implanted collagen membrane. A single 
implant consists of two component membranes; one anastomosis component (AF) and one 
outflow vein component (VF) (Figure 4). Following hydration, the membranes will “self-curl” 
into a cylindrical configuration. This facilitates implantation around the blood vessel without the 
need for suturing the free edges, avoiding the creation of a potentially restrictive external band. 
Figure 4: 
Product Implantation Scheme 
 
The size of the AF component is 30 x 10 mm (planar surface area of 3 cm2). The same sized AF 
component is used for radiocephalic and brachiocephalic fistulae. The selection of the VF 
component will be guided by intra-operative measurements obtained following successful 
completion of the construction of the arteriovenous (AV) fistula. 
The VF component is wrapped around the outflow vein (juxta-anastomotic segment) starting at 
the heel of the anastomosis. Since the diameter of the vein as well as the length of the outflow 
vein mobilized during surgery can vary between patients, four different VF component sizes, 
appropriate for a range of blood vessel dimensions will be available (planar surface area ranges 
from 3 cm2 to 6 cm2) (Table 8). Selection of the VF component will be based on the outflow vein 
diameter and length of the outflow vein that has been exposed and mobilized. 
Table 8: 
Description of the Component Membranes 
Implant Location 
Component Code 
Size (mm)a 
Membrane Planar 
Surface Area (cm2) 
Sirolimus Content 
(µg)b 
Anastomosis 
AF3010 
30 x 10 
3 
225 
Outflow vein 
VF1520 
15 x 20 
3 
225 
 
VF1530 
15 x 30 
4.5 
337.5 
 
VF2020 
20 x 20 
4 
300 
 
VF2030 
20 x 30 
6 
450 
a Size is expressed as circumference (C) x axial length (L). 
b Target sirolimus density of 75 µg/cm2 

Protocol No. VT-304 
 
Vascular Therapies, Inc. 
The ACCESS Trial 
 
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Depending on the size of the VF component implanted, the nominal sirolimus dose will be 
450 μg (total implant area = 6 cm2), 525 μg (total implant area = 7 cm2), 562.5 μg (total implant 
area = 7.5 cm2), or 675 μg (total implant area = 9 cm2) (Table 9). 
 
Table 9: 
Product Matrix and Nominal Sirolimus Dosages 
Implant 
Option 
Components 
Implant 
Area (cm2) 
Dose (µg) 
Total 
Implant 
Area (cm2) 
Total Dose 
(µg) 
A 
AF3010 + VF1520 
3 + 3 
225 + 225 
6 
450 
B 
AF3010 + VF2020 
3 + 4 
225 + 300 
7 
525 
C 
AF3010 + VF1530 
3 + 4.5 
225 + 337.5 
7.5 
562.5 
D 
AF3010 + VF2030 
3 + 6 
225 + 450 
9 
675 
 
Product implantation instructions are provided in the Instructions For Use (see Appendix C) 
enclosed with each SeCI component membrane package. 
 
9.2. 
Subject Enrollment 
9.2.1. 
Index Procedure 
The conduct of the AV fistula creation surgery, including type of anesthesia and the surgical 
technique must be documented. The technical components of the surgery include the type of 
suture used for the anastomosis, method used to occlude arterial inflow and outflow, etc. 
Hydrostatic distension of the vein and use of rigid dilators to size or probe the vein is 
permitted, however, balloon dilation of the vein is not permitted. The immediate pre-operative 
and intra-operative medications administered as part of the surgical procedure will be 
documented. These medications include heparin and any topical vasodilators. 
Once the surgeon declares patency of the newly constructed fistula and that hemostasis is 
satisfactory, the surgical outcome is judged to be successful and the subject will be eligible for 
enrollment in the study. Confirmation of successful AV fistula creation will be determined by the 
presence of a palpable thrill and any one of the following: 
• a satisfactory auditory signal using a handheld Doppler, or 
• visual augmentation of the juxta-anastomotic segment following application of a 
proximal tourniquet, or, 
• verification of fistula patency using duplex ultrasound 
Should the AV fistula creation procedure fail, the subject will be considered a screen failure. 
 

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9.2.2. 
Treatment Assignment 
The designated surgical coordinator will retain control of the investigational product during the 
conduct of the index procedure. Until use, the investigational product must be kept in a 
controlled area with limited access and the tamper evident seal must not be broken until 
treatment assignment. 
 
9.2.2.1. 
Run-in Subjects 
The first subject eligible for enrollment under each participating surgeon at each investigational 
site in the study will receive the SeCI. The designated surgical study coordinator will break the 
tamper evident seals, the surgical team will prepare the product per instructions provided in the 
Instructions for Use (see Appendix C), and the surgeon will implant the investigational product. 
 
9.2.2.2. 
Randomization 
Following successful creation of an AV fistula, subjects will be randomized in a 1:1 ratio to 
treatment or control using permuted block randomization stratified by surgeon and fistula 
location (radiocephalic / brachiocephalic). At least 80% of the subjects randomized will receive a 
radiocephalic fistula and at most 20% of the randomized subjects will receive a brachiocephalic 
fistula. The above randomization scheme will be applicable to subjects on hemodialysis at the 
time of enrollment or not on hemodialysis at the time of enrollment separately. The 
randomization scheme will be monitored and controlled via the IVR/IWR system. 
The designated surgical study coordinator will contact the IVR/IWR System to receive the 
randomization code and treatment assignment for the subject. 
• If the subject is randomized to the treatment group, the designated surgical study 
coordinator will break the tamper evident seals, the surgical team will prepare the 
product per instructions provided in the Instructions for Use (see Appendix C), and 
the surgeon will implant the investigational product. 
• If the subject is randomized to the control group, the surgeon will complete the 
surgery per standard practice, (without implanting the investigational product). The 
designated surgical study coordinator will ensure that the tamper evident seals on the 
investigational product packaging have not been broken and will return the 
investigational product to inventory. 
Following completion of surgery, the designated surgical study coordinator will confirm using 
the IVR/IWR System that: 
• the surgical procedure was successfully completed, and, 
• the randomization number was used 
Once a randomization number has been used, it will not be re-used. Authorized study personnel 
will ensure that the assigned randomization number is recorded in the subject’s source document. 

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The ACCESS Trial 
 
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Upon completion of the index procedure, the surgical incision will be closed according to the 
surgeon’s standard practice. 
If the subject is randomized to the control group, the designated surgical study coordinator will 
ensure that the tamper evident seal on the component membrane packaging has not been broken 
and will return the investigational product to inventory. 
 
9.2.3. 
Blinding/Unblinding 
This study is a single-blind investigation since it will not be possible to blind the implanting 
surgeon, the designated surgical coordinator, operating room staff, and unblinded monitor with 
respect to the assigned treatment group. 
Blinded personnel include but are not limited to the subject, the nephrologist, the staff at the 
dialysis centers, and the sponsor and/or designee who handle study monitoring, data 
management, and analysis. 
An individual with knowledge of the randomization code/treatment assignment will not 
exclusively participate in decisions relating to fistula outcomes (e.g., fistula 
maturation/non-maturation, determination of fistula abandonment, need for supplementary 
interventions, etc.). 
In case of an emergency, when knowledge of the actual treatment becomes medically necessary, 
a blinded investigator will be able to obtain details of the treatment assigned to an individual 
subject. The Medical Monitor will be immediately informed that the blind needs to be broken 
who will then authorize the blind to be broken and treatment assignment disclosed to the blinded 
investigator. Under no circumstances will the blind be broken prior to notification and consent of 
the Medical Monitor. 
Any direct verbal or written communication regarding treatment identification beyond what is 
required at an institution for the recording of the surgical procedure is prohibited.  
The post-operative note in the hospital chart, the official surgical report, as well as the letter to 
the referring MD will include the usual description of the AV fistula surgery along with the 
statement “subject is participating in investigational study protocol VT-304”. There will be no 
reference made as to whether the subject received the investigational implant product or not. 
The randomization code that was assigned to the subject (without details about the subject’s 
treatment assignment) will also be recorded in the source document. 
The unblinded surgical study coordinator will maintain the subject’s treatment assignment in an 
Overall Accountability Log in a secured, controlled area that has restricted access. The carton 
containing the investigational product will include a 6-part label with space provided for the 
subject’s number, initials and the assigned randomization code. The surgical study coordinator 
will place this label on the Overall Accountability Log for future accountability. An unblinded 
monitor will perform the accountability review (see Section 9.5). 
 

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9.3. 
Packaging and Labeling 
Each component membrane of the Sirolimus-eluting Collagen Implant is a sterile, single-use 
only product, packaged in an amber vial, which is stored in a Tyvek pouch. The Tyvek pouch is 
the primary sterile barrier. The Tyvek pouch is packaged in a foil pouch. The foil pouch is placed 
within a carton. The product is gamma sterilized and is non-pyrogenic. Each carton contains one 
(1) component membrane. 
Each component of the product (amber vial, foil pouch, and carton) is labeled with the following 
information: product name, component code, size, lot number, storage conditions, sponsor’s 
identification and address, and the statement, “Caution: New Drug – Limited by Federal (or 
United States) law to investigational use.”  
Each package contains a 6-part label, which includes the following information: product name, 
component code, and lot number. One section should be removed and placed on the appropriate 
Accountability Log for study product accountability. 
 
9.4. 
Storage Conditions 
The SeCI supply must be stored in the original packaging between 2°C and 8°C (36-46°F) in a 
secured, controlled area with restricted access. 
 
9.5. 
Accountability 
In accordance with ICH-GCP, the investigational site will account for all investigational supplies 
throughout the study. Details of receipt, storage, administration, and return of the SeCI will be 
recorded in an Overall Accountability Log provided by the sponsor and/or designee. The Overall 
Accountability Log will be maintained by the Surgical Study Coordinator in a secured, 
controlled area that has restricted access. An unblinded monitor will perform all functions related 
to drug accountability in order to maintain the blind throughout the study. 
 
9.6. 
Return and Destruction 
After an unblinded monitor has performed final accountability and the investigator and/or 
designee have reconciled any discrepancies, all unused investigational supply will be returned to 
the sponsor. Documentation of the returned investigational supply will accompany the shipment 
and a copy will be kept at the site. The site will not destroy any used or unused investigational 
supply unless the sponsor provides written authorization to the contrary. 
In the event of a potential defect in the quality of investigational supply, the sponsor may initiate 
a recall procedure. In this case, the investigator will be responsible for promptly addressing any 
request made by the sponsor to recall investigational product. 
 

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9.7. 
Concomitant Medications 
Information on concomitant medications must be collected from the time of screening up to the 
2 month visit. Following the 2 month visit through end of study participation, reporting 
requirements change to concomitant medications associated with reportable AEs only (vascular 
access related AEs and SAEs). All concomitant medications, whether prescription or 
non-prescription (including pharmacological doses of vitamins) with the exception of 
medications listed below, are to be recorded in the eCRF, using the brand name and stating 
dosage, indication and duration of intake. 
The following medications DO NOT need to be recorded in the eCRF: 
• Standard medications and IV fluids typically required for sedation, induction and 
maintenance of anesthesia during product implantation procedure 
• Medications given during routine dialysis treatments (e.g., normal saline, hypertonic 
saline, etc.) 
Antibiotics given, as prophylaxis for the AV fistula surgery must be recorded. 
 
9.7.1. 
Prohibited Concomitant Medication 
The following concomitant medications/therapies are prohibited: 
• Intra-surgical use of non-removable hemostats (fibrin glue, etc.) 
 
9.8. 
Treatment Compliance 
The Sirolimus-eluting Collagen Implant is a single-use intra-operative implant, administered by 
the surgical investigator. Treatment compliance is not applicable for this study. 
 
10. 
ASSESSMENT OF EFFICACY 
10.1. 
Primary Endpoint 
The primary endpoint of the study is Fistula Suitability for Dialysis at 6 months (FSD6) defined 
as a composite of: 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 150. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 150, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 6 month follow up visit. Suitability for dialysis 

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will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 
Evaluation of Fistula Suitability for Dialysis at 6 months: 
• For subjects undergoing hemodialysis during the suitability ascertainment period, 
suitability for dialysis will be based on the subject’s dialysis session records 
• For subjects who are not on hemodialysis on the day of enrollment (i.e. on the day of 
fistula creation) and who do not initiate hemodialysis by day 150, suitability for 
dialysis will be based on duplex ultrasound results performed at the 6 month follow 
up visit. 
 
10.2. 
Secondary Endpoints 
10.2.1. 
Fistula Suitability for Dialysis at 12 months 
Fistula Suitability for Dialysis at 12 months (FSD12), defined as a composite of 
a. For subjects who are on hemodialysis by day 330, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 330. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 330, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 12 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 
 
10.2.2. 
Fistula Maturation by Day 90 
Fistula Maturation by Day 90, defined as a composite of: 
a. For subjects who are on hemodialysis by day 90: 
− Three consecutive dialysis sessions using 2-needles with a mean dialysis machine 
blood pump speed of ≥300 mL/min, the first of these three dialysis sessions 
completed on or before 90 days from the time of creation of the AV fistula, or 
− Two-needle dialysis on or before 90 days with no further use of the catheter prior 
to achieving three consecutive dialysis sessions using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min. 
b. For subjects who do not initiate hemodialysis by day 90, fistula access vein diameter 
(AVD) of ≥6 mm (internal diameter) and an access blood flow of ≥500 mL/min 
determined by a vascular ultrasound performed at the 3-month follow up visit. 
Evaluation of Fistula Maturation is based on subject’s dialysis session records 

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10.2.3. 
Secondary Patency 
Secondary patency, defined as the interval from the time of access placement until access 
abandonment. 
Secondary patency will be evaluated based on  
• Clinical evaluation of the fistula,  
• Subject’s dialysis session records (for subjects who are undergoing hemodialysis), 
• Imaging results (Duplex ultrasound and/or angiogram - if applicable and available), 
and, 
• Access event data. 
 
10.2.4. 
Re-intervention Rate 
Re-intervention rate is defined as the total number of vascular access interventions performed 
during study participation to maintain or re-establish patency of the index fistula, as well as 
interventions to assist fistula maturation divided by the total subject participation time in the 
study. It is expressed as number of interventions per subject-year of exposure. Abandonment of 
the index fistula will count for one intervention. 
If a subject’s index fistula is abandoned and the subsequent subject follow-up is incomplete, that 
subject’s participation time will be censored at the time follow-up begins to be incomplete. Each 
subject’s follow-up time will be determined PRIOR to database lock and unblinding. 
Re-intervention rates will be calculated 6 months and 12 months following fistula creation. 
Duration of fistula evaluation is defined as the time from fistula creation to end of study, fistula 
abandonment, or upon reaching a censored event. 
 
10.3. 
Tertiary Endpoints 
10.3.1. 
Time To First Dialysis (TTFD) 
Time To First Dialysis (TTFD) is defined as the time from fistula creation to the time when the 
fistula can support three consecutive dialysis sessions using 2-needles with a mean dialysis 
machine blood pump speed of ≥300 mL/min. 
TTFD will be calculated as the time to first of three consecutive dialysis sessions meeting the 
above defined criteria and will be evaluated only for subjects who are on dialysis at the time of 
study enrollment or those who initiate dialysis on or before 28 days from the time of the AV 
fistula procedure. 
The evaluation of TTFD will be based on the subject’s dialysis session records. 
 

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10.3.2. 
Fistula Suitability for Dialysis at 6 months with preserved primary patency 
Fistula suitability for Dialysis at 6 months with preserved primary patency, defined as a 
composite of 
a. For subjects who are on hemodialysis by day 150, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 150. 
b. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 150, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 6 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 
Primary Patency is defined as freedom from the first occurrence of access thrombosis or an 
intervention performed to maintain or re-establish access patency or assist fistula maturation. 
Evaluation of Fistula Suitability for Dialysis at 6 months with preserved primary patency: 
• Subject’s dialysis session records (for subjects who are undergoing hemodialysis), 
• 6 month duplex ultrasound results for subjects whose index fistula is not in use for 
hemodialysis on day 150, and, 
• Access event data. 
 
10.3.3. 
Fistula Suitability for Dialysis at 12 months with preserved primary patency 
Fistula suitability for Dialysis at 12 months, defined as a composite of 
c. For subjects who are on hemodialysis by day 330, suitability for dialysis will be 
determined by the ability to use the fistula for dialysis using 2-needles with a mean 
dialysis machine blood pump speed of ≥300 mL/min for at least two-thirds of the 
dialysis sessions performed during a 30 day suitability ascertainment period that will 
commence on day 330. 
d. For subjects who are not on hemodialysis on day of enrollment and who do not 
initiate hemodialysis by day 330, suitability for dialysis will be determined by a 
vascular ultrasound performed at the 12 month follow up visit. Suitability for dialysis 
will be defined as a fistula with an access vein diameter (AVD) of ≥6 mm (internal 
diameter) and an access blood flow of ≥500 mL/min. 
Primary Patency is defined as freedom from the first occurrence of access thrombosis or an 
intervention performed to maintain or re-establish access patency or assist fistula maturation. 
Evaluation of Fistula Suitability for Dialysis at 12 months with preserved primary patency: 
• Subject’s dialysis session records (for subjects who are undergoing hemodialysis), 
• 12 month duplex ultrasound results for subjects whose index fistula is not in use for 
hemodialysis on day 330, and, 

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•  Access event data. 
 
10.3.4. 
Primary Patency 
Primary Patency, defined as the interval from the time of fistula creation until the first 
occurrence of fistula thrombosis or an intervention performed to restore/maintain patency.  
The following events will NOT cause loss of primary patency: 
• Intervention to ligate or occlude collateral veins, 
• An invasive angiogram without an intervention (i.e., diagnostic study only), 
• Procedures performed to treat steal syndrome. 
Evaluation of Primary patency will be based on one or more of the following:  
• Clinical evaluation of the fistula, 
• Subject’s dialysis session records (for subjects who are undergoing hemodialysis), 
• Access event data. 
 
10.4. 
Additional Definitions 
10.4.1. 
Mean Dialysis Machine Blood Flow 
Mean dialysis machine blood flow is defined as the mean of all blood flow measurements 
recorded after the first 30 minutes and prior to the last 30 minutes of the dialysis session. 
Dialysis machine blood flow (mL/min) will be obtained from the dialysis unit’s electronic or 
paper records. Measurements made during the first 30 minutes of a dialysis session will be 
excluded from the determination of the mean dialysis machine blood flow since the pump speed 
is often increased gradually during the early portion of the dialysis session. Measurements 
obtained during the last 30 minutes of the dialysis session will be excluded from the 
determination of the session mean pump speed since the pump speed may be decreased due to 
fluctuations in blood pressure or in preparation for discontinuing the dialysis session. 
 
10.4.2. 
Fistula Abandonment 
The index AV fistula will be classified as abandoned if any of the following conditions are met: 
• For subjects undergoing hemodialysis during the course of study participation: 
− The fistula was never used for 2-needle dialysis during the study period (fistula 
will be considered abandoned on the day of creation); 
− The fistula can no longer be used for 2-needle dialysis and there is no expectation 
of future use  
− Placement of a new vascular access for hemodialysis 

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− The fistula undergoes surgical revision of the anastomosis. 
• For subjects who were not on hemodialysis on day of enrollment and who never 
initiated hemodialysis during the course of study participation: 
− The fistula was designated as being abandoned by the investigator. The 
investigator’s decision to abandon the fistula may be based on: 
o The results of a clinical evaluation of the fistula 
o In some instances, at the discretion of the investigator, the decision to abandon 
the fistula may be based on the results of an imaging study (ultrasound or 
angiogram)  
− The fistula undergoes surgical revision of the anastomosis 
− Placement of a new vascular access for hemodialysis. 
 
10.4.3. 
Censored Events 
Subjects experiencing censoring events before an endpoint is observed will be included in the 
statistical analysis up to the time at which they achieve the censoring event. They will be 
censored (excluded) from the analysis after that time point. These censoring rules apply to all 
efficacy endpoints. 
Censored events include: 
• Death 
• Renal transplantation 
• Transfer to peritoneal dialysis 
 
11. 
ASSESSMENT OF SAFETY 
Safety evaluations will be based on treatment emergent adverse events (TEAEs) up to the 
2 month visit and vascular access events reported during the study. Treatment emergent is 
defined as any adverse event that emerges after the subject is enrolled (run-in and randomized) in 
the study. The run-in subjects’ adverse events will be included in the safety evaluation. Vascular 
access events include access dysfunction, thrombosis, access-related hand ischemia, infiltration 
requiring a rest period, fistula-related bleeding, infection, problems with wound healing, 
aneurysm, pseudoaneurysm, and all interventional procedures performed on the study fistula. 
During follow-up, after the 2 month visit, the following will be reported and recorded: vascular 
access events, concomitant medications and therapies associated with vascular access, serious 
adverse events (SAEs) and AEs reported during an SAE. At each follow-up visit up to the 
2 month visit, AEs and concomitant medications will be recorded. Changes in comparison to 
baseline and the 2 month visit that are considered to be clinically significant will be reported as 
AEs. 

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12. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
12.1. 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical 
study. It includes: 
• Any unfavorable and unintended sign, symptom or disease temporally associated with 
the use of the investigational product, whether or not considered to be caused by the 
investigational product 
• AEs commonly observed and anticipated based on the pharmacological effect of the 
investigational product 
• Any laboratory abnormality, vital sign, or finding from physical examination assessed 
as clinically significant by the investigator (note: findings from assessments and 
examinations done during screening are not AEs, but are recorded as medical history) 
• Accidental injuries, reasons for any change in medication (drug and/or dose), reasons 
for any medical, nursing or pharmacy consultation, or reasons for admission to 
hospital or surgical procedures 
• Overdoses and medication errors with and without clinical consequences. 
 
12.2. 
Collection and Recording of Adverse Events 
12.2.1. 
Collection of Adverse Events 
The investigator must monitor the condition of the subject throughout the study from the time of 
obtaining informed consent until the last visit. Findings from assessments and examinations done 
during screening are not AEs, but are recorded as medical history. Safety evaluations will be 
based on treatment emergent adverse events (TEAEs) up to the 2 month visit and vascular access 
events reported during the study. Vascular access events include access dysfunction, thrombosis, 
access-related hand ischemia, infiltration requiring a rest period, fistula-related bleeding, 
infection, problems with wound healing, aneurysm, pseudoaneurysm, and all interventional 
procedures performed on the study fistula. Treatment emergent is defined as any adverse event 
that emerges after the subject is enrolled (run-in and randomized) in the study. Following the 
2 month visit the following will be reported and recorded: vascular access events, concomitant 
medications and therapies associated with vascular access, serious adverse events (SAEs) and 
AEs reported during an SAE. 
The sources of AEs may cover: 
• The subject’s response to questions about his/her health (a standard non-leading 
question such as “How have you been feeling since your last visit?” is asked at each 
visit) 

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• Symptoms spontaneously reported by the subject 
• Investigations and examinations where the findings are assessed by the investigator to 
be clinically significant changes or abnormalities 
• Other information relating to the subject’s health becoming known to the investigator 
(e.g., hospitalization, etc.) 
 
12.2.2. 
Recording of Adverse Events 
The investigator must record all AEs in the Adverse Event Log provided in each subject’s eCRF 
from the time of enrollment up to the 2 month visit. Following the 2 month visit through end of 
study, reporting requirements change to only reportable AEs (vascular access events and SAEs). 
Information to be recorded includes: 
• Adverse event 
• Date of onset 
• Severity 
• Causal relationship to investigational product 
• Action taken to investigational product 
• Other action taken 
• Date of outcome 
• Outcome 
• Seriousness 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
Adverse Event 
Adverse events must be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record. 
If a subject suffers from the same AE more than once and the subject recovers in between the 
events, the AEs should be recorded separately. If an AE changes in intensity, a worst-case 
approach should be used when recording the event, i.e., the highest intensity and the longest 
duration of the event. 
Note the following: A procedure is not an AE; the reason for conducting the procedure is. 
Hospitalization is not an AE; the reason for hospitalization is. Death is not an AE, but the cause 
of death is (an exception is sudden death of unknown cause or any death of unknown cause, 
which is an SAE). 
Date of Onset 
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the 
date the sample was taken or the examination was performed.  

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Severity 
The following 3-point rating scale must be used for rating of the intensity of each adverse event: 
• Mild: Awareness of signs or symptoms, but no disruption of usual activity 
• Moderate: Event sufficient to affect usual activity (disturbing) 
• Severe: Inability to work or perform usual activities (unacceptable) 
Causal Relationship to Investigational Product 
The following 4-point scale must be used for rating the causal relationship of the AE to the 
investigational product: 
• Unrelated: Clearly and incontrovertibly due only to extraneous causes, and does not 
meet criteria listed under unlikely, possible or probable. 
• Unlikely: Does not follow a reasonable temporal sequence from administration. May 
have been produced by the subject’s clinical state, environmental factors, or other 
therapies administered.  
• Possible: Follows a reasonable temporal sequence from administration. May have 
been produced by the subject’s clinical state, environmental factors, or other therapies 
administered. 
• Probable: Clear-cut temporal association with improvement on cessation of 
investigational product (explanted). Follows a known pattern of response to the 
investigational product. 
• Direct: Clear relationship to the investigational product. Event follows a known 
pattern of response to the investigational product. 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to investigational product. 
Adverse events with the causality assessed as possible, probable, or direct are categorized as 
related to investigational product and are called adverse drug reactions (ADRs). 
Action Taken to Investigational Product 
The action taken to the investigational product in response to an AE must be classified as one of 
the following: 
• None 
• Access Intervention 
• Concomitant Medication 
• Transfusion Performed 
• Emergency Room Visit 
• IP Explanted 
• Unknown 

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• Other 
Other Action Taken 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the AE, this medication must be entered in the Concomitant 
Medication Log. 
Date of Outcome 
The date the subject recovered or died. 
Outcome 
The outcome of an AE must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at 
initiation of study treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering (condition still exists and is improving) 
• Not recovered (condition still exists, has not improved; condition is irreversible, 
recovery/resolution not possible) 
• Unknown 
• Fatal 
 
12.2.3. 
Pregnancy and Pregnancy Outcome 
Every effort must be made to avoid pregnancy during the study. If a pregnancy does occur, the 
sponsor must be informed within 3 calendar days, using an SAE Report Form provided by the 
sponsor and/or designee. Note that pregnancy itself is not an SAE. Contact details for the 
follow-up on the pregnancy should be provided. The mother and the fetus must be followed up at 
least until the birth of the infant and one month after the birth of the infant. In general, the 
follow-up will include the course, duration and the outcome of the pregnancy and the health of 
the infant. If a pregnancy results in an abnormal outcome, which the Investigator and/or sponsor 
consider to be related to the investigational product, this outcome will be treated as an expedited 
report (See Section 12.3.2.2). 
 

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12.3. 
Serious Adverse Events 
12.3.1. 
Serious Adverse Event Definition 
An event is 
defined a serious 
adverse event if it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the investigational product. The death of a 
subject enrolled in a study is per se not an event, but an outcome. 
is life-threatening 
The term “life-threatening” refers to an AE in which the subject was at immediate 
risk of death at the time of the event. It does not refer to an event, which may have 
caused death if it were more severe. 
requires in-patient 
hospitalization or 
prolongation of 
existing 
hospitalization 
The term “hospitalization” means that the subject was admitted to hospital or that 
existing hospitalization was extended as a result of an event. Hospitalization 
describes a period of at least 24 hours. Over-night stay for observation, stay at 
emergency room or treatment on an out-patient basis do not constitute a 
hospitalization. However, medical judgment must always be exercised and, when 
in doubt, the case should be considered serious (i.e., if the case fulfills the criterion 
for a medically important event). Hospitalizations for administrative or social 
purposes do not constitute an SAE. Hospital admissions and/or surgical operations 
planned before study inclusion are not considered AEs, if the illness or disease 
existed before the subject was enrolled in the study, provided that the condition did 
not deteriorate during the study. 
results in persistent 
or significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to conduct 
normal life functions. If in doubt, the decision should be left to medical judgment 
by the investigator. 
is a congenital 
anomaly/birth 
defect 
Congenital anomaly/birth defect observed in any offspring of the subject conceived 
during treatment with the IP. 
is an important 
medical event 
Important medical events are events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include AEs that suggest a significant 
hazard, contraindication or precaution, occurrence of malignancy or development 
of drug dependency or drug abuse. Medical and scientific judgment should be 
exercised in deciding whether events qualify as medically important. 
Important medical events include any suspected transmission of an infectious agent 
via a medicinal product. Any organism virus or infectious particle (e.g., prion 
protein transmitting Transmissible Spongiform Encephalopathy), pathogenic or 
non-pathogenic, is considered an infectious agent. A transmission of an infectious 
agent may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a subject exposed to a medicinal product. 
 

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An AE caused by an overdose or medication error is considered serious if a criterion listed in the 
definitions above is fulfilled. 
 
12.3.2. 
Collection, Recording and Reporting of Serious Adverse Events 
12.3.2.1. SAE Reporting by the Investigator 
The investigator and/or designee must begin reporting all Serious Adverse Events starting the 
day of enrollment. Events that meet the SAE criteria listed prior to enrollment, should be 
documented in Medical History. The investigator is responsible to review these events and 
ensure the subject remains eligible for participation prior to proceeding with enrollment should 
the event occur in the 45 day screening period. All SAEs must be reported immediately to the 
sponsor and/or designee as soon as it becomes known and not later than within 24 hours of their 
knowledge of the occurrence of an SAE. 
The investigator and/or designee is responsible for submitting the completed SAE Report Form 
with the fullest possible details within 3 calendar days of his/her knowledge of the SAE. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g., laboratory parameters, invasive procedures, scans and x-rays, and autopsy results can be 
uploaded in the eCRF or provided to the sponsor and/or designee using the contact details in 
Table 1. In any case, the investigator and/or designee, upon request from the sponsor and/or 
designee, must supply this information. On any copies provided, details such as subject’s name, 
address, and hospital ID number must be concealed and instead the subject number should be 
provided. 
The investigator and/or designee will supply the sponsor and/or designee and the IRB with any 
additional requested information such as results of post-mortem examinations and hospital 
records. 
 
12.3.2.2. Expedited Reporting by Sponsor 
The sponsor and/or designee will report all serious adverse events and unexpected events with 
a reasonable possible causality to the investigational product as judged by either the 
investigator or the sponsor to the relevant parties within the stipulated timelines. 
SAEs will be considered reportable regardless of whether or not the investigational product was 
used in accordance with the provisions in the protocol, Investigator’s Brochure and labeling. 
 
12.4. 
Follow-up of Adverse Events and Serious Adverse Events  
12.4.1. 
Follow-up of Adverse Events with Onset during the Study 
During the study, the investigator and/or designee must follow-up on each AE until it is resolved 
or until the medical condition of the subject is stable. 

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After the subject’s last visit, the investigator and/or designee must follow-up on any AE 
classified as serious or considered to have a reasonable possible causality to the investigational 
product until it is resolved or until the medical condition of the subject is stable. All such 
relevant follow-up information must be reported to the sponsor and/or designee. If the event is a 
chronic condition, the investigator and sponsor may agree that further follow-up is not required. 
 
12.4.2. 
Collection of Serious Adverse Events with Onset after Last Study Visit 
If an investigator and/or designee become aware of an SAE after the subject’s last visit, and s/he 
assesses the SAE to have a reasonable possible causality to the investigational product, the case 
will have to be reported to the sponsor and/or designee, regardless how long after the end of the 
study this takes place. 
 
12.4.3. 
Tissue Explant and Histology 
If the study product or a segment of native vessel or any other tissue is removed for any reason 
during the course of the study, the explanted tissue and/or product will be sent for 
histopathological and microbiological analysis. In the event of an explant, the investigator and/or 
designee must follow expedited reporting procedures outlined in Section 12.3.2 for SAEs. 
 
12.5. 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will: 
• Evaluate safety of enrolled subjects at periodic intervals (at least every six months), 
• Review the final Clinical Study Report, at the conclusion of the study. 
13. 
STATISTICS 
13.1. 
Statistical Analysis Plan 
The content of this section is the basis for the Statistical Analysis Plan (SAP) of this study. The 
SAP provides full details of the analyses, data displays, and algorithms to be used for data 
derivations. The SAP includes the definition of major and minor protocol deviations and the link 
between major protocol deviations and the analysis sets. Medically trained staff will identify 
major and minor protocol deviations before study closure. 
 
13.2. 
Determination of Sample Size 
All power calculations are via EAST® 6.4. Assuming the TRUE underlying FSD6 rates are 45% 
for control and 76% for treatment (based on prior data), the sample size on N=200 patients 
contributing to the analysis  has >99% power to yield a statistically significant (alpha=0.05 2-

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sided) difference between treatments.  Allowing for uncertainty in the prior data, if the TRUE 
underlying FSD6 rates are 45% and 65%, there is approximately 82% power.  The minimum 
OBSERVED difference that would yield statistical significance is approximately 45% vs 59%. 
13.3. 
Data Analysis Considerations 
13.3.1. 
Analysis Sets 
13.3.1.1. Full Analysis Set 
The full analysis set will consist of all subjects who are randomized to treatment or control. Full 
details are provided in the SAP. 
 
13.3.1.2. Safety Set 
The safety set will consist of all subjects who are enrolled in the study, i.e., run-in subjects plus 
subjects who are randomized to treatment or control. Full details are provided in the SAP. 
 
13.3.2. 
Key Endpoints 
The primary endpoint is FSD6, as defined in Section 6. Each endpoint will be tested at overall 
alpha level of 0.05 (2-sided). Other efficacy endpoints are as mentioned in the endpoints section 
(Section 6). 
 
13.3.3. 
Main Analysis 
The null hypothesis for FSD6 is that the population proportions of subjects with FSD6 for the 
treatment group receiving the sirolimus eluting collagen implant [pI, where “I” indicates implant 
treatment] and the control group (pC, where “C” indicates control group) that does not receive the 
implant are equal. The alternative is that the proportion of subjects with FSD6 is not equal for the 
treatment group and the control group.  
Algebraically, these hypotheses are stated as follows, where “H0” indicates the null hypothesis 
and “Ha” indicates the alternative hypothesis: 
H0: pI = pC 
Ha: pI ≠ pC 
“I” indicates implant treatment, and “C” indicates control treatment.  
For the primary endpoint of FSD6, the proportions will be compared between treatment and 
control using a logistic regression model with factors for treatment and stratum. 
 

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13.3.4. 
Secondary Efficacy Endpoints 
Time to event secondary endpoints will be analyzed by stratified log-rank test. Binary endpoints 
will be compared between treatments via the same logistic regression model as for the primary 
efficacy endpoints. Continuous secondary endpoints will be compared via analysis of covariance 
for a model including factors for treatment, strata, and baseline covariate if available, or non-
parametric rank tests if normality or homogeneity assumptions appear substantially violated. 
Overall study-wise type 1 error control across secondary endpoints will be addressed via step-
down testing. That is, the secondary endpoints will be tested one at a time in step-down order, 
until the first non-significant result, after which step-down testing will stop for purposes of 
supporting conclusions. 
Individual patient listings will be provided for the primary and secondary endpoints. 
 
13.3.5. 
Safety Analysis 
13.3.5.1. Adverse Events 
All treatment emergent adverse events (TEAEs) recorded during the study will be coded 
according to Medical Dictionary for Regulatory Activities and all AEs will be listed. Treatment 
emergent is defined as any adverse event that emerges after the subject is enrolled in the study. 
TEAEs will be tabulated by system organ class (SOC), and individual preferred terms within 
each SOC. The crude incidence rate of patients who experienced AEs coded with the same 
preferred term will be tabulated by treatment group. TEAEs will also be tabulated by worst 
experienced severity. A separate summary will present treatment-emergent AEs judged related 
(missing relationship is considered as related) to study treatment.  
Adverse events leading to premature discontinuation from the study will be listed and 
summarized in a manner similar to that used for TEAEs. 
SAEs will be listed and summarized in a manner similar to that used for TEAEs, separated into 
treatment-emergent SAEs, and SAEs occurring before successful creation of the AV fistula and 
after. 
Reasons for death will be listed and summarized in a manner similar to that used for AEs, 
separated for treatment-emergent deaths. 
Reasons for premature discontinuation from the study will be listed and summarized by 
frequency tables. 
 
13.3.5.2. Baseline Variables and Concomitant Medications 
Continuous demographic variables (e.g., age, weight) and disease characteristics (e.g., time since 
diagnosis, etc.) will be summarized using descriptive statistics. Qualitative demographic 
characteristics (e.g., sex, race) and disease characteristics will be summarized by counts and 
percentages. Other baseline patient characteristics (e.g., medical history) will only be listed. All 
medications will be coded according to the WHO drug code and the drug-class code. They will 

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be summarized for each treatment group, the number and percentages of subjects having 
received each medication. 
 
13.3.6. 
Exploratory Analyses 
Exploratory data-driven analyses can be performed with the caveat that any statistical inference 
will be of supportive nature rather than confirmatory. 
 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of the sponsor 
and/or designee will evaluate the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the sponsor and/or designee. This will be 
documented in a Clinical Study Agreement between the sponsor and the investigator. 
During the study, a monitor from the sponsor and/or designee will have regular contact with the 
investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, ICH-GCP, applicable 
SOPs, and regulatory requirements that data are being accurately recorded in the eCRF, 
and that investigational product accountability checks are being performed 
• The Investigator will permit the monitor timely access to all data needed to perform 
source data verification. This includes a comparison of the data in the eCRF with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study. This will require direct access to all original records for each patient (e.g., clinic 
charts) and dialysis runsheets. 
• Record and report all protocol deviations 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to the sponsor and/or designee and those SAEs that met 
criteria for reporting have been forwarded to the IRB 
The Investigator is expected to be able to meet with the monitor during these visits. The monitor 
will be available between visits if the investigator(s) or other staff needs information or advice. 
 

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14.2. 
Audits and Inspections 
Authorized representatives of the sponsor, a regulatory authority, or an Institutional Review 
Board may visit the site to perform audits or inspections, including source data verification. The 
purpose of a sponsor audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice guidelines of the International Conference on Harmonization, and any applicable 
regulatory requirements. The investigator should contact the sponsor and/or designee 
immediately if contacted by a regulatory agency about an inspection. 
 
14.3. 
Confidentiality of Subject Data 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). In the 
event that a subject revokes authorization to collect or use protected health information (PHI), 
the investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of subject authorization. For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the sponsor and/or designee may conduct a quality assurance audit. Please see Section 14.2 for 
more details regarding the audit process. 
 
15.1. 
Protocol Amendments 
Any change to this Protocol will be documented in a Protocol Amendment, issued by the 
sponsor, and approved by the IRB prior to its implementation. 
Substantial amendments will be submitted for consideration to the approving IRBs and 
Regulatory Authorities, in accordance with local regulations. An approval is required for a 
Substantial Amendment, e.g., one which could affect the safety of the subjects, or which entails a 
change to the scope/design of the study, or where a new principal or coordinating investigator is 
included. 
 
15.2. 
Deviations from the Protocol 
Deviations from the protocol should not occur. If deviations occur, the investigator must inform 
the monitor, and the implications of the deviation must be reviewed and discussed. All deviations 

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must be documented (or included in eCRF data). There should be a description of the deviation, 
the relevant time points (visit numbers, start and stop), reason for deviation, and the corrective 
action taken. Deviation reports and supporting documentation must show documentation of PI 
review and be kept in the Investigator’s File and in the Trial Master File and recorded into the 
eCRF. 
 
15.3. 
Premature Study Termination 
Both the investigator (with regard to his/her participation) and the sponsor reserve the right to 
terminate the study at any time. Should this become necessary, the procedures will be agreed 
upon after consultation between the two parties. In terminating the study, the sponsor and the 
investigator will ensure that adequate consideration is given to the protection of the best interests 
of the subjects. Regulatory authorities and IRB’s will be informed. 
In addition, the sponsor reserves the right to terminate the participation of individual study sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate. 
 
16. 
ETHICS 
16.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with Good Clinical Practice (GCP) requirements 
described in the current revision of International Conference on Harmonisation of Technical 
Requirements of Pharmaceuticals for Human Use (ICH) Guidelines and all applicable 
regulations, including current United States Code of Federal Regulations (CFR), Title 21, Parts 
11, 50, 54, 56, and 312 and Title 45, Part 164. Compliance with these regulations and guidelines 
also constitutes compliance with the ethical principles described in the current revision of the 
Declaration of Helsinki. This study will also be carried out in accordance with local legal 
requirements. 
 
16.2. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB as appropriate. The investigator must 
submit written approval to the sponsor and/or designee before he or she can enroll any subject 
into the study. 
The investigator and/or designee is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB must approve all advertising 
used to recruit subjects for the study. The protocol must be re-approved by the IRB upon receipt 
of amendments and annually, as local regulations require. 

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The investigator and/or designee is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. The sponsor and/or designee will provide this information to the investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
according to local regulations and guidelines. 
 
16.3. 
Written Informed Consent 
An English master version of the Subject Information and Informed Consent documents can be 
found in Appendix A. If the IRB and/or the study sites make changes to the Subject Information 
and Informed Consent documents, the amended documents must be submitted back to the 
sponsor and/or designee for approval. 
The Investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study, which are relevant to the subject’s decision to participate. The study subject must be 
given ample time to consider participation in the study, before the consent is obtained. The 
subject must be able to provide consent independently; no legally authorized representatives are 
allowed. The Informed Consent Form must be signed and dated by the subject before he/she is 
exposed to any study-related procedure, including screening tests for eligibility. 
The Investigator will explain that the subjects are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without the 
need to justify their decision. 
The subject will receive a copy of his/her signed consent. 
If new information becomes available that may be relevant to the study subject’s willingness to 
continue participation in the study, an updated subject information and consent form will be 
forwarded to the IRB(s) (and regulatory authorities, if required). The study subjects will be 
informed about this new information and re-consent will be obtained. Re-consent must be 
documented. 
Each subject will be informed via the Informed Consent Form that the following personnel may 
review his/her source records and data: Monitor(s), Quality Assurance Auditor(s) mandated by 
the sponsor, or regulatory authority inspector(s), in accordance with applicable regulatory 
requirements. Data protection will be handled in compliance with national/local regulations. 
 
17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Direct Access to Source Data/Documents 
The Investigator agrees to allow the sponsor and/or designee to inspect the investigational 
product storage area, investigational product stocks, accountability records, subject charts and 
study source documents, and other records relative to study conduct. The investigator will make 

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the source documents for this trial available to the sponsor and/or designee, regulatory 
authority(ies), or health authority inspectors. 
Subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection on 
request by FDA or other government regulatory agency auditors, the sponsor and/or designee, 
and the Institutional Review Board (IRB). 
The information developed in this clinical study will be used by the sponsor in the clinical 
development of the investigational product and therefore may be disclosed by the sponsor as 
required for disclosure to other clinical investigators, to other pharmaceutical companies, to the 
FDA, to other foreign regulatory agencies and to other government agencies. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the sponsor and shall be the sole property of 
the sponsor. The Investigator agrees, upon the sponsor’s request and at the sponsor's expense, to 
execute such documents and to take such other actions, as the sponsor deems necessary or 
appropriate to obtain patents in the sponsor’s name covering any of the foregoing. 
 
17.2. 
Retention of Records 
The investigator will retain all study documents for at least 2 years after the last approval of a 
marketing application in an ICH region (i.e., United States, Europe, or Japan), and until there are 
no pending or contemplated marketing applications in an ICH region. If no application is filed or 
if the application is not approved for such indication, the investigator will retain all study 
documents for at least 2 years after the investigation is discontinued and regulatory authorities 
have been notified.  
The investigator will notify the sponsor prior to destroying any study records. Should the 
investigator wish to assign the study records to another party or move them to another location, 
the sponsor and/or designee must be notified in writing in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements will be made between the investigator and the sponsor for 
storage. If source documents are required for continued care of the subject, appropriate copies for 
storage off site will be made. 
 

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18. 
REPORTING AND PUBLICATION 
18.1. 
Clinical Study Report 
The data and information collected during this study will be reported in a Clinical Study Report 
prepared by the sponsor. 
 
18.2. 
Confidentiality and Ownership of Study Data 
Any confidential information relating to the investigational product or the study, including any 
data and results from the study will be the exclusive property of the sponsor. The investigator 
and any other persons involved in the study will protect the confidentiality of this proprietary 
information belonging to the sponsor. 
 
18.3. 
Publications and Public Disclosure 
18.3.1. 
Publication Policy 
At the end of the study, one or more manuscripts for joint publication may be prepared in 
collaboration between the Investigator(s) offered authorship and sponsor or one of its chosen 
affiliates. In a multi-site study based on the collaboration of many sites, any publication of 
results must acknowledge all sites. Results from multi-site studies must be reported in entirety in 
a responsible and coherent manner, and results from subsets should not be published in advance 
or without clear reference to the primary data. Sponsor reserves the right to be last author(s) in 
all publications related to this study, with a maximum of three employees of sponsor per 
publication. In the event of any disagreement in the content of any publication, both the 
investigator’s and sponsor’s opinion will be fairly and sufficiently represented in the publication. 
Any external CRO or laboratory involved in the conduct of this study has no publication rights 
regarding this study. 
If the Investigator wishes to independently publish/present any results from the study, the draft 
manuscript/presentation must be submitted in writing to sponsor for comment prior to 
submission. Comments will be given within four weeks from receipt of the draft manuscript. 
This statement does not give the sponsor any editorial rights over the content of a publication, 
other than to verify the accuracy of the data or to restrict the disclosure of sponsor’s intellectual 
property. If the matter considered for publication is deemed patentable by the sponsor, scientific 
publication will not be allowed until after a filed patent application is published. Under such 
conditions the publication will be modified or delayed at the Investigator’s discretion, to allow 
sufficient time for sponsor to seek patent protection of the invention. 
 
18.3.2. 
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical studies be registered in a public, clinical trials registry. Thus, 

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it is the responsibility of the sponsor to register the study in an appropriate registry, i.e., 
www.clinicaltrials.gov, which is sponsored by the National Institutes of Health. 
 

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