A Boston Scientific Clinical Trial of Renal Denervation Using the Vessix Reduce™ Catheter and Vessix™ Generator for the Treatment of HyperTensioN: REINFORCE
Phase: NA
Conditions: Hypertension
Sponsor: Boston Scientific Corporation

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REDUCE-HTN: REINFORCE Study 
Renal Denervation Using the Vessix Reduce™ Catheter and Vessix™ 
Generator for the Treatment of HyperTensioN: REINFORCE 
CLINICAL PROTOCOL 
IDE G130240 
Sponsored By 
Boston Scientific 
One Scimed Place 
Maple Grove, MN 55311 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
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Contact Information 
Role 
Contact  
Clinical Contact 
Nicole Kilburn 
Clinical Trial Manager 
Peripheral Interventions Clinical 
Boston Scientific 
One Scimed Place 
Maple Grove, MN 55311 USA 
970-294-4082 
Nicole.Kilburn@bsci.com 
 
Jennifer Hansen 
Director, Clinical Trials 
Peripheral Interventions Clinical 
Boston Scientific 
One Scimed Place 
Maple Grove, MN 55311 USA 
763-494-2172 
Jennifer.Hansen@bsci.com 
Coordinating Principal 
Investigator 
Martin B. Leon, MD 
Director, Center for Interventional Vascular Therapy 
Division of Cardiology 
Columbia University Medical Center 
New York Presbyterian Hospital 
161 Ft. Washington Ave. 
Herbert Irving Pavilion  
6th Floor 
New York, NY 10032 USA 
Coordinating Principal 
Investigator 
Michael Weber, MD 
SUNY Downstate College of Medicine  
State University of New York 
Health Science Center 
Brooklyn, New York 
Investigational Sites 
A list of investigational sites is maintained and provided as 
required by 21 CRF 812. 
Vendors/Labs 
A list of vendors/labs involved in the trial is maintained and 
provided in the Manual of Operations.  
 
 
 
 
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Original Release: November 7, 2014  
Version AB Release: July 6, 2015 
Version AC Release:  January 14, 2016 
Version AD Release: January 10, 2018 (Not implemented) 
Version AE/AF: Release not applicable/administrative only 
Version AG: October 29, 2018 (Not implemented)  
Version AH: January 23, 2019  
2. Revision History 
Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
AA 
7-Nov-2014 
N/A 
N/A 
Initial Release 
AB 
6-Jul-2015 
Synopsis   
Updated Clinical 
Contact Information 
To reflect current contact 
information 
 
 
Synopsis 
 
Corrected rescue 
medication language 
To ensure consistency 
within the protocol 
 
 
 
Table 11.1-1/ 
11.4.5 / 11.9 / 
11.11 
Added Laboratory 
Assessments: Renin, 
Aldosterone 
To allow for assessment of 
renal denervation’s effect 
on the angiotensin system 
 
 
11.11 
Corrected 6-month 
follow up window 
To ensure consistency 
within the protocol 
 
 
 
Figure 12.2-1 
Updated Addition of 
Medications Algorithm 
To ensure patient safety  
 
 
13.1.1.1 
Corrected null and 
alternate hypothesis 
To ensure consistency 
within the protocol 
 
 
 
14.3 / 14.3.4 
Added central 
laboratory 
To allow for central 
analysis of selected serum 
assessments 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
AC 
14-Jan-2016 
Synopsis / 8.1 
 
 
Synopsis / 7.3 
 
 
Synopsis / 
11.10 / 12.2 
 
Figure 8.1-1 
 
 
 
11.5.1 
Table 11.18-1 
 
 
12.2 
Increase number of 
centers to 20 
 
Update Additional 
Assessments 
 
 
Updated Medication 
Addition Process 
 
Updated Study Design 
Figure 
 
Removed Timeline 
Requirement 
 
Added Laboratory 
Source Documentation 
Requirements 
 
Updated Medication 
Addition Process  
To help facilitate timely 
enrollment 
 
To ensure consistency 
with changes to 
Medication Addition 
Algorithm 
 
To clarify intent of 
protocol 
 
To allow an ABPM one 
time optional rescreen  
 
To ensure consistent 
assessment windows 
 
To document data 
disposition 
 
 
To allow investigator 
discretion when 
prescribing anti-
hypertensive medications 
AD 
10-Jan-2018 
N/A 
N/A 
Changes proposed to 
FDA, not approved/not 
implemented. 
AE/AF 
N/A 
N/A 
N/A 
Document control system 
administrative changes 
only.  No content changes. 
AG 
29-Oct-2018 
N/A 
N/A 
Changes proposed to 
FDA, not approved/not 
implemented. 
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Revision History 
Revision 
Number 
Release Date 
Section 
Change 
Reason for Change 
AH 
 23-Jan-2019 
Contact 
Information 
 
 
Synopsis / 9.1 / 
12.1 / Table 
12.1-1 / 12.14-
12.17 
 
 
 
 
Synopsis / 14.1 
 
 
 
 
 
19.4 /19.4.1 / 
26.0 
 
Update sponsor contact 
 
 
 
Updated minimum 
follow-up 
visit/assessment 
requirements to 24 
months and added DUS 
at 24 months 
 
 
Updated statistical 
methods with removal 
of the primary efficacy 
statistical hypothesis 
testing 
 
Updated confidentiality 
language  
 
Reflect current study 
contact 
 
 
To reduce subject and site 
effort and collect only the 
necessary data post 
enrollment termination of 
pilot study to ensure 
subject safety 
 
 
Due to enrollment 
termination, insufficient 
power to make a 
statistically meaningful 
conclusion. 
 
To ensure consistent with 
current requirements 
 
 
 
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3. Protocol Synopsis 
REDUCE-HTN: REINFORCE 
Objective(s) 
To assess safety and efficacy of the Vessix™ Renal Denervation 
System for the treatment of uncontrolled hypertension [off-treatment 
office systolic blood pressure (OSBP) ≥150 mmHg and ≤180 mmHg] 
Test Device 
Vessix Renal Denervation System: 
• 
Vessix Reduce™ Catheter (4.0, 5.0, 6.0 and 7.0 mm) 
• 
Vessix™ Generator (bipolar radio frequency) 
Control Therapy Masked procedure (renal angiogram) 
Device Sizes 
The Vessix Reduce Catheter is available in balloon diameters of 4.0 
mm, 5.0 mm, 6.0 mm and 7.0 mm with a balloon length of 25 mm and 
a total catheter working length of approximately 90 cm. The number of 
electrodes on each balloon varies from 4 to 6 bipolar electrodes, 
depending on balloon diameter.  The catheter is compatible with a 7F 
guide sheath. 
Study Design 
Prospective, multicenter, single blinded, randomized, controlled, pilot 
study 
Planned Number 
of Subjects 
Up to 100 randomized subjects 
Planned Number 
of Centers / 
Countries 
Up to 20 centers in the US 
Primary Efficacy 
Assessment 
Mean reduction in average 24-hour ambulatory systolic blood pressure 
(ASBP) at 8 weeks post randomization 
Due to enrollment termination (51 subjects randomized), the primary 
efficacy statistical hypothesis testing will not be conducted. All 
assessments will be observational.   
Safety 
Assessments 
Safety Assessments analyzed at all follow-up time points: 
• 
All-cause death 
• 
Renal failure 
• 
Hospitalization for hypertensive crisis  
• 
Hospitalization due to severe hypotension/syncope 
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REDUCE-HTN: REINFORCE 
Safety Assessments analyzed at 4 weeks: 
• 
Significant embolic event resulting in end-organ damage or 
intervention to prevent it 
• 
Renal artery dissection or perforation requiring intervention 
• 
Vascular complications requiring surgical repair, interventional 
procedure, thrombin injection, or blood transfusion 
Safety Assessments analyzed at 6 months: 
• 
Significant new renal artery stenosis assessed by duplex 
ultrasound (DUS) and confirmed by the angiographic core 
laboratory [>70% stenosis by computed tomographic 
angiography (CTA) or digital subtraction angiography (DSA)] 
through 6 months post randomization 
Note: All Safety Assessments will be adjudicated by an independent 
Clinical Events Committee (CEC).    
Additional 
Assessments 
Additional Assessments analyzed at all follow-up time points: 
• 
Mean reduction in office-based systolic blood pressure (OSBP) 
from baseline 
• 
Mean reduction in office-based diastolic blood pressure 
(ODBP) from baseline 
• 
Percent of subjects at target blood pressure 
• 
Episodes of Congestive Heart Failure (CHF) 
• 
Stroke 
• 
Myocardial Infarction (MI) 
Additional Assessments analyzed at 3 and 6 months: 
• 
Anti-hypertensive medications  
Additional Assessments analyzed at 6 and 12 months: 
• 
Mean reduction in average 24-hour ambulatory systolic blood 
pressure (ASBP) from baseline 
Mean reduction in average 24-hour ambulatory diastolic blood 
pressure (ADBP) from baseline 
Randomization 
2:1 (Test:Control) 
• 
Test:  Renal Denervation  
• 
Control:  Masked Procedure (renal angiogram) 
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REDUCE-HTN: REINFORCE 
Method of 
Assigning 
Patients to 
Treatment 
Subjects meeting the eligibility criteria will be randomized at index 
procedure using an Interactive Randomization System  
Follow-up 
Schedule 
All enrolled subjects will be evaluated at 2 (14 ±7 days), 4 (28 ±7 days) 
and 8 (56±7 days) weeks post randomization. 
Subjects will be further evaluated at 3 (90±14 days), 4 (120 ±14 days), 
5 (150 ±14 days), 6 (180 ±14 days), 12 (365 ±30 days), 18 (545 ±30 
days), 24 (730±30 days), 30 (910±30 days), and 36 (1095 ±30 days) 
months post randomization. 
All subjects are required to complete follow up through the 24-month 
time point. After approval of protocol version AH, no further follow up 
will be required for subjects who have completed at least 24 months of 
follow up post randomization.  Subjects not yet through the 24-month 
follow up time point will be required to complete follow up through the 
24-month visit and will undergo a DUS at the 24-month follow up time 
point. 
Study Duration 
It is estimated that it will take approximately 4 years to complete this 
study. 
Medication 
Wash-out Phase 
and Medication 
Additions 
After signing the study Informed Consent Form, patients receiving 
pharmacotherapy for their hypertension will be discontinued from 
current antihypertensive medications.  These patients will be required 
to complete a 4-week wash-out phase prior to randomization.  If a 
patient is not on antihypertensive medication at the time of Informed 
Consent, the wash-out period is not applicable. 
Subjects will remain off antihypertensive medications through the 
primary efficacy assessment (8 weeks post randomization) unless 
rescue changes are required.  Investigators have ultimate discretion 
regarding the type of antihypertensive medication and timing of adding 
rescue medications to ensure subject safety. 
If subjects are not at target (target defined as OSBP <140 mmHg) from 
the time of the primary efficacy assessment (8 weeks post 
randomization) through the 6-month assessment, medications will be 
added and doses escalated as described in Section 13.3.   
Key Inclusion 
Criteria 
• 
Age ≥18 and ≤75 years 
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REDUCE-HTN: REINFORCE 
• 
OSBP ≥150 mmHg and ≤180 mmHg based on an average of 3 
office-based blood pressure measurements 
• 
Average 24-hour ASBP ≥135 mmHg and ≤170 mmHg 
• 
For each kidney, a main renal artery, with or without accessory 
renal arteries, with diameter ≥3.0 mm and ≤7.0 mm and length 
≥20.0 mm 
• 
Agrees to have all study procedures performed, and is 
competent and willing to provide written, informed consent 
Key Exclusion 
Criteria 
• 
Previous renal artery intervention or clinically significant renal 
artery abnormalities that would interfere with safe cannulation 
of the renal artery 
• 
Stenosis >30% or renal artery aneurysm in either renal artery 
• 
Fibromuscular dysplasia (FMD) 
• 
Platelet count of <90,000 or >500,000 per microliter (µL) of 
blood or history of bleeding diathesis 
• 
Known causes of secondary HTN  
• 
Type 1 diabetes mellitus 
• 
eGFR <40 mL/min/1.73m2, as calculated using the MDRD 
(Modification of Diet in Renal Disease) methodology1  
• 
Only one kidney or prior transplantation  
• 
Contraindicated for anticoagulant therapy and other 
recommended study medications 
• 
Known hypersensitivity or contraindication to contrast dye that, 
in the opinion of the investigator, cannot be adequately pre-
medicated 
• 
Pregnant or planning to become pregnant  
• 
History of myocardial infarction (MI), unstable angina pectoris, 
hypertensive crisis, or a cerebrovascular accident (CVA) in the 
previous 3 months 
• 
Known ejection fraction of <30% or heart failure that required 
hospitalization in the previous 6 months 
• 
Scheduled for or has planned surgery or cardiovascular (CV) 
intervention in the next 6 months 
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REDUCE-HTN: REINFORCE 
• 
≥1 episode(s) of orthostatic hypotension not related to 
medication changes, coupled with symptoms, within the past 
year or identified during screening 
• 
Severe valvular heart disease 
• 
History of any serious medical condition, which in the opinion 
of the investigator, may adversely affect the safety of the 
participant and/or the scientific integrity of the study 
• 
Active implantable device [e.g., implantable cardioverter-
defibrillator (ICD), cardiac resynchronization therapy 
defibrillator (CRT-D), spinal cord stimulators, cochlear 
implants] 
• 
Current participation in another drug or device trial 
Multiple 
Interventions 
During Index 
Procedure 
There are no concomitant procedures allowed immediately prior to or 
during the renal denervation procedure. 
 
Statistical 
Methods  
Due to enrollment termination (51 subjects randomized), the primary 
efficacy statistical hypothesis testing will not be conducted.  
Descriptive analysis will be performed for data review purposes. 
 
 
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4. Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
REVISION HISTORY ............................................................................................................3 
3. 
PROTOCOL SYNOPSIS .........................................................................................................6 
4. 
TABLE OF CONTENTS .......................................................................................................11 
Table of Figures ..............................................................................................................16 
Table of Tables ................................................................................................................16 
5. 
INTRODUCTION ................................................................................................................17 
5.1. Hypertension and the Evolution of Renal Denervation .....................................17 
5.2. Clinical Study Summary ......................................................................................18 
5.2.1. 
Vessix Vascular, Inc. REDUCE-HTN ......................................................18 
5.2.1. 
Competitive Studies ..................................................................................19 
5.2.1.1. 
Symplicity™ HTN-1, HTN-2 and HTN-3 ...............................19 
5.2.1.2. 
EnligHTN™ FIM .....................................................................20 
6. 
DEVICE DESCRIPTION ......................................................................................................21 
6.1. Vessix Reduce Catheter ........................................................................................21 
6.2. Vessix Generator ...................................................................................................23 
6.3. Patient Extension Cable ........................................................................................23 
6.4. Power Supply .........................................................................................................23 
6.5. Roll Cart .................................................................................................................24 
6.6. Guide Sheath .........................................................................................................24 
6.7. Device Labeling .....................................................................................................24 
7. 
OBJECTIVES .....................................................................................................................24 
8. 
ENDPOINTS .......................................................................................................................24 
8.1. Primary Efficacy Assessment ...............................................................................25 
8.2. Safety Assessments ................................................................................................25 
8.3. Secondary Assessments .........................................................................................25 
9. 
DESIGN .............................................................................................................................26 
9.1. Scale and Duration ................................................................................................26 
9.2. Treatment Assignment .........................................................................................28 
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9.2.1. 
Treatment and Control ..............................................................................28 
9.2.1.1. 
Treatment .................................................................................28 
9.2.1.2. 
Control .....................................................................................28 
9.2.2. 
Target and Non-target Arteries .................................................................28 
9.3. Justification for the Study Design ........................................................................28 
10. SUBJECT SELECTION ........................................................................................................29 
10.1. Study Population and Eligibility ..........................................................................29 
10.2. Inclusion Criteria ..................................................................................................29 
10.3. Exclusion Criteria .................................................................................................29 
11. SUBJECT ACCOUNTABILITY .............................................................................................31 
11.1. Informed Consent .................................................................................................31 
11.2. Point of Enrollment ...............................................................................................31 
11.3. Withdrawal ............................................................................................................31 
11.4. Subject Status and Classification .........................................................................31 
12. STUDY METHODS .............................................................................................................32 
12.1. Data Collection ......................................................................................................32 
12.1.1. Medical Equipment Description ...............................................................34 
12.1.1.1. Office-based Blood Pressure Monitoring ................................34 
12.1.1.2. 24-Hour Ambulatory Blood Pressure Monitoring ...................35 
12.2. Study Candidate Screening ..................................................................................35 
12.3. Informed Consent .................................................................................................35 
12.3.1. Post-Consent Eligibility Validation ..........................................................36 
12.4. Screening ................................................................................................................36 
12.4.1. Demographics and Medical History (within 50 or 21 days prior to 
randomization) ..........................................................................................36 
12.4.2. Medication Wash-Out Period [a minimum of 4 weeks (28 days) prior to 
randomization] ..........................................................................................36 
12.4.3. Limited Physical Examination (within 21 days prior to randomization) .36 
12.4.4. Blood Pressure Monitoring (within 21 days prior to randomization) .......36 
12.4.4.1. Office-Based BP and Heart Rate .............................................36 
12.4.4.2. 24-Hour Ambulatory BP Monitoring .......................................37 
12.4.5. Laboratory Assessments and Calculations (within 21 days prior to 
randomization/enrollment) .......................................................................37 
12.4.5.1. eGFR Calculation .....................................................................37 
12.4.6. Non-Invasive Imaging (within 6 months prior to informed consent) .......37 
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12.4.6.1. Computed Tomographic Angiography (CTA) .........................37 
12.4.7. Quality of Life Assessment (within 7 days prior to randomization) ........38 
12.5. Treatment Period ..................................................................................................38 
12.5.1. Diagnostic Renal Angiogram, Masked Procedure and Renal Denervation 
Procedure ..................................................................................................38 
12.5.1.1. Diagnostic Renal Angiogram ...................................................38 
12.5.1.2. Masked Procedure ....................................................................39 
12.5.1.3. Renal Denervation Procedure ..................................................39 
12.5.2. Data Collection .........................................................................................41 
12.6. Hospital Discharge ................................................................................................42 
12.7. Follow-up Visit Week 2 (14 ±7 days) ...................................................................42 
12.8. Follow-up Visit Week 4 (28 ±7 days) ...................................................................42 
12.9. Follow-up Visit Week 8 (56 ±7 days) ...................................................................42 
12.10. 
Follow-up Visits Months 3, 4 and 5 (90 ±14 days, 120 ±14 days, 150 
±14 days) ..................................................................................................43 
12.11. 
Follow-up Visit Month 6 (180 ±14days) ................................................43 
12.12. 
Follow-up Visit Month 12 (365 ±30 days) .............................................44 
12.13. 
Follow-up Visit Month 18 (540 ±30 days) (Visit/Assessments Not 
Required After Approval of Protocol vAG) .........................................44 
12.14. 
Follow-up Visit Month 24 (730 ±30 days)(Visit/Assessments Not 
Required After Approval of Protocol vAG) .........................................44 
12.15. 
Follow-up Visit Month 30 (900 ±30 days)(Visit/Assessments Not 
Required After Approval of Protocol vAG) .........................................45 
12.16. 
Follow-up Visit Month 36 (1095 ±30 days)(Visit/Assessments Not 
Required After Approval of Protocol vAG) .........................................45 
12.17. 
Study Completion ...................................................................................46 
12.18. 
Source Documents ..................................................................................46 
13. MEDICATION ADDITIONS .................................................................................................46 
13.1. Rescue Medications ...............................................................................................46 
13.2. Medications for Subjects Not at Target ..............................................................47 
13.3. Medication Adjustment Visits ..............................................................................48 
14. STATISTICAL CONSIDERATIONS ......................................................................................49 
14.1. Endpoints ...............................................................................................................49 
14.1.1. Primary Efficacy Assessment ...................................................................49 
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14.2. General Statistical Methods .................................................................................49 
14.2.1. Analysis Sets .............................................................................................49 
14.2.2. Randomization Scheme ............................................................................49 
14.2.3. Control of Systematic Error/Bias ..............................................................49 
14.2.4. Number of Subjects per Study Site ...........................................................50 
14.3. Data Analyses ........................................................................................................50 
14.3.1. Additional Assessments/Measurements ...................................................50 
14.3.2. Interim Analyses .......................................................................................50 
14.3.3. Subgroup Analyses ...................................................................................50 
14.3.4. Analysis Software .....................................................................................50 
14.3.5. Changes to Planned Analyses ...................................................................51 
15. DATA MANAGEMENT .......................................................................................................51 
15.1. Data Collection, Processing, and Review ............................................................51 
15.2. Data Retention .......................................................................................................51 
15.3. Core and Central Laboratories ...........................................................................52 
15.3.1. Renal Duplex Ultrasound .........................................................................52 
15.3.2. Angiography .............................................................................................52 
15.3.3. Ambulatory Blood Pressure Monitoring ..................................................52 
15.3.4. Serum Analysis .........................................................................................53 
16. AMENDMENTS ..................................................................................................................53 
17. DEVIATIONS .....................................................................................................................53 
18. DEVICE/EQUIPMENT ACCOUNTABILITY .........................................................................53 
19. COMPLIANCE ....................................................................................................................54 
19.1. Statement of Compliance ......................................................................................54 
19.2. Investigator Responsibilities ................................................................................54 
19.2.1. Delegation of Responsibility ....................................................................56 
19.3. Institutional Review Board ..................................................................................56 
19.4. Sponsor Responsibilities .......................................................................................57 
19.4.1. Role of Boston Scientific Representatives ...............................................57 
19.5. Insurance ................................................................................................................57 
20. MONITORING ....................................................................................................................58 
21. POTENTIAL RISKS AND BENEFITS ...................................................................................58 
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21.1. Anticipated Adverse Events .................................................................................58 
21.2. Risk Minimization Actions ...................................................................................59 
21.3. Anticipated Benefits ..............................................................................................59 
21.4. Risk to Benefit Rationale ......................................................................................59 
22. SAFETY REPORTING .........................................................................................................59 
22.1. Definitions and Classification ..............................................................................59 
22.2. Relationship to Study Device(s) ...........................................................................61 
22.3. Investigator Reporting Requirements .................................................................61 
22.4. Boston Scientific Device Deficiencies ...................................................................62 
22.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators ...................63 
23. INFORMED CONSENT ........................................................................................................63 
24. COMMITTEES ...................................................................................................................64 
24.1. Safety Monitoring Process ....................................................................................64 
24.2. Data Monitoring Committee ................................................................................65 
24.3. Clinical Events Committee ...................................................................................65 
24.4. Steering Committee ...............................................................................................65 
25. SUSPENSION OR TERMINATION ........................................................................................66 
25.1. Premature Termination of the Study ..................................................................66 
25.1.1. Criteria for Premature Termination of the Study ......................................66 
25.2. Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval ................................................................................................................66 
25.3. Requirements for Documentation and Subject Follow-up ................................67 
25.4. Criteria for Suspending/Terminating a Study Center .......................................67 
26. PUBLICATION POLICY ......................................................................................................67 
27. ABBREVIATIONS AND DEFINITIONS .................................................................................69 
27.1. Abbreviations ........................................................................................................69 
27.2. Definitions ..............................................................................................................72 
28. BIBLIOGRAPHY .................................................................................................................77 
 
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Table of Figures 
Figure 6.1-1 Vessix Reduce Catheter with Bi-Polar Electrodes ............................................. 22 
Figure 6.1-2 Vessix Reduce Catheter Components ................................................................ 23 
Figure 9.1-1: REDUCE-HTN: REINFORCE Study Design .................................................. 27 
Figure 13.2-1 Addition of Medications Algorithm ................................................................. 48 
 
Table of Tables 
Table 6.1-1 Vessix Reduce Catheter Dimensional Features ................................................... 22 
Table 10.2-1: Inclusion Criteria .............................................................................................. 29 
Table 10.3-1: Exclusion Criteria ............................................................................................. 30 
Table 12.1-1: REDUCE-HTN: REINFORCE Study Data Collection for Scheduled Visits .. 33 
Table 12.5-1: Vessix Reduce Catheter Sizing ........................................................................ 40 
Table 12.17-1: Source Documentation Requirements ............................................................ 46 
Table 22.1-1: Safety Reporting Definitions ............................................................................ 60 
Table 22.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event .......... 61 
Table 22.3-1: Investigator Reporting Requirements ............................................................... 62 
Table 27.1-1: Abbreviations ................................................................................................... 69 
Table 27.2-1: Definitions ........................................................................................................ 72 
 
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5. Introduction 
5.1. Hypertension and the Evolution of Renal Denervation 
Management of patients with resistant hypertension continues to be a significant clinical 
challenge for the health care field and is a major global public health burden. Hypertension is 
a leading attributable cause of mortality worldwide, causing 7.5 million deaths 
annually.2,3,4,5,6_ENREF_1  
 
As early as the 1930s, surgical procedures of splanchnicectomy and radical sympathectomy 
were conducted to reduce blood pressure in patients.  This research demonstrated that 
procedures targeted at reducing sympathetic nerve activity achieved blood pressure 
reductions in the treated patients, demonstrating improved long-term outcomes.7,8 However, 
these methods were abandoned because they were associated with high perioperative 
morbidity and mortality and long-term complications.2,3,8,9 Radio frequency9 current has been 
used for decades in the operating room to safely and effectively create surgical lesions and to 
facilitate hemostasis.10,11 The technique of catheter based RF ablation to treat arrhythmias 
was developed as an adaptation of electrosurgical cautery.  
 
In the late 1990s, the connection between hypertension and the sympathetic nervous system, 
specifically the renal nerves, was reconfirmed._ENREF_12 Shortly thereafter, catheter-based 
RF ablation was applied to renal nerves as a hypertension treatment.12  Clinical evidence 
continues to confirm that the renal efferent sympathetic nerves and afferent sensory nerves 
that lie within and immediately adjacent to the wall of the renal artery are crucial for 
initiation and maintenance of systemic hypertension.2,3,12 Renal sympathetic efferent nerve 
activity participates in renin release, sodium retention and reduced blood flow which in turn, 
contributes to the development and maintenance of hypertension .4 Renal sympathetic 
afferents are recognized as seminal in conveying central sympathetic drive in patients with 
both chronic kidney disease and end-stage renal disease.4 Thus, inhibition of the renal 
sympathetic efferent or afferent nerves (or both) represents an attractive treatment of 
established hypertension. 
 
Today, despite the availability of numerous antihypertensive drugs, dietary and lifestyle 
changes, hypertension remains an issue in a considerable number of patients. New innovative 
therapeutic approaches such as renal nerve ablation may be particularly relevant for these 
patients as their hypertensive state puts them at high risk of major cardiovascular events.2  A 
recent article by Kostis et al. reported that in hypertensive patients being treated by 
medication, each month of active treatment was associated with approximately 1 day of life 
expectancy gain.13 Renal ablation has the potential to provide a long term effect on 
hypertension which could increase the patient’s life expectancy and reduce the economic 
burden of a progressive disease state. 
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5.2. Clinical Study Summary 
5.2.1. Vessix Vascular, Inc. REDUCE-HTN  
The REDUCE-HTN study (NCT 01541865) was initiated by Vessix Vascular, Inc. Laguna 
Hills, CA in February 2012. 
 
REDUCE-HTN is a prospective, non-randomized, single arm, multicenter study evaluating 
the safety and feasibility of renal denervation using the Vessix Renal Denervation System in 
subjects with medication resistant hypertension. The first in man (FIM) cohort enrolled 18 
subjects at six centers in Europe (5) and Australia (1) between February 22, 2012 and May 
10, 2012.  Subjects considered for enrollment had office-based systolic blood pressure 
(OSBP) ≥160 mmHg while maintaining compliance with a stable drug regimen of ≥3 
antihypertensive medications, including one diuretic (unless intolerance was documented), at 
maximally tolerated doses for a minimum of two weeks prior to enrollment. Subjects were 
required to have single main renal arteries of diameters ≥3.5 mm and ≤7.0 mm and lengths 
≥20.0 mm without significant stenosis (<30% via angiography) or abnormalities to be 
eligible for enrollment. Subjects with eGFR <45 mL/min/1.73m2, Type I diabetes mellitus, 
known/diagnosed secondary hypertension, prior renal artery intervention, or accessory renal 
arteries >2 mm in diameter that supplied >20% perfusion to the kidney were excluded.  
Following CE marking of the Vessix Renal Denervation System, the REDUCE-HTN 
protocol was amended to allow expanded enrollment in the Post Market Study (PMS).  Key 
protocol modifications for the PMS included enrollment of subjects with renal artery length 
≥15 mm or accessory renal arteries, clarification of the exclusion criterion related to 
abnormal electrocardiogram (“clinically significant”) and substitution of the 1-month renal 
artery duplex ultrasound (DUS) requirement with a 6-month DUS requirement. 
Subject recruitment in the REDUCE-HTN Post Market Study was completed on April 8, 
2013, with a total of 146 subjects enrolled and treated at 23 centers in Europe (17), Australia 
(4), and New Zealand (2), including continued follow-up on the 18 subjects in the FIM 
cohort and 128 newly enrolled post-market study subjects.  
All subjects will be followed at 2 weeks and 1, 3, 6, 12, 18 and 24 months.  Follow-up 
assessments will include office blood pressure measurement, blood assays and urinalysis for 
renal function, renal DUS at 6 months, and ambulatory blood pressure monitoring (ABPM) 
at 6 and 12-months. Subjects are required to maintain compliance with all antihypertensive 
medications throughout the follow-up period. 
At 6 months, the mean office SBP was 157.5±23.5 mmHg, a reduction of 24.7±22.1 mmHg 
compared with baseline (P<.0001), thus met the efficacy primary endpoint for the study. 
Twenty four-hour ambulatory SBP was reduced by 8.4±14.4 mmHg at 6 months (P<.0001). 
No pre-specified acute safety events occurred. However, one subject (0.7%) was hospitalized 
for a hypertensive emergency unrelated to medication and/or non-compliance within 1 month 
of the procedure. One subject (0.7%) had renal artery stenosis which required an 
intervention. Three other subjects had flow-limiting stenosis in the renal artery at 6 months 
which did not require intervention. 14 
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Subject follow-up in the REDUCE-HTN Study continues and data monitoring activities are 
ongoing through 2 years post procedure.   
5.2.1. Competitive Studies 
5.2.1.1. Symplicity™ HTN-1, HTN-2 and HTN-3  
In a proof of concept study (Simplicity HTN-1)6, 50 subjects were enrolled at five European 
and Australian centers between June 2007 and November of 2008 with follow-up 
surveillance occurring at 1, 3, 6, 9 and-12-months. Of these enrolled subjects, 45 received 
bilateral percutaneous RF ablative treatments to the renal sympathetic nervous system. All 
subjects were followed with office blood pressure measurements, renal angiography between 
14-30 days post procedure and magnetic resonance angiography (MRA) at 6 months; blood 
assays for renal function were collected at each follow-up. A subgroup of 10 subjects was 
assessed for a reduction of noradrenaline spillover as a measurement of effectiveness of the 
renal denervation procedure. 
HTN-1 clinical outcomes for treated subjects demonstrated a sustained reduction of office 
blood pressure of -14/-10, -21/-10, -22/-11, -24/-11 and -27/-17 mmHg at 1, 3, 6, 9 and 12 
months, respectively. In those subjects assessed for noradrenaline spillover, a mean reduction 
of 47% (95% CI 28-65%) was observed. For the 5 non-treated subjects, a mean rise in office 
based blood pressure of +3/-2, +2/+3, +14/+9 and +26/+17 mmHg was observed at 1, 3, 6 
and 9 months, respectively.  Long term 36-month follow-up data from the Symplicity HTN-1 
trial demonstrated a sustained effect of blood pressure reduction on the original treatment 
cohort.5,15 
HTN-1 safety outcomes were satisfactory with one occurrence of an intraprocedural renal 
artery dissection occurring before RF energy delivery without further sequelae. There were 
no other renovascular complications or serious adverse events reported.  
Building upon previous studies, the two and three year durability of blood pressure reduction 
via renal sympathetic renal nerve ablation was reported by Krum et al.5,15 _ENREF_2 A total 
of 153 patients with resistant hypertension were enrolled in the open label study. Follow-up 
assessments occurred at 1, 3, 6, 12, 18, 24 and 36 months. Renal nerve ablation resulted in 
highly significant blood pressure reductions that were maintained over the 3-year follow-up 
period.  
The mean blood pressure reductions reached 32 mmHg for systolic and 14 mmHg for 
diastolic at 36 months. Ninety-three percent of the patients had an office blood pressure 
reduction of ≥10 mmHg. The changes in both systolic and diastolic blood pressures were 
highly significant for all time points post procedure. Blood pressures were reduced on 
average by 21/10, 24/11, 26/11, 27/12, 26/14, 30/13 and 32/14 mmHg at 1, 3, 6, 12, 18, 24 
and 36 months respectively.15  
The procedure was without complication in 97% of patients (149/153). Complications 
included renal artery dissection, pseudoaneurysm/hematomas at the femoral access site, 
minor spasm or edema, progression of a preexisting renal artery stenosis and flank pain. 
Renal function remained stable during the first year of follow-up with a mean eGFR 
reduction of 2.9 ml/min/1.73 m2 (95% CI -6.2 to +0.3) for the 64 patients who were available 
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at 12 months. However, in the ten patients who completed the 24-month follow-up, there was 
a drop of 16 ml/min/1.73 m2 in eGFR values. The two and three-year durability study 
demonstrates that significant blood pressure reductions were sustained out to 24 and 36 
months which supports the durability of reduction in blood pressure due to renal nerve 
ablation. The procedure is well tolerated and generally safe. 
Based on the positive outcomes observed in HTN-1, a larger randomized trial (HTN-2) was 
conducted.  Simplicity HTN-216 was a multicenter prospective randomized trial designed to 
assess the effectiveness and safety of catheter-based renal denervation to produce a reduction 
in blood pressure in subjects with ‘treatment resistant hypertension’. Of the 190 subjects 
screened for eligibility, 106 were randomly allocated to renal denervation (n=52) or control 
(n=54) groups between June 9, 2009 and January 15, 2010.  The primary efficacy endpoint 
consisted of the change in seated office-based measurement of systolic blood pressure at 6 
months. The 6-month primary endpoint was assessed in 49 of the 52 subjects who underwent 
renal denervation and 51 of 54 controls. Office based blood pressure in the renal denervation 
group reduced by -32/-12 mmHg (baseline of 178/96 mmHg), whereas blood pressures did 
not differ from baseline in the control group (+1/0 mmHg, baseline of 178/97 mmHg).  
After the primary endpoint was met, 46 control patients (cross over group) underwent renal 
denervation. Esler et al17_ENREF_18 reported that the 6-month follow up of the cross over 
group showed a significant drop in blood pressure (190.0/99.9 mmHg to 166.3/91.5 mmHg). 
The one-year follow-up of the initial RDN group continued to show significantly lower blood 
pressure when compared to baseline office BP; although BP at 12 months was slightly 
elevated from the 6-month average (-31.7/-11.7 at 6 months compared to -28.1/-9.7 at 12 
months).   
As with HTN-1, a favorable safety profile was observed in HTN-2. Safety outcomes for 
HTN-2 demonstrated no serious procedure or device related complications or elevated 
occurrence rates of adverse events. In the treatment group, one subject had a possible 
progression of an underlying atherosclerotic lesion but required no further treatment.  
The Simplicity HTN-318 trial is a pivotal study designed as a prospective, randomized, 
masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based 
bilateral renal denervation for the treatment of resistant hypertension despite compliance with 
at least 3 antihypertensive medications of different classes at maximal tolerable doses.  Bhatt 
et al19 report 535 patients were enrolled into the trial; 2 treatment : 1control (masked 
procedure).  The primary efficacy endpoint of mean change at 6 months in systolic office 
blood pressure was not met.  The reduction for the treatment group was -14.13±23.93 mmHg 
and for the control was -11.74±25.94 mmHg; P=0.26.  The study continued to demonstrate 
safety of the technology with a 1.4% major adverse event rate for the renal denervation group 
and 0.6% for the masked procedure group.  Ongoing discussions continue as to why these 
results do not replicate those of previous trials.  Medication compliance and adjustments are 
thought to have played a role.20 
5.2.1.2. EnligHTN™ FIM  
The first-in-human, prospective, multi-center, non-randomized study to evaluate the safety 
and efficacy of the EnligHTN multi-electrode system to interrupt the renal sympathetic nerve 
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fibers in patients with drug-resistant hypertension was conducted in 46 patients (67% male, 
mean age 60 years, and mean baseline office blood pressure 176/96 mmHg) with drug-
resistant hypertension. The primary efficacy objective was change in office blood pressure 
from baseline to 6 months. Safety measures included all adverse events with a focus on the 
renal artery and other vascular complications and changes in renal function. Renal artery 
denervation, using the EnligHTN system significantly reduced the office blood pressure from 
baseline to 1, 3, 6 and 12 months by -28/10, -27/10, -26/10 mmHg and -27/-11, respectively 
(P=0.0001). No acute renal artery injury or other serious vascular complications occurred.  
Three patients had device and/or procedural related adverse events through the 12-month 
follow-up.  The events were hypotension, progression of renal artery stenosis and progression 
of hypertensive renal artery disease.  Small, non-clinically relevant, changes in average 
estimated glomerular filtration rate were reported from baseline (87±19 mL/min/1.73 m2) to 
6 months post-procedure (82±20 mL/min/1.73 m2) and 12 months post-procedure (86±21 
mL/min/1.73 m2).21,22 
6. Device Description 
The Vessix Renal Denervation System consists of the Vessix Reduce Catheter, a non-
compliant balloon catheter with bipolar electrodes mounted on the exterior of the balloon, the 
Vessix Generator (including power supply), and an optional patient extension cable. Study 
sites will also be provided with Vessix Guide Sheaths and a mobile roll cart for transporting 
the Vessix Generator. 
 
The Vessix Renal Denervation System is designed to deliver radio frequency (RF) energy to 
create precisely located and defined local lesions in the renal artery in order to inactivate the 
sympathetic nerves located in the adventitial layer of the renal artery. 
 
The Vessix Renal Denervation System is CE-marked, TGA-approved and approved for use 
in other regions, but is investigational in the US. 
6.1. Vessix Reduce Catheter 
The Vessix Reduce Catheter is a sterile, single use, over-the-wire percutaneous transluminal 
balloon catheter designed to transmit RF energy via surface-mounted electrodes to treat 
resistant hypertension. The balloon exterior surface carries bipolar electrodes that deliver RF 
energy to the renal arteries after low pressure (3 ATM) inflation via standard balloon 
angioplasty techniques. The electrodes are centered axially on a noncompliant PET balloon 
and are gold for radiopacity, thereby facilitating fluoroscopic visualization (see Figure 6.1-1).  
The number of electrodes on each balloon varies from 4 to 6 bipolar electrodes, depending on 
balloon diameter. 
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Figure 6.1-1 Vessix Reduce Catheter with Bi-Polar Electrodes 
The Vessix Reduce Catheter is available in balloon diameters of 4.0 mm, 5.0 mm, 6.0 mm 
and 7.0 mm, with a balloon length of 25 mm and a total catheter working length of 
approximately 90 cm. 
The catheter design incorporates standard angioplasty balloon features and is compatible 
with conventional interventional devices. The balloon is inflated to maximize electrode 
contact with the artery wall and temporarily occludes blood flow through the renal artery for 
optimal RF energy conduction. A mix of saline and contrast media is administered through a 
separate lumen in the catheter shaft by connecting an off-the-shelf inflation device to the 
Luer lock fitting on the catheter hub. 
Concentric to the balloon is a guidewire lumen which extends from the atraumatic distal tip 
axially to the proximal Luer lock hub port. The guidewire lumen enables the device to be 
advanced and retracted over a standard, off-the-shelf 0.014-inch or 0.018-inch guidewire. 
The overall diameter of the catheter shaft is compatible with 7F internal diameter guide 
sheaths and associated hemostatic control devices. All the fluid connection ports have a Luer 
lock and allow use of off-the-shelf inflation and hemostasis devices. The catheter is sterilized 
via E-Beam radiation. 
The key dimensional features of the Vessix Reduce Catheter are listed in Table 6.1-1 and the 
catheter components are illustrated in Figure 6.1-2. 
Table 6.1-1 Vessix Reduce Catheter Dimensional Features 
Attribute 
Vessix Reduce Catheter 
Balloon Diameters 
4.0 mm, 5.0 mm, 6.0 mm, or 7.0 mm 
Balloon Length 
25 mm 
Electrode Treatment Length 
21 mm 
Bipolar Electrode Length 
4 mm 
Number of Bipolar Electrodes 
4.0 mm diameter 
4 
5.0 mm, 6.0 mm and 7.0 mm 
diameter 
6  
Nominal Balloon Pressure 
3 ATM 
Rated Burst Pressure 
5 ATM 
Catheter Working Length 
90 cm 
Connector Cable Length 
145 cm 
Guidewire Compatibility 
0.014” and 0.018” 
Guide Sheath Compatibility 
7 French 
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Figure 6.1-2 Vessix Reduce Catheter Components 
 
6.2. Vessix Generator 
The Vessix generator is a portable bipolar RF generator which interfaces with the catheter to 
deliver low-power (typically 0.5-2 watts per electrode) RF energy into the renal artery at a 
treatment frequency of 480 kHz. The generator consists of a bright 9” diagonal LCD screen, 
minimalistic and user-friendly graphical user interface (GUI), and an assortment of indicator 
lights (LEDs) and physical buttons. 
 
The generator is classified as a Type BF applied part per ANSI/ASMI IS 60601-1:2009 3rd 
Edition. 
 
The catheter is connected to the generator either directly or via an intermediate accessory 3 
meter patient extension cable. The generator is pole-mounted to a mobile roll stand and does 
not reside within the sterile field.   
6.3. Patient Extension Cable 
The patient extension cable is a 3 meter cable that connects the Vessix Reduce Catheter to 
the Vessix Generator and allows for the RF equipment to be located outside the sterile field. 
Use of the patient extension cable is optional.   
6.4. Power Supply 
A medically-certified power supply will convert wall mains AC to local 15 VDC to power 
the Vessix Generator.  The power supply is not an investigational device. 
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6.5. Roll Cart 
The Vessix Generator is mounted onto the top of a mobile roll cart. A bracket is also 
mounted onto the roll cart in order to secure the Vessix Generator power supply (external 
power supply brick). A basket is mounted below the Vessix Generator for holding non-sterile 
items and spooling up the patient extension cable.  The roll cart is not an investigational 
device. 
6.6. Guide Sheath 
The Vessix Guide Sheath will be provided to study sites, along with the system components 
outlined above. The Vessix Guide Sheath has an inner diameter of 0.10 inch (2.5 mm), 
Model # H749RDNDCR14500 (RDC) or H749RDNDCL14500 (LIMA). The Vessix Guide 
Sheath is not an investigational device. It is recommended that the Vessix Reduce Catheter 
be used with the Vessix Guide Sheath. 
6.7. Device Labeling 
The Vessix Reduce Catheter Directions for Use (DFU), Operator’s Manual (OM) and 
packaging are labeled as investigational. Use of these devices outside of this clinical study is 
strictly prohibited. A copy of the DFUs and OM will be provided in the local language and 
are included in the study Manual of Operations. The catheter packaging will include 
peelable, self-adhesive labels for each unit shipped. The labeling will include the following 
information in English. 
• Product Name 
• Universal Part Number (UPN) 
• Serial or tracking identification number 
• Lot number 
• Product dimensions  
• Expiration (use by) date 
7. Objectives 
The objective of the REDUCE-HTN: REINFORCE Clinical Study is to assess safety and 
efficacy of the Vessix™ Renal Denervation System for the treatment of uncontrolled 
hypertension [off-treatment office systolic blood pressure (OSBP) ≥150 mmHg and ≤180 
mmHg]. 
8. Endpoints 
The endpoints of the study are based upon the safety and efficacy of the Vessix Renal 
Denervation System. 
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8.1. Primary Efficacy Assessment 
The primary efficacy assessment is the mean reduction in average 24-hour ambulatory 
systolic blood pressure (ASBP) at 8 weeks post randomization. 
8.2. Safety Assessments 
Safety Assessments analyzed at all follow-up time points: 
• 
All-cause death 
• 
Renal failure 
• 
Hospitalization for hypertensive crisis  
• 
Hospitalization due to severe hypotension/syncope 
 
Safety Assessments analyzed at 4 weeks: 
• 
Significant embolic event resulting in end-organ damage or intervention to prevent it 
• 
Renal artery dissection or perforation requiring intervention 
• 
Vascular complications requiring surgical repair, interventional procedure, thrombin 
injection, or blood transfusion 
Safety Assessments analyzed at 6 months: 
• 
Significant new renal artery stenosis assessed by duplex ultrasound (DUS) and 
confirmed by the angiographic core laboratory [>70% stenosis by computed 
tomographic angiography (CTA) or digital subtraction angiography (DSA)] through 6 
months post randomization 
• 
Subjects will be required to have a 6-month duplex ultrasound to assess for 
evidence of significant stenosis, defined as ≥60% as reported by the duplex 
ultrasound (DUS) core laboratory.  A significant stenosis (≥60%) detected by 
DUS will trigger the performance of a confirmatory CTA or DSA. 
• 
If a diagnostic duplex ultrasound cannot be adequately achieved at the 6- 
month follow-up, then a CTA or DSA must be conducted. 
NOTE: All Safety Assessments will be adjudicated by an independent Clinical Events 
Committee (CEC)    
8.3. Secondary Assessments 
Additional Assessments analyzed at all follow-up time points: 
• 
Mean reduction in office-based systolic blood pressure (OSBP) from baseline 
• 
Mean reduction in office-based diastolic blood pressure (ODBP) from baseline 
• 
Percent of subjects at target blood pressure 
• 
Episodes of Congestive Heart Failure (CHF) 
• 
Stroke 
• 
Myocardial Infarction (MI) 
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Additional Assessments analyzed at 3 and 6 months: 
• 
Anti-hypertensive medications  
Additional Assessments analyzed at 6 and 12 months: 
• 
Mean reduction in average 24-hour ambulatory systolic blood pressure (ASBP) from 
baseline 
• 
Mean reduction in average 24-hour ambulatory diastolic blood pressure (ADBP) from 
baseline 
9. Design 
The REDUCE-HTN: REINFORCE Clinical Study is a prospective, single blinded, 
multicenter, randomized, controlled, pilot study. 
9.1. Scale and Duration   
The REDUCE-HTN: REINFORCE Clinical Study will enroll up to 100 subjects.  This study 
will be conducted at up to 20 study centers in the United States.  The expected duration of 
this clinical study is anticipated to be approximately 4 years.  Figure 9.1-1 below outlines the 
study screening and treatment flow. 
After approval of protocol version AH, subjects will be required to complete a minimum of 
24 months follow up post randomization. 
 
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Anatomical 
criteria met?
RDN
Control
Follow-up at: 2, 4, 8 weeks & 3, 4, 5, 6, 12, 18, 24, 30, 36 months
Screen Failure 
1 time optional 
rescreen for 
technical 
failure
Screen 
Failure 1 
time 
optional 
rescreen
Pre-Screen
Informed Consent
Medical history & 
OBP assessments
Medication 
wash-out                    
(if applicable)
Eligibility OBP & 
limited physical 
exam
OBP criteria 
met?
ABPM
ABPM criteria 
met?
Baseline labs & QOL
Lab criteria 
met?
Non-invasive 
imaginng 
Screen 
Failure 1 
time 
optional 
rescreen
Screen 
Failure
Diagnostic 
angiogram
Final eligibility 
confirmed?
Randomization/
enrollment
Screen 
Failure
Yes
No
No
No
Yes
Yes
Yes
Within 14 days
Yes
No
Screen 
Failure
Clinical criteria 
met?
 
Figure 9.1-1: REDUCE-HTN: REINFORCE Study Design 
 
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9.2. Treatment Assignment 
The REDUCE-HTN: REINFORCE Clinical Study is a randomized study with treatment arm 
assignments.  Subjects who meet all the inclusion criteria and do not meet any exclusion criteria 
will be assigned to treatment in a 2:1 (Treatment:Control) scheme.   
Randomization will be accomplished using an Interactive Randomization System. Subjects will 
be considered enrolled at the time of randomization.   
9.2.1. Treatment and Control 
9.2.1.1. Treatment 
The device to be evaluated will consist of the Vessix Renal Denervation System: 
• Vessix Reduce Catheter (4.0, 5.0, 6.0 and 7.0 mm) 
• Vessix Generator (bipolar radio frequency) 
9.2.1.2. Control 
The control for the primary efficacy assessment is a masked procedure. 
9.2.2. Target and Non-target Arteries 
For each kidney, main renal arteries and accessory renal arteries (as applicable) which meet all 
the inclusion criteria and do not meet any of the exclusion criteria will be treated in this study.   
9.3. Justification for the Study Design 
The REDUCE-HTN: REINFORCE Clinical Study is intended to demonstrate the effects of renal 
denervation in the absence of potentially confounding antihypertensive medications. The design, 
including an antihypertensive medication wash-out phase, is similar to pharmaceutical study 
designs looking at early efficacy of compounds. The number of safety events in patients off 
therapy during the primary efficacy assessment period is low in the pharmaceutical studies.23,24 
 
A masked procedure will be used as the control for this study. Subjects and study personnel 
obtaining OBP will be blinded to treatment assignment. The primary efficacy endpoint will be 
evaluated using ABPM which minimizes any placebo effect25. Subject blinding, the blinded 
blood pressure assessor and the utilization of ABPM will provide unbiased data in support of 
efficacy.   
 
Because REDUCE-HTN: REINFORCE Clinical Study is the first study to evaluate the Vessix 
Renal Denervation System in this off medication population, actions will be taken throughout the 
course of the study to minimize risks to enrolled subjects. These risk minimization efforts are 
summarized in Section 21.2.  
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10. Subject Selection  
10.1. Study Population and Eligibility  
The subject population for this clinical study will be drawn from the Investigators’ general or 
professional referral population.  The inclusion and exclusion criteria are included, respectively, 
in Sections 10.2 and 10.3 below.  
10.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 10.2-1) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (see Section 10.3) is met.  
Table 10.2-1: Inclusion Criteria 
• 
Age ≥18 and ≤75 years 
• 
OSBP ≥150 mmHg and ≤180 mmHg based on an average of 3 office-
based blood pressure measurements 
• 
Average 24-hour ASBP ≥135 mmHg and ≤170 mmHg 
• 
For each kidney, a main renal artery, with or without accessory renal 
arteries, with diameter ≥3.0 mm and ≤7.0 mm and length ≥20.0 mm 
• 
Agrees to have all study procedures performed, and is competent and 
willing to provide written, informed consent 
 
10.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 10.3-1) will be excluded from this 
clinical study. 
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Table 10.3-1: Exclusion Criteria 
Exclusion 
Criteria 
• 
Previous renal artery intervention or clinically significant renal artery 
abnormalities that would interfere with safe cannulation of the renal 
artery 
• 
Stenosis >30% or renal artery aneurysm in either renal artery 
• 
Fibromuscular dysplasia (FMD) 
• 
Platelet count of <90,000 or >500,000 per microliter (µL) of blood or 
history of bleeding diathesis 
• 
Known causes of secondary HTN  
• 
Type 1 diabetes mellitus 
• 
eGFR <40 mL/min/1.73m2, as calculated using the MDRD 
(Modification of Diet in Renal Disease) methodology1  
• 
Only one kidney or prior transplantation  
• 
Contraindicated for anticoagulant therapy and other recommended 
study medications 
• 
Known hypersensitivity or contraindication to contrast dye that, in the 
opinion of the investigator, cannot be adequately pre-medicated 
• 
Pregnant or planning to become pregnant  
• 
History of myocardial infarction (MI), unstable angina pectoris, 
hypertensive crisis, or a cerebrovascular accident (CVA) in the 
previous 3 months 
• 
Known ejection fraction of <30% or heart failure that required 
hospitalization in the previous 6 months 
• 
Scheduled for or has planned surgery or cardiovascular (CV) 
intervention in the next 6 months 
• 
≥1 episode(s) of orthostatic hypotension not related to medication 
changes, coupled with symptoms, within the past year or identified 
during screening 
• 
Severe valvular heart disease 
• 
History of any serious medical condition, which in the opinion of the 
investigator, may adversely affect the safety of the participant and/or 
the scientific integrity of the study 
• 
Active implantable device [e.g., implantable cardioverter-defibrillator 
(ICD), cardiac resynchronization therapy defibrillator (CRT-D), spinal 
cord stimulators, cochlear implants] 
• 
Current participation in another drug or device trial  
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11. Subject Accountability 
11.1. Informed Consent 
All subjects will be required to sign an informed consent form prior to the conduct of any study 
specific tests or procedures that are not standard of care. No study specific data will be collected 
without first obtaining written consent for study participation.  
11.2. Point of Enrollment 
Once a subject has signed the IRB approved study informed consent form, and has met all 
clinical inclusion and no clinical exclusion criteria, the subject will be considered eligible to be 
enrolled in the trial. If a subject is found to meet exclusion criteria during the angiographic 
eligibility assessment, the subject will be considered a screen failure and should not be enrolled.  
If the subject is found to meet the inclusion criteria during the diagnostic angiographic phase of 
the procedure, he/she should be randomized to Treatment or Control using the Interactive 
Randomization System at which time the subject is considered enrolled in the study. 
11.3. Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study or 
lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
related to investigational device safety or performance, the investigator shall ask for the subject’s 
permission to follow his/her status/condition outside of the clinical study.   
Reasons for withdrawal may include but are not limited to: 
• 
Physician discretion  
• 
Subject choice to withdraw consent  
• 
Lost to follow-up or death  
While study withdrawal is discouraged, subjects may withdraw from the study at any time with 
or without reason, and without prejudice to further treatment.  
Additional data may not be collected after the point at which the subject has been withdrawn 
from the study, or withdraws his/her consent. All open adverse events should be closed or 
documented as chronic (ongoing). Data collected up to the point of subject withdrawal may be 
used.  
11.4. Subject Status and Classification 
Subjects will be classified in the study based upon subject conditions that relate to the subject 
selection process/consent process or further procedures.  The definitions are: 
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Screen Failure: A subject who has signed the informed consent and undergoes screening 
evaluation(s), but is found to not meet the eligibility criteria. 
Intent: A subject who has signed the informed consent and is randomized/enrolled in the study. 
Per-protocol:  A subject who meets the eligibility criteria and is randomized/enrolled in the study 
and received the assigned treatment (renal denervation or masked procedure). 
12. Study Methods 
12.1. Data Collection 
The visit and data collection schedule for the REDUCE-HTN: REINFORCE Study is provided 
in Table 12.1-1.  Subjects may be followed for up to 36 months but are only required to complete 
follow up through the 24 month visit.   
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Table 12.1-1: REDUCE-HTN: REINFORCE Study Data Collection for Scheduled Visits 
 
 
Screening / 
Baseline 
RDN and 
Masked 
Procedure 
 
Hospital 
Discharge 
 
2 Wks 
(14±7 
days) 
4 Wks 
(28±7 
days) 
8 Wks 
(56 ±7 
days)  
3 Mon 
(90 ±14 
days) 
4 Mon 
(120 
±14 
days) 
5 Mon 
(150 
±14 
days) 
6 Mon 
(180 
±14 
days)  
12 
Mon 
(365 
±30 
days) 
18 
Mon 
(540 
±30 
days) 
24 
Mon 
(730 
±30 
days) 
30 
Mon 
(900 
±30 
days) 
36 
Mon 
(1095 
±30 
days) 
Office Seated BP 
x 3; Standing BP; 
Heart Rate; 
Height & Weight; 
Limited Physical 
Exam  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X3 
24-hour 
Ambulatory BP  
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Quality of Life 
(PGWBI) 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X3 
Renin2 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Aldosterone2 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Serum Creatinine 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X3 
CBC with 
platelets, BMP, 
HbA1c 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X3 
Pregnancy Test 
(as applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTA 
X 
 
 
 
 
 
 
 
 
X1 
 
 
X4 
 
 
Renal Angiogram 
(DSA) 
 
X 
 
 
 
 
 
 
 
X1 
 
 
X4 
 
 
Renal Duplex 
Ultrasound (DUS) 
 
 
 
 
 
 
 
 
 
X 
 
 
X4 
 
 
Adverse events 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X3 
Blinding Index 
Assessment 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
1 A Renal DUS is required for subjects who receive treatment. If DUS shows a ≥60% stenosis per the core laboratory or is inconclusive per the core laboratory after repeat DUS, 
CTA or DSA are required.  
2 Renin and Aldosterone Serum tests will be collected at screening/baseline, 8 weeks and 6 months post-randomization.  Subjects that are enrolled/randomized prior to the 
implementation of protocol version AB will not undergo Renin or Aldosterone testing  
3 Visit/assessment not required after approval of protocol version AH. 
4 Only subjects who received treatment and reach the 24 month follow up after approval of protocol version AH will be required to undergo a DUS at 24 months. If the DUS shows 
a ≥60% stenosis per the core laboratory or is inconclusive per the core laboratory after repeat DUS, a CTA or DSA is required.  
 
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12.1.1. Medical Equipment Description 
12.1.1.1. Office-based Blood Pressure Monitoring 
Office-based blood pressure (OBP) measurements will be collected during screening, at 
hospital discharge and each study follow-up visit with an automatic oscillometric Omron 
HEM-705CP-II monitor (Omron Healthcare, Vernon Hills, IL, USA) with a printer for 
documentation. Blood pressure will be measured according to the Standard Joint National 
Committee VII26 and the European Society of Cardiology and European Society of 
Hypertension27 recommendations.  The devices should be properly maintained and regularly 
calibrated according to the manufacturer’s recommendations. 
 
Office-based blood pressure must be obtained by study personnel that are blinded to 
treatment assignment through the 6-month follow-up visit. Site blinding guidelines are 
described in the Manual of Operations. 
 
Refer to the instruction manual for the OBP monitor for set up and care information, and 
instructions for preparing the subject for blood pressure (BP) measurements, applying the BP 
cuff, taking the BP measurements and using the monitor in special conditions (i.e., SBP 
>220mmHg).   
 
NOTE: A properly sized BP cuff should be selected based upon the subject’s arm 
circumference. 
 
During subject preparation the subject should: 
• avoid smoking, eating or vigorous exercise for 30 minutes prior to the BP 
measurements  
• sit quietly for 5 minutes prior to the measurements 
• sit in a chair with feet flat on the floor  
• rest arm on a table so that the cuff is at the same level as the heart 
• avoid talking during the measurements 
 
NOTE: The BP should be measured in both upper arms at the screening visit to detect 
possible differences in the measurements.  The arm with the higher values should be used for 
baseline and all subsequent measurements.  It is recommended to obtain follow-up BP 
measurements at the same time of day as the baseline measurements are obtained. 
 
Three (3) BP measurements will be obtained using the same arm at least 2-3 minutes apart 
during a single visit.  The provided monitor must be used for all OBP measurements. If the 
lowest and highest systolic BP (SBP) measurements are more than 15 mmHg apart, 
additional readings should be performed. The last 3 consecutive consistent SBP 
measurements will be averaged to determine the final value to be used to assess eligibility. If 
the lowest and highest SBP measurements are more than 20 mmHg apart after a total of six 
measurements, the measurements will not be used to assess study eligibility, but the subject’s 
OBP may be reassessed for study eligibility at a subsequent time point.  If the lowest and 
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highest SBP values remain more than 20 mmHg apart after 6 measurements at a subsequent 
assessment, the patient will be excluded from the study.  
 
To assess for orthostatic hypotension during screening and follow-up, a standing BP 
measurement must be obtained within 3 minutes of assuming a standing position using the 
standardized equipment provided for the study. 
 
NOTE: The heart rate will be recorded at the same time as all blood pressure measurements. 
12.1.1.2. 24-Hour Ambulatory Blood Pressure Monitoring  
24-hour ambulatory blood pressure monitoring (ABPM) will be performed at screening, the 4 
and 8-week, and 6 and 12-month follow-up visits post randomization.  A qualified ABPM 
core laboratory will be utilized. The core laboratory will provide validated ABPM equipment 
to all study sites.    
The ABPM measurements will be collected with the Microlife® Watch BP-03 (Microlife 
Intellectual Property GMBH, Great Neck, NY, USA) with readings taken as described in 
ABPM Core Laboratory Manual and overall 24-hour averages calculated for each subject.  
Minimum acceptance criteria, as described in the Manual of Operations, are required for 
inclusion of the ABPM data.  If the minimum acceptance criteria are not met, the ABPM 
procedure may be repeated if the study visit window allows. 
ABPM data will be transmitted to, reviewed and managed by the core laboratory, and 
reported to Boston Scientific Corporation (BSC) or delegate for analysis purposes.   
The ABP monitor set up, care information, instructions for preparing the subject for ABPM 
measurements, applying the ABPM cuff, fitting the ABP monitor and transmitting the ABPM 
data are outlined in the ABPM Core Laboratory Manual.   
12.2. Study Candidate Screening 
Subjects will be pre-screened for participation in the study through a review of medical 
records and attainment of clinical data to support the eligibility criteria (inclusion and 
exclusion criteria) through normal standard of care procedures.  
12.3. Informed Consent 
All subjects who appear to meet the eligibility criteria based on pre-screening will have the 
study explained to them. They will be provided a copy of the written informed consent form 
(ICF) and extended an invitation to sign the form to allow further assessments to be 
conducted to determine their eligibility to participate in the study.  
 
Study personnel should explain to the subject that even if the subject agrees to participate in 
the study and signs the ICF, screening assessments prior to randomization/enrollment, 
including the diagnostic angiogram, may demonstrate that the subject is not a suitable 
candidate for the study. 
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12.3.1. Post-Consent Eligibility Validation 
Participation in the study begins with signing the informed consent as described in Section 
11.1.  During the screening period (see Section 12.4) eligibility for the study is assessed.  If 
the subject does not meet the eligibility criteria, the subject will be considered a screen 
failure and no further follow-up will be required. 
12.4. Screening 
All screening assessments are to be conducted at the study site by the study staff.  The tests 
required at screening are summarized in Table 12.1-1 and described in Sections 12.4 to 
12.4.7. 
If the subject is found to not meet study eligibility criteria during the screening period, 
including during diagnostic angiography, the subject will be considered a screen failure and 
should not be randomized/enrolled.  A Screening Log will be maintained in the EDC system 
to document selected information about subjects who fail to meet the REDUCE-HTN: 
REINFORCE Clinical study eligibility, including the reason for screen failure.   
12.4.1. Demographics and Medical History (within 50 or 21 days prior to 
randomization) 
Demographic data (age, gender, race, etc.) will be collected within 50 days (for patients 
requiring wash-out) or 21 days (for patients not requiring wash-out) of randomization.  A 
comprehensive medical history will be collected to verify inclusion/exclusion criteria. 
12.4.2. Medication Wash-Out Period [a minimum of 4 weeks (28 days) prior to 
randomization] 
All patients that meet medical history requirements and sign the study Informed Consent 
Form will be discontinued from current antihypertensive medications, as applicable.  There 
will be a 4-week wash-out phase prior to randomization.  If a patient is not on 
antihypertensive medication at the time of Informed Consent, the wash-out period is not 
applicable. 
12.4.3. Limited Physical Examination (within 21 days prior to randomization) 
A limited physical examination, including weight and height will be conducted.  
12.4.4. Blood Pressure Monitoring (within 21 days prior to randomization) 
12.4.4.1. Office-Based BP and Heart Rate 
Office-based blood pressure measurements collected during the screening period will be used 
to determine whether or not the subject meets the inclusion criteria. Office-based blood 
pressures will be measured using an electronic sphygmomanometer (Omron HEM-705CP-II 
monitor (Omron Healthcare, Vernon Hills, IL, USA) according to the instructions in Section 
12.1.1.1.  A heart rate will be recorded at the time of each blood pressure measurement. The 
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office-based blood pressure measurements documenting study eligibility must be performed 
after the medication wash-out period if applicable and within 21 days prior to randomization. 
12.4.4.2. 24-Hour Ambulatory BP Monitoring 
24-hour Ambulatory BP Monitoring, during the screening period, will be used to determine 
whether or not subjects meet the study inclusion criteria. 24-Hour Ambulatory Blood 
Pressure Monitoring will be performed as outlined in the Ambulatory Blood Pressure 
Monitoring Core Laboratory Manual.  The ABP measurement documenting eligibility must 
be performed after the medication wash-out period if applicable and within 21 days prior to 
randomization. 
12.4.5. Laboratory Assessments and Calculations (within 21 days prior to 
randomization/enrollment) 
All subjects will have screening blood assays conducted including basic metabolic panel 
(BMP) of sodium, potassium, calcium, chloride, bicarbonate, glucose, blood urea nitrogen 
(BUN) and serum creatinine.  The serum creatinine (plus demographic, height and weight 
data) will be used to calculate an estimated glomerular filtration rate (eGFR).  In addition, 
renin, aldosterone, HbA1c and complete blood count (CBC) with platelet count will be 
collected.   
A urine or serum pregnancy test will be performed on all prospective female subjects of 
child-bearing potential within 24 hours of randomization. 
12.4.5.1. eGFR Calculation 
The Modification of Diet in Renal Disease (MDRD) Study1 equation will be used to calculate 
the eGFR for all subjects enrolled in the study. The MDRD calculation utilizes the serum 
creatinine reported in mg/dL and is normalized to a 1.73 m2 body surface area, which is an 
accepted average adult body surface area. See the definition and formula in Table 27.2-1: 
Definitions Table 27.2-1.   
12.4.6. Non-Invasive Imaging (within 6 months prior to informed consent)  
12.4.6.1. Computed Tomographic Angiography (CTA) 
A computed tomographic angiography (CTA) of the kidneys must be performed using 
standard techniques to confirm that all anatomical inclusion criteria have been met, and that 
none of the exclusion criteria have been met. The CTA may have been performed within 6 
months of the patient signing Informed Consent. If a CTA has not been previously 
performed, it is recommended that the CTA be performed once office and ambulatory BP 
eligibility has been confirmed. 
Visual assessment will be used to determine if criteria are met. This initial anatomic 
assessment should be recorded in the subject medical records to document that study 
eligibility criteria have been met. CTA images must be sent to the angiographic core 
laboratory for evaluation. 
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NOTE:  Final anatomic eligibility will be confirmed during diagnostic angiography (see 
Section 12.5.1.1). 
12.4.7. Quality of Life Assessment (within 7 days prior to randomization) 
Quality of Life (QOL) Survey: Psychological General Well-Being Index (PGWBI)28 will be 
administered to the subject within seven (7) days prior to randomization. 
12.5. Treatment Period 
For the REDUCE-HTN: REINFORCE Clinical Study, subjects will be randomized to either 
the control group, who will receive a masked procedure or to the treatment group, who will 
receive renal denervation. All subjects will be washed out from antihypertensive medications 
and remain off medications through the primary efficacy assessment at 8 weeks post 
randomization unless rescue medication is required as described in Section 13.1. 
12.5.1. Diagnostic Renal Angiogram, Masked Procedure and Renal Denervation 
Procedure  
Patients meeting all clinical eligibility and anatomic eligibility based on non-invasive 
imaging will undergo diagnostic renal angiography. If anatomic eligibility is confirmed 
during the diagnostic angiogram, the patient will be immediately randomized and enrolled to 
the control or to the renal denervation treatment. 
12.5.1.1. Diagnostic Renal Angiogram 
A diagnostic aortogram should be performed to obtain visual confirmation of all renal 
arteries. A selective arteriogram will be performed on each renal artery using a diagnostic 
catheter in order to confirm anatomic eligibility is met.   
NOTE: If new anatomical exclusion criteria are identified during the angiogram the patient 
should not be randomized. 
Upon catheter/sheath removal, either manual compression or commercialized closure devices 
can be used to achieve hemostasis at the puncture site. Standard-of-care post-intervention 
monitoring procedures should be followed. 
Angiographic images must be sent to the angiographic core laboratory for evaluation. 
12.5.1.1.1 Diagnostic Angiogram Medications 
Investigators should prescribe procedural medications consistent with current clinical 
practice for renal endovascular procedures. Consider pre-treatment with anxiolytic 
medications. Subjects must be sedated. Intra-arterial vasodilators may be administered during 
angiogram to prevent spasm. 
Investigators should ensure close monitoring of the amount of contrast for subjects with low 
baseline eGFRs. 
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12.5.1.2. Masked Procedure 
The masked procedure will consist of the diagnostic renal angiogram performed to confirm 
anatomic eligibility (see Section 12.5.1.1). 
12.5.1.2.1 Masked Procedure Medications 
Investigators should prescribe procedural medications as described for the diagnostic 
angiogram in Section 12.5.1.1.1. 
12.5.1.3. Renal Denervation Procedure 
Investigators should practice standard of care for procedures not defined in the protocol, 
Vessix Reduce Catheter Directions for Use (DFU) or Vessix Generator Operators Manual 
(OM). The DFU and OM contain more detailed Vessix Reduce Catheter preparation, Vessix 
Generator operation, cable connections, power algorithms and trouble-shooting instructions. 
Investigators should consider placement of a Foley catheter and make additional allowances 
for appropriate analgesic.  
12.5.1.3.1 Renal Denervation Procedure Medications 
Investigators should prescribe procedural medications consistent with current clinical 
practice for subjects randomized to renal denervation treatment. Anti-coagulation therapy 
administered during the procedure should be consistent with current clinical practice for renal 
endovascular procedures. There is no protocol requirement for heparin reversal or antiplatelet 
therapy post-procedure. Investigators may consider a low dose aspirin regimen if they feel 
that prophylactic platelet anti-aggregation is warranted. 
There is no clinical evidence to date suggesting the need for anticoagulant/ antiplatelet 
medications post-treatment. 
Subject must be able to tolerate analgesics during the treatment. Consider pre-treatment with 
both anxiolytic medications and analgesic medications, such as morphine sulfate or fentanyl. 
Subjects must be sedated. Intra-arterial vasodilators may be administered during the 
procedure or prior to final angiogram after completing the procedure to prevent spasm. 
Investigators should ensure close monitoring of the amount of contrast for subjects with low 
baseline eGFRs. 
12.5.1.3.2 Renal Artery Access 
• 
Use a femoral puncture technique to insert an appropriately sized (5 or 6F) introducer 
sheath. An activated clotting time (ACT) of >200 seconds is recommended prior to 
the initiation of the renal denervation procedure. 
• 
The appropriate Vessix Reduce Catheter to be used for the treatment should be 
identified from the information in Table 12.5-1 below. 
 
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Table 12.5-1: Vessix Reduce Catheter Sizing 
 
Recommended Catheter Sizing Table 
Artery Size 
Balloon Size 
3.0 - 4.0 mm 
4.0 mm 
3.8 - 5.0 mm 
5.0 mm 
4.7 - 6.0 mm 
6.0 mm 
5.6 - 7.0 mm 
7.0 mm 
 
• 
The short sheath should be exchanged for the recommended 7F guide sheath (Vessix 
Guide Sheath). 
• 
Introduce a 0.014 inch or 0.018 inch guide wire into the renal vasculature via the 
guide sheath.  The wire should be placed beyond the bifurcation.  Once access is 
secured, the Vessix Reduce Catheter should be prepared for treatment.  
12.5.1.3.3 Placement of Vessix Reduce Catheter 
• 
Insert the Vessix Reduce Catheter over the guide wire through the sheath. If 
resistance is encountered, do not force passage. Resistance may indicate a problem 
and may result in damage to the balloon circuitry if it is forced. If significant 
resistance is encountered, remove and replace the Vessix Reduce Catheter. 
• 
Advance the Vessix Reduce Catheter over the guide wire until the balloon is fully 
inside the renal artery, and the distal electrode is located 3 - 5 mm proximally to the 
first bifurcation, using direct fluoroscopic visualization. Do not torque the Vessix 
Reduce Catheter during insertion or placement. 
• 
Utilize the proximal and distal electrodes on the balloon as a reference to optimally 
position the Vessix Reduce Catheter. 
NOTE: Due to the length of the balloon catheter and average length of the renal 
artery, no more than two non-overlapping treatments per artery are expected. 
12.5.1.3.4 Vessix Reduce Catheter Activation and RF Treatment 
• 
Once connection to the Vessix Generator is confirmed, the Vessix Reduce Catheter 
can be inflated moving in 0.5 ATM increments up to a pressure of 3.0 ATM. 
• 
When proper apposition is confirmed by the Vessix Generator upon balloon inflation, 
fluoroscopy should be used to demonstrate that the catheter is at the optimal position 
and that blood flow is occluded. Discontinue use of the Vessix Reduce Catheter if 
excessive pressure is required to inflate the balloon. 
• 
Perform the denervation treatment. (See Vessix Generator Operators Manual). 
• 
Initiate the treatment by pressing the Treat Button on the front of the Vessix 
Generator. (See the Vessix Generator Operators Manual).  
• 
If the more proximal portion of the artery needs to be denervated to achieve treatment 
of the full length of the renal artery, avoid overlap of treatment zones. It is 
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recommended that the gap between treatment zones is approximately 5mm. (NOTE: 
To allow for a partial treatment it is acceptable for the balloon to be located partially 
outside of the renal artery in the aorta). 
• 
Upon completion of the treatment, deflate the balloon by 0.5 ATM decrements and 
carefully retract the balloon back into the guide sheath, preferably in a coaxial 
manner. If resistance is encountered, advance the balloon 5 to 10 mm back into the 
renal artery, and carefully retract the balloon again into the sheath with care to avoid 
drawing the sheath into the artery. The guide wire should remain in the renal artery 
until a selective renal arteriogram has been completed. 
• 
Perform post procedural imaging on the treated renal artery. 
• 
Treat the contralateral renal artery at this time if the Vessix Reduce Catheter is 
appropriately-sized. If treatment of the contralateral renal artery requires a different 
balloon size, remove the Vessix Reduce Catheter, and insert an appropriately sized 
catheter. 
• 
Treat accessory renal arteries at this time if study anatomical criteria are met.  Ensure 
the Vessix Reduce Catheter is appropriately-sized. If treatment of the accessory renal 
artery requires a different balloon size, remove the Vessix Reduce Catheter, and insert 
an appropriately sized catheter. 
12.5.1.3.5 Vessix Reduce Catheter Deflation and Removal 
• 
Slowly deflate the balloon to negative pressure. 
• 
Carefully retract the Vessix Reduce Catheter through the guide sheath and out of the 
body.  
• 
Upon guide sheath removal, either manual compression or commercialized closure 
devices can be used to achieve hemostasis at the puncture site. Standard-of-care post-
intervention monitoring procedures should be followed. 
 
Angiographic images must be sent to the angiographic core laboratory for evaluation. 
NOTE: Re-treatment with renal denervation is not allowed through the protocol follow-
up period. 
12.5.2. Data Collection 
The following data will be collected during and after the procedure. 
• 
Procedural times 
• 
Device usage data 
• 
Generator display data, including the number of electrodes activated 
• 
Renal anatomical measurements 
• 
Medications 
• 
ACT – should be therapeutic at > 200 seconds once the femoral access is in place 
prior to the introduction of the investigational device  
• 
Adverse events 
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12.6. Hospital Discharge 
Prior to hospital discharge, the following will be reviewed and documented:  
• 
Limited physical examination including height and weight  
• 
Blood assays (serum creatinine, CBC and platelets, BMP and HbA1c) 
• 
Office-based sitting and standing blood pressure (obtained by blinded study 
personnel) and heart rate 
• 
Medications administered since last visit including medications administered during 
the hospitalization 
• 
Adverse events  
• 
Blinding index assessment 
Subjects should be made familiar with the follow-up study visit schedule and instructed to 
report any unusual pain or symptomology, medication changes, etc. to the study Investigator 
between study follow-up visits. Antihypertensive medications should only be added and/or 
adjusted by study Investigators as described in Figure 13.2-1. 
12.7. Follow-up Visit Week 2 (14 ±7 days) 
The 2-week follow-up office visit (14 ±7 days) will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Office-based sitting and standing blood pressure (obtained by blinded study 
personnel) and heart rate 
• 
Medications administered since last visit  
• 
Adverse events 
12.8. Follow-up Visit Week 4 (28 ±7 days) 
The 4-week follow-up office visit (28 ±7 days) will include the following assessments: 
• 
24-Hour Ambulatory BP Monitoring  
• 
Limited physical exam including height and weight 
• 
Office-based sitting and standing blood pressure (obtained by blinded study personnel 
in the US) and heart rate 
• 
Medications administered since last visit  
• 
Adverse events 
12.9. Follow-up Visit Week 8 (56 ±7 days) 
The 8-week follow-up office visit (56 ±7 days) will include the following assessments: 
• 
24-Hour Ambulatory BP Monitoring  
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• 
Limited physical exam including height and weight 
• 
Quality of Life Assessment 
• 
Blood assays (serum creatinine, CBC and platelets, renin, aldosterone, BMP and 
HbA1c) 
• 
Office-based sitting and standing blood pressure (obtained by blinded study personnel 
in the US) and heart rate 
• 
Medications administered since last visit 
• 
Adverse events 
• 
Blinding index assessment  
After completion of the 8-week follow-up assessments, subjects not at target (target defined 
as OSBP <140 mmHg) will have antihypertensive medications reintroduced as described in 
Section Medication Additions13. 
12.10. Follow-up Visits Months 3, 4 and 5 (90 ±14 days, 120 ±14 days, 150 ±14 days) 
The 3-month (90 ±14 days), 4-month (120 ±14 days) and 5-month (150 ±14 days) follow-up 
visits will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Office-based sitting and standing blood pressure (obtained by blinded study personnel 
in the US) and heart rate 
• 
Medications administered since last visit 
• 
Adverse events 
After completion of the 3, 4 and 5-month OBP follow-up assessments, subjects not at target 
(target defined as OSBP <140 mmHg) will have antihypertensive medications adjusted or 
reintroduced as described in Section 13.2. 
12.11. Follow-up Visit Month 6 (180 ±14days) 
The 6-month follow-up office visit (180 ±14 days) will include the following assessments: 
• 
24-Hour Ambulatory BP Monitoring 
• 
Limited physical exam including height and weight 
• 
Quality of Life Assessment 
• 
Blood assays (serum creatinine, CBC and platelets, renin, aldosterone, BMP and 
HbA1c) 
• 
Office-based blood sitting and standing pressure (obtained by blinded study 
personnel) and heart rate 
• 
Medications administered since last visit 
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• 
Renal Duplex Ultrasound (DUS) - for subjects who received renal denervation 
treatment 
o Subjects will be required to have a 6-month duplex ultrasound to assess for 
evidence of significant stenosis, defined as ≥60% as reported by the duplex 
ultrasound (DUS) core laboratory.  A significant stenosis (≥60%) detected by 
DUS will trigger the performance of a confirmatory CTA or DSA. 
o If a diagnostic duplex ultrasound cannot be adequately achieved at the 6- 
month follow-up, then a CTA or DSA must be conducted. 
• 
Adverse events 
• 
Blinding index assessment 
NOTE: Control subjects do not require a duplex ultrasound.  Unblinding should occur 
after all other 6-month follow-up assessments are completed. 
12.12. Follow-up Visit Month 12 (365 ±30 days) 
The 12-month follow-up office visit (365 ±30 days) will include the following assessments: 
• 
24-Hour Ambulatory BP Monitoring  
• 
Limited physical exam including height and weight 
• 
Quality of Life Assessment 
• 
Blood assays (serum creatinine, CBC and platelets, BMP and HbA1c) 
• 
Office-based sitting and standing blood pressure and heart rate 
• 
Medications administered since last visit 
• 
Adverse events 
12.13. Follow-up Visit Month 18 (540 ±30 days)  
The Month 18 follow-up office visit (540 ±30 days) will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Office-based sitting and standing blood pressure and heart rate 
• 
Medications administered since last visit  
• 
Adverse events 
 
12.14. Follow-up Visit Month 24 (730 ±30 days) 
The 24-month follow-up office visit (730 ±30 days) will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Quality of Life Assessment 
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• 
Blood assays (serum creatinine, CBC and platelets, BMP and HbA1c) 
• 
Office-based sitting and standing blood pressure and heart rate 
• 
Medications administered since last visit  
• 
Renal Duplex Ultrasound (DUS) - for subjects who received renal denervation 
treatment and reached the 24-month follow-up visit following approval of protocol 
version AH:  
o Subjects will be required to have duplex ultrasound to assess for evidence of 
significant stenosis, defined as ≥60% as reported by the duplex ultrasound 
(DUS) core laboratory.  A significant stenosis (≥60%) detected by DUS will 
trigger the performance of a confirmatory CTA or DSA. 
o If a diagnostic duplex ultrasound cannot be adequately achieved at the 24-
month follow-up, then a CTA or DSA must be conducted. 
• 
Adverse events 
12.15. Follow-up Visit Month 30 (900 ±30 days) [Visit/Assessments Not Required After 
Approval of Protocol vAH] 
The 30-month follow-up office visit (900 ±30 days) will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Office-based sitting and standing blood pressure and heart rate 
• 
Medications administered since last visit  
• 
Adverse events 
12.16. Follow-up Visit Month 36 (1095 ±30 days) [Visit/Assessments Not Required After 
Approval of Protocol vAH] 
The 36-month follow-up office visit (1095 ±30 days) will include the following assessments: 
• 
Limited physical exam including height and weight 
• 
Quality of Life Assessment 
• 
Blood assays (serum creatinine, CBC and platelets, BMP and HbA1c) 
• 
Office-based sitting and standing blood pressure and heart rate 
• 
Medications administered since last visit  
• 
Adverse events 
 
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12.17. Study Completion 
All subjects, independent of group to which they were randomized will be followed through 
a minimum of 24 months post randomization.  BSC will notify the study sites when the 
follow-up period has ended for all subjects.  
 
12.18. Source Documents 
Table 12.18-1 includes, but is not limited to, a summary of source document requirements.  
Where copies of the original source document as well as printouts of original electronic 
source documents are retained, these shall be signed and dated by a member of the 
investigation center team with a statement that it is a true reproduction of the original source 
document.  Data documented in the eCRF relevant to device deficiencies, relationship of AE 
to study device(s), may be considered source data for the study. 
Table 12.18-1: Source Documentation Requirements 
Requirement 
Disposition 
Written Informed Consent 
Retain at study site 
24-hour Ambulatory BP Monitor Report 
Retain at study site  
Medical visit information (vital signs, medication 
administration, physical exam, etc.) gathered in the 
clinic/hospital 
Retain at study site 
Laboratory Test Results and Calculated eGFR 
Retain at study site 
Renal Duplex Ultrasound (DUS) report 
Retain at Core Laboratory 
Angiography Reports for Digital Subtraction 
Angiography (DSA) and Computed Tomographic 
Angiography (CTA)  
Retain at Core Laboratory 
Renin and Aldosterone Test Results 
Retain at Core Laboratory 
Abbreviations: BP=Blood Pressure; eGFR=Estimated Glomerular Filtration Rate 
13. Medication Additions 
13.1. Rescue Medications 
Subjects will remain off antihypertensive medications through the primary efficacy 
assessment (8 weeks post randomization) unless rescue changes are required.  Rescue 
medications will be introduced if a subject’s OSBP is ≥180mmHg at two consecutive visits.  
The OBP recheck visit must occur within 3 days of the initial elevated reading.  The recheck 
OBP should be measured according to the methodology described in Section 12.1.1.1.  If 
rescue medications are required, the investigator should initiate therapy immediately with 
appropriate agents (typically a 2-drug antihypertensive combination) and it is also 
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recommended that the Investigator consults with the Study HTN Coordinating Principal 
Investigator.   
NOTE: Investigators have ultimate discretion regarding the type of antihypertensive 
medication and timing of adding rescue medications to ensure subject safety. 
13.2. Medications for Subjects Not at Target 
If subjects are not at target from the time of the primary efficacy assessment (8 weeks post 
randomization) through the 6-month assessment, antihypertensive medications will be added 
and doses escalated.   Target blood pressure is defined as OSBP <140 mmHg.  
Note: At the 8 week follow up time point, the investigator may use ABPM data, along with 
OSBP data, to determine the need for anti-hypertensive medications.    
Medications and dose escalation must continue until target BP is reached and throughout the 
6-month follow-up period.  After anti-hypertension medications are introduced and a subject 
reaches target, no additional medication additions or adjustments should be made prior to the 
6-month follow-up assessment other than for rescue of excessively high blood pressures or 
for symptomatic hypotension.  
The recommended medication addition and adjustment protocol is described in Figure 
13.2-1.  The type and dose of antihypertensive medication is based on Investigator discretion.  
The recommended algorithm is suggested through the 6-month follow-up visit.   
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Amlodipine 5mg or other 
calcium channel blocker in 
equivalent dose 
ACE/ARB maximum dose
thiazide diuretic 12.5mg or 
other thiazide-like agent in 
equivalent dose
thiazide diuretic 25 mg or 
other thiazide-like agent in 
equivalent dose
Amlodipine 10mg or other 
calcium channel blocker in 
equivalent (high) dose 
Consult with Study 
HTN Co-PI
 
Figure 13.2-1 Addition of Medications Algorithm 
 
13.3. Medication Adjustment Visits 
Subjects requiring medication additions or adjustments will require a follow-up visit 2 weeks 
after the antihypertensive drug has been introduced or the dose modified.  Investigators must 
obtain OBP according to the details in Section 12.1.1.1 during the 2-week follow-up visit.  
Two-week follow-up visits and medication additions/adjustments should continue until blood 
pressure reaches target. 
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14. Statistical Considerations 
14.1. Endpoints 
14.1.1. Primary Efficacy Assessment 
Due to enrollment termination with approximately half of the planned subjects randomized, 
the primary efficacy assessment will be observational only. No formal tests of hypotheses 
will be performed. 
The primary efficacy assessment for the study is mean reduction in average 24-hour ASBP 
through 8 weeks post randomization in subjects treated with renal denervation (Test) and 
subjects treated with masked procedure (Control).  
14.2. General Statistical Methods 
14.2.1. Analysis Sets 
The primary and pre-specified additional assessments will be analyzed on an intent-to-treat 
(ITT) basis and on a per-protocol basis. For the ITT analysis, all subjects who sign the 
written ICF and are randomized in the study will be included in the analysis population, 
regardless of whether the subjects receive the assigned treatment.  For the per-protocol 
analysis, only randomized subjects who meet the eligibility criteria and receive the assigned 
treatment will be included in the analysis population.   
The ITT population will be the primary analysis set for the purpose of assessing superiority 
of Test to Control for 8-week average 24-hour ASBP reduction. All other endpoint analyses 
will be based on ITT population. 
14.2.2. Randomization Scheme 
Randomization to treatment will be stratified by study site. A computer generated list of 
random treatment allocations (i.e., a randomization schedule) will be used to assign subjects 
to treatments in a 2:1 ratio of Test to Control. This list will be specific to the subject’s site. 
Random permuted blocks of varying sizes will be employed to ensure approximate balance 
of treatment allocation within each site. 
14.2.3. Control of Systematic Error/Bias 
Selection of subjects will be made from the Investigators’ general or professional referral 
population. All subjects meeting the inclusion/exclusion criteria and having signed the ICF 
will be eligible to enroll in the study. Consecutively eligible subjects should be enrolled into 
the study to minimize selection bias. Study subjects will be randomly assigned to a treatment 
group within the investigational site. In determining subject eligibility for the study, the 
investigator’s assessment of imaging will be used. However, the Angiographic Core 
Laboratory will independently analyze the angiograms for all renal denervation procedures 
and the data obtained from the core laboratory will be used for analyses in order to control 
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for inter-observer variability. An independent CEC composed of medical experts will 
adjudicate safety assessments, as defined in the CEC Charter.  
14.2.4. Number of Subjects per Study Site 
Study sites will not be allowed to randomize more than 10 subjects without prior approval 
from the Sponsor (10% of the total number of randomized subjects). No center will be 
allowed to enroll more than 20 subjects (20% of the total number of randomized subjects).   
14.3. Data Analyses 
Baseline data will be summarized by treatment group for the randomized study. Subject 
demographics, clinical history, procedure assessment, and medication compliance will be 
summarized using descriptive statistics (e.g., mean, standard deviation, n, minimum, 
maximum) for continuous variables and frequency tables for discrete variables. The analysis 
unit may be (but will not be limited to) by subject, catheter, or treatment.  
Test and Control in the randomized study will be compared as needed with a Chi-square test 
or a Fisher exact test for discrete variables and a Student t-Test for continuous variables. The 
differences between Test and Control in the randomized study and their 95% confidence 
intervals will be presented as needed. 
14.3.1. Additional Assessments/Measurements  
No formal tests of hypotheses will be performed for additional assessments. Statistical 
comparisons may be performed for exploratory purposes. No inferences are planned on the 
additional assessments and therefore alpha-adjustments for multiple comparisons will not be 
used. 
Blinding index measures will be collected prior to discharge and at 8 weeks and 6 months 
post-randomization to assess whether the blinding efforts are ultimately successful.  
14.3.2. Interim Analyses  
One interim analysis was pre-specified in the Statistical Analysis Plan. 
14.3.3. Subgroup Analyses 
No formal tests of hypotheses will be performed for subgroup analyses. All subgroup 
analyses will be observational. 
14.3.4. Analysis Software 
All statistical analyses will be performed using the Statistical Analysis Software (SAS), 
version 9.2 or later (Copyright © 2002-2010 by SAS Institute Inc., Cary, North Carolina 
27513, USA. All rights reserved). 
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14.3.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended Statistical Analysis Plan approved prior to performing the 
analyses. Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the deviation. 
15. Data Management 
15.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system.  
The clinical database will reside on a production server hosted by Medidata. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by Boston Scientific Corporation (BSC) or its representative. The associated RAVE software 
and database have been designed to meet regulatory compliance for deployment as part of a 
validated system compliant with laws and regulations applicable to the conduct of clinical 
studies pertaining to the use of electronic records and signatures. Database backups are 
performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case 
report forms (eCRFs) in compliance with local regulations. A written signature on printouts 
of the eCRFs must also be provided if required by local regulation. Changes to data 
previously submitted to the sponsor require a new electronic signature by the Investigator 
acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and will 
be issued to the site for appropriate response. Site staff will be responsible for resolving all 
queries in the database. 
15.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative site, in original 
format all essential study documents and source documentation that support the data 
collected on the study subjects in compliance with ICH/GCP guidelines.  Documents must be 
retained for at least 2 years after the last approval of a marketing application or until at least 2 
years have elapsed since the formal discontinuation of the clinical investigation of the 
product. These documents will be retained for a longer period of time by agreement with 
BSC or in compliance with other local regulations. It is BSC’s responsibility to inform the 
Investigator when these documents no longer need to be maintained. The Investigator will 
take measures to ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Investigator withdraws responsibility for maintaining these 
essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change.  
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15.3. Core and Central Laboratories 
Core and central laboratories will be established for the central assessment of key data 
collected during this clinical study.  Detailed guidelines for the collection, analysis and 
interpretation of the following data will be provided in the Renal Duplex Ultrasound Core 
Laboratory Manual of Operations, the Angiographic Core Laboratory Manual of Operations, 
the Ambulatory Blood Pressure Monitoring Core Laboratory Manual of Operations, and the 
Central Laboratory Manual of Operations.  The following core laboratories have been 
assigned for this study: 
15.3.1. Renal Duplex Ultrasound 
A renal duplex ultrasound core laboratory has been established to assess renal duplex 
ultrasounds performed at 6 months and 24 months* following renal denervation treatment 
during the follow-up period. 
*Note: The 24 month DUS will be completed only for subjects who received renal 
denervation and reached the 24 month follow up after approval of protocol version AH.  
15.3.2. Angiography 
An angiographic core laboratory has been established to provide quantitative and qualitative 
analysis of the following tests:  
• 
Computed Tomographic Angiography (CTA) – screening and at 6 months and 24 
months*, if renal duplex ultrasound core laboratory results indicate a stenosis ≥60% 
or are inconclusive when repeated at the recommendation of the core laboratory 
• 
Renal Angiogram (DSA) – renal denervation procedure; review of clinical events; 
and at 6 months and 24 months*, if renal duplex ultrasound results indicate a stenosis 
≥60% or are inconclusive when repeated at the recommendation of the core 
laboratory 
 
*Note: The 24 month CTA or DSA only applies to subjects who received renal denervation 
and reached the 24 month follow up after approval of protocol version AH.  
15.3.3. Ambulatory Blood Pressure Monitoring 
A core laboratory has been established to manage the ABPM system and software setup, 
ABPM device configuration, study site and BSC personnel/representative training, and data 
processing of ABPM data including downloads, interpretation and reporting to BSC and 
study sites.  Subjects will undergo ABPM at screening and at 4 and 8 weeks, and 6 and 12 
months post randomization. 
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15.3.4. Serum Analysis 
A central laboratory has been established to manage selected laboratory assessments 
(including Renin and Aldosterone).  Subjects will undergo serum testing at screening, 8 
weeks and 6 months post randomization.   
16. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/FDA) of the revised protocol must be obtained prior to implementation. 
17. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB of any deviation from the investigational plan to protect the 
life or physical well-being of a subject in an emergency, and those deviations which affect 
the scientific integrity of the clinical investigation. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using EDC. Sites may also be 
required to report deviations to the IRB, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, center re-training, or 
discontinuation) will be put into place by the sponsor. 
18. Device/Equipment Accountability 
The investigational devices/equipment shall be securely maintained, controlled, and used 
only in this clinical study. Device accountability records for all investigational devices must 
be maintained at the study site. The quantity of devices received by the study site, those 
returned to the supplier, and those used at the study site will be recorded in the device 
accountability record. The Investigator must explain in writing the reasons for any 
discrepancy noted in device accountability. 
The sponsor shall keep records to document the physical location of all investigational 
devices from shipment of investigational devices to the investigation sites until return or 
disposal. 
Records shall be kept by the investigator to document the physical location and conditions of 
storage of all investigational devices/equipment.  
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The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices/equipment, which shall include 
the following 
• Date of receipt 
• Identification of each investigational device/piece of equipment (batch number or unique 
code) 
• Expiry date, as applicable 
• Date or dates of use 
• Subject identification 
• Date on which the investigational device/piece of equipment was returned or destroyed, 
as applicable 
• Date of return of unused, expired, or malfunctioning investigational devices/equipment, if 
applicable. 
Written procedures may be required by national regulations. 
19. Compliance 
19.1. Statement of Compliance 
This study will be conducted in accordance with ethical principles that have their origins in 
the Declaration of Helsinki, and pertinent individual country laws and regulations. The study 
shall not begin until the required approval/favorable opinion from the IRB and/or regulatory 
authority has been obtained, if appropriate. Any additional requirements imposed by the IRB 
or regulatory authority shall be followed, if appropriate. 
19.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the investigational 
plan/protocol, ISO 14155, ethical principles that have their origins in the Declaration of 
Helsinki, any conditions of approval imposed by the reviewing IRB, and prevailing local 
and/or country laws and/or regulations, whichever affords the greater protection to the 
subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following:  
• Prior to beginning the study, sign the Investigator Agreement and Protocol Signature 
page documenting his/her agreement to conduct the study in accordance with the 
protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the center team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
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interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency. 
• Report to BSC, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE. 
• Report to the IRB and regulatory authorities any SAEs and device deficiencies that could 
have led to a SADE, if required by the national regulations or this protocol or by the IRB, 
and supply BSC with any additional requested information related to the safety reporting 
of a particular event. 
• Maintain the device accountability records and control of the device, ensuring that the 
investigational device is used only by authorized/designated users and in accordance with 
this protocol and instructions/directions for use. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
monitor and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form 
(ICF). 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• As applicable, provide the subject with necessary instructions on proper use, handling, 
storage, and return of the investigational device when it is used/operated by the subject. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
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treatment, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
19.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the investigator is responsible for providing appropriate 
training and adequate supervision of those to whom tasks are delegated. The investigator is 
accountable for regulatory violations resulting from failure to adequately supervise the 
conduct of the clinical study.  
19.3. Institutional Review Board 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to the 
sponsor documentation verifying that their IRB is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB and/or competent authority approval of the protocol (or permission 
to conduct the study) and Informed Consent Form, must be received by the sponsor before 
recruitment of subjects into the study and shipment of investigational product/equipment. 
Prior approval must also be obtained for other materials related to subject recruitment or 
which will be provided to the subject. 
Annual IRB approval and renewals will be obtained throughout the duration of the study as 
required by local/country or IRB requirements. Copies of the Investigator’s reports and the 
IRB continuance of approval must be provided to the sponsor.  
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19.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC and will be kept confidential in accordance with all 
applicable laws and regulations. Only authorized BSC personnel and/or a BSC representative 
including Contract Research Organization (CRO) will have access to these confidential 
records. Authorized regulatory personnel have the right to inspect and copy all records 
pertinent to this study. Study data collected during this study may be used by BSC for the 
purposes of this study, publication, and to support future research and/or other business 
purposes, such as overseeing and improving the performance of its device, new medical 
research and proposals for developing new medical products and procedures. All data used in 
the analysis and reporting of this study or shared with a third-party researcher will be without 
identifiable reference to specific subject name. 
Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
19.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the protocol, 
and follow-ups. Support may include HCP training, addressing HCP questions, or providing 
clarifications to HCPs concerning the operation of BSC equipment/devices (including 
programmers, analyzers, and other support equipment). 
BSC personnel may perform certain activities to ensure study quality. These activities may 
include the following. 
• Observing testing or medical procedures to provide information relevant to protocol 
compliance 
• Reviewing collected data and study documentation for completeness and accuracy 
Boston Scientific personnel will not do the following.  
• Practice medicine 
• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject  
• Independently collect critical study data (defined as primary or secondary endpoint data) 
• Enter data in electronic data capture systems or on paper case report forms 
19.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
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20. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the 
protocol and applicable regulations. In addition, the monitor verifies that study records are 
adequately maintained, that data are reported in a satisfactory manner with respect to 
timeliness, adequacy, and accuracy, and that the Investigator continues to have sufficient 
staff and facilities to conduct the study safely and effectively. The Investigator/institution 
guarantees direct access to original source documents by BSC personnel, their designees, and 
appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and 
relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
21. Potential Risks and Benefits 
21.1. Anticipated Adverse Events  
Anticipated adverse events that could possibly occur during the study include, but are not 
limited to: 
• 
Ablation or thermal injury to vessel, adjacent tissue or other structures from energy 
application 
• 
Allergic reaction (drug, contrast, device or other) 
• 
Arrhythmia 
• 
Arteriovenous (AV) or arterioenteric fistula 
• 
Cardiopulmonary arrest 
• 
Death 
• 
Embolism (air, plaque, thrombus, device or other) 
• 
Hematoma 
• 
Hematuria 
• 
Hemorrhage 
• 
Hypertension  
• 
Hypotension 
• 
Infection and/or Sepsis  
• 
Myocardial infarction (MI) 
• 
Pain 
• 
Pseudoaneurysm 
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• 
Renal artery aneurysm  
• 
Renal artery stenosis or acceleration of atherosclerotic disease 
• 
Renal failure or renal insufficiency 
• 
Renal infarction (including due to embolization of plaque or coagulated/charred blood 
or tissue) 
• 
Transient ischemic attack (TIA) and/or Cerebrovascular accident (CVA)   
• 
Vasospasm 
• 
Vessel trauma (perforation, dissection, or rupture) 
• 
Vessel thrombosis or occlusion 
21.2. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 
21.3. Anticipated Benefits 
Subjects participating in this study may experience a similar therapy response as subjects 
treated with other devices marketed for renal denervation treatment for resistant 
hypertension. Some potential advantages of the Vessix renal denervation procedure may 
include shorter treatment times and reduced pain.   
21.4. Risk to Benefit Rationale 
The published data to date for renal denervation treatment for resistant hypertension have 
demonstrated Major Adverse Event rates as low as 1.4% in the treated cohort.19 Long-term 
24-month data has also demonstrated a sustained reduction of SBP to support the efficacy of 
renal denervation therapy.5 Risks associated with the renal denervation procedure are 
expected to be similar to those related with renal stenting, and the benefits of the treatment 
have been shown to outweigh the risks. 
22. Safety Reporting 
22.1. Definitions and Classification 
Adverse event definitions are provided in Table 22.1-1. Administrative edits were made to 
combine definitions from ISO 14155-2011 and MEDDEV 2.7/3 12/2010. 
 
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Table 22.1-1: Safety Reporting Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the 
investigational medical device.  
NOTE 1: This includes events related to the investigational medical 
device or comparator. 
NOTE 2: This definition includes events related to the procedures 
involved (any procedure in the clinical investigation plan). 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 
insufficient or inadequate instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event that: 
• Led to death, 
• Led to serious deterioration in the health of the subject, that either 
resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function 
 
• Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without serious 
deterioration in health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious 
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Table 22.1-1: Safety Reporting Definitions 
Term 
Definition 
Note: For US IDE studies only, 
otherwise remove UADE from 
table 
problem associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with respect to 
its identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. For centers in Austria cancer must always 
be reported as a Serious Adverse Event. Death should not be recorded as an AE, but should 
only be reflected as an outcome of a specific SAE (see Table 22.1-1 for AE definitions).  
Any AE experienced by the study subject after informed consent, whether during or 
subsequent to the procedure, must be recorded in the eCRF. 
Refer to Section 21 for the known risks associated with the study device(s). 
22.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device as related or 
unrelated. See criteria in Table 22.2-1:  
Table 22.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect of 
another device/drug and is not related to the investigational product. 
Related 
• The adverse event is determined to be potentially related to the investigational 
product, and an alternative etiology is equally or less likely compared to the 
potential relationship to investigational product, or 
• There is a strong relationship to investigational product, or recurs on re-
challenge, and another etiology is unlikely, or 
• There is no other reasonable medical explanation for the event. 
 
22.3. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 22.3-1.  
Relevant source documents (de-identified) for specific events must be provided to BSC as 
described in the Manual or Operations. 
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Table 22.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Adverse 
Device Effect / Unanticipated 
Serious Adverse Device 
Effect  
Note: UADE is for US IDE 
studies only, otherwise 
remove UADE from the table 
Complete AE eCRF page with all 
available new and updated 
information.  
 
• Within 1 business day of first 
becoming aware of the event. 
• Terminating at the end of the 
study 
Serious Adverse Event 
including Serious Adverse 
Device Effects 
Complete AE eCRF page with all 
available new and updated 
information.  
• Within 2 business days of first 
becoming aware of the event or 
as per local/regional 
regulations. 
• Reporting required through the 
end of the study 
Provide all relevant source 
documentation (unidentified) for 
reported event 
• When documentation is 
available 
Device Deficiencies 
(including but not limited to 
failures, malfunctions, and 
product nonconformities) 
Note:  Any Investigational 
Device Deficiency that might 
have led to a serious adverse 
event if a) suitable action had 
not been taken or b) 
intervention had not been 
made or c) if circumstances 
had been less fortunate is 
considered a reportable event. 
 
Complete device deficiency eCRF 
with all available new and updated 
information.  
• Within 2 business days of first 
becoming aware of the event 
and as per local/regional 
regulations. 
• Reporting required through the 
end of the study 
Adverse Event 
Complete AE eCRF page, which 
contains such information as date of 
AE, treatment of AE resolution, 
assessment of seriousness and 
relationship to the device.  
• In a timely manner after 
becoming aware of the 
information  
• Reporting required through the 
end of study for CEC AEs 
• Reporting required through 1-
year post randomization for 
non-CEC AEs  
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
 
22.4. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and labeling errors) will be documented and reported to BSC. If 
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possible, the device(s) should be returned to BSC for analysis. Instructions for returning the 
investigational device(s) will be provided. If it is not possible to return the device, the 
investigator should document why the device was not returned and the final disposition of the 
device. Device failures and malfunctions should also be documented in the subject’s medical 
record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not to be reported as adverse events. However, if there is an adverse 
event that results from a device failure or malfunction, that specific event would be recorded 
on the appropriate eCRF. 
And any Investigational Device Deficiency that might have led to a serious adverse event if 
a) suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate is considered a reportable event. 
22.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating investigators 
and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB, and regulatory authorities of 
UADE and SAE as required by local/regional regulations.  
23. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
all subjects or their legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any investigational devices, 
study-required procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
approved by BSC or its delegate (e.g. CRO), the center’s IRB, or central IRB, if applicable. 
Boston Scientific will provide a study-specific template of the ICF to investigators 
participating in this study. The ICF template may be modified to meet the requirements of the 
investigative center’s IRB. Any modification requires approval from BSC prior to use of the 
form. The ICF must be in a language understandable to the subject and if needed, BSC will 
assist the center in obtaining a written consent translation. Translated consent forms must 
also have IRB approval prior to their use. Privacy language shall be included in the body of 
the form or as a separate form as applicable.   
The process of obtaining Informed Consent shall at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
• be conducted by the Principal Investigator or designee authorized to conduct the process,  
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• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study.  
The ICF shall always be signed and personally dated by the subject or legal representative 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by 
the investigator and/or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the center and a copy of the signed and dated document and 
any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor and local regulatory authorities (e.g. IRB), as appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB. The new version of the ICF must be approved by the 
IRB. Boston Scientific approval is required if changes to the revised ICF are requested by the 
center’s IRB. The IRB will determine the subject population to be re-consented. 
Study personnel should explain to the subject that even if the subject agrees to participate in 
the study and signs the ICF, screening assessment prior to randomization may demonstrate 
that the subject is not a suitable candidate for the study.  A Screening/Enrollment Log will be 
maintained to document select information about candidates who fail to meet entry criteria.  
24. Committees 
24.1. Safety Monitoring Process 
To promote early detection of safety issues, the Data Monitoring Committee, Clinical Events 
Committee and BSC Medical Monitor will provide evaluations of safety events. Success of 
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this program requires dynamic collection of unmonitored data as soon as the event is 
reported. This is expedited through BSC’s safety team, which is responsible for coordinating 
the collection of information for the subject dossier from the centers and core laboratories. 
During regularly scheduled monitoring visits, clinical research monitors will support the 
dynamic reporting process through their review of source document information. 
24.2. Data Monitoring Committee 
The independent Data Monitoring Committee (DMC) is responsible for the oversight review 
of all AEs. The DMC will include leading experts in peripheral interventions or 
interventional cardiology, hypertension, and biostatistics who are not participating in the 
study and who have no affiliation with BSC. During the course of the study, the DMC will 
review accumulating safety data to monitor the incidence of CEC events and other trends that 
would warrant modification or termination of the study.  Responsibilities, qualifications, 
membership and committee procedures are outlined in the DMC Charter.  
Interim data will be analyzed by the independent DMC statistician.  Any DMC 
recommendations for study modification or termination because of concerns over subject 
safety or issues relating to data monitoring or quality control will be submitted in writing to 
the BSC. In consultation with the Study Coordinating Principal Investigators, BSC will 
evaluate the recommendation and make a final decision.  However, if the DMC at any time 
determines that a potentially serious risk exists to subjects in this study, the DMC chairman 
will immediately notify BSC. 
24.3. Clinical Events Committee 
An independent Clinical Events Committee (CEC) is an independent group of individuals 
with pertinent expertise that reviews and adjudicates important endpoints and relevant 
adverse events reported by study investigators. The CEC will review a safety event dossier, 
which may include copies of subject source documents provided by study sites, depending on 
event timing for, reported case of renal failure, embolic event, vascular complications, renal 
dissection, renal stenosis, hypertensive crisis, severe hypotension/syncope and death. 
Committee membership will include practitioners of peripheral interventions or 
interventional cardiology, and hypertension as well as other experts with necessary 
therapeutic and subject matter expertise to adjudicate the event categories outlined above.  
CEC responsibilities, qualifications, membership and committee procedures are outlined in 
the CEC Charter.   
24.4. Steering Committee 
A Steering Committee composed of the Sponsor’s Clinical Management, the study Co-
Principal Investigators and interventional radiologists, interventional cardiologists, vascular 
surgeons and hypertension specialists will be convened.  Responsibilities may include 
oversight of the overall conduct of the study with regard to protocol development, study 
progress, subject safety, overall data quality and integrity, as well as disseminating any study 
results through appropriate scientific sessions and publications.   Steering Committee 
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members may participate in the review and approval of all requests for data analysis, abstract 
and manuscript preparation, and submission.  As appropriate, the Steering Committee may 
request participation of REDUCE-HTN: REINFORCE Study Investigators on the 
Committee.  
25. Suspension or Termination 
25.1. Premature Termination of the Study 
Boston Scientific reserves the right to terminate the study at any stage but intends to exercise 
this right only for valid scientific or administrative reasons and reasons related to protection 
of subjects. Investigators, associated IRBs, and regulatory authorities, as applicable, will be 
notified in writing in the event of study termination. 
25.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue development of the 
device. 
25.2. Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval 
Any investigator or IRB in the REDUCE-HTN: REINFORCE Study may discontinue 
participation in the study or withdrawal approval of the study, respectively, with suitable 
written notice to Boston Scientific. Investigators, associated IRBs, and regulatory authorities, 
as applicable, will be notified in writing in the event of these occurrences. 
 
 
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25.3. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by Boston Scientific. 
The IRB and regulatory authorities, as applicable, will be notified. Detailed information on 
how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB terminates participation in the study, participating investigators, 
associated IRBs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by Boston Scientific. 
In the event an investigator terminates participation in the study, study responsibility will be 
transferred to a co-investigator, if possible. In the event there are no opportunities to transfer 
investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by Boston Scientific. 
The investigator must return all documents and investigational product to Boston Scientific, 
unless this action would jeopardize the rights, safety, or welfare of the subjects. 
25.4. Criteria for Suspending/Terminating a Study Center 
Boston Scientific reserves the right to stop the inclusion of subjects at a study center at any 
time after the study initiation visit if no subjects have been enrolled for a period beyond 3 
months after center initiation, or if the center has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing 
equipment, as applicable, will be returned to BSC unless this action would jeopardize the 
rights, safety or well-being of the subjects. The IRB and regulatory authorities, as applicable, 
will be notified. All subjects enrolled in the study at the center will continue to be followed. 
The Principal Investigator at the center must make provision for these follow-up visits unless 
BSC notifies the investigational center otherwise. 
26. Publication Policy 
In accordance with the Corporate Policy on the Conduct of Human Subject Research, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication 
or presentation relating to a BSC study or its results. In accordance with the Corporate Policy 
for the Conduct of Human Subject Research, BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. Boston 
Scientific adheres to the Contributorship Criteria set forth in the Uniform Requirements of 
the International Committee of Medical Journal Editors (ICMJE; http://www.icmje.org). In 
order to ensure the public disclosure of study results in a timely manner, while maintaining 
an unbiased presentation of study outcomes, BSC personnel may assist authors and 
investigators in publication preparation provided the following guidelines are followed. 
• All authorship and contributorship requirements as described above must be followed. 
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• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Steering Committee 
at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
The data, analytic methods, and study materials for this clinical trial may be made available 
to other researchers in accordance with the Boston Scientific Data Sharing Policy 
(https://www.bostonscientific.com/).  
 
 
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27. Abbreviations and Definitions  
27.1. Abbreviations 
Abbreviations are shown in Table 27.1-1.   
Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACT 
Activated Clotting Time 
ADBP 
Ambulatory Diastolic Blood Pressure 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
ASBP 
Ambulatory Systolic Blood Pressure 
ATM 
Atmospheres 
AV 
Arteriovenous 
BMP 
Basic Metabolic Panel 
BP 
Blood Pressure 
BSC 
Boston Scientific Corporation 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CM 
Centimeters 
CRO 
Contract Research Organization 
CRT-D 
Cardiac Resynchronization Therapy-Defibrillator 
CTA 
Computed Tomographic Angiography 
CV 
Cardiovascular 
CVA 
Cerebrovascular Accident 
DBP 
Diastolic Blood Pressure 
DFU 
Directions For Use 
DMC 
Data Monitoring Committee 
DSA 
Digital Subtraction Angiography 
DUS 
Duplex Ultrasound 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
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Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
F 
French 
FDA 
Food and Drug Administration 
FIM 
First in Man 
FMD 
Fibromuscular Dysplasia 
GCP 
Good Clinical Practices 
HbA1c 
Hemoglobin A1c 
HCP 
Healthcare Professional 
HTN 
Hypertension 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
kHz 
Kilohertz 
LCD 
Liquid-crystal Display 
LED 
Light-emitting Diode 
M 
Meters 
MAE 
Major Adverse Event 
MAOI 
Monoamine Oxidase Inhibitor 
MDRD 
Modification of Diet in Renal Disease 
MEDDEV 
Medical Device Directives 
µL 
Microliters 
MI 
Myocardial Infarction 
MM 
Millimeters 
MRA  
Magnetic Resonance Angiography 
NSAID 
Non-steroidal Anti-inflammatory Drug 
OBP 
Office-based Blood Pressure 
ODBP 
Office-based Diastolic Blood Pressure 
OM 
Operators Manual 
OSBP 
Office-based Systolic Blood Pressure 
PGWBI 
Psychological General Well-Being Index 
PMS 
Post Market Study 
RDN 
Renal Denervation 
RF 
Radio Frequency 
SADE 
Serious Adverse Device Effect 
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Table 27.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
 
VDC 
Volts Direct Current 
 
 
 
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27.2. Definitions 
Terms are defined in Table 27.2-1.  
 
Table 27.2-1: Definitions 
Term 
Definition 
Congestive Heart 
Failure Episode 
Defined as overnight hospital stay or prolongation of an existing 
hospitalization for signs and symptoms of heart failure with the 
use of IV diuretics and/or inotropes 
Death 
Cardiac death - defined as death due to any of the following: 
1. Acute myocardial infarction. 
2. Cardiac perforation/pericardial tamponade. 
3. Arrhythmia or conduction abnormality. 
4. Cerebrovascular accident through hospital discharge or 
cerebrovascular accident suspected of being related to the 
procedure. 
5. Death due to complication of the procedure, including 
bleeding, vascular repair, transfusion reaction, or bypass 
surgery. 
6. Any death in which a cardiac cause cannot be excluded. 
 
Non-cardiac death - defined as a death not due to cardiac causes 
(as defined above). 
 
NOTE:  See Major Adverse Event definition. 
Embolic Event 
An embolic event causing end-organ damage (unanticipated 
kidney/bowel infarct, lower extremity ulceration or gangrene, or 
loss of kidney function). 
 
NOTE: For Embolic Event, loss of kidney function is defined as 
Serum Creatinine increased to more than 200% to 300% (>2- to 3-
fold) from baseline.29 
 
NOTE:  See Major Adverse Event definition. 
Estimated Glomerular 
Filtration Rate  
eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if 
female) × (1.212 if African American/Black) (conventional units)1  
Known Causes of 
Secondary 
Hypertension 
Include but are not limited to: 
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Table 27.2-1: Definitions 
Term 
Definition 
• 
Renal disorders (advanced chronic kidney disease, renal 
artery stenosis, polycystic kidney(s), urinary tract 
infection, hematuria, analgesic abuse) 
• 
Endocrine disorders (pheochromocytoma, 
hyperaldosteronism, Cushing’s syndrome, acromegaly, 
hyperparathyroidism, hyperthyroidism or hypothyroidism) 
• 
Drug/Substance Intake such as certain antidepressants, 
carbenoxolone (UK), cyclosporine, erythropoietin, 
hormonal contraceptives, buspirone, carbamazepine, 
bromocriptine, clozapine, estrogens, NSAIDS, ethanol, 
nasal decongestants with adrenergic effects, MAOIs, 
adrenoceptor stimulants, gluco- and 
mineralocorticosteroids, nicotine use, cocaine, 
amphetamines, and black liquorice when consumed in 
excess 
• 
Other causes such as neurological disorders, obstructive 
sleep apnea, scleroderma, neurofibromatosis, pregnancy, 
cancers, aortic coarctation, bradycardia or ischemia 
Hypertensive Crisis 
Hypertensive crisis includes hypertensive emergencies and 
hypertensive urgencies. 
 
Hypertensive emergencies are characterized by severe elevations 
in BP (180/120 mm Hg) complicated by evidence of impending or 
progressive target organ dysfunction.26 They require immediate 
BP reduction (not necessarily to normal) to prevent or limit target 
organ damage. Examples include hypertensive encephalopathy, 
intracerebral hemorrhage, acute myocardial infarction, acute left 
ventricular failure with pulmonary edema or unstable angina 
pectoris.  
 
Hypertensive urgencies are those situations associated with severe 
elevations in BP without progressive target organ dysfunction.  
 
NOTE:  See Major Adverse Event definition. 
Investigational Devices Vessix Renal Denervation System 
• 
Vessix Reduce Catheter (4.0, 5.0, 6.0 and 7.0 mm) 
• 
Vessix Generator (bipolar radio frequency) 
Major Adverse Event 
Through 4 weeks post randomization: 
• 
All-cause death 
• 
Renal failure  
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Table 27.2-1: Definitions 
Term 
Definition 
• 
Hospitalization for hypertensive crisis 
• 
Hospitalization due to severe hypotension/syncope  
• 
Significant embolic event resulting in end-organ damage 
or intervention to prevent it 
• 
Renal artery dissection or perforation requiring 
intervention 
• 
Vascular complications requiring surgical repair, 
interventional procedure, thrombin injection, or blood 
transfusion 
 
Through 6 months post randomization: 
• 
Significant new renal artery stenosis >70% assessed by 
duplex ultrasound (DUS) and confirmed by the 
angiographic core laboratory [computed tomographic 
angiography (CTA) or digital subtraction angiography 
(DSA)]   
Orthostatic 
Hypotension 
A fall in systolic blood pressure of at least 20 mmHg or diastolic 
blood pressure of at least 10 mmHg (as compared to sitting blood 
pressure measurement) within 3 minutes of assuming a standing 
position22 
 
Renal Artery 
Dissection 
(NHLBI Grade Types) 
Type A - Small radiolucent area within the lumen of the vessel 
disappearing with the passage of the contrast material. 
Type B - Appearance of contrast medium parallel to the lumen of 
the vessel disappearing within a few cardiac cycles. 
Type C - Dissection protruding outside the lumen of the vessel 
persisting after passage of the contrast material. 
Type D - Spiral shaped filling defect with or without delayed run-
off of the contrast material in the antegrade flow. 
Type E - Persistent luminal filling defect with delayed run-off of 
the contrast material in the distal lumen. 
Type F - Filling defect accompanied by total vessel occlusion. 
 
NOTE:  See Major Adverse Event definition. 
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Table 27.2-1: Definitions 
Term 
Definition 
Renal Artery 
Perforation 
Angiographic perforation: perforation detected by clinical site or 
the Angiographic Core Laboratory at any point during the 
procedure. 
Clinical perforation: perforation requiring additional treatment 
(including efforts to seal the perforation), or resulting in 
significant hemodynamic compromise, abrupt closure, or death.   
 
NOTE:  Only clinical perforations will be considered endpoint 
events. 
 
NOTE:  See Major Adverse Event definition. 
Renal Artery Stenosis 
>70% narrowing in the renal artery as confirmed by CTA or DSA. 
 
NOTE:  See Major Adverse Event definition. 
Renal Failure 
Serum Creatinine increased to more than 300% (>3-fold) from 
baseline, or more than or equal to 4.0 mg/dL (354 μmol/l) with an 
acute increase of at least 0.5 mg/dl (44 μmol/L) or on renal 
replacement therapy.29 
NOTE:  See Major Adverse Event definition. 
Source Data 
All information in original records of clinical findings, 
observation or other activities in a clinical investigation necessary 
for the reconstruction and evaluation of the clinical investigation 
Source Document 
Printed, optical or electronic document containing source data. 
Examples: Hospital records, laboratory notes, device 
accountability records, photographic negatives, radiographs, 
records kept at the investigation site, at the laboratories and at the 
medico-technical departments involved in the clinical 
investigation 
Stroke 
A new focal neurological deficit or loss of brain function with 
presumed vascular origin persisting more than 24 hours and with a 
neuro-imaging study that does not indicate a different etiology.  
The 24-hour criterion is not applicable if the subject undergoes 
cerebrovascular surgery or expires secondary to a stroke within 
the first 24 hours following the onset of the symptoms.  It includes 
subjects presenting with clinical signs and symptoms suggestive 
of subarachnoid hemorrhage, intracerebral hemorrhage, or 
cerebral infarction.  It does not include stroke events in cases of 
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Table 27.2-1: Definitions 
Term 
Definition 
blood disorders such as leukemia and excludes subjects with a 
history of stroke secondary to trauma. 
Target Blood  
Pressure 
OSBP <140mmHg 
Vascular 
Complications 
Clinically significant groin hematoma, arteriovenous fistula, 
pseudoaneurysm, or excessive bleeding requiring surgical repair, 
interventional procedure, thrombin injection, or blood transfusion 
(requiring more than 2 units of packed red blood cells within any 
24 hour period during the first 7 days post-renal denervation 
treatment). 
 
NOTE:  See Major Adverse Event definition. 
Abbreviations are defined in Table 27.1-1. 
 
 
 
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28 Lundgren-Nilsson A, Jonsdottir I, Ahlborg G, et al. Construct validity of the psychological 
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29 Ostermann M, Chang R; Riyadh ICU Program Users Group. Correlation between the AKI 
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