Conditions: AV Fistula
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
The Objectives of this study are:

1. To determine if vorapaxar safely improves arteriovenous (AV) fistula functional maturation when administered during the maturation process compared with placebo.
2. To determine if vorapaxar safely improves AV fistula patency, allowing for secondary procedures to aid in fistula maturation compared with placebo.
3. To determine if vorapaxar safely facilitates successful cannulation of AV fistulas for hemodialysis compared with placebo.

This is a randomized placebo-controlled double-blind pilot trial. Study procedures will be conducted at Stanford University Medical Center, and standard-of-care (SOC) procedures will be conducted at Stanford and it's affiliated hospitals (Veteran's Affairs Palo Alto Health Care System and the Stanford Vascular Surgery Clinic at Valley Medical Center). The investigators expect to enroll 128 patients. Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula creation. Patients will be stratified based on fistula location (lower arm versus upper arm).

Detailed description:
Objectives:

1. To determine if vorapaxar safely improves arteriovenous (AV) fistula functional maturation when administered during the maturation process compared with placebo.
2. To determine if vorapaxar safely improves AV fistula patency, allowing for secondary procedures to aid in fistula maturation compared with placebo.
3. To determine if vorapaxar safely facilitates successful cannulation of AV fistulas for hemodialysis compared with placebo.

This is a randomized placebo-controlled double-blind pilot trial. Study procedures will be conducted at Stanford University Medical Center, and standard-of-care (SOC) procedures will be conducted at Stanford and it's affiliated hospitals (Veteran's Affairs Palo Alto Health Care System and the Stanford Vascular Surgery Clinic at Valley Medical Center). The investigators expect to enroll 128 patients. Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula creation. Patients will be stratified based on fistula location (lower arm versus upper arm).

Participation in this study will not affect standard care of patients with AV fistulae receiving hemodialysis. The only additional treatment is administration of the study drug or placebo and additional monitoring, including one additional ultrasound, for 6 months.

Arms:
arm 1: This arm will receive the study drug: Vorapaxar sulfate.

The investigators expect to enroll 128 patients. Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula creation. Patients will be stratified based on fistula location (lower arm versus upper arm). arm 2: This arm will receive the matching placebo.

The investigators expect to enroll 128 patients. Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula creation. Patients will be stratified based on fistula location (lower arm versus upper arm).

Interventions: intervention 1: Vorapaxar sulfate intervention 2: Placebo
Intervention descriptions: intervention 1: The study drug (12-week supply of study drug) will be dispensed to enrolled patients on the first day following surgery. intervention 2: The placebo will match the study drug, vorapaxar sulfate, in appearance. A 12-week supply will be dispensed to enrolled patients on the first day following surgery.

Protocol document:
Prot_001.pdf: 
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A Double-blind, Randomized, Placebo Controlled 
Pilot Trial to Evaluate the Safety and Efficacy of 
Vorapaxar in Maturation of Arteriovenous Fistulae for 
Hemodialysis Access 
 
NCT02475837 
May 3, 2018 
 
Kenneth Mahaffey, MD, Principal Investigator 
Stanford University 
Stanford, California 94305 
 


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 Merck Investigator Studies Program(MISP)Protocol
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
 
A double-blind, randomized, placebo controlled pilot trial to evaluate the safety and 
efficacy of vorapaxar in maturation of arteriovenous fistulae for hemodialysis access 
(VorapAccess) 
 
Request Date: 
 
September 19, 2014 (Revision May 3, 2018) 
 
Institution Name 
 
Stanford University School of Medicine 
 
Investigator 
Contact 
Information: 
 
 
Principal Investigator: 
 
Matthew W. Mell, MD, MS 
Associate Professor of Surgery 
Division of Vascular Surgery 
300 Pasteur Drive, 
 
Stanford, CA  94305-5642 
 
 
e-mail:  mwmell@stanford.edu 
 
Co-Investigators: 
 
Glenn Chertow, MD, MPH 
Norman S. Coplon/Satellite Healthcare Professor of Medicine 
Chief, Division of Nephrology 
 
 
 
 
 
Kenneth W. Mahaffey, MD 
Professor of Medicine / Vice Chair Clinical Research, Department of Medicine  
300 Pasteur Drive, 
 
Stanford, CA 94305-5110 
 
e-mail:  kenneth.mahaffey@stanford.edu 
 
Manisha Desai, PhD 
Associate Professor, Department of Medicine 
Director of the Quantitative Sciences 
 
 
 
 
 


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Section #2- Core Protocol 
 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
 
Objectives: 
 
1. To determine if vorapaxar safely improves arteriovenous (AV) fistula 
functional maturation when administered during the maturation process 
compared with placebo. 
2. To determine if vorapaxar safely improves AV fistula patency, allowing for 
secondary procedures to aid in fistula maturation compared with placebo. 
3. To determine if vorapaxar safely facilitates successful cannulation of AV 
fistulas for hemodialysis compared with placebo. 
4. To determine the safety profile of vorapaxar for patients requiring 
hemodialysis. 
 
Hypotheses: 
 
1.  Vorapaxar initiated two days following AV fistula creation will result in improved 
fistula functional maturation without increased risk of bleeding or other major adverse 
events. 
 
2.  Vorapaxar initiated  two days following AV fistula creation will result in improved 
fistula patency and will increase the utility of secondary procedures to aid in fistula 
maturation, without increased risk of bleeding or other major adverse events. 
 
3.  Vorapaxar initiated  two days following AV fistula creation will facilitate successful 
cannulation of AV fistulas for hemodialysis without increased risk of bleeding or other 
major adverse events. 
 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Background 
 
End-stage renal disease affects nearly 500,000 persons in the US and more than 2 
million persons worldwide.  In the US and most developed countries, hemodialysis is 
the predominant dialytic modality.  While effective at sustaining life for most patients, 
hemodialysis rarely restores health.  Roughly one in five patients on dialysis die each 
year; patients who survive experience poor functional status, impaired physical and 
cognitive function and severely impaired health-related quality of life.  Moreover, the 
cost of the ESRD program exceeds $40B in the US annually (1). 
 
Hemodialysis vascular access is often referred to as the ‘Achilles Heel” of dialysis 
care.  The Brescia-Cimino (radiocephalic end-to-side) fistula is considered to be the 
gold standard vascular access (2); upper arm arteriovenous fistulae are often 
created instead.  Polytetrafluoroethylene (PTFE) grafts are next best, but are 
frequently complicated by graft “thrombosis,” commonly caused not by hematologic 
abnormalities, but rather by intimal hyperplasia at the venous anastomosis.  
Unfortunately, the majority of patients have insufficient time to undergo pre-emptive 
creation of an arteriovenous fistula or graft, and most patients start hemodialysis with 
either a temporary or “semi-permanent” tunneled catheter, often placed in one of the 
internal jugular veins. 
 
For patients who do undergo fistula creation, either in advance of (optimally) or after 
starting hemodialysis, a sizeable fraction of arteriovenous fistulae never mature 
sufficiently to be usable for hemodialysis.  It is common for patients to undergo three 
or more attempts at fistula creation, extending the time during which they experience 
a heightened risk of infection and venous stenosis/thrombosis of the internal jugular 
veins or in some cases other complications including superior vena cava syndrome.  
Therapeutic agents that could facilitate maturation of arteriovenous fistulae could 


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vastly improve the health and well-being of patients on hemodialysis, and could well 
result in enhanced survival. 
 
Preliminary Data 
 
Numerous small studies have attempted to improve short- and longer-term function 
of arteriovenous fistulae and grafts with a variety of therapeutic agents, including 
warfarin, aspirin, fish oil, dipyridamole and several newer antiplatelet agents, 
including ticlopidine and more recently clopidogrel (3-7).  In order to address the 
pressing need for improved outcomes, the National Institutes of Health (NIH) 
National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) 
assembled the “Dialysis Access Consortium” more than 10 years ago – a consortium 
of highly qualified investigators whose aim was to design two major clinical trials to 
address failure of arteriovenous fistulae and grafts, respectively (8).  Dr. Chertow 
served on the Data Safety and Monitoring Board for both of the DAC trials. 
 
The DAC investigators conducted a randomized, placebo-controlled trial of 
clopidogrel in patients receiving arteriovenous fistulae (9) (another trial examining 
arteriovenous grafts will not be discussed here).  Interestingly, clopidogrel was 
shown to enhance short-term patency of arteriovenous fistulae, but failed to result in 
improved maturation, sufficient for the fistula to be consistently used for maintenance 
hemodialysis.  Roughly six of 10 patients assigned to the trial (all at outstanding 
clinical centers) failed to have a usable fistula at 3-4 months, highlighting the need 
for more effective therapy.  Despite the DAC fistula study having been stopped 
prematurely for “efficacy” (on the primary outcome of early fistula patency), few 
patients receive clopidogrel for this purpose in clinical practice. 
 
Vorapaxar, Cardiovascular Disease and ESRD 
 
PAR-1 receptors are expressed by platelets, endothelial cells and atheromatous 
plaques suggesting important roles in tissue response to injury, inflammation and 
thrombosis (10).  Vorapaxar may have a role in preventing vascular access 
complications.   
 
Vorapaxar has been studied in two large cardiovascular outcome trials – TRA-2P 
and TRACER (11, 12).  In both trials, vorapaxar reduced the composite of CV death, 
MI and stroke with an excess in bleeding.  Patients with renal dysfunction were not 
excluded.  Vorapaxar has been approved by the FDA for secondary prevention in 
patients with stable cardiovascular disease.  Recent analyses from TRACER showed 
non-heterogeneity of treatment effects on safety and efficacy outcomes in patients 
with and without renal dysfunction (Mahaffey KW, ESC abstract presentation)  
Additionally, Kosoglou et al. showed in a relatively small study that the 
pharmacokinetics of vorapaxar were not altered by ESRD, suggesting that dosing 
could proceed without modification in this population (13). 
 
 
 
2.3 Study Design 
 
This is a randomized placebo-controlled double-blind pilot trial.  Study procedures 
will be conducted at Stanford University Medical Center, and Santa Clara Valley 
Medical Center (SCVMC). All standard-of-care (SOC) procedures will be conducted 
at the respective sites. However, the final 6-month study visit will be conducted at 
Stanford for all participants irrespective of whether they were enrolled at Stanford or  
SCVMC .We expect to enroll 50 patients.  Patients will be assigned to treatment 
groups with a 1:1 randomization in blocks of 4 at the conclusion of the AV fistula 
creation.  Patients will be stratified based on fistula location (lower arm versus upper 
arm).   
 
Inclusion Criteria 
 
1. Age >18 
2. Receiving or planning to receive maintenance hemodialysis 


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3. Ability to sign informed consent 
4. 3 mm venous diameter within recipient vein 
 
 
Exclusion Criteria 
 
1. History of stroke, transient ischemic attack or intracranial hemorrhage 
2. History of or high level of suspicion for, severe arterial insufficiency of the 
hand 
3. Indication or ongoing therapy with other antiplatelet agents, other than 
aspirin 81 mg daily 
4. Indication or ongoing therapy with anticoagulants, including warfarin, low 
molecular weight heparin, factor Xa inhibitors or direct thrombin and other 
inhibitors. 
 
 
2.4 Study Flowchart 
 
 
 
 
2.5 Study 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment and Screening:  Recruitment will be by invitation and referral from 
individuals’ treating physicians at Stanford and SCVMC .  Generally, initial screening 
will be performed at the time of consultation for dialysis access.  Patients who 
appear to meet the study criteria and express interest in participation will be referred 
to the study team to be contacted for full screening. 
 
Consent:  For eligible patients informed consent will be obtained prior to the day of 
surgery, generally by phone and mail or in person at the preoperative visit. 
 
Baseline demographics (preoperative visit, standard of care): 
The following data, which is collected as standard of care at the preoperative visit, 
will be utilized for baseline data with patient approval via the consent process: 
 
Age, sex, race, ethnicity, past medical history, medications, previous 
hemodialysis access surgery 
 
Baseline blood pressure in each arm and vascular exam 
 
Baseline vein measurements 
 
Operative details (standard of care): 
The following data, which is collected during the AV Fistula Creation Procedure as 
standard of care, will be utilized for operative data with patient approval via the 
consent process: 
 
Location of anastamosis (lower or upper arm) 
 
Vein used (cephalic or basilic) 
 
Type of fistula (radiocephalic, brachiocephalic, brachiobasilic, other) 
Screening 
AV Fistula Creation /Randomization 
6-week ± 2-weeks SOC Visit 
3-month ± 2-weeks Follow-up 
Phone Call 
4-month ± 2-weeks Follow-up 
Phone Call 
6-month ± 4-weeks Study 
Visit, Ultrasound & End of 
Study 


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2.5 Study 
Procedures 
 
 
Quality of artery (normal, moderate calcification, severe calcification) 
 
Palpable thrill through completion (yes or no) 
 
Audible bruit (yes or no) 
 
BARC Bleeding Classification 
 
GUSTO Bleeding Classification 
 
 
Randomization:  Randomization will be performed after successful creation of an 
arteriovenous fistula, on the day of surgery. 
 
 
Treatments to be compared:  Half of enrolled patients will receive the study drug 
(vorapaxar [Zontivity™] 2.5 mg daily) and half will receive a look-alike placebo. 
 
Study drug:  The study drug (12-week supply of study drug or placebo) will be 
dispensed to enrolled patients on the  day of surgery. Participants will be instructed 
to start taking their study medications on Day-two post-surgery. 
 
6-weeks Follow-up Clinic Visit + Ultrasound (standard of care) 
Patients will return approximately 6 weeks after randomization to the site of their AV 
fistula creation procedure for a standard-of-care visit where the following data will be 
collected and provided to the study team: 
 
Patency of fistula (yes/no) 
 
Fistula being used for dialysis at least 6 times in 3 weeks (yes/no) 
 
Diameter of fistula by ultrasound 
 
Velocities of fistula by ultrasound 
 
Adverse events 
 
Additional procedures performed to aid in fistula maturation (yes/no) 
o 
Type of procedure 
o 
Successful (yes/no) 
 
BARC and Gusto Bleeding Classification 
 
3-month Follow-up Phone Call (study visit): 
Approximately 3 months after randomization patients will have a study phone call 
with a member of the research team where the following data will be collected: 
 
Patency of fistula (yes/no) 
 
Fistula being used for dialysis at least 6 times in 3 weeks (yes/no) 
 
Adverse events 
 
Additional procedures performed to aid in fistula maturation (yes/no) 
o 
Type of procedure 
o 
Successful (yes/no) 
 
BARC and Gusto Bleeding Classification 
 
4-month Follow-up Phone Call (study visit): 
Approximately 4 months after randomization patients will have a study phone call 
with a member of the research team where the following data will be collected: 
 
Patency of fistula (yes/no) 
 
Fistula being used for dialysis at least 6 times in 3 weeks (yes/no) 
 
Adverse events 
 
Additional procedures performed to aid in fistula maturation (yes/no) 
o 
Type of procedure 
o 
Successful (yes/no) 
 
BARC and Gusto Bleeding Classification 
 
6-month Follow-up Clinic Visit + Ultrasound + End of Study (study visit): 
Patients will have a final study visit at approximately 6 months, at Stanford University 
Medical Center Vascular Clinic where the following data will be collected: 
 
Patency of fistula  (yes/no) 
 
Fistula being used for dialysis at least 6 times in 3 weeks (yes/no) 


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 
Diameter of fistula by ultrasound 
 
Velocities of fistula by ultrasound 
 
Adverse events 
 
Additional procedures performed to aid in fistula maturation (yes/no) 
o 
Type of procedure 
o 
Successful (yes/no) 
 
BARC and Gusto Bleeding Classification 
 
 
 
 
 
Participation in this study will not affect standard care of patients with AV fistulae 
receiving hemodialysis. The only additional treatment is administration of the study 
drug or placebo and additional monitoring, including one additional ultrasound, for 6 
months. 
 
Adverse events reporting process:  The PI will review aggregated AEs each 
month, and AEs will be reported to the sponsor and the IRB per research guidelines. 
Participation for the individual will terminate if they have a serious adverse reaction 
that prevents future participation. In the event of adverse effects, their primary 
physician will be notified 
 
 
2.6 Study Duration 
 
We estimate 24 months will be required to recruit patients with an additional six 
months to complete follow-up of the last enrolled subject for a total of 30 months for 
recruitment and final assessments.  
 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
 
 
Data management and statistical coordination of the study will be performed by 
members of the Quantitative Sciences Unit (QSU) in the Department of Medicine at 
Stanford University School of Medicine and in the Data Coordinating Center in the 
Department of Medicine.  The REDCap data managements system will be used to 
create the data platform for storage of the clinical information.   
 
Vascular Ultrasound studies will be performed at the site of surgery, either at  
Stanford University Hospital or  SCVMC .  Studies will be interpreted by the ordering 
vascular surgeon and reviewed by the Principal Investigator. 
 
Randomization codes will be generated in block size of 4 by a statistician in the 
QSU. 
 
Statistical analyses will be performed by MS level and PhD level statisticians in the 
QSU.  Randomized treatment allocation will only be unblinded when all follow-up is 
complete, data have been cleaned and the trial statistician, Co-Investigators and 
Principal Investigator are in agreement.   
Variables/Time Points of Interest 
 
Primary Efficacy Outcome 
Time to AV fistula functional maturation (defined as successful cannulation of the AV 
fistula for six hemodialysis sessions within three weeks). 
 
Secondary Efficacy Outcomes 
 
AV fistula use within 180 days of surgery. 
 
AV fistula patency at 150-180 days, with at least 50% increase in vein diameter by 
ultrasound compared with preoperative vein diameter measurement. 


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AV fistula functional or anatomic maturation at 180 days as determined by the PI 
 
Safety Outcomes 
 
Bleeding events (GUSTO and BARC Criteria) 
 
BARC Bleeding Classification: 
 
Type 0: No bleeding 
 
 
Type 1: Bleeding that is not actionable and does not cause the patient to 
seek unscheduled performance of studies, hospitalization, or treatment by a 
healthcare professional; may include episodes leading to self-discontinuation 
of medical therapy by the patient without consulting a healthcare 
professional 
 
Type 2: Any overt, actionable sign of hemorrhage (e.g., more bleeding than 
would be expected for a clinical circumstance, including bleeding found by 
imaging alone) that does not fit the criteria for type 3, 4, or 5 but does 
meet at least one of the following criteria: (1) requiring nonsurgical, medical 
intervention by a healthcare professional, (2) leading to hospitalization or 
increased level of care, or (3) prompting evaluation 
 
Type 3 
Type 3a 
Overt bleeding plus hemoglobin drop of 3 to 5 g/dL* (provided 
hemoglobin drop is related to bleed) 
Any transfusion with overt bleeding 
 
Type 3b 
Overt bleeding plus hemoglobin drop >5 g/dL* (provided hemoglobin 
drop is related to bleed) 
Cardiac tamponade 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
Bleeding requiring intravenous vasoactive agents 
 
Type 3c 
Intracranial hemorrhage (does not include micro-bleeds or hemorrhagic 
transformation, does include intraspinal) 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
Intraocular bleed compromising vision 
 
 
GUSTO Bleeding Classification 
 
Severe: Bleeding* that was fatal, intracranial, or that caused hemodynamic 
compromise requiring intervention (e.g., systolic blood pressure <90 mm Hg that 
required blood or fluid replacement, or vasopressor/inotropic support,** or surgical 
intervention). 
 
Moderate: Bleeding* requiring transfusion of whole blood or packed red blood cells 
without hemodynamic compromise (as defined above). 
 
Mild: Bleeding*:  Bleeding without blood transfusion or hemodynamic compromise. 
 
*In all cases, bleeding must be clinically overt. 


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**Need for vasopressor/inotropic support for hemodynamic compromise, even if 
blood pressure 
 
 
Statistical Methods: 
 
Descriptive statistics such as means, medians, standard deviations and interquartile 
ranges will be presented for continuous measurements, and frequency statistics will 
be presented for categorical characteristics.  Graphical tools such as histograms and 
boxplots will be used to assess distributional aspects of continuous variables.   
 
 
Cumulative incidence plots will be derived to depict time to fistula use, stratified by 
treatment arm and fistula location.   
 
The primary outcome is time to AV fistula maturation, defined as successful 
cannulation of the AV fistula for six hemodialysis sessions within three weeks.   
 
Subjects who are lost to follow up or who die prior to maturation will be censored at 
the time of death or last recorded activity. 
 
Our primary analysis will be based on the intention-to-treat principle.  To that end, 
patients will be analyzed according to their randomized treatment assignment, and 
all patients randomized to treatment assignment will be included in the analysis even 
if they are lost to follow up or die before the end of their observation period.  We will 
use a log-rank test stratified by location of fistula to assess whether time to 
maturation of AV fistula differs between treatment arms (vorapaxar versus placebo).  
The test will be two-sided and conducted at the 0.05 level of significance. 
 
A Cox proportional hazards regression model of treatment arm and other covariates 
of interest will be employed secondarily to estimate an adjusted treatment effect.  
 
Other secondary analyses involve the use of logistic regression techniques to 
evaluate the effect of treatment on secondary endpoints – use of AV fistula within 
180 days and AV fistula patency within 150-180 days. 
 
Power/Sample Size: 
We have sufficient power to address our primary aim.  Based upon a sample size of 
n=25 patients per group for this pilot study, we have approximately 70% power to 
detect a hazard ratio of 2.05 between treatment arms, assuming that only 50% of 
subjects will experience maturation by six months post randomization in the placebo 
group.  If only 40% of subjects experience maturation by six months post 
randomization we have over 70% power to detect a hazard ratio of 2.15.  
 
 
2.8 Specific Drug 
Supply 
Requirements  
 
Merck will provide the study drug and matching placebo in study kits.  At conclusion 
of the study or upon drug expiration, the Merck GRS will be responsible for issuing a 
Drug Disposition Letter to the investigator for US based studies.  The study 
investigators will be responsible for the destruction of the supplies at the study center 
pursuant to the ICH/GCP Guidelines, local regulations and the investigator’s 
institutional policies.  The study investigators will responsible for keeping accurate 
records of the clinical supplies, the amount dispensed to and returned by the 
patients, and the disposition at the end of the study. 
 


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2.9 Adverse 
Experience 
Reporting 
 
A Data Safety Monitoring Board (DSMB) comprised of one vascular surgeon, one 
physician with expertise about vorapaxar and one experienced in clinical trials will 
review unblinded data after 10 patients have completed follow-up 6-month 
ultrasound and after 30 patients have completed follow-up 6-month ultrasound 
evaluation. 
 
Model study agreement will be used for reporting of adverse events.  
 
 
2.10 Itemized Study 
Budget  
 
See attached. 
 
 
2.11 References 
 
1.  United States Renal Data System 2013 Annual Report, Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National 
Institute of Diabetes and Digestive and Kidney Diseases. 
2.  Brescia MJ, Cimino JE, Appel K, Hurwich BJ.  Chronic hemodialysis using 
venipuncture and a surgically created arteriovenous fistula.  N Engl J Med 1966; 
275:1089. 
3.  Andrassy K, Malluche H, Bornefeld H,  et al.  Prevention of clotting of AV cimino 
fistulae with acetylsalicyl acid: results of a prospective double blind study.  Klin 
Wochenschr 1974;52:348. 
4.  Crowther MS, Clase CM, Margetts PJ.  Low-intensity warfarin is ineffective for the 
prevention of PTFE graft failure in patients on hemodialysis: a randomized controlled 
trial.  J Am Soc Nephrol 2002; 2002; 13:2331. 
5.  Fiskerstrand CE, Thompson IW, Burnet ME, Williams P, Anderton JL. Double-
blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for 
hemodialysis.  Artif Organs. 1985; 9:61. 
6.  Osborn G, Escofet X, DaSilva A.  Medical adjuvant treatment to increase patency 
of arteriovenous fistulae and grafts.  Cochrane Database Syst Rev 2008; 
4:CD002786. 
7.  Kaufman JS. Antithrombotic agents and the prevention of access 
thrombosis.  Semin Dial. 2000; 13:40. 
8.  Dember LM, Kaufman JS, Beck GJ, et al.  Design of the Dialysis Access 
Consortium (DAC) clopidogrel prevention of early AV fistula thrombosis trial.  Clin 
Trials. 2005; 2:413. 
9.  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. 
10.  Hirano K. The roles of proteinase-activated receptors in vascular physiology and 
pathophysiology. Arterioscler Thromb Vasc Biol 2007; 27: 27. 
11.  Morrow DA, Braunwald E, Bonaca MP et al.  Vorapaxar in the secondary 
prevention of atherothrombotic events.  N Engl J Med 2012;366:1404. 
12.  Tricoci P, Huang Z, Held C, et al.  Thrombin-receptor antagonist vorapaxar in 
acute coronary syndromes.  N Engl J Med 2012; 366:20. 
13.  Kosoglou T, Kraft WK, Kumar B, et al.  Pharmacokinetics and 
pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-
stage renal disease.  Eur J Clin Pharmacol 2012; 68:1049. 
 
2.12 Publication 
Plan 
 
We will publish at least one manuscript describing clinical trial design and results.  
Our projected target date for publication is six months after closing the trial.  We plan 
to submit the study to the Journal of Vascular Surgery or Clinical Journal of the 
American Society of Nephrology.  We anticipate two abstracts:  one each for annual 
meetings of the Society of Vascular Surgery and American Society of Nephrology  
 
 
See attached. 


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2.13 Curriculum 
Vitae 
 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly or through the Global 
Research Specialist at  www.merckiisp.com   
 
Non U.S. protocols should be submitted to the MSD office by the investigators. 

SAP_000.pdf: 
A Double-blind, Randomized, Placebo Controlled 
Pilot Trial to Evaluate the Safety and Efficacy of 
Vorapaxar in Maturation of Arteriovenous Fistulae 
for Hemodialysis Access 
 
Statistical Analysis Plan 
NCT02475837 
June 11, 2018 
 
Ken Mahaffey, MD, Principal Investigator 
Stanford University 
Stanford, California 94305 
 


June 11, 2018.  Version 3.0 
 
2 
Statistical Analysis Plan 
 
A double-blind, randomized, placebo controlled pilot trial to evaluate the safety and 
efficacy of vorapaxar in maturation of arteriovenous fistulae for hemodialysis access 
(VorapAccess) 
 
Principal Investigator: 
Matthew W. Mell, MD, MS 
Associate Professor of Surgery 
Division of Vascular Surgery 
e-mail:  mwmell@stanford.edu 
 
Co-Investigators: 
Glenn Chertow, MD, MPH 
Norman S. Coplon/Satellite Healthcare Professor of Medicine 
Chief, Division of Nephrology 
e-mail:  
 
 
Kenneth W. Mahaffey, MD 
Professor of Medicine / Vice Chair Clinical Research, Department of Medicine  
e-mail:  kenneth.mahaffey@stanford.edu 
 
Manisha Desai, PhD 
Associate Professor, Department of Medicine 
Director of the Quantitative Sciences Unit 
e-mail:  
 
 
Senior Biostatistician:   
 
Quantitative Sciences Unit 
e-mail: 
 
 
Biostatistician: 
 
Quantitative Sciences Unit 
e-mail:  
 
 
 


June 11, 2018.  Version 3.0 
 
3 
Table of Contents 
 
 
AMENDMENT HISTORY ..................................................................................................................................... 4 
1. Introduction ....................................................................................................................................................... 5 
1.1. Background ................................................................................................................................................ 5 
1.2. Objectives .................................................................................................................................................... 5 
1.3. Hypotheses ................................................................................................................................................. 6 
2. Study Design ....................................................................................................................................................... 6 
2.1. Study Design .............................................................................................................................................. 6 
2.2. Study Participants .................................................................................................................................... 6 
2.3. Study Endpoints ....................................................................................................................................... 7 
3. Statistical Analysis ........................................................................................................................................... 9 
3.1. Data monitoring and quality ................................................................................................................ 9 
3.2. Handling of Missing Data ...................................................................................................................... 9 
3.3. Descriptive Statistics .............................................................................................................................. 9 
4. Statistical conventions ................................................................................................................................ 10 
5. Adverse events data and reporting process ....................................................................................... 11 
References ............................................................................................................................................................ 11 
Appendix 1: Tables and figures .................................................................................................................... 12 
 
 
 


June 11, 2018.  Version 3.0 
 
4 
 
AMENDMENT HISTORY 
November 3, 2016:  Final version of SAP.  Version 1.0 
May 16, 2018:          Vorapaccess SAP revised. Version 2.0 
Added a new secondary outcome 
Added a sentence on the deviation from the planned analysis due to low 
enrollment and early stopping of trial. 
June 11, 2018:          Updated the definition of the secondary outcome “‘AV fistula functional or  
anatomic maturation at 180 days as determined by the PI” 
 
 


June 11, 2018.  Version 3.0 
 
5 
1. Introduction 
 
1.1. Background 
End-stage renal disease affects nearly 500,000 persons in the US and more than 2 million 
persons worldwide.  In the US and most developed countries, hemodialysis is the 
predominant dialytic modality.  While effective at sustaining life for most patients, 
hemodialysis rarely restores health.  Roughly one in five patients on dialysis die each year; 
patients who survive experience poor functional status, impaired physical and cognitive 
function and severely impaired health-related quality of life.  Moreover, the cost of the 
ESRD program exceeds $40B in the US annually (1). 
 
Hemodialysis vascular access is often referred to as the ”Achilles Heel” of dialysis care.  The 
Brescia-Cimino (radiocephalic end-to-side) fistula is considered to be the gold standard 
vascular access (2); upper arm arteriovenous fistulae are often created instead.  
Polytetrafluoroethylene (PTFE) grafts are next best, but are frequently complicated by 
graft “thrombosis,” commonly caused not by hematologic abnormalities, but rather by 
intimal hyperplasia at the venous anastomosis.  Unfortunately, the majority of patients 
have insufficient time to undergo pre-emptive creation of an arteriovenous fistula or graft, 
and most patients start hemodialysis with either a temporary or “semi-permanent” 
tunneled catheter, often placed in one of the internal jugular veins. 
 
For patients who do undergo fistula creation, either in advance of (optimally) or after 
starting hemodialysis, a sizeable fraction of arteriovenous fistulae never matures 
sufficiently to be usable for hemodialysis.  It is common for patients to undergo three or 
more attempts at fistula creation, extending the time during which they experience a 
heightened risk of infection and venous stenosis/thrombosis of the internal jugular veins 
or in some cases other complications including superior vena cava syndrome.  Therapeutic 
agents that could facilitate maturation of arteriovenous fistulae could vastly improve the 
health and well-being of patients on hemodialysis, and could well result in enhanced 
survival. 
 
1.2. Objectives 
1. To determine if vorapaxar safely improves arteriovenous (AV) fistula functional 
maturation when administered during the maturation process compared with 
placebo. 
2. To determine if vorapaxar safely improves AV fistula patency, allowing for 
secondary procedures to aid in fistula maturation compared with placebo. 
3. To determine if vorapaxar safely facilitates successful cannulation of AV fistulas for 
hemodialysis compared with placebo. 
4. To determine the safety profile of vorapaxar for patients requiring hemodialysis. 


June 11, 2018.  Version 3.0 
 
6 
 
1.3. Hypotheses 
1.  Vorapaxar initiated two days following AV fistula creation will result in improved 
fistula functional maturation without increased risk of bleeding or other major 
adverse events. 
 
2.  Vorapaxar initiated two days following AV fistula creation will result in improved 
fistula patency and will increase the utility of secondary procedures to aid in fistula 
maturation, without increased risk of bleeding or other major adverse events. 
 
3.  Vorapaxar initiated two days following AV fistula creation will facilitate successful 
cannulation of AV fistulas for hemodialysis without increased risk of bleeding or 
other major adverse events. 
 
2. Study Design 
 
2.1. Study Design  
This is a randomized placebo-controlled double-blind pilot trial.  Half of enrolled patients 
will receive the study drug (vorapaxar [Zontivity™] 2.5 mg daily) and half will receive a 
look-alike placebo. 
 
Patients will be assigned to treatment groups with a 1:1 randomization in blocks of 4 at the 
conclusion of the AV fistula creation.  Patients will be stratified based on fistula location 
(lower arm versus upper arm). Randomization will be performed after successful creation 
of an arteriovenous fistula, on the day of surgery. We expect to randomize 50 patients.  
 
The study drug (12-week supply of study drug or placebo) will be dispensed to enrolled 
patients on the day of surgery. Participants will be instructed to start taking their study 
medications on Day-two post-surgery. 
 
2.2. Study Participants 
Patients meeting inclusion and exclusion criteria at Stanford University Medical Center or 
Santa Clara Valley Medical Center (SCVMC) will be eligible to participate in the study. Study 
procedures will be conducted at Stanford University Medical Center and SCVMC. All 
standard-of-care (SOC) procedures will be conducted at the respective sites. However, the 
final 6-month study visit will be conducted at Stanford for all participants irrespective of 
whether they were enrolled at Stanford or SCVMC. 
 
Inclusion Criteria 
1. Age >=18 years 
2. Receiving or planning to receive maintenance hemodialysis 
3.   Candidate for arteriovenous fistula 
4. Ability to sign informed consent 


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7 
5. At least 3 mm venous diameter within recipient vein 
 
Exclusion Criteria 
1. History of stroke, transient ischemic attack or intracranial hemorrhage 
2. History of or high level of suspicion for severe arterial insufficiency of the hand 
3. Indication or ongoing therapy with other antiplatelet agents, other than aspirin 81 
mg daily 
4. Indication or ongoing therapy with anticoagulants, including warfarin, low 
molecular weight heparin, factor Xa inhibitors or direct thrombin and other 
inhibitors 
5.   Indication or ongoing therapy with strong inhibitors or strong inducers of CYP3A 
 
Study participants will be followed up at approximately 6 weeks, 3 months, 4 months and 6 
months after randomization. At each of these visits, data will be collected on the following 
measures: 
 Patency of fistula (yes/no) 
 Fistula being used for dialysis at least 6 times in 3 weeks (yes/no) 
 Adverse events 
 Additional procedures performed to aid in fistula maturation (yes/no) 
o Type of procedure 
o Successful (yes/no) 
 BARC and GUSTO Bleeding Classification 
 
In addition, at the 6 week and 6 month follow up visits, data will be collected on: 
 Diameter of fistula by ultrasound 
 Velocity of fistula by ultrasound 
 
 
2.3. Study Endpoints 
The primary efficacy outcome is time to AV fistula functional maturation (defined as 
successful cannulation of the AV fistula for six hemodialysis sessions within three weeks). 
 
The secondary efficacy outcomes are: 
 AV fistula use within 180 days of surgery 
 AV fistula patency at 150-180 days, with at least 50% increase in vein diameter by 
ultrasound compared with preoperative vein diameter measurement 
 Update: New secondary outcome added: AV fistula functional or anatomic 
maturation at 180 days as determined by the PI 
 
The safety outcomes are bleeding events as determined by BARC and GUSTO criteria.   
BARC Bleeding Classification 
 Type 0: No bleeding 
 


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8 
 Type 1: Bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a healthcare 
professional; may include episodes leading to self-discontinuation of medical 
therapy by the patient without consulting a healthcare professional 
 
 Type 2: Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare 
professional, (2) leading to hospitalization or increased level of care, or (3) 
prompting evaluation 
 
 Type 3 
o Type 3a: Overt bleeding plus hemoglobin drop of 3 to 5 g/dL* (provided 
hemoglobin drop is related to bleed) Any transfusion with overt bleeding 
 
o Type 3b: Overt bleeding plus hemoglobin drop >5 g/dL* (provided hemoglobin 
drop is related to bleed); Cardiac tamponade; Bleeding requiring surgical 
intervention for control (excluding dental/nasal/skin/hemorrhoid); Bleeding 
requiring intravenous vasoactive agents 
 
o Type 3c: Intracranial hemorrhage (does not include micro-bleeds or 
hemorrhagic transformation, does include intraspinal); Subcategories confirmed 
by autopsy or imaging or lumbar puncture; Intraocular bleed compromising 
vision 
 
 Type 4  CABG bleeding 
 Type 5: Fatal bleeding 
 
 
GUSTO Bleeding Classification 
 Severe: Bleeding* that was fatal, intracranial, or that caused hemodynamic 
compromise requiring intervention (e.g., systolic blood pressure <90 mm Hg that 
required blood or fluid replacement, or vasopressor/inotropic support,** or surgical 
intervention). 
 
 Moderate: Bleeding* requiring transfusion of whole blood or packed red blood cells 
without hemodynamic compromise (as defined above). 
 
 Mild: Bleeding*:  Bleeding without blood transfusion or hemodynamic compromise. 
 
*In all cases, bleeding must be clinically overt. 
**Need for vasopressor/inotropic support for hemodynamic compromise, even if blood 
pressure 
 


June 11, 2018.  Version 3.0 
 
9 
3. Statistical Analysis 
 
3.1. Data monitoring and quality 
We will perform periodic data quality checks for missing data using reports generated in 
REDCap where data are being collected.  After 4 patients have completed follow-up we will 
review the data for completeness and value checks. Thereafter, we will conduct two 
additional data quality checks: after an additional 10 and 30 patients have completed 
follow-up. 
Ongoing data monitoring will be conducted by the monitoring coordinator at SCCR to 
ensure compliance.  
 
3.2. Handling of Missing Data 
We anticipate minimal missing data in this study.  We expect that a small proportion of 
subjects randomized for the study (1-2 subjects) will not complete all visits.  We will fully 
describe missing data for each variable and any pertinent patterns of missingness (e.g. how 
missingness is related to specific baseline measurements or time, if at all).  The statistical 
methods we will use are particularly flexible for missing data and allow for systematic 
missingness that is related to observed features. 
 
3.3. Descriptive Statistics 
We will provide descriptive statistics such as means, medians, standard deviations and 
interquartile ranges for continuous measurements, and frequency statistics for categorical 
characteristics.  We will use graphical tools such as histograms and boxplots to assess 
distributional aspects of continuous variables.   
 
 
3.4. Statistical Analysis: 
 
We will derive cumulative incidence plots to depict time to fistula use, stratified by 
treatment arm and fistula location.   
 
The primary outcome is time to AV fistula maturation, defined as successful cannulation of 
the AV fistula for six hemodialysis sessions within three weeks.   
 
Subjects who are lost to follow up or who die prior to maturation will be censored at the 
time of death or last recorded activity. 
 
Our primary analysis will be based on the intention-to-treat principle.  To that end, patients 
will be analyzed according to their randomized treatment assignment, and all patients 
randomized to treatment assignment will be included in the analysis even if they are lost to 
follow up or die before the end of their observation period.  We will use a log-rank test 
stratified by location of fistula to assess whether time to maturation of AV fistula differs 
between treatment arms (vorapaxar versus placebo).  The test will be two-sided and 
conducted at the 0.05 level of significance. 


June 11, 2018.  Version 3.0 
 
10
 
A Cox proportional hazards regression model of treatment arm and other characteristics of 
interest (if required) will be employed secondarily to estimate an adjusted treatment effect.  
 
Other secondary analyses involve the use of logistic regression techniques to evaluate the 
effect of treatment on secondary endpoints – use of AV fistula within 180 days, AV fistula 
patency within 150-180 days and AV fistula functional or anatomic maturation at 180 days 
as determined by the PI. We will also compare rates of bleeding by treatment arm using t-
tests or Wilcoxon rank sum tests as appropriate. 
 
 
UPDATED: Based on low enrollment and early termination of the study, the planned 
analysis as described above will not be conducted.  Instead, we will conduct a 
descriptive analysis only. 
 
UPDATED: The secondary outcome ‘‘AV fistula functional or anatomic maturation at 
180 days as determined by the PI” will be defined using clinically adjudicated after a 
review of the medical record. 
  
Power/Sample Size 
 
We have sufficient power to address our primary aim.  Based upon a sample size of n=25 
patients per group for this pilot study, we have approximately 70% power to detect a 
hazard ratio of 2.05 between treatment arms, assuming that only 50% of subjects will 
experience maturation by six months post randomization in the placebo group.  If only 40% 
of subjects experience maturation by six months post randomization we have over 70% 
power to detect a hazard ratio of 2.15. 
 
4. Statistical conventions  
 
This section details general conventions to be used for the statistical analyses and 
presentation of the data. Departures from these general conventions may be given in the 
specific detailed sections of this analysis plan. 
 
1. SAS Version 9 or R Version 3 will be the statistical software package used for all data 
analyses. 
2. Continuous variables will be presented with mean, standard deviation, median 
(25th percentile, 75th percentile), minimum and maximum values. Categorical variables 
will be presented as number of subjects and percentage of number of subjects by levels 
of the variable. 
3. The number and percentage of responses will be presented in the form XX (XX) 
where the percentage is in the parentheses.  Unless otherwise specified, the 
denominator for percentages will be the number of subjects in a given treatment group 
within the analysis population of interest. The denominator will be included when it 
differs from the standard analysis population. 


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11
4. All summary tables will include the analysis population sample size (i.e., number of 
subjects). 
5. Change from baseline will be calculated for each period as follows:  
            Change from baseline = Post-baseline value  baseline value.             
6. Date variables will be formatted as DD-MON-YYYY for presentation.  In the case of 
missing day, month, and/or year information, “NA” will be presented.  For example, a 
date with a missing month and day will be presented as NANAYYYY. 
7. Unless otherwise stated, statistical comparisons will be performed using two-sided 
significance tests. An alpha level of 0.05 will determine significance unless otherwise 
noted for a specified analysis. 
8. When count data are presented, the percentage will be suppressed when the count 
is zero in order to draw attention to the non-zero counts.   
9. Unless specified otherwise, data will be presented by treatment and control 
subjects. 
 
 
5. Adverse events data and reporting process 
 
Adverse events data will be collected at each follow up visit as described above in the 
section on Study Participants. 
 
The PI will review aggregated AEs each month, and AEs will be reported to the sponsor and 
the IRB per research guidelines. Participation for the individual will terminate if he/she has 
a serious adverse reaction that prevents future participation. In the event of adverse 
effects, the patient’s primary physician will be notified. 
 
 
References 
1.  United States Renal Data System 2013 Annual Report, Atlas of Chronic Kidney Disease 
and End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of 
Diabetes and Digestive and Kidney Diseases. 
2.  Brescia MJ, Cimino JE, Appel K, Hurwich BJ.  Chronic hemodialysis using venipuncture 
and a surgically created arteriovenous fistula.  N Engl J Med 1966; 275:1089. 
 
 


June 11, 2018.  Version 3.0 
 
12
 
 
Appendix 1: Tables and figures 
 
Table 1. Demographic characteristics of study population 
 
Characteristics 
Treatment 
Control 
 
Left arm 
N (%) 
Right arm 
N (%) 
Left arm 
N (%) 
Right arm 
N (%) 
Age (years) 
Mean (SD) 
Median (IQR) 
 
 
 
 
Site 
Stanford University 
Santa Clara Valley 
 
 
 
 
Male 
 
 
 
 
Race 
White 
Black 
Asian 
American Indian 
Pacific Islander 
Other 
Unknown 
 
 
 
 
Ethnicity 
Hispanic 
Non-Hispanic 
    Unknown 
 
 
 
 
BMI 
Mean (SD) 
Median (IQR) 
 
 
 
 
 
 
 


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13
Table 2. Baseline clinical characteristics of study population 
Characteristics 
Treatment 
Control 
 
Left arm 
N (%) 
Right arm 
N (%) 
Left arm 
N (%) 
Right arm 
N (%) 
Had previous surgery 
Ipsilateral tunnel catheter access 
Permanent ipsilateral AV fistula 
access 
Permanent ipsilateral AV graft 
access 
Contralateral tunnel catheter access 
Permanent contralateral AV fistula 
access 
Permanent contralateral AV graft 
access 
Other surgery type 
 
 
 
 
Medical history 
None 
Routinely hypotensive 
Diabetes 
Coronary artery disease 
COPD 
Congestive heart failure 
Peripheral artery disease 
Stroke 
Intracranial hemorrhage 
Hypertension 
Cancer 
Peptic ulcer disease 
Other 
 
 
 
 
Concomitant Medications 
None 
Daily aspirin 
Statins 
Insulin 
Oral diabetic medications 
Antifungal agents 
ACE inhibitors 
ARBs 
Beta blockers 
Calcium channel blockers 
Other antihypertensive 
Diuretics 
Antiarrhythmics 
Other medications 
 
 
 
 


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14
Table 3. Efficacy and safety outcomes 
 
Treatment 
Control 
Hazard ratio 
(95% CI) 
 
Left arm 
N (%) 
Right 
arm 
N (%) 
Left 
arm 
N (%) 
Right 
arm 
N (%) 
 
Efficacy outcomes 
 
 
 
 
 
Time to fistula maturation 
(days) 
Mean (SD) 
Median (IQR) 
 
 
 
 
 
AV fistula use within 180 
days of surgery  
 
 
 
 
 
AV fistula patency at 150-
180 days, with at least 50% 
increase in vein diameter 
by ultrasound compared 
with preoperative vein 
diameter measurement 
 
 
 
 
 
 
Safety outcomes 
 
 
 
 
Odds ratio 
(95% CI) 
BARC bleeding 
Type 0 
Type 1 
Type 2 
Type 3a 
Type 3b 
Type 3c 
Type 4 
Type 5 
 
 
 
 
 
GUSTO bleeding 
Mild 
Moderate 
Severe  
 
 
 
 
 
 
 
 
 


June 11, 2018.  Version 3.0 
 
15
Table 4. Adverse events and other outcomes 
 
Treatment 
Control 
Odds ratio 
(95% CI) 
 
Left arm 
N (%) 
Right 
arm 
N (%) 
Left 
arm 
N (%) 
Right 
arm 
N (%) 
 
Serious adverse events 
 
 
 
 
 
Unexpected adverse events 
 
 
 
 
 
Other adverse events 
None 
Anemia 
Depression 
Rash 
Iron deficiency 
Retinopathy 
Retinal disorder 
Diplopia/oculomotor 
disturbances 
Other  
 
 
 
 
 
Other outcomes 
Hospitalization 
Unstable angina 
Myocardial infarction 
Cardiac catheterization 
PCI 
CABG 
Non-coronary 
vascularization 
Stroke 
TIA 
Transfusion 
 
 
 
 
 
 
 
 
 
 
Figure 1. Kaplan-Meier plot of time to fistula maturation by treatment arm and location of 
fistula 
 
Figure 2. All outcomes with forest plot for point estimate and 95% confidence interval