Clinical trial NCT02414841
Conditions: Chronic Kidney Disease
Keywords: radiocephalic arteriovenous fistula AVF hemodialysis PRT-201 vonapanitase vascular access kidney renal PATENCY-2 secondary patency fistula abandonment use for hemodialysis
Sponsor: Proteon Therapeutics
Start date: 2015-08-01; Completion date: 2019-05-01
Enrollment: 696 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is designed to assess the safety and effectiveness of an experimental drug called vonapanitase (PRT-201) in patients both receiving or expecting to receive hemodialysis who have chronic kidney disease and who are undergoing surgery to create a new access point to their bloodstream for hemodialysis. Vonapanitase is a protein that has been shown in previous research studies to help keep vessels patent when applied to the outside surface of the blood vessels (arteries and veins) in patients who undergo surgery to create an arteriovenous fistula (AVF). The purpose of this study is to determine whether vonapanitase when applied to a limited segment of your blood vessel (about 2 inches) immediately after surgery is safe and improves the patency of your AVF.

Detailed description:

Arms: arm 1: Vonapanitase administered at the time of radiocephalic fistula creation arm 2: Placebo administered at the time of radiocephalic fistula creation
Interventions: intervention 1: Vonapanitase intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Proteon Therapeutics, Inc. 
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Clinical Protocol PRT-201-320 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol No. PRT-201-320 
 
 
Multicenter, Double-Blind, Placebo-Controlled Study of Vonapanitase (PRT-
-201) Administered Immediately after Radiocephalic Arteriovenous Fistula 
Creation in Patients with Chronic Kidney Disease 
 
 
Edition No. 05 
 09 May 2018 
 
 
SPONSOR: 
Proteon Therapeutics, Inc.  
200 West Street 
Waltham, MA USA 02451 
Telephone: (781) 890–0102 
Fax: (781) 890-4146 
 
 
 
 
Disclosure Statement 
The confidential information in the following document is provided for your review as an 
Investigator, potential Investigator, or consultant. Do not disclose the information contained in 
this document to others without the written permission of Proteon Therapeutics, Inc., except as 
required for review by your staff or Institutional Review Board or in obtaining informed consent 
from study patients. 


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SIGNATURE PAGE FOR INVESTIGATOR 
Protocol No. PRT-201-320 
Title: Multicenter, Double-Blind, Placebo-Controlled Study of Vonapanitase (PRT-201) 
Administered Immediately after Radiocephalic Arteriovenous Fistula Creation in Patients with 
Chronic Kidney Disease 
Edition No.: 05 
Date:  09 May 2018 
I have read and understand the protocol and agree to conduct the study as outlined. I understand 
that the information in this protocol is confidential and must not be disclosed, other than to those 
directly involved in the execution or the scientific/ethical review of the study, without written 
authorization from the Sponsor. 
 
Investigator name, 
institution, address, 
and telephone 
number must be 
printed or typed. 
Name:____________________________________________ 
Institution:________________________________________ 
Address:__________________________________________ 
City, State:________________________________________ 
Telephone:________________________________________ 
 
Signature:_______________________________Date_____________________________ 
 
 


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Protocol Summary 
Name of 
Sponsor: 
Proteon Therapeutics, Inc. 
Study Number 
and Title: 
PRT-201-320: Multicenter, Double-Blind, Placebo-Controlled Study 
of Vonapanitase (PRT-201) Administered Immediately after 
Radiocephalic Arteriovenous Fistula Creation in Patients with 
Chronic Kidney Disease 
Clinical Phase: 
Phase 3 
Investigators 
and Study 
Centers: 
The study will be conducted at approximately 40 sites. 
Number of 
Patients: 
Six hundred (600) patients with chronic kidney disease (CKD) will be 
treated. 
Objective: 
To assess the efficacy and safety of vonapanitase administered 
immediately after radiocephalic arteriovenous fistula (AVF) creation. 
Endpoints: 
The co-primary efficacy endpoints are secondary patency and AVF 
use for hemodialysis.  Secondary patency is defined as the time from 
AVF creation until AVF abandonment.  AVF use for hemodialysis is 
defined as the ability of the study AVF to be successfully cannulated 
and used for hemodialysis for a minimum of 90 days or at least 30 
days prior to a patient’s last visit, if hemodialysis had not been 
initiated at least 90 days prior to the last visit. 
Additional efficacy endpoints are unassisted AVF use for 
hemodialysis, primary unassisted patency, AVF maturation by 
ultrasound criteria, unassisted AVF maturation by ultrasound criteria, 
the rate of procedures performed to the AVF, and the rate of 
procedures to restore or maintain AVF patency. 
Safety endpoints are incidence of adverse events (AEs) that include 
clinically significant adverse changes in physical examination, duplex 
Doppler ultrasound, clinical laboratory evaluations, and 
immunogenicity testing results. 
Methodology: 
This is a randomized, double-blind comparison of vonapanitase 
versus placebo. Eligible patients are either receiving hemodialysis or 
expecting to initiate hemodialysis and require the creation of a 
radiocephalic AVF. Patients are randomized in a 2:1 ratio to either 
vonapanitase 0.03 mg or placebo. Patients are stratified based on 
hemodialysis status at the time of randomization. 
The study consists of a 4-week screening period, a 1-day treatment 


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CONFIDENTIAL 
period, and up to 12 months of follow-up. Patients whose study AVF 
has not been abandoned at Month 12 will be enrolled into a registry 
and will remain in the registry for 2 years, or until the AVF has been 
abandoned, whichever comes first.  
Screening: At the beginning of the 4-week screening period patients 
will provide written consent and be assessed for eligibility. The 
assessments include: evaluation of inclusion/exclusion criteria, review 
of medical history, physical examination, and clinical laboratory 
evaluations including serum pregnancy testing in women of 
childbearing potential. Results from the screening visit and 
evaluations conducted as part of routine standard of care are used to 
determine study eligibility and are completed as close to the time of 
AVF creation as possible, but no longer than 28 days prior to the 
scheduled surgery. 
Treatment: On the day of surgery, the surgeon connects the end of a 
transected cephalic vein to the side of a radial artery in the arm, 
exposing approximately 3 cm of the outflow vein. The surgery to 
create the AVF will proceed according to the standard practice of the 
institution and surgeon. Immediately after creation of the 
radiocephalic AVF, the surgeon treats the exposed inflow artery, 
anastomosis, and outflow vein with the study drug for 10 minutes by 
administering a series of drops. Evaluation of the AVF is conducted 
prior to the patient leaving the recovery area. 
Follow-up: Patients return at Weeks 2 and 4, and Months 3, 6, 9, and 
12 post surgery for clinical safety assessments and evaluation of the 
AVF and upper extremity. A duplex Doppler ultrasound is performed 
at Week 4 and Month 3. 
The Proteon Medical Monitor provides continuing review of safety 
data in a blinded manner throughout the trial. In addition, a Data 
Monitoring Committee (DMC), independent of Proteon and operating 
under a pre-specified charter, reviews accumulated safety data at an 
appropriate interval. 
Main Criteria 
for Inclusion/ 
Exclusion: 
Inclusion:  
1. Age of at least 18 years. 
2. Life expectancy of at least 6 months. 
3. Diagnosis of CKD. 
4. Planned creation of a new radiocephalic AVF (revision of an 
existing AVF is not eligible). 
5. Ability to understand and comply with the requirements of the 
entire study and to communicate with the study team. 
6. Written informed consent using a document that has been 


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approved by the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). 
7. If female and of childbearing potential (premenopausal and 
not surgically sterile) must have a negative serum pregnancy 
test at the screening visit and be willing to use contraception 
from the time of the screening visit to 2 weeks following 
study drug administration. Acceptable methods of birth 
control include abstinence, barrier methods, hormones, or 
intra-uterine device.  
Exclusion: 
1. Malignancy or treatment for malignancy within the previous 
12 months with the exception of the following cancers if they 
have been resected: localized basal cell or squamous cell skin 
cancer, or any cancer in situ. 
2. Presence of any significant medical condition that might 
significantly confound the collection of safety and efficacy 
data in this study. 
3. Previous treatment with vonapanitase (PRT-201). 
4. Treatment with any investigational drug within the previous 
30 days or investigational antibody therapy within the 
previous 90 days prior to signing informed consent. 
Product, Dose, 
and Mode of 
Administration: 
Vonapanitase (PRT-201) is a recombinant human chymotrypsin-like 
elastase family member 1 (CELA1) elastase intended for local 
application immediately following surgical creation of a radiocephalic 
AVF. Vonapanitase is supplied as a lyophilized powder in a single 
use glass vial with a rubber stopper. The placebo is identical in 
appearance and composition to vonapanitase but lacks the active 
ingredient. 
The investigational drug is administered topically by the surgeon to 
the external surface of surgically exposed blood vessels as a single 
application. 
Randomization: Randomizations occur utilizing an interactive voice response system 
(IVRS) or interactive web response system (IWRS). Patients are 
randomized by site in a 2:1 ratio to either vonapanitase 0.03 mg or 
placebo, stratified by hemodialysis status at the time of randomization 
and balance will be maintained by blocking within site. 
Duration of 
Treatment: 
Single application administered over 10 minutes. 


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Statistical 
Methods: 
Demographic data, medical history, and other baseline characteristics 
will be summarized by treatment received. Statistical comparisons 
between treatment groups will be performed to assess baseline 
imbalances. Safety evaluations will be based on AEs, clinically 
significant adverse changes in the patient’s physical examination, 
duplex Doppler ultrasound, clinical laboratory evaluations, and 
immunogenicity testing results. 
The co-primary efficacy endpoints are AVF secondary patency and 
AVF use for hemodialysis.  Secondary patency is defined as the time 
from AVF creation until AVF abandonment. AVF use for 
hemodialysis is defined as the ability of the study AVF to be 
successfully cannulated and used for hemodialysis for a minimum of 
90 days or at least 30 days prior to a patient’s last visit, if 
hemodialysis had not been initiated at least 90 days prior to the last 
visit.  
Additional efficacy endpoints are unassisted AVF use for 
hemodialysis, primary unassisted patency, AVF maturation by 
ultrasound criteria, unassisted AVF maturation by ultrasound criteria, 
the rate of procedures performed to the AVF, and the rate of 
procedures to restore or maintain AVF patency. 
Secondary patency time will be estimated by the 25th, 50th (median), 
and 75th percentiles calculated by using the Kaplan-Meier life test 
methods to estimate the survival functions. A log-rank test will be 
used to test the equality of the survival curves between vonapanitase 
and placebo. A graph of the survival probability over time will be 
presented.  
 
The number and percentage of patients with AVF use for 
hemodialysis will be summarized by treatment group. Vonapanitase 
vs. placebo will be tested using a Chi-square test.   
 


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TABLE OF CONTENTS 
Signature Page for Investigator .............................................................................................2 
Protocol Summary ................................................................................................................3 
Table of Contents ..................................................................................................................7 
List of Abbreviations ..........................................................................................................10 
1. Background and Rationale ...........................................................................................11 
 
Description of Investigational Drug ..................................................................11 
 
Study Rationale .................................................................................................12 
2. Study Objective ............................................................................................................12 
3. Investigational Plan ......................................................................................................12 
 
Methodology .....................................................................................................12 
4. Study Population ..........................................................................................................13 
 
General Considerations .....................................................................................13 
 
Inclusion Criteria ...............................................................................................14 
 
Exclusion Criteria..............................................................................................14 
 
Concurrent Medications ....................................................................................14 
 
Excluded Medications .......................................................................................15 
5. Study Schedule.............................................................................................................15 
 
Screening: Visit 1 (Up to Day -28) ...................................................................15 
 
AVF Surgery: Visit 2 (Day 1) ...........................................................................16 
5.2.1 
Pre-Surgery ...........................................................................................16 
5.2.2 
Surgical Procedures ...............................................................................16 
5.2.3 
Post-Operative Assessments .................................................................17 
 
Follow-up: Visit 3 /Week 2 (Day 14 ± 3 Days) ................................................17 
 
Follow-up: Visit 4 /Week 4 (Day 28 ± 3 Days) ................................................18 
 
Follow-up: Visit 5 / Month 3 (Day 90 ± 14 Days) ............................................18 
 
Follow-up: Visit 6 / Month 6 (Day 180 ± 14 Days), Visit 7 / Month 9 
(Day 270 ± 14 Days), and Visit 8 / Month 12 (Day 360 ± 14 Days) ................19 
 
Handling of Withdrawals ..................................................................................19 
 
Handling of AVF Abandonment .......................................................................20 
 
Kidney Transplantation .....................................................................................20 
 
Long-Term Outcomes And Pharmacoeconomic Analyses ...............................20 
6. Procedures and Evaluations .........................................................................................21 
 
Assessment of Efficacy .....................................................................................21 
6.1.1 
AVF Disposition ...................................................................................21 
6.1.2 
Abandonment ........................................................................................21 
6.1.3 
Ultrasound Evaluation ...........................................................................22 


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Assessment of Safety ........................................................................................22 
6.2.1 
AVF and Upper Extremity Examination...............................................22 
6.2.2 
Adverse Events......................................................................................23 
6.2.3 
Medical History and Physical Examination ..........................................23 
6.2.4 
Special Assays or Procedures ...............................................................23 
6.2.5 
Clinical Laboratory Evaluation .............................................................24 
6.2.6 
Duplex Doppler Ultrasound ..................................................................24 
6.2.7 
Unscheduled Assessments ....................................................................24 
7. Investigational Drug.....................................................................................................24 
 
Identity of Investigational Drug ........................................................................24 
 
Placebo ..............................................................................................................25 
 
Formulation, Packaging, and Labeling .............................................................25 
 
Patient Randomization and Blinding ................................................................25 
 
Unblinding ........................................................................................................25 
 
Product Shipping, Storage, and Stability ..........................................................25 
 
Dosage, Preparation, and Administration of Investigational Drug ...................26 
 
Drug Accountability/Retention .........................................................................27 
 
Drug Returns and Destruction ...........................................................................27 
8. Adverse Events ............................................................................................................27 
 
Definition of Adverse Event .............................................................................27 
 
Recording of Adverse Events and Observation Period .....................................28 
 
Serious Adverse Event ......................................................................................28 
8.3.1 
Reference Safety Information ...............................................................28 
8.3.2 
Serious Adverse Event Definition .........................................................28 
8.3.3 
Reporting Procedures ............................................................................29 
8.3.4 
Serious Adverse Event Collection Timeframe ......................................30 
8.3.5 
Pregnancy ..............................................................................................30 
 
Severity .............................................................................................................30 
 
Causality ............................................................................................................31 
 
Deaths and Life-Threatening Events .................................................................32 
 
Unexpected Adverse Event ...............................................................................32 
 
Data Monitoring committee ..............................................................................32 
9. Statistical Analysis .......................................................................................................32 
 
Sample Size .......................................................................................................33 
 
Analysis Sets .....................................................................................................33 
 
Statistical Methodology ....................................................................................34 
9.3.1 
Demographics and Baseline Characteristics .........................................34 
9.3.2 
Safety Analyses .....................................................................................34 


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9.3.3 
Efficacy Analyses..................................................................................35 
9.3.4 
Clinical Endpoint Review .....................................................................37 
10. Administrative Requirements ......................................................................................38 
 
Good Clinical Practice ......................................................................................38 
 
Ethical Considerations ......................................................................................38 
 
Patient Informed Consent and Information .......................................................38 
 
Patient Confidentiality ......................................................................................39 
 
Protocol Compliance .........................................................................................39 
 
Study Monitoring and On-Site Audits ..............................................................39 
 
Case Report Form Completion .........................................................................40 
 
Data Quality Assurance.....................................................................................40 
 
Study Completion or Premature Closure ..........................................................41 
 Record Retention ...............................................................................................41 
11. Use of Information and Publication .............................................................................42 
12. References ....................................................................................................................43 
 
Appendix A: Schedule of Assessments ...........................................................................45 
Appendix B: Laboratory Evaluations ..............................................................................46 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AVF 
Arteriovenous Fistula 
CKD 
Chronic Kidney Disease 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DMC 
Data Monitoring Committee 
EAS 
Evaluable Analysis Set 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
MedDRA 
Medical Dictionary of Regulatory Activities 
mg 
Milligrams 
mL 
Milliliters 
mM 
Millimolar 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
USRDS 
United States Renal Data System 


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1. BACKGROUND AND RATIONALE 
An arteriovenous fistula (AVF), in particular a radiocephalic AVF, is the most desirable form of 
vascular access for hemodialysis. [1, 2] However, approximately 50% of AVFs will lose primary 
patency within the first year. [3-6] This is due primarily to neointimal hyperplasia, a form of 
vascular scarring, most commonly at the arteriovenous anastomosis and adjacent outflow vein, 
that leads to progressive lumen stenosis and manifests as diminished AVF blood flow, venous 
hypertension, and thrombosis. [7] Patency loss is addressed via interventional procedures such as 
thrombectomy and balloon angioplasty, and surgical revision. [8] Interventions to restore or 
maintain patency are characterized by poor post-intervention patency. [9] Approximately 50% of 
the AVFs require re-intervention within 1 year possibly due to vessel injury caused by the 
intervention. [10-12] 
An AVF is abandoned when it can no longer be used for hemodialysis as it may be unable to 
provide adequate blood flow and/or it is deemed unsafe for the patient, and the associated 
problem cannot be corrected by an intervention, including medical, surgical, or radiological 
intervention, or rest. Abandonment is synonymous with secondary patency loss. [9] 
Approximately 25% of AVFs will lose secondary patency within the first year. [3, 6] 
Radiocephalic AVFs are even more likely to lose primary and secondary patency within the first 
year. [13] 
Patency loss is a significant risk factor for non-use of the AVF for hemodialysis. Approximately 
50% of all new AVFs will never become usable for hemodialysis. [5, 14] In patients on 
hemodialysis, this requires hemodialysis to occur through a hemodialysis catheter until another 
permanent hemodialysis access site can be established. 
A local treatment that safely prolongs patency of a radiocephalic AVF would be welcomed by 
patients and health care providers. Successful treatment could increase the success of AVF 
surgery, increase the chance that patients would dialyze with an AVF, and reduce the number of 
procedures to the AVF. 
 
DESCRIPTION OF INVESTIGATIONAL DRUG 
Vonapanitase (VOE-nah-pan-uh-tayse) is the generic name (United States Annotated 
Name/International Nonproprietary Name) for the investigational drug under development. It has 
previously been referred to in other documentation by its company code name, PRT-201. The 
investigational drug consists of lyophilized vonapanitase or placebo. Each vial of vonapanitase 
contains 0.036 mg of protein. Reconstitution with 3 mL sterile water yields 0.012 mg/mL 
vonapanitase solution containing 10 mM sodium phosphate, 55 mM NaCl, 3% mannitol, 
1% trehalose, and 0.01% polysorbate 80. The placebo is identical in appearance to vonapanitase 
but lacks the active ingredient. 
At the time of dosing 2.5 mL (0.03 mg) is withdrawn and topically administered. 


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STUDY RATIONALE 
Vonapanitase is a locally acting recombinant human elastase that in the appropriate dose and 
setting can enlarge blood vessels, increase blood flow, or inhibit neointimal hyperplasia. In an 
AVF Phase 2 study, patients undergoing creation of a radiocephalic AVF and treated with 
vonapanitase 0.03 mg experienced prolonged AVF primary unassisted patency (time from access 
creation to a first patency loss event), fewer procedures to restore or maintain patency, prolonged 
secondary patency, and increased proportion with AVF maturation (by ultrasound criteria) and 
use for hemodialysis compared with placebo treated patients. [13, 15] In a recently completed 
Phase 3 study (PRT-201-310) preliminary results showed patients undergoing creation of a 
radiocephalic AVF and treated with vonapanitase 0.03 mg experienced prolonged secondary 
patency and an increased proportion of patients using their fistula for hemodialysis.  The 
radiocephalic AVF is the form of access recommended by the National Kidney Foundation’s 
Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines [2] and preferred by 
clinicians. No dose-related increases in adverse events (AEs) were observed in the study.  Based 
on the results of prior clinical studies, this phase 3 study will examine the effect of vonapanitase 
0.03 mg on radiocephalic AVF secondary patency and AVF use for hemodialysis (co-primary 
efficacy endpoints), and other additional efficacy endpoints (unassisted AVF use for 
hemodialysis, primary unassisted patency, AVF maturation by ultrasound criteria, unassisted 
AVF maturation by ultrasound criteria, the rate of procedures performed to the AVF, and the rate 
of procedures to restore or maintain AVF patency). 
2. STUDY OBJECTIVE 
To assess the efficacy and safety of vonapanitase administered immediately after radiocephalic 
AVF creation. 
3. INVESTIGATIONAL PLAN 
Vonapanitase is a recombinant human elastase intended for local application immediately 
following surgery to create a radiocephalic AVF. 
 
METHODOLOGY 
This is a phase 3, randomized, double-blind comparison of vonapanitase versus placebo. Eligible 
patients are stratified by hemodialysis status and randomized in a 2:1 ratio to either vonapanitase 
0.03 mg or placebo. Investigators at approximately 40 centers will enroll 600 patients with 
chronic kidney disease (CKD) who require the creation of a radial artery to cephalic vein 
(radiocephalic) AVF. 
The study consists of a 4-week screening period, a 1-day treatment period, and up to 12 months 
of follow-up. Results from the screening visit and evaluations conducted as part of routine 
standard of care are used to determine patient eligibility and are completed as close to the time of 


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AVF creation as possible, but no longer than 28 days prior to the scheduled surgery (see 
Section 5.1). Significant medical events since Screening will be reviewed and recorded as part of 
the patient’s medical history. Patient randomization will occur at the time of surgery utilizing an 
interactive voice response system (IVRS) or interactive web response system (IWRS). 
In most cases, the AVF surgical procedure is conducted in an operating room as an outpatient 
procedure. The surgeon connects the end of a transected cephalic vein to the side of a radial 
artery in the arm, exposing approximately 3 cm of the outflow vein. The AVF surgery proceeds 
according to the standard practice of the institution and surgeon. Immediately after creation of 
the AVF, the surgeon treats the exposed inflow artery, anastomosis, and outflow vein topically 
with the study drug for 10 minutes by administering a series of drops. The intent is to keep the 
vessels wet for 10 minutes. After dosing, the surgeon irrigates the surgical site with generous 
amounts of saline before and after closing the surgical incision. Evaluation of the AVF site is 
conducted prior to the patient leaving the recovery area. 
Additional clinical safety assessments and evaluation of the AVF occur at Weeks 2 and 4, and 
Months 3, 6, 9, and 12 post study drug administration. All AEs are collected until Week 4; AEs 
associated with the AVF extremity and all AEs that result in death are collected until Month 12. 
Following the Month 12 visit, patients whose study AVF has not been abandoned will be 
enrolled into a registry in which clinical events and outcomes pertaining to the AVF treated with 
the study drug will be collected. Study staff will contact the patient, their physician(s), their 
dialysis unit or other sources as appropriate every 3 months to collect information about the 
initiation of hemodialysis and procedures performed on the AVF treated with the study drug. The 
patient will remain in the registry for 2 years, or until the AVF has been abandoned, whichever 
comes first. 
An ultrasound will be performed at the Week 4 and Month 3 visits according to a standard 
duplex Doppler ultrasound protocol. A blinded central reader will assess outflow vein luminal 
diameters, blood flow volume, and hemodynamically significant lumen stenosis. Results from 
the central reader will not be shared with the clinical site. 
The Proteon Medical Monitor will provide continuing review of safety data, in a blinded manner, 
throughout the trial. An independent Data Monitoring Committee (DMC) comprised of a 
biostatistician, and two medical doctors, at least one of whom is an expert in the field of 
hemodialysis access, will review accumulated blinded safety data once 150 patients have been 
treated and have completed the Week 4 visit. 
4. STUDY POPULATION 
 
GENERAL CONSIDERATIONS 
Six hundred (600) patients will be treated at approximately 40 centers. Patients are recruited 
from the nephrology and vascular surgery practices and through the referral network at facilities 


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treating patients with CKD. Each participating facility is evaluated with respect to its ability to 
enroll the necessary patients. Strategies for patient recruitment and retention are discussed during 
routine monitoring visits. Men and women meeting all of the inclusion criteria and none of the 
exclusion criteria will be allowed to participate. 
 
INCLUSION CRITERIA 
1. 
Age of at least 18 years. 
2. 
Life expectancy of at least 6 months. 
3. 
Diagnosis of CKD. 
4. 
Planned creation of a new radiocephalic AVF (revision of an existing AVF is not eligible). 
5. 
Ability to understand and comply with the requirements of the entire study and to 
communicate with the study team. 
6. 
Written informed consent using a document that has been approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC). 
7. 
If female and of childbearing potential (premenopausal and not surgically sterile) must 
have a negative serum pregnancy test at the screening visit (Visit 1) and be willing to use 
contraception from the time of the screening visit to 2 weeks following study drug 
administration. Acceptable methods of birth control include abstinence, barrier methods, 
hormones, or intra-uterine device. 
 
EXCLUSION CRITERIA 
1. 
Malignancy or treatment for malignancy within the previous 12 months with the exception 
of the following cancers if they have been resected: localized basal cell or squamous cell 
skin cancer, or any cancer in situ. 
2. 
Presence of any significant medical condition that might significantly confound the 
collection of safety and efficacy data in this study. 
3. 
Previous treatment with vonapanitase (PRT-201). 
4. 
Treatment with any investigational drug within the previous 30 days or investigational 
antibody therapy within the previous 90 days prior to signing informed consent. 
 
CONCURRENT MEDICATIONS 
Concomitant medications should be recorded from the date of Screening (Visit 1) through 
Week 4 (Visit 4). 


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EXCLUDED MEDICATIONS 
The following medications should not be applied topically in the surgical field or be contained in 
the lavage fluid during the creation of the AVF. These medications have been shown to inhibit 
the activity of vonapanitase. 
• Procaine 
• Bicarbonate solution 
• Vancomycin 
Intravenous (IV) vancomycin and topical lidocaine in normal saline, but not bicarbonate 
solution, are acceptable. 
In addition, ultrasound acoustic gel has been shown to inhibit the activity of vonapanitase and 
should not be used in the surgical field. After the surgical incision is closed, ultrasound acoustic 
gel can be used. 
5. STUDY SCHEDULE 
The assessments to be performed during the study are outlined below. The day the patient 
receives study drug (the day of surgery to create the AVF) is considered “Day 1.” Refer to 
Appendix A for the table describing the Schedule of Assessments.  
 
SCREENING: VISIT 1 (UP TO DAY -28) 
All patients sign written informed consent before any protocol-specific screening procedures are 
conducted. Results from the screening period and evaluations conducted as part of routine 
standard of care are used to determine study eligibility and are completed as close to the time of 
AVF creation as possible, but no longer than 28 days prior to the scheduled surgery.  
All patients will have the following procedures completed in the screening period once written 
informed consent has been obtained: 
1. 
Collection of demographic information, hemodialysis vascular access history, and medical 
history. 
2. 
Collection of concomitant medication information. 
3. 
Physical examination, including height and weight. 
4. 
Collection of blood samples for anti-vonapanitase antibody detection (see Section 6.2.4) 
and clinical laboratory evaluations including a serum pregnancy test in women of 
childbearing potential (see Section 6.2.5 and Appendix B for details). Refer to the 
Laboratory Manual for collection, processing, and shipping information. 


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AVF SURGERY: VISIT 2 (DAY 1) 
5.2.1 
PRE-SURGERY 
Any change in clinical condition since Screening (Visit 1) is assessed. Significant medical events 
since Visit 1 are recorded as part of the patient’s medical history. 
The patient is randomized at the time of surgery, utilizing an IVRS or IWRS. 
5.2.2 
SURGICAL PROCEDURES 
In most cases, the AVF surgical procedure is conducted in an operating room as an outpatient 
procedure. The surgeon connects the end of a transected cephalic vein to the side of a radial 
artery in the arm, exposing approximately 3 cm of the outflow vein, with the intent of creating a 
fistula that would be cannulated below the elbow. The AVF surgery proceeds according to the 
standard practice of the institution and surgeon. The surgical parameters that are important to 
record during the intraoperative phase are described in the case report form (CRF) completion 
guidelines; source document worksheets are provided by Proteon to help facilitate data 
collection. 
5.2.2.1 
Study Drug Administration 
See Section 4.5 (Excluded Medications) for medications that should be avoided during surgery. 
Procedures after AVF creation but before closure of incision: 
1. 
The surgical site should be rinsed generously with saline. 
2. 
The surgical site should be dry without ongoing bleeding during study drug administration. 
3. 
Study drug, 2.5 mL of solution, is administered using a sterile syringe (3 mL suggested) 
fitted with a 22 gauge angiocatheter. 
4. 
The surgeon administers the study drug in a series of drops to the exposed inflow artery 
(1 drop), anastomosis (1 drop), and the outflow vein (4 drops) every 20 seconds for 
10 minutes, for a total of approximately 180 drops. After 5 minutes of dosing the surgeon 
should check that approximately 1.25 mL of dosing solution has been administered. The 
number of drops should be adjusted accordingly based on this check (i.e., extra drop(s) 
every 20 seconds if less than 1.25 mL was used in the first 5 minutes, or fewer drops if 
more than 1.25 mL was used). 
5. 
The objective of study drug administration is to keep the vessels wet with the solution for 
the entire 10 minutes of treatment and to deliver the entire dose. Any dosing solution 
remaining in the syringe should be administered with the final application. If the drug 
pools around the AVF it does not need to be aspirated unless it is blood tinged since blood 
inhibits vonapanitase activity. 


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6. 
At the end of 10 minutes, the surgeon irrigates the surgical site with saline lavage 
continuously for 1 minute to remove any study drug.  
7. 
The surgeon closes the incision per usual clinical practice and washes the incision and 
surrounding skin with saline. 
Figure 1: 
Schematic of Study Drug Administration 
 
5.2.3 
POST-OPERATIVE ASSESSMENTS 
Evaluation of the newly created radiocephalic AVF, including an assessment of AVF patency, is 
conducted according to routine surgical practice prior to the patient leaving the recovery area. 
 
FOLLOW-UP: VISIT 3 /WEEK 2 (DAY 14 ± 3 DAYS) 
The purpose of this visit is to perform protocol-specific safety assessments and to assess the 
short term effects of study drug administration and collect information regarding AVF patency 
and use for hemodialysis. The patient will have an AVF and upper extremity examination (see 
Section 6.2.1) and be asked for information about intercurrent medical events and changes in 
clinical condition since the day of surgery (Visit 2). Events that meet the definition of an AE 
should be fully documented in the patient’s medical record. The following assessments are 
completed at this visit: 
1. 
AVF and upper extremity examination (See Section 6.2.1). 
2. 
Record procedures performed on the AVF since surgical creation. 
3. 
Record AEs occurring since the last visit. Previously reported AEs that are ongoing are 
evaluated for status. 
4. 
Record concomitant medications. 


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5. 
Collect blood samples for anti-vonapanitase antibody detection (see Section 6.2.4) and 
clinical laboratory evaluation (see Section 6.2.5 and Appendix B for details). Refer to the 
Laboratory Manual for collection, processing, and shipping information. 
 
FOLLOW-UP: VISIT 4 /WEEK 4 (DAY 28 ± 3 DAYS) 
The purpose of this visit is to perform protocol-specific safety assessments and collect 
information regarding AVF patency, maturation, and use for hemodialysis. The patient is asked 
for information about intercurrent medical events and changes in clinical condition since Week 2 
(Visit 3). Events that meet the definition of an AE should be fully documented in the patient’s 
medical record.  
The following procedures are completed at this visit: 
1. 
AVF and upper extremity examination (see Section 6.2.1). 
2. 
Physical examination (see Section 6.2.1). 
3. 
Record procedures performed on the AVF since surgical creation and date of successful 
initial cannulation, if applicable. 
4. 
Record AEs occurring since the last visit. Previously reported AEs that are ongoing are 
evaluated for status. 
5. 
Record concomitant medications. 
6. 
Collect blood sample for anti-vonapanitase antibody detection (see Section 6.2.4 for 
details). 
7. 
Duplex Doppler ultrasound performed according to a standard ultrasound protocol. 
 FOLLOW-UP: VISIT 5 / MONTH 3 (DAY 90 ± 14 DAYS) 
The purpose of this visit is to perform protocol-specific safety assessments and to collect any 
information regarding AVF patency, maturation, and use for hemodialysis. The patient is asked 
for information about any intercurrent medical events and changes in clinical condition since 
their last visit. Events associated with the AVF extremity that meet the definition of an AE 
should be fully documented in the patient’s medical record. 
The following procedures are completed at this visit: 
1. 
AVF and upper extremity examination (see section 6.2.1). 
2. 
Record procedures performed on the AVF since surgical creation and date of successful 
initial cannulation, if applicable. 
3. 
Record AEs associated with the AVF extremity occurring since the last visit. Previously 
reported AEs that are ongoing are evaluated for status. 


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4. 
Duplex Doppler ultrasound performed according to a standard ultrasound protocol. 
 
FOLLOW-UP: VISIT 6 / MONTH 6 (DAY 180 ± 14 DAYS), VISIT 7 / MONTH 9 
(DAY 270 ± 14 DAYS), AND VISIT 8 / MONTH 12 (DAY 360 ± 14 DAYS) 
The purpose of these visits is to perform protocol-specific safety assessments and to collect any 
information regarding AVF patency and use for hemodialysis. The patient is asked for 
information about intercurrent medical events and changes in clinical condition that have 
occurred since their last visit. Events associated with the AVF extremity that meet the definition 
of an AE should be fully documented in the patient’s medical record. 
The following procedures are completed at this visit: 
1. 
AVF and upper extremity examination (see Section 6.2.1). 
2. 
Record procedures performed on the AVF since surgical creation and date of successful 
initial cannulation, if applicable. 
3. 
Record AEs associated with the AVF extremity occurring since the last visit. Previously 
reported AEs that are ongoing are evaluated for status. 
4. 
If a patient tests positive for anti-vonapanitase antibodies at the Week 4 visit (or at 
Week 2 without a Week 4 result), an additional blood sample is drawn at the Month 6 visit 
(See section 6.2.4 and the Laboratory Manual for collection, processing and shipping 
information). 
5. 
If a patient tests positive for anti-vonapanitase antibodies at the Month 6 visit (or at 
Week 4 without a Month 6 test result), an additional blood sample is drawn at the 
Month 12 visit (See section 6.2.4 and the Laboratory Manual for collection, processing and 
shipping information).  
 
HANDLING OF WITHDRAWALS 
It is important to collect safety data on any patient who withdraws from the study before their 
last scheduled visit. A withdrawal is defined as a patient leaving the study with an AVF that has 
not been abandoned. 
If voluntary withdrawal occurs, the patient should be asked to return for their next scheduled 
evaluation (e.g., next study visit) in order to complete an end-of-study evaluation, and be given 
appropriate care until the symptoms of any AE resolves or the patient’s condition becomes 
stable. At minimum, the patient should be questioned over the telephone about any changes in 
clinical condition since their last visit, the status of any ongoing AEs, information regarding the 
initiation of hemodialysis, and procedures performed on the AVF. 
Discontinuation because of an AE is of particular interest and every effort should be made to 
follow the patient until the event resolves, the patient’s condition stabilizes or is fully 


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characterized, the event returns to baseline value (if a baseline value is available), or it is shown 
that the event is not attributable to the study drug or study conduct. Appropriate supportive 
and/or definitive therapy is administered as required. 
 
HANDLING OF AVF ABANDONMENT 
If a patient’s study AVF is abandoned, the following visit schedule should be followed: 
• If the study fistula is abandoned prior to Week 4 (Visit 4), the patient is expected to 
return for all office visits through Week 4 (Visit 4). If the fistula is thrombosed or ligated 
and abandoned prior to Week 4, an ultrasound is not required at the Week 4 visit. If the 
fistula is abandoned for another reason then an ultrasound is required at the Week 4 visit. 
The patient’s participation will be considered complete at the Week 4 visit. 
• If the study fistula is abandoned after Week 4 (Visit 4), the patient is expected to return 
for their next scheduled visit. If the decision to abandon the fistula is made at an office 
visit (i.e., patient comes in for the Month 3 visit and the investigator decides the fistula is 
not salvageable) then this will serve as their final office visit and the end-of-study 
evaluations can be completed. The patient’s participation will be considered complete. 
 
KIDNEY TRANSPLANTATION 
If a patient receives a kidney transplant before Week 4 (Visit 4), the patient is expected to return 
for all office visits through Week 4 (Visit 4). If a patient receives a kidney transplant after 
Week 4 (Visit 4), the patient is expected to return for their next scheduled visit. All ultrasounds 
should be performed as scheduled. Patients who receive a kidney transplant will not be followed 
in a registry. 
 
LONG-TERM OUTCOMES AND PHARMACOECONOMIC ANALYSES 
Patients signing informed consent will have agreed to the collection of long-term clinical 
outcome information and the sharing of identifying information (Social Security Number or 
Health Insurance Claim/Beneficiary Identification Code) with the Centers for Medicare and 
Medicaid Services (CMS) and/or the United States Renal Data System (USRDS), unless 
otherwise stated or agreed upon in the ICF. Each patient’s study information will be linked with 
information from a CMS and/or USRDS database. The linked information will be de-identified 
and used to analyze long-term outcomes not directly captured in the study (e.g., hospitalizations, 
and procedures after study completion) and to conduct pharmacoeconomic analyses of the costs 
associated with vascular access management, including access creations, patency loss events, and 
abandonments. 
In addition, patients will have agreed to the long term collection of data pertaining to the AVF 
treated with the study drug in a registry for 2 years. Following the Month 12 visit, patients whose 
study AVF has not been abandoned will be enrolled into a registry in which clinical events and 


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outcomes pertaining to the AVF treated with the study drug will be collected. Clinical site staff 
will contact the patient, the hemodialysis unit, or a relevant physician every 3 months (± 14 days) 
to collect information on the date of successful initial cannulation of the study AVF, current use 
of the study AVF for hemodialysis, reasons for non-use, and procedures performed on the study 
AVF (e.g., thrombectomy, angioplasty). Information will be collected for 2 years or until the 
AVF is abandoned, whichever comes first. 
6. PROCEDURES AND EVALUATIONS 
 
ASSESSMENT OF EFFICACY 
The co-primary efficacy endpoints are AVF secondary patency and AVF use for hemodialysis. 
Secondary patency is defined as the time from AVF creation until AVF abandonment. AVF use 
for hemodialysis is defined as the ability of the study AVF to be successfully cannulated and 
used for hemodialysis for a minimum of 90 days or at least 30 days prior to a patient’s last visit, 
if hemodialysis had not been initiated at least 90 days prior to the last visit.  Additional efficacy 
endpoints are unassisted AVF use for hemodialysis, primary unassisted patency, AVF maturation 
by ultrasound criteria, unassisted AVF maturation by ultrasound criteria, the rate of procedures 
performed to the AVF, and the rate of procedures to restore or maintain AVF patency. 
6.1.1 
AVF DISPOSITION 
Disposition of the study AVF is recorded following surgery and at Weeks 2 and 4, and at 
Months 3, 6, 9, and 12. AVF disposition includes whether or not the study AVF is patent, the 
patient is on hemodialysis, central venous catheter use, the study AVF is being used for 
hemodialysis or reason not being used, the date of first successful cannulation, and most recent 
Kt/V or URR, as available. 
Data on AEs of thrombosis, and procedures performed on the study AVF (e.g., angiography, 
thrombectomy, angioplasty) including the clinical reason the patient was referred for a procedure 
are collected at all follow-up visits. 
Use of the AVF for hemodialysis is defined as the ability of the study AVF to be successfully 
cannulated and used for hemodialysis with two needles for a minimum of 3 months. If a patient 
does not initiate hemodialysis at least 3 months before their last office visit then the AVF must 
have been in use for at least 1 month and still be in use at their last office visit to meet the 
definition of usable. 
6.1.2 
ABANDONMENT 
Abandonment of the study AVF is evaluated at Weeks 2 and 4 and at Months 3, 6, 9, and 12. 
Abandonment is defined as a fistula that can no longer be used for hemodialysis as it may be 
unable to provide adequate blood flow and/or it is deemed unsafe for the patient, and the 


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associated problem cannot be corrected by an intervention, including medical, surgical, or 
radiological intervention, or rest. [9] If a patient’s study AVF requires a surgical revision 
whereby the anastomosis treated with the study drug is taken down and a new anastomosis is 
created, the fistula should be considered abandoned for the purposes of the study. The follow-up 
visit schedule outlined in Section 5.8 should be followed. 
6.1.3 
ULTRASOUND EVALUATION 
AVF maturation is evaluated by ultrasound according to a standard ultrasound protocol at 
Week 4 (Visit 4) and Month 3 (Visit 5). All ultrasound examinations will be sent to a core 
imaging lab for review by an experienced ultrasound expert (VasCore, Massachusetts General 
Hospital, Boston, MA USA). The core imaging laboratory will remain blinded to the study 
treatment during ultrasound analysis.  
 
ASSESSMENT OF SAFETY 
Safety evaluations are based on clinical examination of the AVF and upper extremity, AEs, 
physical examination, duplex Doppler ultrasound, clinical laboratory evaluation, and 
immunogenicity testing results. Safety measurements are described below. 
6.2.1 
AVF AND UPPER EXTREMITY EXAMINATION 
AVF patency is evaluated by clinical examination immediately following surgery and at 
Weeks 2 and 4, and Months 3, 6, 9, and 12. The examination of the AVF is performed by a 
qualified member of the study team. The examination of the AVF includes an evaluation of the 
thrill and pulse at the anastomotic site, the bruit 10 cm downstream from the anastomotic site, 
and outflow vein distension with the arm below and above the level of the heart. Clinically 
significant abnormal adverse physical findings of the AVF are noted as AEs. 
Particular attention is given to evidence of vascular steal syndrome, excessive swelling, 
aneurysm, pseudoaneurysm, hematoma, seroma, infection, and abnormal wound healing. The 
following definitions are used for assessing patients enrolled into this protocol: 
Definitions and Classification: 
1. 
Vascular steal syndrome: cold and painful extremity distal to the AVF. 
2. 
Aneurysm: a progressive pathological expansion of the AVF vein due to weakness, but not 
disruption, of the vein wall. 
3. 
Pseudoaneurysm: an out-pouching of the AVF vein involving a defect in all three layers of 
the vein wall with bleeding that is contained by a blood clot or surrounding structures. 
4. 
Hematoma: a localized mass of extravasated blood. 
5. 
Seroma: a localized accumulation of serum. 


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6. 
Infection: infections will be classified as involving the skin (cellulitis), incision, or deep 
tissue. Deep tissue infections will include, but not be limited to, infected seromas, infected 
hematomas, and endovascular infections. 
7. 
Abnormal wound healing: such as: 
• Inflammation (erythema, warmth, induration, or tenderness). 
• Excessive scar tissue (i.e., keloid formation). 
• Lack of direct union between opposing edges of the incision. 
6.2.2 
ADVERSE EVENTS 
Monitoring of treatment emergent AEs is conducted throughout the study. All AEs, regardless of 
causality, are collected through Week 4 (Visit 4). After Week 4 and for up to Month 12 (Visit 8), 
only AEs associated with the AVF extremity and AEs resulting in death are collected, regardless 
of causality. 
All AEs that are not resolved by Month 12 (Visit 8) or not resolved upon discontinuation of the 
patient’s participation in the study are to be followed until any of the following occurs: 
• The event resolves. 
• The patient’s condition stabilizes or is fully characterized. 
• The event returns to baseline value (if a baseline value is available), or it is determined 
that the event is not attributable to the study medication or study conduct. 
Definitions, documentation, and reporting of AEs are described in detail in Section 8. 
6.2.3 
MEDICAL HISTORY AND PHYSICAL EXAMINATION 
A medical history is obtained through review of the patient’s medical records and personal 
interview in order to assess the patient’s eligibility. 
A physical examination is performed at Screening (Visit 1) and Week 4 (Visit 4); clinically 
significant adverse changes from baseline are recorded as AEs. 
6.2.4 
SPECIAL ASSAYS OR PROCEDURES 
A blood sample of 5 mL is drawn at Screening (Visit 1), Week 2 (Visit 3) and Week 4 (Visit 4) 
for anti-vonapanitase antibody detection. These samples will be processed according to the 
instructions provided in the Central Laboratory Manual. 
Patients who demonstrate anti-vonapanitase antibodies at Week 4 (or at Week 2 without a 
Week 4 result) are asked to provide an additional blood sample for testing at Month 6. Patients 
who continue to test positive at Month 6 (or at Week 4 without a Month 6 result), are asked to 
provide an additional blood sample at Month 12. 


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Provisions for the storage and future use of the samples will be described in the informed consent 
form (ICF). No genetic testing is performed with this archived blood sample. 
6.2.5 
CLINICAL LABORATORY EVALUATION 
Blood samples do not have to be obtained following fasting. Blood samples will be drawn at 
Screening (Visit 1), and Week 2 (Visit 3); labeled, processed, and shipped overnight to the 
central laboratory for testing. Instructions for the collection, processing, and shipping of samples 
will be provided in the Laboratory Manual. 
Blood for serum pregnancy will be drawn in females of childbearing potential at Screening. 
Refer to Appendix A for the Schedule of Assessments and Appendix B for information regarding 
the specific laboratory tests. 
Clinical laboratory values that are outside the normal limits are considered abnormal. Abnormal 
clinical laboratory values will be noted as clinically significant or non-clinically significant by 
the Investigator. Non-clinically significant is defined as those abnormalities unlikely to indicate a 
significant medical condition or are consistent with the patient’s underlying medical condition 
and do not warrant any further investigation or treatment. All new clinically significant 
abnormalities not present at baseline will be reported as AEs. 
6.2.6 
DUPLEX DOPPLER ULTRASOUND 
Duplex Doppler ultrasound examinations at Week 4 (Visit 4) and Month 3 (Visit 5) will be sent 
to a blinded central reader. Instructions for the acquisition and transmission of ultrasound 
examinations will be provided in the Ultrasound Guidelines. 
6.2.7 
UNSCHEDULED ASSESSMENTS 
The Investigator may, at his/her discretion, arrange for a patient to have an unscheduled 
assessment(s). This may include repeated screening assessments if a surgery date is rescheduled 
out of the visit window, assessments to further evaluate a patient experiencing an AE considered 
by the Investigator to be possibly related to the use of study drug or collect information about 
AVF patency and use for hemodialysis. The CRF pages specific for unscheduled assessments 
must be completed at the time of the unscheduled visit. 
7. INVESTIGATIONAL DRUG 
 
IDENTITY OF INVESTIGATIONAL DRUG 
Vonapanitase is a recombinant human elastase for clinical use. It is supplied by Proteon 
Therapeutics. For further detail, refer to the PRT-201 (vonapanitase) Investigator's Brochure. 


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PLACEBO 
The placebo is identical in appearance and composition to vonapanitase but lacks the active 
ingredient. It is supplied by Proteon. 
 
FORMULATION, PACKAGING, AND LABELING 
Vonapanitase is supplied as a lyophilized powder in a single use 10 mL glass vial with a rubber 
stopper. Each vial contains 0.036 mg of protein. Proteon will also supply 5 mL vials of sterile 
water. Reconstitution with 3 mL sterile water yields a 0.012 mg/mL vonapanitase solution 
containing 10 mM sodium phosphate, 55 mM NaCl, 3% mannitol, 1% trehalose, and 
0.01% polysorbate 80. Two and a half milliliters (2.5 mL) is used in the application. Further 
detail is provided in the Pharmacy Manual. 
 
PATIENT RANDOMIZATION AND BLINDING 
Both randomization and blinding techniques are used in this study to minimize bias. A computer 
generated randomization schema is centrally available via an IVRS or IWRS. The IVRS/IWRS is 
accessed by individuals who have been issued a username and password. Patient randomization 
is performed at the time of surgery. Patients will be randomized by site and stratified by 
hemodialysis status at the time of randomization and balance will be maintained by blocking 
within site. 
 
UNBLINDING 
In the case of a medical emergency where, in the Investigator’s judgment, the patient’s safety 
may be compromised without immediate knowledge of the exact treatment received, the 
Investigator can contact the Medical Monitor at Proteon Therapeutics to unblind a single patient 
treatment assignment. 
Medical Monitor: Marco Wong, M.D, PhD 
Telephone No.: 1-816-536-3770 
Proteon Therapeutics, Inc. 
Email: MWong@ProteonTx.com 
 
PRODUCT SHIPPING, STORAGE, AND STABILITY 
The Investigator acknowledges that the study drug supplies are investigational and as such must 
be handled strictly in accordance with the protocol and container label. The investigational drug 
must be stored frozen at -15°C to -35°C in a secure area with limited access. 
The investigational drug is distributed from a drug repository and shipped in specialized 
insulated shippers that do not require dry ice or in insulated shippers packed with dry ice to 
maintain the shipper’s internal temperature of -15°C to -35°C. Each shipment will include a 
TempTale to monitor the temperature throughout the shipping period, and a shipment 


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verification form that should be completed, signed and dated, and returned to the drug 
distribution center or designee. This form will capture discrepancies in the number of vials 
received, damage to the packaging or any indication of tampering, and the TempTale 
information. The original form should be maintained at the clinical center with the other drug 
inventory and distribution records. 
The initial shipment of investigational drug will be sent on or about the date of the site initiation 
visit, or equivalent, and will be coordinated with the Investigational Pharmacy, where applicable. 
Plans for how the investigational drug will be distributed including participation of the drug 
repository and distribution center, frequency of product distribution, amount of product shipped, 
and plans for return of used and unused product will be provided in the Pharmacy Manual.  
The expiry date for study drug is included on the product labeling. 
 
DOSAGE, PREPARATION, AND ADMINISTRATION OF INVESTIGATIONAL 
DRUG 
Investigational drug will be administered only to eligible patients under the supervision of the 
Investigator or identified sub-Investigator(s). Eligible patients will be randomized in a 2:1 ratio 
to either vonapanitase 0.03 mg or placebo. The investigational drug will be reconstituted with 
3 mL of sterile water and gently swirled to ensure the investigational drug is completely 
dissolved. The study drug solution should be clear and colorless.  Detailed investigational drug 
preparation instructions will be provided in the Pharmacy Manual. 
Papaverine is often used during the surgical creation of an AVF.  Care should be taken to ensure 
that prior to study drug administration the study drug solution does not come into contact with 
papaverine or any supplies containing or exposed to papaverine.  Exposing the study drug 
solution to papaverine before study drug administration may cause the study drug solution to 
become cloudy.  If the study drug solution ever appears cloudy, it should not be used for dosing.  
Discard any cloudy study drug solution and obtain a replacement.  It is acceptable for the study 
drug solution to come into contact with papaverine in the surgical site.   
The investigational drug will be administered in a volume of 2.5 mL topically using a sterile 
syringe fitted with a 22 gauge angiocatheter. The surgeon will administer a series of drops of 
study drug to the external surface of the exposed inflow artery (1 drop), anastomosis (1 drop) and 
the outflow vein (4 drops) every 20 seconds for 10 minutes, for a total of approximately 
180 drops. The objective is to keep the vessels wet with the solution for the 10 minutes of 
treatment. After 5 minutes of dosing the surgeon should check that approximately 1.25 mL of 
dosing solution has been administered. The number of drops should be adjusted accordingly 
based on this check (i.e., extra drop(s) every 20 seconds if less than 1.25 mL was used in the first 
5 minutes, or fewer drops if more than 1.25 mL was used). The entire dose should be delivered. 
Any dosing solution remaining in the syringe should be administered with the final application. 
If the drug pools around the AVF it does not need to be aspirated unless it is blood tinged. At the 


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end of 10 minutes, the surgeon will irrigate the incision site with saline lavage continuously for 
1 minute to remove the investigational drug. The surgeon will close the incision per usual 
clinical practice and wash the incision and surrounding skin with saline. 
All persons handling study drug should avoid contact with the investigational drug solution. Any 
accidental exposure to the skin, eyes, and mucous membranes should be washed with copious 
amounts of water or saline for at least 1 minute. 
 
DRUG ACCOUNTABILITY/RETENTION  
Accountability for the study drug at the trial site is the responsibility of the Investigator. The 
Investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign some of the drug accountability responsibilities to 
a pharmacist or other appropriate individual. Accountability records will include dates, 
quantities, patient identifiers, and the initials of the individual documenting the record. The 
institution is free to use its drug accountability system, unless otherwise specified by Proteon. 
These records will adequately document that the patients were provided the doses specified in 
the protocol and should reconcile all study drug received from Proteon. Proteon or its Contract 
Research Organization (CRO) designee will review drug accountability records at the site on an 
ongoing basis during on-site monitoring visits. 
 
DRUG RETURNS AND DESTRUCTION 
Used and unused vials of study drug will be stored until the study monitor conducts an on-site 
visit to perform a physical inventory and reconciliation of the drug accountability records. 
Proteon may allow study drug to be destroyed on-site if the site has a documented method of 
destruction. Please refer to the Pharmacy Manual for study specific details regarding vial 
destruction and return. 
8. ADVERSE EVENTS 
 
DEFINITION OF ADVERSE EVENT 
An adverse event (AE) means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational drug, whether or not considered related to the 
investigational drug. This includes any newly occurring event or a previous condition that has 
increased in severity or frequency since the administration of the investigational drug. 


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RECORDING OF ADVERSE EVENTS AND OBSERVATION PERIOD 
The Investigator should question the patient about AEs and intercurrent illnesses since his/her 
last visit and record the information in the patient’s medical record. The questions should be 
generalized such as, “How have you been feeling since your last visit?” The presence or absence 
of specific AEs should not be solicited from patients. The onset and end dates, severity, and 
relationship to study drug must be recorded for each AE. When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event or 
diagnosis. 
AEs will be recorded between administration of the study drug and Week 4 (Visit 4). After 
Week 4 and for up to Month 12 (Visit 8), only AEs associated with the AVF extremity and AEs 
resulting in death will be collected. Medical events that occur between the signing of the 
informed consent and study drug administration will be considered part of the patient’s medical 
history and recorded accordingly. Patients who experience AEs will be monitored with relevant 
clinical assessments and laboratory tests, as determined by the Investigator. Any action taken and 
follow-up results must be recorded in the patient’s medical record. Follow-up laboratory results 
should be filed with the patient’s medical records. 
All AEs that are not resolved by the end of the study, or that were not resolved upon 
discontinuation of the patient’s participation in the study, are to be followed until one of the 
following occurs: the event resolves, the patient’s condition stabilizes or is fully characterized, or 
the event returns to baseline value (if a baseline value is available). 
 
SERIOUS ADVERSE EVENT 
8.3.1 
REFERENCE SAFETY INFORMATION 
The current version of the vonapanitase Investigator’s Brochure should be referenced for all 
safety information pertaining to the study. Proteon will provide a current version of the 
Investigator’s Brochure to all study Investigators. 
8.3.2 
SERIOUS ADVERSE EVENT DEFINITION 
A serious adverse event (SAE) means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related, that results in one or more of the 
following outcomes: 
1. 
Death. 
2. 
A life-threatening AE. Life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 


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3. 
In-patient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned prior to study entry are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected 
manner during the study (e.g., surgery performed earlier than planned). 
4. 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5. 
A congenital anomaly/birth defect. 
6. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the 
development of drug dependency or drug abuse. 
8.3.3 
REPORTING PROCEDURES 
All initial and follow-up SAE reports must be reported on the SAE form and a facsimile sent to 
the appropriate Safety Desk within 24 hours of the site being made aware of it. See contact 
information below: 
Premier Safety Desk 
SAE Fax No.: 1-215-972-8765 
Email: globalpv-us@premier-research.com  
 
Medical Monitor: Marco Wong, M.D, PhD 
Telephone No.: 1-816-536-3770 
Proteon Therapeutics, Inc. 
Email: MWong@ProteonTx.com 
A report of an SAE by telephone must always be confirmed by a written, more detailed report 
within 24 hours of the site being made aware of the event. The Investigator should provide the 
following written documentation at the time of notification, if available: 
• 
SAE Reporting Form 
• 
Concomitant medication pages 
• 
Relevant diagnostic reports 
• 
Relevant laboratory reports 
• 
Admission notes 


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• 
Hospital discharge summary 
Proteon will assume responsibility for appropriate reporting of AEs to regulatory authorities. 
Proteon will also report all SAEs that are unexpected and associated with the use of the study 
drug to investigational sites. 
Follow-up data concerning SAEs (e.g., diagnostic test reports, physician's summaries, etc.) must 
be submitted to Proteon or designee as they become available, preferably electronically. It is the 
responsibility of the Investigator to promptly notify the IRB or IEC of all SAEs, as well as any 
unanticipated problems that involve significant risk to patients, as required by their IRB/IEC. A 
copy of the IRB/IEC notification should be placed in the site’s regulatory binder. 
The Principal Investigator will review each SAE and further evaluate the relationship of the AE 
to study drug and to the patient’s underlying disease. Based on the Investigator’s assessment of 
the AE, a decision will be made concerning the need for further action. The primary 
consideration governing further action is whether new findings affect the safety of other patients 
participating in the clinical study. If the discovery of a new AE related to the study drug raises 
concern over the safety of its continued administration to patients, Proteon will take immediate 
steps to notify the Food and Drug Administration (FDA) and all Investigators participating in 
vonapanitase clinical studies. 
8.3.4 
SERIOUS ADVERSE EVENT COLLECTION TIMEFRAME 
All SAEs, regardless of relationship to the investigational product, will be reported between 
study drug administration and Week 4 (Visit 4). After Week 4 only AEs and SAEs associated 
with the AVF extremity, and those resulting in death will be collected. 
8.3.5 
PREGNANCY 
Pregnancy by definition is not considered to be a SAE unless the criteria in Section 8.3 are met. 
However, pregnancy in patients that have received the study drug must be followed to assess 
congenital anomalies. For purposes of consistency, Proteon or its designated CRO 
representatives will record pregnancies in the SAE System; however, the event will then be 
downgraded if the outcome does not meet the SAE criteria. Pregnancy Questionnaires and 
Pregnancy Outcome forms are provided to each clinical study site in the Study Manual and 
should be forwarded to Proteon or designee. 
 
SEVERITY 
For both AEs and SAEs, the Investigator must determine the severity of the event using the 
following definitions: 
Mild: The event does not interfere in a significant manner with the patient’s normal functioning 
level. It may be an annoyance but does not cause any limitation in usual activity. 


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Moderate: The event produces some impairment of functioning but is not hazardous to health. It 
is uncomfortable or an embarrassment and may cause some limitation in usual activity. 
Severe: The event produces significant impairment or incapacitation and is a definite hazard to 
the patient’s health. 
Life-threatening: The event places the patient, in the view of the Investigator, at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in 
a more severe form, might have caused death. 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, severe, or life-threatening myocardial infarction). Even though the event itself may be 
of relatively minor medical significance (such as a severe headache), this is not the same as 
“serious,” which is based on patient/event outcome or action criteria as described above and is 
usually associated with events that pose a threat to a patient’s life or functioning. A severe AE is 
not necessarily serious. For example, persistent nausea of several hours duration may be 
considered severe nausea but not meet the definition of a SAE. On the other hand, a stroke 
resulting in only a minor degree of persistent disability may be considered mild, but would be 
defined as a SAE based on the above noted criteria. Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. 
 
CAUSALITY 
Association of AEs and SAEs to the study drug will be made using the following definitions: 
Unrelated: An AE that is not related to the use of the study drug. 
Unlikely: An AE that is unlikely to be due to the use of the study drug. An alternative 
explanation, e.g., concomitant drug(s), concomitant disease(s), is plausible. A relationship to the 
study drug is improbable but not impossible. 
Possible: An AE that conceivably could be due to the use of the study drug. An alternative 
explanation, e.g., concomitant drug(s), concomitant disease(s), is not conclusive. The 
relationship of the event in time follows a plausible temporal sequence from administration of 
the study drug so that a causal relationship cannot be excluded, but could have been produced by 
the patient’s clinical condition or other therapy. 
Probable: An AE that might be due to the use of the study drug. An alternative explanation is 
less likely, e.g., concomitant drug(s), concomitant disease(s). The relationship in time is 
suggestive and follows a reasonable temporal association with study drug administration. The 
reaction cannot be reasonably explained by the known characteristics of the patient’s clinical 
state or other modes of therapy administered to the patient. 
Related: An AE that is almost certainly related to the use of the study drug. The AE cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s), concomitant 
disease(s). 


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DEATHS AND LIFE-THREATENING EVENTS 
An event leading to death from any cause or any life-threatening event must always be reported 
as an SAE within 24 hours of the clinical site learning of the event, regardless of whether or not 
related to the study drug (see Section 8.3). 
 
UNEXPECTED ADVERSE EVENT 
An AE is considered “unexpected” if it is not listed in the Investigator's Brochure or is not listed 
at the specificity or severity that has been observed. “Unexpected,” as used in this definition, also 
refers to AEs that are mentioned in the Investigator's Brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
DATA MONITORING COMMITTEE 
An independent DMC will review accumulated blinded safety data after 150 patients have been 
treated and complete Week 4 (Visit 4). The DMC will review adverse event and clinically 
significant laboratory data in a blinded fashion and make a determination whether the data raise 
any vonapanitase related safety concern. The DMC must make a recommendation to continue, 
modify, or stop the study. If a potential safety issue is identified during the course of the study, 
these will be brought to the attention of the Committee Chair and additional meetings may be 
convened.  
A charter for the DMC will be created that will define the membership, schedule of meetings, 
data required for each safety review, and requirements for documenting meeting discussions and 
outcome. 
9. STATISTICAL ANALYSIS 
A formal statistical analysis plan (SAP) will be developed that includes a detailed description of 
all planned analyses, pre-specified exploratory analyses, and any data handling conventions. Any 
deviations from the statistical methods described in the protocol and/or SAP will be documented 
in the clinical study report. 
In general, continuous variables will be summarized using descriptive statistics including the 
number of observations, mean, standard deviation, minimum, median, and maximum values. 
Categorical values will be summarized using number of observations and percentages. Data 
presentations will include columns for placebo and vonapanitase 0.03 mg. 
All statistical tests will be performed at the two-sided, 5% significance level, unless otherwise 
specified. All statistical testing will compare placebo versus vonapanitase unless otherwise 
specified. 


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The primary analysis will be performed once all patients have completed the Month 12 visit 
(Visit 8). The analysis of the registry data will be performed separately. 
All data will be included in data listings. 
 
SAMPLE SIZE 
Final data from the PRT-201-310 study has been used to estimate the sample size and power for 
the co-primary endpoints of secondary patency and AVF use for hemodialysis.  Six hundred 
(600) patients will be stratified based on hemodialysis status at study entry and randomly 
allocated by site in a 2:1 ratio to either vonapanitase 0.03 mg or placebo. When the total sample 
size is approximately 600 (400 vonapanitase and 200 placebo), a two-sided Fleming-Harrington 
weighted log-rank test with ρ = 0 and γ= 0.35 for equality of survival curves with a 0.05 
significance level will have approximately 88% power to detect a 13% difference (61 vs. 74%) in 
the proportion of placebo compared to vonapanitase 0.03 mg treated patients with secondary 
patency at 12 months. [16] A piecewise exponential model with no treatment benefit during the 
first three months (i.e., survival at 3 months for both treatment groups is 88.4%) is assumed. 
A 15% drop out rate has been assumed in the calculations. The study will enroll over 24 months 
and each patient will be followed for a maximum of 12 months.   
Assuming 25% of patients will have insufficient data to determine AVF use for hemodialysis a 
sample size of 450 will have 98% power to detect a 20% difference in the percentage of AVF use 
in placebo compared to vonapanitase 0.03 mg (44 vs. 64% AVF use), using a two sided chi-
square test with an 0.05 significance level. 
 
ANALYSIS SETS 
The Full Analysis Set (FAS), based on Intention to Treat (ITT) methodology, will be defined as 
all randomized patients who have AVF surgery. Patients will be analyzed according to the 
randomized treatment assignment. Analyses of all efficacy endpoints will be performed using the 
FAS as the primary analysis set. Any patients who are randomized but not treated and have AVF 
surgery will only contribute data from Visits 1 and 2.  
An Evaluable Analysis Set (EAS) will be defined as all randomized patients who received any 
amount of study drug and who do not have any protocol violations/deviations, or a technical 
failure of the surgery that could adversely affect the evaluation of the primary analysis. These 
patients will be identified prior to unblinding and the reason for any potential exclusion will be 
documented. Patients will be analyzed according to the treatment actually received. Analyses of 
the co-primary endpoints will be performed using the EAS as a sensitivity analysis. 
The Safety Analysis Set will be defined as all randomized patients who received any amount of 
study drug. Patients will be analyzed according to the treatment actually received. 


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STATISTICAL METHODOLOGY 
9.3.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic data, medical history, and other baseline characteristics will be summarized by 
treatment received and included in the data listings. Statistical comparisons will be performed to 
assess baseline imbalances between treatment groups. 
9.3.2 
SAFETY ANALYSES 
Safety evaluations are based on AEs, physical examination, duplex Doppler ultrasound, clinical 
laboratory evaluations, and immunogenicity testing results. 
9.3.2.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
AE dictionary. Treatment emergent AEs, defined as AEs that occur after administration of the 
study drug, will be tabulated by body system, preferred term, and dose. Events will also be 
summarized by relationship to the study drug and severity (mild, moderate, severe, or life 
threatening). SAEs and events leading to study discontinuation will be summarized by body 
system, preferred term, and treatment group. 
All AEs will be presented in the data listings. 
9.3.2.2 
Physical Examinations 
Required components of the physical exam will be specified in the source worksheets. Clinically 
significant adverse changes from baseline will be reported as AEs. In addition to the physical 
examination at Screening (Visit 1) and Week 4 (Visit 4), an AVF and upper extremity 
examination will be performed immediately following surgery and at all follow-up visits. Details 
on the AVF and upper extremity examination may be found in Section 6.2.1. AVF procedure 
types and all angioplasty locations (angioplasty includes balloon angioplasty/fistulogram and 
surgical patch angioplasty) will be summarized by the total frequency of each as well as the 
number and percentage of patients receiving them in each treatment group. The clinical reasons 
the patients were referred for the first procedure to restore or maintain patency will be 
summarized and presented by decreasing order of frequency for the vonapanitase 0.03 mg group. 
9.3.2.3 
Duplex Doppler Ultrasound 
The variables of lumen diameter and blood flow obtained through duplex Doppler ultrasound at 
Week 4 (Visit 4) and Month 3 (Visit 5) will be summarized and presented in the data listings and 
in tabular summaries by treatment group. The average value of multiple measurements will be 
used for summarization. Clinically significant adverse findings will be recorded as AEs. 


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9.3.2.4 
Clinical Laboratory Evaluations 
Clinical laboratory results will be summarized by treatment group at Screening (Visit 1) and 
Week 2 (Visit 3). The change from baseline in laboratory results will also be presented. All 
clinically significant adverse laboratory abnormalities will be reported as AEs and included in 
the summary of AEs. Out of range laboratory results will be listed. 
All laboratory results will be presented in the data listings. 
9.3.2.5 
Anti-vonapanitase Antibody Detection 
Results of anti-vonapanitase antibodies will be presented in the data listings. 
9.3.3 
EFFICACY ANALYSES 
9.3.3.1 
Primary Endpoints 
The co-primary efficacy endpoints are secondary patency and AVF use for hemodialysis. 
Secondary patency is defined as the time from AVF creation until AVF abandonment.  A patient 
who does not have an abandoned AVF at Month 12 (Visit 8) or end of study will be censored at 
the last visit date the AVF was known not to be abandoned. 
Secondary patency time is estimated by the 25th, 50th (median), and 75th percentiles calculated by 
using the Kaplan-Meier life test methods to estimate the survival functions. A Fleming-
Harrington weighted log-rank test with ρ = 0 and γ= 0.35 will be used to test the equality of the 
survival curves between vonapanitase and placebo. A 95% confidence interval for the median 
will be calculated.  A graph of the survival probability over time will be presented. As a 
sensitivity analysis, the hazard ratio and 95% confidence interval, using a Cox proportional-
hazards model will also be calculated. The analysis of secondary patency will be performed in 
the FAS. Analysis of secondary patency will also be performed in the EAS as a sensitivity 
analysis. As appropriate based on the proportional hazards assessment, restricted means or 
proportional hazards modeling may be employed to identify and adjust for any covariates 
potentially associated with secondary patency. The data from the models will be for descriptive 
purposes only. The Fleming-Harrington weighted log rank test in the FAS will be considered the 
primary analysis for secondary patency. 
AVF use for hemodialysis is defined as the ability of the study AVF to be successfully 
cannulated and used for hemodialysis for a minimum of 90 days or at least 30 days prior to a 
patient’s last visit, if hemodialysis had not been initiated at least 90 days prior to a patient’s last 
visit.  If AVF use is not defined as above, non-use of the AVF for hemodialysis is defined as an 
abandoned fistula prior to use; or if hemodialysis is recorded on 2 consecutive visits and there is 
no cannulation date or duration of use is less than 90 days.  The patients who are not categorized 
as having use or non-use of the AVF have insufficient data to determine AVF use for 
hemodialysis and will be categorized as having indeterminate use. The number and percentage of 


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patients with AVF use or non-use for hemodialysis will be summarized by treatment group in the 
group of FAS patients who are not considered indeterminate.  Vonapanitase vs. placebo will be 
tested using a Chi-square test. Analysis of AVF use will also be performed in the EAS as a 
sensitivity analysis.    
9.3.3.2 
Additional Efficacy Endpoints 
Additional efficacy endpoints are unassisted AVF use for hemodialysis, primary unassisted 
patency, AVF maturation by ultrasound criteria, unassisted AVF maturation by ultrasound 
criteria, the rate of procedures performed to the AVF, and the rate of procedures to restore or 
maintain AVF patency. 
9.3.3.2.1 Unassisted AVF Use for Hemodialysis 
Unassisted AVF use for hemodialysis is defined as AVF use without prior procedures to restore 
or maintain patency.  
The number and percentage of patients with unassisted AVF use for hemodialysis will be 
summarized by treatment group. Vonapanitase versus placebo will be tested using a chi-square 
test.  The analysis of unassisted AVF use will be performed in the FAS. 
9.3.3.2.2 Primary Unassisted Patency 
AVF primary unassisted patency is defined as the time from AVF creation until the first 
occurrence of either access thrombosis or procedure to restore or maintain AVF patency. A 
patient who has a patent AVF at Month 12 or end of study will be censored at the last visit date 
where the AVF was known to be patent.  
Primary unassisted patency time is estimated by the 25th, 50th (median), and 75th percentiles 
calculated by using the Kaplan-Meier life test methods to estimate the survival functions. A 
log-rank test will be used to test the equality of the survival curves between vonapanitase and 
placebo. A 95% confidence interval for the median will be calculated. A graph of the survival 
probability over time will be presented. A hazard ratio and 95% confidence interval, calculated 
using a Cox proportional-hazards model including treatment as the covariate will assess the 
magnitude of the treatment effect.  Proportional hazards modeling may be employed to identify 
and adjust for any covariates potentially associated with primary unassisted patency. The data 
from the proportional hazards models will be for descriptive purposes only. The analysis of 
primary unassisted patency will be performed in the FAS. Analysis of primary unassisted 
patency will also be performed on the EAS as a sensitivity analysis.   
9.3.3.2.3 AVF Maturation 
AVF maturation by ultrasound criteria is defined by two definitions: 


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1. As average cephalic vein luminal diameter ≥ 6 mm and outflow vein volume blood flow 
≥ 600 mL/min by ultrasound. [2] 
2. As average cephalic vein luminal diameter ≥ 4 mm and outflow vein volume blood flow 
≥ 500 mL/min by ultrasound. [1] 
The number and percentage of patients with AVF maturation will be summarized by treatment 
group at Week 4 (Visit 4) and Month 3 (Visit 5). Vonapanitase versus placebo will be tested 
using a chi-square test. Definition 2 at the Month 3 visit is considered primary for analysis. 
Unassisted AVF maturation is defined as AVF maturation by ultrasound criteria without prior 
primary unassisted patency loss. The number and percentage of patients with unassisted AVF 
maturation will be analyzed similarly. AVF maturation and unassisted AVF maturation by 
ultrasound criteria will be performed in the FAS.  This analysis will also be performed on the 
EAS as a sensitivity analysis.   
9.3.3.2.4 Procedure Rate 
The procedure rate is defined as the total number of procedure days divided by time on study per 
person year of follow up. A Wilcoxon rank sum test will be used to compare the treatment 
groups. The rate of procedure days overall and the rate of procedure days to restore or maintain 
AVF patency will be performed in the FAS. 
9.3.3.3 
Multiplicity Adjustments 
Multiplicity, with respect to the co-primary endpoints, will be managed with the Hochberg 
procedure. If both endpoints have a p-value ≤ 0.05 both will be considered statistically 
significant. If one endpoint has a p-value > 0.05 the other endpoint will be considered 
statistically significant only if its p-value is ≤ 0.025. If both p-values are > 0.05 neither will be 
considered statistically significant.   
Multiplicity adjustments for other endpoints will be described fully in the SAP. 
9.3.4 
CLINICAL ENDPOINT REVIEW 
Prior to database lock, a clinical expert in the field of hemodialysis vascular access will review 
all study patients’ CRFs and procedure reports to confirm that the patients are appropriately 
defined with regard to the primary and secondary patency efficacy endpoints by reviewing 
applicable CRFs and procedure reports to ensure that appropriate documentation of clinical 
dysfunction has been recorded.  A charter for this process will be created that will define the 
review process and the requirements for documentation of review. 


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10. ADMINISTRATIVE REQUIREMENTS 
 
GOOD CLINICAL PRACTICE 
The study will be conducted in accordance with the current Good Clinical Practice/International 
Conference on Harmonization (GCP/ICH) Guidelines and relevant regulatory requirement(s). 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study patients are being protected consistent with the principles that have their origin in the 
Declaration of Helsinki and that the clinical study data are credible. The Investigator will be 
thoroughly familiar with the appropriate use of the study drug as described in the protocol and 
Investigator's Brochure. Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. A Trial Master File (TMF) will be 
established at the beginning of the study, maintained for the duration of the study, and retained 
according to appropriate regulations. 
 
ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki. The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety, and well-being of the patients. The study will only be conducted 
at sites where IRB/IEC approval has been obtained. The protocol, Investigator's Brochure, 
informed consent, advertisements (if applicable), written information given to the patients 
(including patient information material), safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/IEC by the Investigator. 
 
PATIENT INFORMED CONSENT AND INFORMATION 
Prior to entry in the study, the Investigator must explain to potential study patients or their 
legally acceptable representative, the study and the implications of participation. Patients will be 
told that their participation is voluntary and they may withdraw consent to participate at any 
time. Patients will be told that their records may be accessed by competent authorities and 
authorized Proteon personnel or its representatives without violating the confidentiality of the 
patient, to the extent permitted by the applicable law(s) and/or regulations. In addition to signing 
the ICF, the patient or legally acceptable representative will be required to authorize access to the 
patient’s protected health information by signing a separate authorization meeting the 
requirements of the Health Insurance Portability and Accountability Act of 1996. Each patient 
(or their legally authorized representative) must sign and date the ICF (and other locally 
required documents) after the nature of the study has been fully explained but prior to 
performing any study-related activities. The patient (or their legally acceptable representative) 
will be given sufficient time to read the ICF and to ask questions. After having obtained consent, 
a copy of the informed consent document must be given to the patient. In case the patient is 
unable to read, an impartial witness must attest to the informed consent. Patients who are unable 


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to comprehend the information provided can only be enrolled after consent of a legally 
acceptable representative. 
The consent form that is used must be approved by both the reviewing IRB/IEC and by Proteon. 
 
PATIENT CONFIDENTIALITY 
The collection and processing of data from patients enrolled in this study will be limited to those 
data that are necessary to investigate the safety, quality, and utility of the investigational drug(s) 
used in this study and to conduct the other investigations described in this protocol, including the 
pharmacoeconomic analysis described in Section 5.10. These data will be processed with 
adequate precautions to ensure confidentiality. 
In order to maintain patient privacy, CRFs, study drug accountability records, study reports, and 
communications will generally identify the patient by initials and the assigned patient number. 
The ICF will inform patients of any departures from this approach, such as the need to identify 
patients by social security number or Health Insurance Claim/Beneficiary Identification Code for 
purposes of the pharmacoeconomic analysis described in Section 5.10. The Investigator will 
grant monitor(s) and auditor(s) from Proteon, its CRO designee or business partners, and 
regulatory authority(ies) access to the patient’s original medical records for verification of data 
gathered on the CRFs and to audit the data collection process. The patient’s confidentiality will 
be maintained and will not be made publicly available except to the extent permitted by 
applicable laws and regulations. 
 
PROTOCOL COMPLIANCE 
The Investigator will conduct the study in compliance with the protocol provided by Proteon, 
and given approval by the IRB/IEC and the appropriate regulatory authority(ies). Modifications 
to the protocol should not be made without the approval of Proteon. Changes to the protocol will 
require written IRB/IEC approval prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to patients. The IRB/IEC may provide, if applicable 
regulatory authority(ies) permit, expedited review and approval for minor change(s) in ongoing 
studies that have the approval of the IRB/IEC. Proteon will submit all protocol modifications to 
the regulatory authority(ies) in accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact Proteon, if circumstances permit, to discuss the planned 
course of action. Any departures from the protocol must be fully documented in the patient’s 
medical records and CRF. 
 
STUDY MONITORING AND ON-SITE AUDITS 
Monitoring and auditing procedures developed by Proteon or its CRO designee will be followed, 
in order to comply with GCP guidelines. Routine monitoring visits will be made to assure 


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compliance with the study protocol, to review and compare the patient’s CRF or other data 
collection vehicle with source documents, to ensure adequate records of clinical supplies are 
maintained, and to assess the continued suitability of the investigational site. The Investigator 
agrees to allow the site monitors, and other authorized personnel or designees, access to the 
patient’s medical records, regulatory binder, study binder, CRFs, and source documents as 
needed to assure the conduct of the study is within compliance. 
Upon completion of the study the site monitor will make a final assessment of the conduct of the 
study and inventory all clinical supplies to be returned to Proteon or designee. Unused or used 
vials of study drug will be stored until the study monitor is able to perform a physical inventory 
and reconciliation with the drug accountability records. At the completion of this study, all 
unused or used vials must be returned to Proteon, or designee, or if authorized, disposed of at the 
study site and documented. 
Regulatory authorities, the IRB or IEC and/or Proteon’s quality assurance group, its CRO 
designee, or business partners may request access to all source documents, CRFs, and other 
study documentation for on-site audit or inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities. 
 
CASE REPORT FORM COMPLETION 
Electronic case report forms (eCRFs) will be utilized for this study. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported 
in the patient’s eCRF. Source documentation supporting the CRF data should indicate the 
patient’s participation in the study and should document the dates and details of study 
procedures, AEs, and patient status. No data should be directly recorded into the eCRF without 
supporting source documentation. 
The Investigator, or designated representative as noted in the site delegation log, should 
complete the eCRF as soon as possible after information is collected, preferably on the same day 
that a study patient is seen for an examination, treatment, or any other study procedure. Any 
outstanding entries must be completed immediately after the final examination. An explanation 
should be given for all missing data. 
 
DATA QUALITY ASSURANCE 
This clinical study will be monitored according to current Proteon or designated CRO Standard 
Operating Procedures (SOPs), GCP/ICH Guidelines, and all applicable regulatory requirements. 
Steps to be taken to assure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures and the administration of 
informed consent with the Investigator and associated site personnel prior to study start, periodic 
monitoring visits by Proteon personnel or its designated CRO representatives, and clinical site 
audits. During the study, the Investigator shall permit Proteon or its representatives to verify the 


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progress of the study on site as frequently as necessary. Qualified personnel will review CRF 
data or other appropriate data collection vehicles for accuracy and completeness remotely 
utilizing the electronic data capture (EDC) system and against source documents during on-site 
monitoring visits. Data discrepancies will be resolved with the Investigator or designees, as 
appropriate. The Investigator shall make the CRF, other data collection vehicles and source 
documents available, provide missing or corrected data, and sign the data collection tools. Data 
management and other qualified personnel will review CRF data for completeness, logical 
consistency, and safety; automated validation programs are used to help identify missing data, 
protocol violations, out-of-range data, and other data inconsistencies. Personal information will 
be treated as strictly confidential and will not be publicly available. The CRF must be amended 
after inconsistencies have been resolved. 
An independent Quality Assurance (QA) department, Proteon business partner designees, and/or 
regulatory authorities may review this study. This implies that auditors/inspectors will have the 
right to inspect the investigational site(s) at any time during and/or after completion of the study 
and will have access to source documents, including the patient's medical file(s). By participating 
in this study, Investigators agree to this requirement. Measures will be undertaken to protect 
patient data handed over by the Investigator to Proteon and to inspectors against disclosure to 
unauthorized third parties and patient confidentiality will be maintained at all times. 
 
STUDY COMPLETION OR PREMATURE CLOSURE 
The Investigator will complete the study and submit the final eCRFs in satisfactory compliance 
with the protocol within approximately 2 weeks of study completion. 
Proteon reserves the right to close the investigational site or terminate the study at any time. 
Reasons for the closure of an investigational site or termination of a study by Proteon may 
include: 
1. 
Determination of unexpected, significant, or unacceptable risk to patients. 
2. 
Failure to enter patients at an acceptable rate. 
3. 
Insufficient adherence to protocol requirements. 
4. 
Insufficiently complete and/or evaluable data. 
5. 
Plans to modify, suspend, or discontinue the development of the study drug. 
Should the study be closed prematurely, all study materials must be returned to Proteon. 
 RECORD RETENTION 
A record of the eCRFs and all source documents (e.g., ICFs, laboratory reports, progress notes, 
medical history, physical and diagnostic findings, diagnoses and dates of therapy prior to and 
during this study, drug dispensing/disposition records) that support the data collected for each 


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Clinical Protocol PRT-201-320 
 
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patient must be retained in the files of the responsible Investigator for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational drug. These documents 
should be retained for a longer period, however, if required by applicable regulatory 
requirements. The Investigator should take measures to prevent accidental or premature 
destruction of these records. Under no circumstances shall the Investigator re-locate or dispose of 
any study documents before having obtained Proteon written approval. If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility. Proteon must be notified in writing if a custodial 
change occurs. If it becomes necessary for Proteon or a regulatory authority to review any 
documentation relating to this study, the Investigator must permit, with the approval of the 
patient, access to such records. Any difficulty in storing original records must be discussed with 
the study monitor prior to the initiation of the study. 
11. USE OF INFORMATION AND PUBLICATION 
All information regarding vonapanitase supplied by Proteon to the Investigator or generated by 
the Investigator in accordance with the conduct of the study is privileged and confidential 
information of Proteon. The Investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without written consent from Proteon. It is understood that 
there is an obligation to provide Proteon with complete data obtained during the study. The 
information obtained from the clinical study will be used by Proteon in connection with the 
development of vonapanitase and may be disclosed by Proteon to regulatory authority(ies), other 
Investigators, corporate partners, or consultants as required. 
The Investigator’s right and obligations with respect to publishing or otherwise presenting 
information regarding the study are detailed in the Publication provisions of the Clinical Study 
Agreement among the Investigator, the clinical site, and Proteon. The Investigator shall comply 
with such provisions. 
 
 


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12. REFERENCES 
1. 
Allon M, Robbin ML. Increasing arteriovenous fistulas in hemodialysis patients: problems 
and solutions. Kidney Int 2002;62:1109–1124. 
2. 
NKF-KDOQI. Clinical practice guidelines for vascular access. Am J Kidney Dis 
2006a;48(suppl 1). 
3. 
Pisoni RL, Young EW, Dykstra DM, et al. Vascular access use in Europe and the United 
States: Results from the DOPPS. Kidney Int. 2002;61:305-316. 
4. 
Jackson RS, Sidawy AN, Amdur RL, et al. Angiotensin receptor blockers and antiplatelet 
agents are associated with improved primary patency after arteriovenous hemodialysis 
access placement. J Vasc Surg 2011;54:1706-12. 
5. 
Ruddy JM, Brothers TE, Robison JG, Elliott BM. Increasing the proportion of autologous 
arteriovenous fistulas does not diminish fistula patency. Vasc Endovascular Surg 
2011;45:51-4. 
6. 
Schinstock CA, Albright RC, Williams AW, et al. Outcomes of arteriovenous fistula 
creation after the Fistula First Initiative. Clinical J Am Soc Nephrol 2011;6:1996-2002. 
7. 
Roy-Chaudhury P, Sukhatme VP, Cheung AK. Hemodialysis vascular access dysfunction: 
a cellular and molecular viewpoint. J Am Soc Nephrol 2006;17:1112–1127. 
8. 
Beathard GA. Management of complications of endovascular dialysis access procedures. 
Semin Dial 2003;16:309-313. 
9. 
Lee T, Mokrzycki M, Moist L, et al. Standardized definitions for hemodialysis vascular 
access. Semin Dial 2011;24:1-10. 
10. Asif A, Roy-Chaudhury P, Beathard GA. Early arteriovenous fistula failure: a logical 
proposal for when and how to intervene. Clin J Am Soc Nephrol 2006;1:332–339. 
11. De Rango P, Parente B, Cieri E, et al. Percutaneous approach in the maintenance and 
salvage of dysfunctional autologous vascular access for dialysis. J Vasc Access 
2012;13:381-7. 
12. Heye S, Maleux G, Vaninbroukx J, et al. Factors influencing technical success and 
outcome of percutaneous balloon angioplasty in de novo native hemodialysis arteriovenous 
fistulas. Eur J Radiol 2012;81:2298-303. 
13. Hye RJ, Peden EK, O’Connor TP, et al. Human type I pancreatic elastase treatment of 
arteriovenous fistulae in patients with chronic kidney disease. J Vasc Surg 2014; 60:454-
461. 
14. Dember LM, Beck GJ, Allon M, et al. Effect of clopidogrel on early failure of 
arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA 
2008;299:2164-2171 


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15. Peden EK, O’Connor TP, Browne BJ, et al. Arteriovenous fistula patency in the 3 years 
following vonapanitase and placebo treatment. J Vasc Surg 2016 
http://dx.doi.org/10.1016/j.jvs.2016.08.101 
16. Lin RS, León LF.  Estimation of treatment effects in weighted log-rank tests. 
Contemporary Clinical Trials Communications.  2017; 8: 147-155. 
 
 
 
 
 


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Appendix A: Schedule of Assessments 
Visit 
Screen 
Surgery 
Follow-up 
Week 2 
Week 4 
Month 3 
Month 6 
Month 9 
Month 12 
Visit Day1 
Day -28 
Day 1 
Day 14 
Day 28 
Day 90 
Day 180 
Day 270 
Day 360 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Informed Consent 
X 
 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
X 
 
 
 
 
 
 
Medical/Disease 
History 
X 
X 
 
 
 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
 
 
 
 
Physical Examination 
X 
 
 
X 
 
 
 
 
Clinical Laboratory 
Evaluations2 
X 
 
X 
 
 
 
 
 
Anti-vonapanitase 
Antibody Sample2 
X 
 
X 
X 
 
X3 
 
X3 
Administer Study Drug 
 
X 
 
 
 
 
 
 
Collection of 
Intraoperative Events 
 
X 
 
 
 
 
 
 
AVF and Upper 
Extremity Examination4 
 
X 
X 
X 
X 
X 
X 
X 
Ultrasound 
 
 
 
X 
X 
 
 
 
Adverse Events 
Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
1 Visit Day 14 is ± 3 days. Visit Day 28 is ± 3 days. Visit Days 90, 180, 270, and 360 are ± 14 days. 
2 Blood samples will be drawn and processed locally and sent to a central laboratory for testing. 
3 Patients who test positive for anti-vonapanitase antibodies at Week 4, or at Week 2 without a Week 4 test result will be asked to provide an 
additional blood sample for testing at Month 6. If the patient continues to test positive at Month 6, or was positive at Week 4 without a 
Month 6 test result, s/he will be asked to provide an additional blood sample at Month 12. 
4 Data regarding procedures performed on the study fistula (e.g., angioplasty, thrombectomy) will be collected. 
 


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Appendix B: Laboratory Evaluations 
Blood Chemistry 
Hematology 
Endocrinology 
Blood Sample 
Albumin 
Alkaline phosphatase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Bilirubin 
Blood glucose 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Cholesterol 
Triglycerides 
Chloride 
Creatinine 
Creatinine kinase 
Gamma-glutamyl 
transferase 
Lipase 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium  
Total serum protein 
Uric acid 
Complete blood count 
Hemoglobin 
Hematocrit 
White blood cell 
automated differential 
Platelet count 
Serum beta-human 
chorionic gonadotropin  
(at screening visit only 
in women of 
childbearing potential) 
For anti-vonapanitase 
antibody testing 
 
 
 
 
Coagulation Tests (at 
Screening Visit only) 
 
 
 
Prothrombin time/ 
Activated partial 
thromboplastin time 
International normalized 
ratio