IntErnational Non-randomized, Single-arm, Long-term Follow-up Study of Patients With Uncontrolled HyperTensioN
Conditions: Hypertension, Blood Pressure
Sponsor: Abbott Medical Devices

           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 1 of 78 
 
 
CIP No: 1201 
Revision: C 
16 Nov 2012 
 
EnligHTN II 
IntErnational non-randomized, single arm, long-term follow-up study of patients 
with uncontrolled HyperTensioN 
Clinical Investigation Plan (CIP) 
 
 
 
 
 
SPONSOR 
 
St. Jude Medical, Cardiology Division Inc.  
d/b/a St. Jude Medical, Cardiovascular Division, Inc. 
(“SJM”) 
177 East County Road B 
St. Paul, MN  55117 
U.S.A. 
+01 (651) 483-2000 
 
 
 
 
 
 
COORDINATING INVESTIGATOR 
PROFESSOR WORTHLEY                      ___________________________________________ 
                                                           Signature & Date 
 
 
 
 
 
COORDINATING INVESTIGATOR 
DR. LOBO                                             ___________________________________________ 
                                                        Signature & Date 
 
                                                            
 
 
 
 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 2 of 78 
 
 
Clinical Investigation Plan Signature Page 
 
 
Study Title: 
EnligHTN II – IntErnational, non randomized, single arm, long term follow 
up study of patients with uncontrolled HyperTensioN 
 
Study Number: 
1201 
 
Study Device: 
EnligHTN™ Renal Denervation System  
 
 
 
 
 
 
I have read and agree to adhere to the Clinical Investigational Plan and all regulatory 
requirements applicable in conducting this clinical study.  I will provide copies of this clinical 
investigational plan and all pertinent information to study personnel and will discuss this 
information with them and ensure they are fully informed regarding the device and the conduct 
of the study according to other applicable regulations, to applicable laws.   
 
 
 
 
 
 
 
 
 
____________________________________ 
Site Principal Investigator Name (please print) 
 
 
 
____________________________________ 
__________________ 
Site Principal Investigator Signature 
Date 
 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 3 of 78 
 
 
Table of Contents 
 
1 
Synopsis .............................................................................................................................. 6 
2 
Background ....................................................................................................................... 11 
3 
Investigational Design ....................................................................................................... 12 
3.1 
Purpose ...................................................................................................................... 12 
3.2 
Objectives ................................................................................................................... 13 
Primary Objective .............................................................................................................. 13 
Secondary Objective ......................................................................................................... 13 
3.3 
Investigational Type .................................................................................................... 13 
3.4 
Patient Population ....................................................................................................... 13 
3.5 
Patient Screening ........................................................................................................ 14 
3.6 
Inclusion and Exclusion Criteria / Point of Enrollment .................................................. 14 
3.6.1 
Inclusion Criteria ...................................................................................................... 14 
3.6.2 
Exclusion Criteria ..................................................................................................... 14 
3.7 
Procedural Exclusions ................................................................................................. 15 
3.8 
Expected duration of the Investigation ......................................................................... 15 
3.9 
Expected duration of each subject’s participation ........................................................ 15 
3.10 
Number of subjects required to be included in the Investigation .............................. 15 
3.11 
Estimated time needed to select this subject population .......................................... 15 
3.12 
Devices Used .......................................................................................................... 15 
3.12.1 
EnligHTN™ Renal Artery Ablation Catheter ............................................................. 16 
3.12.2 
EnligHTN™ RF Ablation Generator ......................................................................... 16 
3.12.3 
EnligHTN™ Guiding Catheter (optional) .................................................................. 16 
3.13 
Intended Use ........................................................................................................... 16 
4 
Procedures ........................................................................................................................ 17 
4.1 
Enrollment/Baseline Visit ............................................................................................. 19 
4.1.1 
Medical History ........................................................................................................ 19 
4.1.2 
Physical Assessment ............................................................................................... 20 
4.1.3 
Office Blood Pressure .............................................................................................. 20 
4.2 
Two Week Screening Period ....................................................................................... 20 
4.2.1 
Medication Regimen Monitoring (≥14-Day Period) ................................................... 20 
4.2.2 
Ambulatory Blood Pressure ..................................................................................... 21 
4.3 
Confirmatory Visit ........................................................................................................ 21 
4.3.1 
Blood and Urine Analysis ......................................................................................... 21 
4.3.2 
Transthoracic-echocardiogram (TTE) ...................................................................... 22 
4.3.3 
NYHA Assessment .................................................................................................. 22 
4.3.4 
Quality of Life Questionnaire .................................................................................... 22 
4.3.5 
Baseline Renal Artery Anatomy Evaluation .............................................................. 22 
4.4 
Subject Group Assignment .......................................................................................... 23 
4.4.1 
Group A: (minimum of 100 subjects) ........................................................................ 23 
4.4.2 
Group B: (minimum of 50 subjects) .......................................................................... 23 
4.4.3 
Group C: (minimum of 50 subjects) ......................................................................... 23 
4.5 
Renal Denervation Procedure ..................................................................................... 24 
4.6 
Product Training .......................................................................................................... 25 
4.7 
Discharge .................................................................................................................... 25 
4.8 
Follow-up visits ........................................................................................................... 25 
4.8.1 
Physical Assessment ............................................................................................... 25 
4.8.2 
Medications ............................................................................................................. 25 
4.8.3 
Office Blood Pressure .............................................................................................. 25 
4.8.4 
24 hour Ambulatory Blood Pressure ........................................................................ 25 
4.8.5 
Blood and Urine Analysis ......................................................................................... 26 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
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4.8.6 
Echocardiogram (TTE) ............................................................................................ 26 
4.8.7 
NYHA Assessment .................................................................................................. 26 
4.8.8 
EQ-5D 5L   Quality of Life Questionnaire ................................................................. 26 
4.8.9 
Renal artery evaluation ............................................................................................ 26 
4.8.10 
Adverse Events ....................................................................................................... 27 
4.9 
Clinical Investigation Termination ................................................................................ 27 
4.10 
Description of post investigational provision of medical care .................................... 28 
5 
Clinical Investigation Conduct ............................................................................................ 28 
5.1 
Ethics Committee ........................................................................................................ 28 
5.2 
Ethical Basis ............................................................................................................... 29 
5.3 
Insurance .................................................................................................................... 29 
5.4 
Statements of Compliance .......................................................................................... 29 
5.5 
Adherence to the Clinical Investigation Plan ................................................................ 29 
5.5.1 
Repeated non-compliance ....................................................................................... 30 
5.6 
Informed Consent Process .......................................................................................... 30 
5.6.1 
General Process ...................................................................................................... 30 
5.7 
Adverse Event, Adverse Device Effect ........................................................................ 32 
Definitions.......................................................................................................................... 32 
5.8 
Subject Death ............................................................................................................. 34 
5.8.1 
Procedure for recording and reporting Subject Death .............................................. 34 
5.9 
Document and data control ......................................................................................... 34 
5.9.1 
Traceability of documents and data ......................................................................... 34 
5.9.2 
Recording data ........................................................................................................ 35 
5.9.3 
Review of data ......................................................................................................... 35 
5.10 
Monitoring ................................................................................................................ 35 
5.10.1 
Designated Monitors ................................................................................................ 35 
5.10.2 
Monitoring Plan ........................................................................................................ 35 
5.11 
Competent Authority (CA) Inspections ..................................................................... 36 
5.12 
Investigation Termination ......................................................................................... 36 
5.12.1 
Resuming the Clinical Investigation after Suspension .............................................. 36 
5.12.2 
Investigation Conclusion .......................................................................................... 37 
6 
Risks and Benefits of the Clinical Investigation .................................................................. 37 
6.1 
Anticipated Adverse Events and Adverse Device Effects ............................................ 37 
6.2 
Steps that will be taken to control or mitigate the risks ................................................ 37 
7 
Statistical Analysis ............................................................................................................. 38 
7.1 
Study design ............................................................................................................... 38 
7.2 
Sample size estimation ............................................................................................... 38 
7.3 
Analysis Population ..................................................................................................... 38 
7.4 
Data Analysis and Reporting ....................................................................................... 39 
7.4.1 
Primary objective ..................................................................................................... 39 
7.4.2 
The Secondary objectives ....................................................................................... 39 
7.4.2.1 
Safety Acute data (30 days post procedure)......................................................... 39 
7.4.2.2 
Safety Midterm (6 months) and Long term (2 and 5 years) data ........................... 40 
7.4.3 
Other Analyses ........................................................................................................ 40 
7.4.4 
Analysis Software .................................................................................................... 41 
8 
Data Management ............................................................................................................. 42 
8.1 
Data Management Plan............................................................................................... 42 
8.2 
Source Documents ...................................................................................................... 42 
8.3 
Source Data and Subject Files .................................................................................... 42 
8.4 
Confidentiality of Data ................................................................................................. 43 
9 
Document Retention .......................................................................................................... 45 
10 
Amendments to the Clinical Investigational Plan ............................................................... 45 
11 
Publication Policy .............................................................................................................. 46 
12 
Investigation Organization ................................................................................................. 47 

           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 5 of 78 
12.1 
Investigation Management / Sponsor ....................................................................... 47 
Sponsor Responsibilities ................................................................................................... 47 
12.2 
Clinical Investigators ................................................................................................ 48 
Investigator’s responsibilities ............................................................................................. 48 
Clinical Coordinating Investigator ...................................................................................... 50 
12.3 
Committees ............................................................................................................. 50 
12.3.1 
Steering Committee (SC) ......................................................................................... 50 
12.3.2 
Clinical Event Committee (CEC) .............................................................................. 51 
12.4 
Outsourcing of duties and functions ......................................................................... 51 
12.4.1 
Power of Attorney (POA) ......................................................................................... 51 
13 
Bibliography ....................................................................................................................... 52 
Appendix A: Office Blood Pressure Measurement ..................................................................... 56 
Appendix B: 24 Hour Ambulatory Blood Pressure ..................................................................... 57 
Appendix C: NYHA Assessment Classifications57 ..................................................................... 58 
Appendix D: Patient Information Sheet and Consent Form Template ........................................ 59 
Appendix E: Abbreviations ........................................................................................................ 70 
Appendix F: Declaration of Helsinki ........................................................................................... 71 
Appendix G: Data Collection Method (EDC) .............................................................................. 77 
Appendix H: List of Case Report Forms .................................................................................... 78 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 6 of 78 
1 Synopsis 
Title: 
IntErnational non-randomized, single-arm, long-term follow-up study of patients 
with uncontrolled HyperTensioN 
Acronym: 
EnligHTN  II 
Purpose: 
The purpose of this post market clinical investigation is to further evaluate the 
safety and performance of the EnligHTN™ Renal Denervation System in the 
treatment of patients with uncontrolled hypertension. 
Objectives: 
The objective of this clinical investigation will be to assess the EnligHTN™ Renal 
Denervation System in renal artery ablation for the treatment of uncontrolled 
hypertension.  
Primary Objective: 
 
Mean reduction in office Systolic Blood Pressure at six (6) months across 
all subjects post renal denervation and within sub-groups 
Secondary Objectives: 
 
Safety 
Acute (30 days post procedure):  
 
The assessment of peri-procedural events  
Midterm (6 months): 
 
Assessment of renovascular safety as measured by new renal artery  
stenosis or aneurysm at the site of ablation  
 
Renal function change based on  eGFR 
Long term (2 and 5 years): 
 
Assessment of renovascular safety as measured  by new renal artery  
stenosis or aneurysm at the site of ablation  
 
Renal function change based on  eGFR 
BP reduction 
 
Change in Ambulatory Blood Pressure parameters at 6 months 
 
Change in office Diastolic Blood Pressure at 6 months 
 
Percentage of subjects achieving office Systolic Blood Pressure < 140 at 6 
month visit  
 
Change in Office and Ambulatory Blood Pressure parameters at 12, 24, 
36, 48, 60 months post denervation 
 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
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© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 7 of 78 
Design: 
This is a post market, prospective, multicenter, non-randomized, single arm study 
of the EnligHTN™ Renal Denervation System.  Approximately 500 subjects with 
uncontrolled hypertension will undergo renal artery ablation at approximately 40 
investigational sites located internationally and will be followed up to five (5) years 
post procedure.   
 
The clinical investigation is anticipated to start in October of 2012.  Enrollment is 
anticipated to end in September of 2013.  Subject participation will be up to five 
(5) years post procedure. Clinical investigation completion in 2018. 
Devices 
used: 
EnligHTN™ Renal Artery Ablation Catheter 
EnligHTN™ RF Generator 
EnligHTN™ Guiding Catheter (optional) 
All devices used in this investigation, have received appropriate certification (and 
are market released in the geographies participating in this clinical investigation). 
Patient 
Population:  
The patient population enrolled in this investigation will consist of male and 
female patients 18 years of age or older that meet all of the specified inclusion 
criteria and none of the specified exclusion criteria 
Patient 
Screening 
Patient Screening: 
Patients that will be treated at the investigational site will be screened by a 
member of the investigational team. Patients who do not meet the 
inclusion/exclusion criteria are not eligible to participate. 
 
Patients meeting the inclusion/exclusion criteria will be fully informed about the 
investigation and will be asked to participate in the investigation. A duly signed 
and dated, Ethics committee (EC) and Sponsor approved, Patient Informed 
Consent (PIC) will be obtained. 
 
A patient becomes a subject once he/she has been fully informed about the 
investigation, has agreed to participate, signed & dated the Patient Informed 
Consent (PIC) and therefore has been enrolled in the investigation. 
Inclusion  
Criteria 
 Subject is ≥ 18 years of age at time of consent 
 Subject must be able and willing to provide written informed consent  
 Subject must be able and willing to comply with the required follow-up 
schedule 
 Subject has office Systolic Blood Pressure ≥ 140 mmHg at confirmatory visit 
 Subject has a daytime mean Systolic Ambulatory Blood Pressure > 135 
mmHg within 90 days prior to procedure  
 Subject has established hypertension (diagnosed ≥12 months prior to 
baseline) and is on a guideline based drug regimen at a stable and a fully 
tolerated dose consisting of ≥3 anti-hypertensive medications (including 1 
diuretic), or subject has documented drug intolerance to 2 or more of the 4 
major classes of anti-hypertensives (ACE/ARB, Calcium Channel Blockers, 
Beta Blockers, or diuretic) and is unable to take 3 anti-hypertensive drugs.   
Exclusion 
Criteria 
 Subject has significant renovascular abnormalities such as renal  artery 
stenosis > 30%  
 Subject has undergone prior renal angioplasty, renal denervation,  indwelling 
renal stents, and/or abdominal aortic stent grafts  
 Subject has hemodynamically significant valvular heart disease as determined 
by study investigator 
 Subject has a life expectancy less than 12 months, as determined by the 

           
Clinical Investigation Plan – EnligHTN II
 
 
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© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 8 of 78 
Investigator 
 Subject is participating in another clinical study which has the potential to 
impact their hypertension management (pharmaceutical/device/homeopathic) 
 Subject is pregnant, nursing, or of childbearing potential and is not using 
adequate contraceptive methods 
 Subject has active systemic infection 
 Subject has renal arteries with diameter(s) < 4 mm in diameter  
 Subject has an estimated GFR <15 mL/min per 1.73 m2 using the Modification 
of Diet in Renal Disease (MDRD) formula  
 Subject had a renal transplant or is awaiting a renal transplant 
 Subject has blood clotting abnormalities  
 
 

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                            Group A: (minimum of 100 subjects)
x
Office Systolic Blood Pressure ≥ 160 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated GFR ≥ 45 mL/min per 1.73 m² 
                                           Confirmatory Visit
x
Review of Inclusion / Exclusion criteria – 
24-hour ABP – repeat if medications change
medication review – no changes during BP assessment
Renal artery evaluation review
x
Medical History & Physical Assessment
x
Office Blood Pressure – Complete triplicate reading
x
Quality of Life Questionnaire, EQ-5D 5L
x
Echocardiography (TTE)
x
Blood & Urine collection
x
Protocol Deviation(s), if applicable
Baseline Visit
x
Patient Informed Consent (point of enrollment)
x
Inclusion / Exclusion assessment
x
Medical History & Physical Assessment
x
Medication assessment and documentation – patient is on a 
stable drug regimen
x
Office Blood Pressure – Complete triplicate reading
x
Protocol Deviation(s), if applicable
Group B:(minimum of 50 subjects)
x
Office Systolic Blood Pressure ≥ 140 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated GFR ≥ 45 mL/min per 1.73 m² 
Group C:(minimum of 50 subjects)
x
Office Systolic Blood Pressure ≥ 140 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated ≥15 GFR < 45 mL/min/1.73 m² 
Procedure
x
Renal artery evaluation
x
Procedural Information
x
Adverse Event(s), if applicable
x
Protocol Deviation(s), if applicable
Screen Failure
Patient does not meet the 
Inclusion / Exclusion criteria
Procedural  Failures
Subject is not able to 
have the procedure 
completed
Group assignment
Two Week Screening
- 24-hour ABP (performed w/in 90 days of 
procedure)
- Medication assessment 
Hospital Discharge
x
Blood pressure measurement (4 hour intervals)
x
Physical Assessment
x
Hospital Length of stay
x
Adverse Event(s), if applicable during hospital stay
x
Medication review and documentation
Follow-up visits: 1, 6, 12, 24,36, 48, and 60 Months Post Renal Denervation Procedure
x
Medication Assessment and Documentation at every visit
x
Physical Assessment at every visit
x
Office Blood Pressure at every visit
x
Ambulatory Blood Pressure at 6, 12, 24, 36, 48 and 60 month visits
x
Echocardiography (TTE) at 1, 6, 24 and 60 month visits
x
Quality of Life Assessment (EQ-5D 5L) at 1, 6, 24 and 60 month visits
x
Blood Collection at 6, 12, 24 and 60 month visits
x
Urine Collection at 6, 24 and 60 month visits
x
Renal artery evaluation at 6, 24 and 60 month visits
x
Adverse Event(s), if applicable
x
Protocol Deviation(s), if applicable
If Yes, Group A
If Yes, Group B
If Yes, Group C
If No, Screen Failure
If no, see Group B
If no, see Group C
Does Subject Meet the Following Criteria?





           
Clinical Investigation Plan – EnligHTN II
 
 
SJM CONFIDENTIAL AND PROPRIETARY 
© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 10 of 78 
Visit 
Enrollment / 
Baseline 
Confirmatory 
Procedure 
Discharge 
<72 hrs 
 
1M 
±14d 
 
6M 
±30d 
 
12M 
±60d 
 
24M 
±60d 
 
36M 
±60d 
 
48M 
±60d 
 
60M 
±60d 
PIS & PIC 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X-review for 
changes 
 
 
 
 
 
 
 
 
 
Medical  History 
X 
X-review for 
changes 
 
 
 
 
 
 
 
 
 
Office Blood 
Pressure 
X 
X 
 
X 
 X 
X 
X 
X 
X 
X 
X 
Physical Assessment 
X 
X-review for 
changes 
 
X 
 X 
X 
X 
X 
X 
X 
X 
24-h Ambulatory 
Blood Pressure 
X-performed 
w/in 90 days 
of procedure 
X-repeat if 
there are 
medication 
changes 
 
 
 
X 
X 
X 
X 
X 
X 
Discharge Blood 
Pressure 
 
 
 
X* 
 
 
 
 
 
 
 
***Echocardiography 
(TTE) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
NYHA Assessment 
X 
 
 
 
X 
X 
 
X 
 
 
X 
Serum creatinine 
 
X 
 
 
 
X 
X 
X 
 
 
X 
Estimated GFR 
 
X 
 
 
 
X 
X 
X 
 
 
X 
Hemoglobin A1c 
 
X 
 
 
 
X 
 
 
 
 
 
Fasting Glucose  
 
X 
 
 
 
X 
 
 
 
 
 
Fasting Insulin        
 
X 
 
 
 
X 
 
 
 
 
 
Urine albumin-to-
creatinine ratio 
 
X 
 
 
 
X 
 
X 
 
 
X 
Medications Log 
X 
X-review for 
changes 
 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
questionnaire 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Renal Artery 
Anatomy Evaluation 
 
X – if not 
performed 
w/in 90 days 
X 
 
 
X 
 
X 
 
 
X 
Pregnancy Test 
(urine / blood) 
 
X 
 
 
 
 
 
 
 
 
 
Renal Denervation 
Procedure 
 
 
X 
 
 
 
 
 
 
 
 
Adverse Event 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
CIP Deviation 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
Withdrawal/ 
Termination 
 
 
** 
** 
** 
** 
** 
** 
** 
** 
X 
 
(*) monitored every 4 hours post procedure until discharge, or for a maximum of 24 hours 
(**) as applicable 
(***) Echo will be performed at 6 preselected sites 
 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
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© 2012 – St. Jude Medical Cardiovascular Division: All rights reserved.  No portion of this work may be reproduced in 
whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 11 of 78 
2 Background 
 
Hypertension or high blood pressure is a major risk factor for cardiovascular and 
cerebrovascular events.1-3 It is responsible for approximately one half of the coronary heart 
disease and two thirds of the cerebrovascular disease burdens.4 It is also the world’s number 
one attributable risk for death. The global prevalence of hypertension has been increasing. An 
analysis indicated that more than one quarter (nearly one billion) of the world’s adult population 
had hypertension in 2000. This is projected to increase to 1.56 billion affected individuals with a 
prevalence rate of 29% in 2025.5 This is a major public health challenge in both economically 
developing and developed countries. 
 
Previous studies showed that drug therapy may reduce the risk of major cardiovascular events 
by about 20% and the risk of stroke by about 40% in patients with hypertension.6-10 However, 
these may not apply to all patients with hypertension. A large proportion of patients with 
hypertension still remains untreated or uncontrolled due to many factors.11-12 For patients with 
resistant hypertension despite the use of aggressive drug therapy, which includes at least 3 anti-
hypertensive drugs with a diuretic being one of these drugs, blood pressure management 
remains uncontrolled.13 In the general hypertensive population, the prevalence of resistant 
hypertension is estimated to be about 5% to 12%. In patients with co-morbidity, such as chronic 
renal failure or diabetes, the prevalence of resistant hypertension is even significantly higher. 14-
19 Hypertension is also mainly an asymptomatic disease, which could be difficult to have the 
patient understanding about the importance of complying and adhering to the lifelong drug 
therapy. Alternative approaches to control the blood pressure of these patients are urgently 
needed.20 
 
The kidneys represent the central homeostatic organ regulating blood pressure and blood 
volume.21 The sympathetic innervation of the kidney is implicated in the pathogenesis of 
hypertension through enhanced renin secretion and sodium re-absorption and reduced renal 
blood flow.22-24 Renal sympathetic afferent and efferent nerves run within and adjacent to the wall 
of the renal artery.25-27 Previous experimental functional studies showed that activation of the 
renal sympathetic nerve could cause increase and even spillover of the norepinephrine 
production, which results in the elevation of blood pressure, while renal denervation could 
reduce the norepinephrine level of up to 95%.28-30 Sectioning of the renal afferent nerves 
controlled the increased sympathetic activity in the posterior hypothalamus and allowed good 
control of the elevated blood pressure.31-34 In various experimental models, which include 
spontaneous hypertension, deoxycorticosterone-acetate-induced hypertension, obesity-induced 
hypertension and aortic coarctation models, the magnitude of the hypertension has been 
reduced and the renal blood flow has been increased during the observation period after renal 
denervation.29-30,35 
 
Radical surgical methods for abdominal, thoracic or pelvic sympathetic denervation (radical 
sympathectomy) have been used to treat patients with severe or malignant hypertension more 
than five decades ago.36-44 However, after the advent of modern anti-hypertensive drug therapy, 
radical sympathectomy was mainly reserved for non-responders of the anti-hypertensive drug 
therapy due to the extensive surgical procedure and technique, significant procedural time, long 
hospital stay (generally 2 to 4 weeks) and long recovery time (generally 4 to 8 weeks) in patients 
involved. 
 
Percutaneous catheter-based methods deliver radiofrequency (RF) energy to the renal 
sympathetic nerves for the ablation-induced renal denervation. This minimally invasive and more 
localized approach allows for possibly much shorter procedural time, shorter hospital stay and 
shorter recovery time, which may benefit more patients with uncontrolled hypertension.  
 

           
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Page 12 of 78 
Recent clinical studies reported significant improvement of office blood pressure measurement 
in patients with resistant hypertension after the catheter-based renal denervation procedure 
(about -20/-10 mmHg, -25/11 mmHg, -23/-11 mmHg and -32/-14 mmHg at 1, 6, 12 and 24 
months respectively from baseline systolic/diastolic blood pressures).45-47,56  
 
Further insights into mechanisms of hypertension control through renal denervation were 
published in a recent case report of a 59-year old patient with long-standing uncontrolled 
hypertension on a multi-drug regimen.48 The baseline renal norepinephrine spillover from both 
the left and right kidneys was approximately three times above the normal level, which indicated 
an elevated renal sympathetic neuronal efferent activity. Bilateral renal denervation resulted in a 
progressive and sustained improvement in the systemic blood pressure from 161/107 mmHg at 
baseline to 121/81 mmHg at 12 months and a decrease of the norepinephrine spillover by 48% 
from the left kidney and 75% from the right kidney at 1 month after the renal denervation 
procedure. The muscle sympathetic nerve activity as assessed by microneurography also 
reduced gradually to normal levels 12 months after the renal denervation procedure. 
 
EnligHTN-I (ARSENAL) was a feasibility study to demonstrate the safety and efficacy of the St. 
Jude Medical Radiofrequency Renal Denervation System in the treatment of patients with 
resistant hypertension.  This study is currently being conducted at four (4) investigational sites in 
Australia and Greece. Enrollment was completed on March 1, 2012 with a total of 46 patients 
having undergone the renal denervation procedure.  Subjects will be followed for 24 months post 
procedure.   
 
The one month clinical results from EnligHTN I were presented at the European Association of 
Percutaneous Cardiovascular Interventions, EuroPCR 2012 Congress May 15-18, 2012.  Data 
was presented on 46 patients from four sites (60±10 years, 15 females/ 31 males) with a 
baseline average office Blood Pressure (BP) measurement of 176±16 / 96±14 mmHg, and an 
average of 4±0.6 anti-hypertensive medications.  Fifteen (15) patients had a history of Diabetes 
Mellitus Type II.  Median procedure time was 34.0 with a mean number of ablations completed 
on the right side of 7.7±0.8 and the left side of 7.4±1.4.  One patient had the renal denervation 
procedure completed on the right side only due to tortuous anatomy.   No vascular or renal 
artery complications were observed at the end of the procedure in any of the patients.  At the 
time of discharge the average Blood Pressure measurement was 154/88 mmHg and at the one 
month time point the average office Blood Pressure measurement was 148/87 mmHg.  The 
average systolic / diastolic Blood Pressure between baseline and one month was -28/-10 mmHg 
with 78% of the patients experiencing a ≥ 10 mmHg reduction in systolic Blood Pressure 58. 
 
The three month clinical results from EnligHTN I were presented at the European Society of 
Cardiology (ESC) meeting on 28 August 2012.  At the three month time point the average 
systolic / diastolic Blood Pressure difference between baseline and three month follow-up was -
27/-10 mmHg with 80% of the patients experiencing a ≥ 10 mmHg reduction in systolic Blood 
Pressure.  At 3 months, the mean systolic/diastolic ambulatory Blood Pressure difference 
between baseline and 3 months was -9.9/-5.4 mmHg. 
 
   
3 Investigational Design 
3.1 Purpose 
The purpose of this Clinical investigation is to further evaluate the safety and performance of the 
EnligHTN™ Renal Denervation System in the treatment of patients with uncontrolled 
hypertension. 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 13 of 78 
3.2 Objectives 
Primary Objective 
The primary objective is to evaluate a mean  reduction in office Systolic Blood Pressure at six (6) 
months across all subjects post renal denervation and within sub-groups.  
 
Secondary Objective 
The secondary objectives are: 
 
Safety 
Acute (30 days post procedure):  
 
The assessment of peri-procedural events  
Midterm (6 months): 
 
Assessment of renovascular safety  as measured by new renal artery stenosis or 
aneurysm at the site of ablation   
 
Renal function change based on eGFR 
 
Long term (2 and 5 years): 
 
Assessment of renovascular safety as measured by new renal artery stenosis or 
aneurysm at the site of ablation 
 
Renal function change based on eGFR 
BP reduction 
 
Change in Ambulatory Blood Pressure parameters at 6 months 
 
Change in office Diastolic Blood Pressure at 6 months 
 
Percentage of subjects achieving office Systolic Blood Pressure < 140 at 6 month visit  
 
Change in Office and Ambulatory Blood Pressure parameters at 12, 24, 36, 48, 60 
months post denervation 
 
3.3 Investigational Type 
This is a post market, prospective, multicenter, non-randomized, single arm study of the 
EnligHTN™ Renal Denervation System.  Approximately 500 subjects with uncontrolled 
hypertension will undergo renal artery ablation at approximately 40 investigational sites located 
internationally and will be followed up to five (5) years post procedure.   
 
3.4 Patient Population 
The patient population enrolled in this investigation will consist of male and female patients 18 
years of age or older that meet all of the specified inclusion criteria and none of the specified 
exclusion criteria (Section 3.5).  
 

           
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Page 14 of 78 
3.5 Patient Screening 
All patients treated at the investigational site can be screened by a member of the investigational 
team. This team member needs to be trained on the Clinical Investigational Plan (CIP) and the 
task of subject screening needs to be delegated in writing to this team member by the Principal 
Investigator. 
 
The patient will be given ample time to ask questions and to understand the risks of being a part 
of this investigation. In case the patient agrees to participate, a duly signed and dated Patient 
Informed Consent (PIC) will be obtained. 
 
3.6 Inclusion and Exclusion Criteria / Point of Enrollment 
A patient, who meets all of the inclusion criteria, and none of the exclusion criteria, is eligible to 
participate in this investigation. A patient becomes a subject once he/she has been fully 
informed about the investigation, has agreed to participate, signed & dated the PIC and 
therefore has been enrolled in the investigation. (Refer to section 5.2 for the Informed Consent 
Process) 
 
Once enrolled, a subject is expected to comply with the scheduled visits and required activities 
according to the CIP. The subject should undergo the renal denervation procedure within 30 
days of the baseline visit but must be no longer than 90 days from baseline.  
 
All subjects enrolled in the clinical investigation (including those withdrawn from the clinical 
investigation or lost to follow-up) shall be accounted for and documented in the Patient 
Identification Log, assigning an identification code linked to their names, alternative identification 
or contact information. Because subject privacy and confidentiality of data must be maintained 
throughout the clinical investigation, this log will only remain on site. 
 
This log shall be kept up to date throughout the clinical investigation by the Principal Investigator 
or his/her authorized designee. 
 
3.6.1 Inclusion Criteria 
 
Subject is ≥ 18 years of age at time of consent 
 
Subject must be able and willing to provide written informed consent  
 
Subject must be able and willing to comply with the required follow-up schedule 
 
Subject has office Systolic Blood Pressure ≥ 140 mmHg at confirmatory visit 
 
Subject has a daytime mean Systolic Ambulatory Blood Pressure  > 135 mmHg within 90 
days prior to procedure 
 
Subject has established hypertension (diagnosed ≥12 months prior to baseline) and is on a 
guideline based drug regimen at a stable and a fully tolerated dose consisting of ≥3 anti-
hypertensive medications (including 1 diuretic), or subject has documented drug 
intolerance to 2 or more of the 4 major classes of anti-hypertensives (ACE/ARB, Calcium 
Channel Blockers, Beta Blockers, or diuretic) and is unable to take 3 anti-hypertensive 
drugs.    
 
3.6.2 Exclusion Criteria 
 
Subject has significant renovascular abnormalities such as renal  artery stenosis > 30%  

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 15 of 78 
 
Subject has undergone prior renal angioplasty, renal denervation,  indwelling renal stents, 
and/or abdominal aortic stent grafts  
 
Subject has hemodynamically significant valvular heart disease as determined by Study 
investigator 
 
Subject has a life expectancy less than 12 months, as determined by the Study 
Investigator 
 
Subject is participating in another clinical study which has the potential to impact their 
hypertension management (pharmaceutical / device / homeopathic) 
 
Subject is pregnant, nursing, or of childbearing potential and is not using adequate 
contraceptive methods 
 
Subject has active systemic infection 
 
Subject has renal arteries with diameter(s) < 4 mm in diameter  
 
Subject has an estimated GFR <15 mL/min per 1.73 m2 using the Modification of Diet in 
Renal Disease (MDRD) formula  
 
Subject had a renal transplant or is awaiting a renal transplant 
 
Subject has blood clotting abnormalities 
 
3.7 Procedural Exclusions 
Subjects who have been enrolled in the clinical investigation and the procedure was started but 
do not have the EnligHTN™ Renal Denervation System enter their  body, due to their anatomy, 
circumstances related to the procedure, or physician judgment will be classified as procedurally 
excluded. The reason for the procedural exclusion will be documented on the Procedural CRF.    
The subject will return for a 1 month follow up visit and have a physical assessment and office 
blood pressure completed.     
3.8 Expected duration of the Investigation 
The expected duration of the investigation will be approximately six (6) years. 
3.9 Expected duration of each subject’s participation 
The expected duration of each subject enrolled in the clinical investigation will be five (5) years.  
3.10 Number of subjects required to be included in the Investigation 
Enough subjects will be enrolled to have approximately 500 subjects undergo the renal 
denervation procedure in the investigation. Procedurally excluded subjects will not count 
towards the expected number of treated subjects.  
3.11 Estimated time needed to select this subject population 
The estimated time needed to enroll the number of subjects will be approximately 8 months. 
 
3.12 Devices Used 
 
The EnligHTN™ Renal Denervation System is designed to deliver radiofrequency (RF) energy 
to the renal nerves to achieve targeted denervation. The system consists of the EnligHTN™ RF 
Ablation Generator (generator), the EnligHTN™ Renal Artery Ablation Catheter (ablation 
catheter), and the EnligHTN™ Guiding Catheter (optional).  
 
The following market approved St. Jude Medical devices to be first used in this investigation are:   

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 16 of 78 
 
 
3.12.1 EnligHTN™ Renal Artery Ablation Catheter 
 
The EnligHTN™ Renal Artery Ablation Catheter is a single use device that has an expandable 
electrode basket with four Platinum-Iridium (Pt-Ir) ablation electrodes. The electrodes deliver 
low-level radiofrequency energy to the renal arteries through a percutaneous vascular access 
site. The distal segment of the ablation catheter is deflectable to assist in proper basket 
positioning. The handle is used to actuate the expansion and relaxation of the basket, and to 
actuate the deflection of the ablation catheter at the distal end. The ablation electrodes and the 
tip are radiopaque to provide visualization under fluoroscopy. 
 
 
3.12.2 EnligHTN™ RF Ablation Generator 
 
The EnligHTN™ RF Ablation Generator delivers RF energy to the EnligHTN Renal Artery 
Ablation Catheter using a proprietary algorithm developed to produce a consistent, transmural 
ablation pattern during the renal denervation procedure. 
 
 
3.12.3 EnligHTN™ Guiding Catheter (optional) 
 
The EnligHTN™ Guiding Catheter system is comprised of two (2) components: a guiding 
catheter and a dilator.  The guiding catheter is constructed of three (3) components: a 
polytetrafluoroethylene (PTFE) liner, a stainless steel braid, and a multi durometer polymer 
jacket. The proximal end of the catheter terminates in a hemostasis hub and a hemostasis valve. 
An extension tube and 3-way stopcock valve is attached to the sideport of the hemostasis hub. 
The distal end of the catheter terminates in a renal curve with a radiopaque marker embedded in 
the polymer jacket approximately 2 mm from the catheter tip. The dilator is a polymer tube with 
an inside diameter sized for guidewire clearance. The proximal end terminates in a snap fitting 
to mate with the guiding catheter hemostasis hub. The distal end is tapered to facilitate insertion 
through an introducer sheath. 
 
3.13 Intended Use  
 
The ablation catheter is indicated for use in renal denervation procedures for the treatment of 
hypertension.   
 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 17 of 78 
4 Procedures 
Table 1: Data/CRF Collection 
Visit 
Enrollment / 
Baseline 
Confirmatory 
Procedure 
Discharge 
<72 hrs 
 
1M 
±14d 
 
6M 
±30d 
 
12M 
±60d 
 
24M 
±60d 
 
36M 
±60d 
 
48M 
±60d 
 
60M 
±60d 
PIS & PIC 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X-review for 
changes 
 
 
 
 
 
 
 
 
 
Medical  History 
X 
X-review for 
changes 
 
 
 
 
 
 
 
 
 
Office Blood 
Pressure 
X 
X 
 
X 
 X 
X 
X 
X 
X 
X 
X 
Physical Assessment 
X 
X-review for 
changes 
 
X 
 X 
X 
X 
X 
X 
X 
X 
24-h Ambulatory 
Blood Pressure 
X- 
performed 
w/in 90 days 
of procedure 
X-repeat if 
there are 
medication 
changes 
 
 
 
X 
X 
X 
X 
X 
X 
Discharge Blood 
Pressure 
 
 
 
X* 
 
 
 
 
 
 
 
***Echocardiography 
(TTE) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
NYHA Assessment 
X 
 
 
 
X 
X 
 
X 
 
 
X 
Serum creatinine 
 
X 
 
 
 
X 
X 
X 
 
 
X 
Estimated GFR 
 
X 
 
 
 
X 
X 
X 
 
 
X 
Hemoglobin A1c 
 
X 
 
 
 
X 
 
 
 
 
 
Fasting Glucose  
 
X 
 
 
 
X 
 
 
 
 
 
Fasting Insulin        
 
X 
 
 
 
X 
 
 
 
 
 
Urine albumin-to-
creatinine ratio 
 
X 
 
 
 
X 
 
X 
 
 
X 
Medications Log 
X 
X-review for 
changes 
 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
questionnaire 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Renal Artery 
Anatomy Evaluation 
 
X – if not 
performed 
w/in 90 days 
X 
 
 
X 
 
X 
 
 
X 
Pregnancy Test 
(urine / blood) 
 
X 
 
 
 
 
 
 
 
 
 
Renal Denervation 
Procedure 
 
 
X 
 
 
 
 
 
 
 
 
Adverse Event 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
CIP Deviation 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
** 
Withdrawal/ 
Termination 
 
 
** 
** 
** 
** 
** 
** 
** 
** 
X 
 
(*) monitored every 4 hours post procedure until discharge, or for a maximum of 24 hours 
(**) as applicable 
(***) Echo will be performed at 6 preselected sites 
 

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                            Group A: (minimum of 100 subjects)
x
Office Systolic Blood Pressure ≥ 160 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated GFR ≥ 45 mL/min per 1.73 m² 
                                           Confirmatory Visit
x
Review of Inclusion / Exclusion criteria – 
24-hour ABP – repeat if medications change
medication review – no changes during BP assessment
Renal artery evaluation review
x
Medical History & Physical Assessment
x
Office Blood Pressure – Complete triplicate reading
x
Quality of Life Questionnaire, EQ-5D 5L
x
Echocardiography (TTE)
x
Blood & Urine collection
x
Protocol Deviation(s), if applicable
Baseline Visit
x
Patient Informed Consent (point of enrollment)
x
Inclusion / Exclusion assessment
x
Medical History & Physical Assessment
x
Medication assessment and documentation – patient is on a 
stable drug regimen
x
Office Blood Pressure – Complete triplicate reading
x
Protocol Deviation(s), if applicable
Group B:(minimum of 50 subjects)
x
Office Systolic Blood Pressure ≥ 140 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated GFR ≥ 45 mL/min per 1.73 m² 
Group C:(minimum of 50 subjects)
x
Office Systolic Blood Pressure ≥ 140 mmHg 
x
Subject is taking ≥ 3 anti-hypertensive medications (this 
must include one diuretic) or documented drug intolerance 
to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-hypertensive drugs.
x
Subject has an estimated ≥15 GFR < 45 mL/min/1.73 m² 
Procedure
x
Renal artery evaluation
x
Procedural Information
x
Adverse Event(s), if applicable
x
Protocol Deviation(s), if applicable
Screen Failure
Patient does not meet the 
Inclusion / Exclusion criteria
Procedural  Failures
Subject is not able to 
have the procedure 
completed
Group assignment
Two Week Screening
- 24-hour ABP (performed w/in 90 days of 
procedure)
- Medication assessment 
Hospital Discharge
x
Blood pressure measurement (4 hour intervals)
x
Physical Assessment
x
Hospital Length of stay
x
Adverse Event(s), if applicable during hospital stay
x
Medication review and documentation
Follow-up visits: 1, 6, 12, 24,36, 48, and 60 Months Post Renal Denervation Procedure
x
Medication Assessment and Documentation at every visit
x
Physical Assessment at every visit
x
Office Blood Pressure at every visit
x
Ambulatory Blood Pressure at 6, 12, 24, 36, 48 and 60 month visits
x
Echocardiography (TTE) at 1, 6, 24 and 60 month visits
x
Quality of Life Assessment (EQ-5D 5L) at 1, 6, 24 and 60 month visits
x
Blood Collection at 6, 12, 24 and 60 month visits
x
Urine Collection at 6, 24 and 60 month visits
x
Renal artery evaluation at 6, 24 and 60 month visits
x
Adverse Event(s), if applicable
x
Protocol Deviation(s), if applicable
If Yes, Group A
If Yes, Group B
If Yes, Group C
If No, Screen Failure
If no, see Group B
If no, see Group C
Does Subject Meet the Following Criteria?

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 19 of 78 
4.1 Enrollment/Baseline Visit 
 
Prior to enrollment in the clinical investigation, site personnel will evaluate potential candidates 
by reviewing the patient medical records against the inclusion and exclusion criteria.  It is 
expected that the medical records will contain adequate and accurate information to determine if 
the patient meets these criteria. 
 
If a patient meets all inclusion criteria and does not meet any of the exclusion criteria, the patient 
shall be eligible for the investigation.  
 
If the patient agrees to participate, the study site personnel shall follow the informed consent 
process set forth in Section 5.2 and obtain the signature and date from the patient on the 
approved Patient Informed Consent (PIC) form (previously approved by Ethics Committee and 
the Sponsor).  If the patient does not sign and date the Patient Informed Consent (PIC), they 
cannot participate in the investigation. No further CIP required activities are allowed. 
 
A patient becomes a subject once he/she has been fully informed about the investigation, has 
agreed to participate, signed & dated the PIC and therefore has been enrolled in the 
investigation.    
 
NOTE: As soon as the subject signs the Patient Informed Consent, adverse events need to be 
reported according to the guidelines mentioned in Section 5.3. 
 
The EC should be notified appropriately about any CIP deviations with regards to obtaining 
informed consent. 
 
If new information becomes available during the clinical study that can significantly affect a 
patient’s future health and medical care, that information will be provided to the patient(s) in 
written form. 
 
The following information will be collected at the baseline visit either from hospital records or 
through patient interaction documented in the hospital records.  All baseline activities are 
performed after the patient is enrolled in the investigation.  Tests and procedures required at 
baseline can be completed within 90 days of enrollment but must be completed prior to 
procedure.  
 
4.1.1 Medical History 
 
A complete medical history of the subject will be reviewed and recorded including: 
 
 
Hypertension, 
renal, 
cardiovascular, 
neurological, 
obstructive 
sleep 
apnea, 
hyperlipidemia, diabetes (Type I and II), smoking, thyroid disease, liver disease, chronic 
obstructive pulmonary disease, and alcohol consumption 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 20 of 78 
 
4.1.2 Physical Assessment 
 
The subject will have a physical assessment recording at the baseline visit to capture the 
following: 
 
Age  
 
Gender 
 
Height (only at baseline) 
 
Weight 
4.1.3 Office Blood Pressure 
 
Office Blood Pressure measurements will be recorded as the average Blood Pressure of three 
measurements.  If there is a change in medication after the office Blood Pressure assessment is 
completed an additional set of office Blood Pressure measurements is required to determine 
eligibility.   
 
Measurements should be taken according to Standard Joint National Committee VII Guidelines / 
ESC and ESH Guidelines54, 55, refer to Appendix A for Office Blood Pressure instructions. 
 
4.2 Two Week Screening Period 
4.2.1 Medication Regimen Monitoring (≥14-Day Period) 
 
The anti-hypertensive drug regimen of the subject will be monitored for a period of at least 14 
days at baseline. Medication logs will be provided for the subject to record their daily anti-
hypertensive drug regimen during the monitoring period. Upon the completion of the monitoring 
period (≥14 days), the subject will return to the study center with the medication logs for the 
continued baseline evaluation.  
 
The medication log will be reviewed to assess the subject’s compliance with their current 
medication regimen. The clinical investigation does allow the inclusion of subjects that are not 
on guideline based therapy due to intolerance.  Intolerance to medications is defined as a 
relative or an absolute contraindication to an anti-hypertensive medication.  This assessment will 
be left to the discretion of the Study Investigator.   
It is recommended that the subjects maintain their enrollment anti-hypertensive regimen for a 
minimum of 180 days post procedure unless clinically necessary for changes to occur.   
 
Investigators will urge subject compliance to prescribed medical regimen at the onset of the 14 
day monitoring period and throughout the trial.  If the subject is non-compliant without medical 
rationale, the subject may be excluded. 
 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Page 21 of 78 
4.2.2 Ambulatory Blood Pressure 
To ensure proper patient selection for inclusion in the study subjects must have a daytime mean 
Ambulatory Blood Pressure (ABP) measurement of > 135 mmHg within 90 days prior to 
procedure.  
 
If there is a change in medication after ABP assessment an additional ABP assessment is 
required to determine eligibility. In addition to the daytime mean ABP, the night time mean, and 
24 hour average ABP value will be collected. When using ABP ensure that at least two 
measurements per hour are taken during the person’s usual waking hours (for example, 
between 08:00 and 22:00) and 1 measurement per hour are taken during the person’s usual 
night time hours. The average value of at least 14 measurements taken during the person’s 
usual waking hours should be used for calculation of mean daytime value.  
 
Measurements should be taken according to Standard Joint National Committee VII Guidelines 
ESC and ESH Guidelines54, 55, refer to Appendix B for 24 Hour Ambulatory Blood Pressure 
instructions. 
 
The ABP can be taken during the two week screening period but must be repeated if there are 
medication changes. .    
 
4.3 Confirmatory Visit 
After the two week screening period the subject will return to the Study Center for the 
confirmatory visit.   
 
The following items will be reviewed or performed at the confirmatory visit to ensure there have 
been no changes prior to moving forward with the EnligHTN Renal Denervation procedure. 
 
 
Inclusion / exclusion criteria  
 
Medication logs 
 
Medical history & physical assessment 
 
Office Blood Pressure measurements will be recorded as the average Blood Pressure of 
three measurements  
 
Review of daytime mean Systolic Ambulatory Blood Pressure (must be repeated if there 
are medication changes)  
If the subject does not meet eligibility after baseline and 2 week screening period they may be 
re-evaluated. The Office Blood Pressure, Medication log and the Ambulatory Blood Pressure will 
need to be repeated if it is determined the subject could be re-evaluated.   
 
 
4.3.1 Blood and Urine Analysis  
 
Blood and urine samples will be collected and analyzed as listed below.   
 
Serum Creatinine 
 
Estimated GFR (eGFR) 

           
Clinical Investigation Plan – EnligHTN II
 
 
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Page 22 of 78 
 
Hemoglobin A1c 
 
Fasting glucose 
 
Fasting insulin  
 
Urine albumin-creatinine ratio 
 
Pregnancy test (only at baseline) 
A true numeric value for the estimated GFR must be provided.  If your local laboratory does not 
report the eGFR value beyond 60 mL/min/1.73 m2 the center should use a sponsor-approved 
calculation tool to generate the value.  The sponsor will provide an approved website(s) for this 
calculation to study centers.   
 
4.3.2 Transthoracic-echocardiogram (TTE) 
Transthoracic-echocardiogram (TTE) examinations will be conducted at approximately 6 sites.   
Each site is responsible for performing the echocardiogram per each institutions standard of 
care echo protocol.  
 
4.3.3 NYHA Assessment 
NYHA Assessment57 will be evaluated at baseline and should be classified based on the 
definitions in Appendix C.  
 
4.3.4 Quality of Life Questionnaire 
 
EQ-5D 5L questionnaire will be completed at baseline.   
 
4.3.5 Baseline Renal Artery Anatomy Evaluation  
 
Adequate renal artery imaging is recommended to occur within 90 days prior to enrollment. 
Renal artery imaging by Duplex Ultrasound (U/S) should be performed to evaluate the subject’s 
renal artery anatomy. Study investigators may consider requesting a computed axial 
tomography scan (CT scan) or utilize the procedural angiogram if the Duplex Ultrasound is 
inconclusive or shows any renal abnormalities.  
 
 
Renal artery evaluation data collected will include but are not limited to: 
 
Type of evaluation - computed axial tomography (CT scan), duplex ultrasonography, 
angiography, Doppler, magnetic resonance (MR) angiography, or non-contrast MRI 
 
Length of artery(s) 
 
Diameter of artery(s) 
 
Number of main renal arteries 
 
Number of accessory renal arteries 
 
Presence and percent of stenosis 
 
Other abnormalities 

           
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Page 23 of 78 
 
4.4 Subject Group Assignment  
 
Subjects who have met all of the baseline and enrollment criteria will be assigned to one of the 
following groups: 
 
4.4.1 Group A: (minimum of 100 subjects) 
 
Office systolic Blood Pressure ≥160 mmHg 
 
Subject is taking ≥3 anti-hypertensive medications (including 1 diuretic), or subject has 
documented drug intolerance to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or diuretic) and is unable to take 3 
anti-hypertensive drugs.   
 
Patient has an estimated GFR ≥45 mL/min per 1.73 m2 using the Modification of Diet in 
Renal Disease (MDRD) formula  
 
4.4.2 Group B: (minimum of 50 subjects) 
 
Office systolic Blood Pressure ≥140 mmHg 
 
Subject is taking ≥3 anti-hypertensive medications (including 1 diuretic), or subject has 
documented drug intolerance to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or diuretic) and is unable to take 3 
anti-hypertensive drugs.   
 
Patient has an estimated GFR ≥45 mL/min per 1.73 m2  using the Modification of Diet in 
Renal Disease (MDRD) formula  
 
4.4.3 Group C: (minimum of 50 subjects) 
 
Office systolic Blood Pressure ≥140 mmHg 
 
Subject is taking ≥3 anti-hypertensive medications (including 1 diuretic), or subject has 
documented drug intolerance to 2 or more of the 4 major classes of anti-hypertensives 
(ACE/ARB, Calcium Channel Blockers, Beta Blockers, or diuretic) and is unable to take 3 
anti-hypertensive drugs.   
 
Patient has an estimated ≥15 GFR <45 mL/min per 1.73 m2  using the Modification of 
Diet in Renal Disease (MDRD) formula  
 
 
 
 

           
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Page 24 of 78 
4.5 Renal Denervation Procedure 
 
The renal nerve ablation should be performed according to the EnligHTN™ Renal Denervation 
System Instructions for Use (IFU).  
 
The renal denervation procedure should always be done with the aid of fluoroscopy. With the 
patient under local anesthesia, an introducer sheath will be inserted into the femoral artery using 
the standard percutaneous technique (modified Seldinger technique). A heparin bolus of 3000 to 
5000 units will then be administered intravenously or per institution’s standard of care. An 8 
French guiding catheter sheath will be inserted to engage each main renal artery sequentially 
with the angiograms recorded. Images of the left and right main renal arteries will be recorded 
using the non-ionic contrast and the diameter and length of each of the main renal arteries will 
be measured.  
Prepare the patient for standard electrosurgery.  Select an appropriate basket size of the Basket 
Renal Denervation Catheter (small size for patient with renal artery diameter between 4mm and 
6mm and large size for patient with renal artery diameter between 5.5mm and 8mm) should be 
chosen. The Basket Renal Denervation Catheter will be inserted with the tip of the catheter 
positioned proximal to the bifurcation of one of the main renal arteries and the corresponding 
images will be recorded. The basket on the Renal Denervation Catheter will then be opened, 
while the impedance of each electrode on the basket will be monitored. To begin the ablation, 
the “START” button on the RF Generator will be pressed with the impedance, temperature and 
RF energy delivery monitored and recorded during the process. The investigator will decide the 
location(s) and number of ablation sites/lesions (4 to 8 ablation sites/lesions are recommended) 
in the main renal artery. When the ablation procedure is completed in this main renal artery, the 
basket on the Catheter will be withdrawn from the artery with the Basket Renal Denervation 
Catheter fully closed. Images of the renal artery using the non-ionic contrast will be recorded. 
Any signs of renal artery irregularities (vasospasm, stenosis or dissection) will be checked.  
 
The same renal artery ablation procedure will be repeated for the other main renal arteries. 
When the ablation procedure for the main renal arteries are also completed, the basket on the 
Renal Denervation Catheter will be withdrawn from the artery with the Basket Renal Denervation 
Catheter fully closed and the catheter will be visually inspected and flushed with heparinized 
saline. Finally, the sheath will be removed according to the center’s standard of care.  
 
Procedural data collected will include but is not limited to: 
 
EnligHTN™ Renal Denervation System device information  
 
Guiding catheter used – manufacture  
 
Number of arteries ablated 
 
Number of ablations performed 
 
Device settings 
 
Procedure time 
 
Ablation time 
 
Fluoroscopic time 
 
Volume of contrast media 
 

           
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Page 25 of 78 
4.6 Product Training 
 
All physician users will undergo product training prior to initial human use and at the time of 
initial human use there is an expectation that each site will be proctored by a SJM clinical 
specialist until there is demonstration of product usage per the IFU and site ancillary procedural 
staff have been trained on the ablation generator.  
 
4.7 Discharge  
 
Following the renal denervation procedure, the subject’s blood pressure will be monitored every 
4 hours post procedure until discharge, or for a maximum of 24 hours. At discharge a physical 
assessment will be performed and the subject’s medication regimen will be reviewed and 
recorded.  Discharge is expected to occur within72 hours post procedure.  
 
Adverse Events – check if any adverse events or adverse device effect occurred since 
enrollment of the patient into the Clinical Investigational study.  Document the event in the 
hospital records and report the adverse event according to specifications in section 5.3.2. 
 
4.8 Follow-up visits 
 
Subjects will return for follow-up at 1 month (±14 days), 6 months (± 30 days) post procedure 
and annual follow-up visits at 12, 24, 36, 48, and 60 months post-procedure (± 60 days).   
 
The following will be evaluated / reviewed according to Table 1: 
4.8.1 Physical Assessment 
 
The subject will have a physical assessment at every follow up visit to capture weight.  
4.8.2 Medications 
Medications will be recorded in addition to documenting changes to medications at each follow-
up visit.   
4.8.3 Office Blood Pressure  
Office Blood Pressure measurements will be recorded as the average blood pressure of three 
measurements at each follow-up visit.  Measurements should be taken according to Standard 
Joint National Committee VII Guidelines / ESC and ESH Guidelines 54, 55 (Refer to Appendix A 
for Office Blood Pressure instructions). 
 
4.8.4 24 hour Ambulatory Blood Pressure   
24 hour Ambulatory Blood Pressure measurements should be taken according to Standard Joint 
National Committee VII Guidelines / ESC and ESH Guidelines 54, 55(Refer to Appendix B for 24 
Hour Ambulatory Blood Pressure instructions) at each follow-up visit. 

           
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Page 26 of 78 
 
In addition to the daytime mean ABP, the night time mean, and 24 hour average ABP value will 
be collected. When using ABP ensure that at least two measurements per hour are taken during 
the person’s usual waking hours (for example, between 08:00 and 22:00) and 1 measurement 
per hour are taken during the person’s usual night time hours. The average value of at least 14 
measurements taken during the person’s usual waking hours should be used for calculation of 
mean daytime value. 
4.8.5 Blood and Urine Analysis 
Blood and urine samples will be collected and analyzed as listed below.    
 
Serum Creatinine – to be collected at 6M, 12M, 24M, and 60M follow-up visit. 
 
Estimated GFR (eGFR) – to be collected at 6M, 12M, 24M, and 60M follow-up visit. 
 
Hemoglobin A1c – to be collected at the 6M follow-up visit only 
 
Fasting glucose – to be collected at the 6M follow-up visit only 
 
Fasting insulin – to be collected at the 6M follow-up visit only 
 
Urine albumin to creatinine ratio – to be collected at the 6M, 24M, and 60M follow-up 
visit.   
A true numeric value for the estimated GFR must be provided.  If your local laboratory does not 
report the eGFR value beyond 60 mL/min/1.73 m2 the center should use a sponsor-approved 
calculation tool to generate the value.  The sponsor will provide an approved website(s) for this 
calculation to study centers.   
 
4.8.6 Echocardiogram (TTE)  
Transthoracic-echocardiogram (TTE) examinations will be conducted at approximately 6 sites at 
the 1M, 6M, 24M, and 60M follow-up visit.   Each site is responsible for performing the 3D 
echocardiogram per each institutions standard of care echo protocol.  
 
4.8.7 NYHA Assessment 
 
NYHA Assessment57 will be evaluated at the 1M, 6M, 24M, and 60M follow-up visit and should 
be classified based on the definitions in Appendix C.  
4.8.8 EQ-5D 5L   Quality of Life Questionnaire  
 
EQ-5D 5L questionnaire will be completed at 1M, 6M, 24M, and 60 M follow-up visit.     
 
4.8.9 Renal artery evaluation  
 
Renal artery evaluation will be completed at the 6M, 24M, and 60M follow-up visit. Duplex 
Ultrasound (U/S) is the recommended imagine modality, however this evaluation can be 
completed by either: computed axial tomography (CT scan), duplex ultrasonography, Doppler, 

           
Clinical Investigation Plan – EnligHTN II
 
 
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whole or in part without the express written permission of St. Jude Medical Cardiovascular Division.                               
Clinical Investigational Plan: EnligHTN II 
 
 
Page 27 of 78 
angiography, magnetic resonance (MR) angiography or non contrast magnetic resonance 
imaging.  
 
If a renal artery evaluation is completed at any other time point this data will also be collected 
during the study.   
 
4.8.10 Adverse Events  
Confirm if any adverse events or adverse device effect occurred since the last visit and 
document in the hospital records.  Report the adverse event according to specifications in 
section 5.3.2. 
 
4.9 Clinical Investigation Termination  
Each subject will be followed for 5 years post renal denervation procedure or until time of death, 
loss of follow up, withdrawal or clinical investigation termination. The clinical investigation will be 
complete after all follow-up visits are performed, all data is received by the Sponsor and the 
database is locked.  The study will be closed when a final report is written on the conclusions 
and analysis of the data.   
 
Participation in this clinical investigation is voluntary.  Subjects are free to withdraw from the 
clinical investigation at any time without reason. Should this occur, the reason for discontinuation 
must be recorded in the source documents.  However, subjects should be strongly encouraged 
to complete the CIP required follow up.  Should a subject wish to withdraw prior to completing 60 
month follow-up, the investigator should request the subject to come in for a final visit and a 
Clinical investigation Termination CRF should be completed by the site and provided to the 
Sponsor.  
At this visit the subject will undergo the following evaluations: 
 
Office Blood pressure measurement 
 
Blood/Urine labs 
In a situation where a clinical investigation withdrawal is due to an adverse event the subject 
should be followed until resolution of that adverse event or determination that the subject’s 
condition is stable.  
Subjects must be informed about their right to withdraw from the investigation at any time and 
for any reason without sanction, penalty or loss of benefits to which the subject is otherwise 
entitled and withdrawal from the investigation will not jeopardize their future medical care or 
relationship with the investigator. Subjects will be asked to specify the reason for the 
termination, but have the right not to answer. 
 
The investigator may decide to withdraw a subject from the investigation at any time.  The 
subject’s future care will not be influenced by a decision, voluntary or otherwise, to withdraw 
from the investigation. All reasonable efforts should be made to retain the subject in the clinical 
investigation until completion of the investigation. 
 
Other reasons for termination or withdrawal include, but are not limited to, the following: 
 
Subject did not meet the inclusion/exclusion criteria  

           
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Page 28 of 78 
 
Subject death (in case of subject death, cause must be documented)   
 
Subject and/or family request 
 
Subject non-compliance 
 
Subject lost to follow-up, defined as the following: a subject will be considered          
“lost to follow-up” after a minimum of 2 documented phone calls of a physician or 
delegate at the study site to the subject or emergency contact and a certified letter 
sent to the last known address 
 
Subject’s participation terminated by Investigator 
 
Study terminated by SJM 
 
The study terminated according to locally applicable regulations 
 
The study may be temporarily stopped or terminated, either at the local, national, or 
international level, at the request of Ethics Committees, regulatory authorities, or 
SJM.   
 
4.10 Description of post investigational provision of medical care 
When the subject’s participation in the clinical investigation has been completed (prematurely) or 
terminated, the subject will return to the medical care as per physician’s recommendation. 
 
5 Clinical Investigation Conduct 
5.1 Ethics Committee 
A duly constituted EC representing the prospective study site must review and approve the 
subject informed consent and research authorization document, the study protocol, the 
prospective investigator’s participation in the study, and any other study related information to be 
provided to the subjects prior to subject enrollment.  Additionally, the Investigator must be aware 
of and adhere to all EC requirements such as, but not limited to:  the submission of progress 
reports, serious adverse events, and protocol deviations. 
EC approval record should clearly identify: 
 
the date of the meeting 
 
constitution of the committee and voting members present at the meeting 
 
the approved version of the Clinical Investigation Plan 
 
the approved version of the Patient Information Sheet and subject Informed Consent 
 
the approved version of the Investigator’s Brochure 
 
the approved version of the Instructions for Use (IFU) 
 
Approval from the EC is necessary prior to the start of the investigation. The original approval is 
to be filed in the Investigator Study Binder and a copy of the approval is provided to SJM prior to 
the first investigational assessment. 

           
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Page 29 of 78 
Any amendments to the protocol should be submitted to the relevant EC.  The EC will be 
informed about SAEs and UADEs in accordance with local and national requirements. 
Prior to SJM receiving data from the study site, the study protocol will be reviewed and approval 
obtained from the study site EC.  There are no additional Board reviews for the study.   
5.2 Ethical Basis 
This clinical investigation will be performed in accordance with the World Medical Association 
Declaration of Helsinki (Appendix F) and applicable local and national legal and regulatory 
requirements. Prior to starting the investigation, the Clinical Investigation Plan will be submitted 
together with associated documents including Patient Information Sheets, and subject Informed 
Consent Forms in the local language to the relevant EC for review. 
 
5.3 Insurance 
St. Jude Medical, as the Sponsor, has taken out insurance for all subjects participating in this 
study in accordance with the requirements of the local laws. 
 
5.4 Statements of Compliance 
The investigation will be performed in accordance with the most current versions of the World 
Medical Association (WMA) Declaration of Helsinki and any regional and/or national regulations, 
as appropriate. 
 
The investigator shall not start enrolling subjects or requesting informed consent prior to 
obtaining Ethics Committee approval and authorization from the sponsor in writing for the 
investigation. 
 
In case additional requirements are imposed by the Ethics Committee, they shall be followed, if 
appropriate. 
 
As sponsor, SJM will maintain   insurance for this investigation in accordance with the 
requirements of the applicable local laws. 
 
5.5 Adherence to the Clinical Investigation Plan 
The Principal Investigator and delegates are required to adhere to the CIP in order to prevent 
subjects being exposed to unreasonable risks. The Principal Investigator and delegates are also 
required to be compliant with the signed Study Agreement, applicable national or local laws and 
regulations, and any conditions required by the appropriate EC or applicable regulatory 
authorities are expected as well.  Instances of failure, intentionally or unintentionally, to adhere 
to the requirements of the CIP are considered a deviation and corrective action(s) may be taken 
to prevent these instances from occurring again. 
 
In some cases failure to comply with the CIP may be considered failure to protect the rights, 
safety and well-being of subjects, since the non-compliance exposes subjects to unreasonable 
risks. For example, failure to adhere to the inclusion/exclusion criteria: these criteria are 
specifically defined by the Sponsor to exclude subjects for whom the device is not beneficial and 
the use involves unreasonable risks. This may be considered failure to protect the rights, safety 

           
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Page 30 of 78 
and well-being of the enrolled subject. Similarly, failure to perform safety assessments intended 
to detect adverse events may be considered failure to protect the rights, safety and well-being of 
the enrolled subject. Investigators should seek minimization of such risks by adhering to the CIP. 
 
Simultaneously, in the event that adhering to the CIP might expose the subject to unreasonable 
risks, the investigator is also required to protect the rights, safety and well-being of the subject 
by intentionally deviating from the requirements of the CIP, so that subjects are not exposed to 
unreasonable risks.   It is the responsibility of the investigator to provide adequate medical care 
to a subject enrolled in an investigation. 
 
The PI shall promptly report any deviations from the CIP to the Sponsor that affects the rights, 
safety or well-being of the subject or the scientific integrity of the clinical investigation, including 
those which occur under emergency circumstances. The reporting of these deviations should be 
done as soon as possible but no later than 72 hours after the investigator becomes aware. The 
investigator shall also promptly notify the EC, as per their requirements.  
 
Any corrective and preventive actions required by the EC must be complied with by the site. 
 
The Sponsor will notify the EC as per their requirements. 
 
5.5.1 Repeated non-compliance 
In the event of repeated non-compliance, as determined by the Sponsor, a Clinical Research 
Associate or sponsor representative will attempt to secure compliance by one or more of the 
following actions: 
 
 
Visiting the investigator 
 
Contacting the investigator by telephone 
 
Contacting the investigator in writing 
 
Retraining of the investigator 
 
If an investigator is found to be repeatedly non-compliant with the signed agreement, the CIP or 
any other conditions of the clinical investigation, the Sponsor will either secure compliance or, at 
its sole discretion, terminate the investigator’s participation in the clinical investigation. 
 
5.6 Informed Consent Process 
5.6.1 General Process 
Provision of the Informed Consent is mandatory. Informed Consent is required from all patients 
prior to participation in the investigation. The process of obtaining Informed Consent shall 
comply with the most recent version of the Declaration of Helsinki, ISO 14155:2011 and all 
applicable regulations.  
 
The Principal Investigator or his/her authorized designee will conduct the Informed Consent 
Process. This process will include a verbal discussion with the patient on all aspects of the 
clinical investigation that are relevant to the patient’s decision to participate in the clinical 
investigation. It is crucial that this discussion is documented in the source documents (hospital 
records). 

           
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Page 31 of 78 
 
Prior to enrolling in the clinical study, patients shall be fully informed of the details of clinical 
study participation as required by applicable regulations and the study center’s EC, and/or Head 
of Medical Institution.  Informed consent must be obtained from each patient prior to any clinical 
study participation using the Patient Information Sheet (PIS) and Patient Informed Consent form 
(PIC) approved by both the Sponsor as well as that study center’s EC, and/or Head of Medical 
Institution.  Prior to the patient signing the PIS, the investigator or authorized delegate will fully 
explain to the patient the nature of the research, clinical study procedures, anticipated benefits, 
and potential risks of participation in the clinical study.    
 
The patient will be provided with the EC approved patient information sheet and informed 
consent form that is written in a language that is understandable to them (native non technical 
language) and sufficient time is provided to the patient to consider participation and ask 
questions if necessary. The study site personnel will provide answers to the patient’s questions.    
  
If a patient is unable to read or write, the consenting shall be obtained through a supervised oral 
process.  An independent witness shall be present throughout the process.  The consent form 
must be signed and dated by the patient and by the person obtaining the consent attesting that 
the information was accurately explained and that informed consent was freely given.  
 
The consent form must be signed and dated by the patient and by the person obtaining the 
consent.  
 
If the patient does not sign and date the PIC, they cannot participate in the investigation. No 
further CIP required activities are allowed.  If the patient has provided written informed consent, 
obtain signature and date from the Principal Investigator or authorized designee on the EC 
approved informed consent form.  
 
In order to avoid any possible coercion or undue improper influence on, or inducement of the 
patient to participate, the Sponsor requests the investigator to only sign the informed consent 
form once the subject has signed and dated the document and therefore decided to participate 
in the investigation. 
 
Informed Consent of a subject shall always be indicated by personally dated signature of the 
subject and by the investigator responsible for conducting the Informed Consent process.  
 
The original signed consent document must be retained on file by the investigator and a copy of 
the signed consent document is provided to the subject (investigator’s responsibility). 
 
The subject’s legal rights will not be waived, nor will it appear that these will be waived. 
 
Important new information that becomes available throughout the clinical investigation will have 
to be provided in writing to new and existing subjects. If relevant, all affected subjects will be 
provided a new consent form to review and re-sign, should they decide to maintain participation 
in the investigation. 
 

           
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Page 32 of 78 
5.7 Adverse Event, Adverse Device Effect  
Definitions 
The definitions provided below are in accordance to ISO 14155:2011 (E). 
5.7.1 Medical device 
Any instrument, apparatus, implement, machine, appliance, implant, software, material or other 
similar or related article. 
 
 
Intended by the manufacturer to be used, alone or in combination, for human beings for one 
or more of the specific purpose(s) of 
 
 
Diagnosis, prevention, monitoring, treatments or alleviation of disease, 
 
Diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury, 
 
Investigation, replacement, modification, or support of the anatomy or of a 
physiological process, 
 
Supporting or sustaining life, 
 
Control of conception, 
 
Disinfection of medical devices and 
 
 
Which does not achieve its primary intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
intended function by such means 
 
5.7.2 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the medical device. 
 
Note: This definition includes events related to the medical device or the comparator. 
Note: This definition includes events related to the procedures involved. 
5.7.3 Serious Adverse Event (SAE) 
An adverse event that led to: 
 
 
Death 
 
A serious deterioration in the health of the subject, that either resulted in: 
o A life-threatening illness or injury OR 
o A permanent impairment to a body structure or a body function OR 
o An in-patient or prolonged hospitalization OR 
o A medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body OR 
o A malignant tumor 
 
Fetal distress, fetal death or a congenital abnormality or birth defect 
 
Note: A planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 

           
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Page 33 of 78 
 
5.7.4 Adverse Device Effect (ADE) 
An adverse event related to the use of an investigational device. 
 
Note: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the medical device. 
 
Note: This definition includes any event resulting from the use error or from intentional misuse of 
the medical device. 
 
5.7.5 Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
5.7.6 Unanticipated Serious Adverse Device Effect (USADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
 
5.7.7 Anticipated Serious Adverse Device Effect (ASADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has been 
previously identified in the risk analysis report. 
 
5.7.8 Procedure for assessing, recording and reporting adverse events, adverse device 
effects, serious adverse events and serious adverse device effects:  
 
Safety surveillance and reporting will be done for all subjects enrolled in this investigation as 
described below. 
 
Safety surveillance within this investigation and the safety reporting performed by the 
investigator, starts as soon as the subject is enrolled in this investigation (date of signature of 
the informed consent). The safety surveillance and the safety reporting will continue until the last 
investigational visit has been performed or the subject is deceased or the subject/investigator 
concludes his participation into the investigation. 
 
For the purpose of this trial, all Serious Events (regardless of relatedness) and all Adverse 
Device Effects (regardless of severity) will be reported via an eCRF to the sponsor.  All Serious 
Adverse Events and all Adverse Device Effects (serious or non-serious) are to be documented 
and reported by the investigator to the sponsor immediately  but no later than   72 hours after 
becoming aware of the event. 
  
Adverse events will be assessed by the investigator for relationship to the device and to the 
procedures involved. 
 

           
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Page 34 of 78 
 
Procedure related: The AE is deemed related to the procedure if it occurred during the 
procedure but was not directly caused by the medical device. 
 
Device related: The AE is deemed device related if it was directly caused by the 
medical device. 
 
Investigators are responsible for promptly reporting all SAEs and ADEs to the sponsor by 
completing the Adverse Event form. All unresolved AEs should be followed by the investigator 
until resolution is reached.  
 
Note: Refer to Table 1 ‘Data Collection’ and Appendix G ‘Data Collection Method’. 
In case of EDC failure, notify Sponsor via Fax or via E2AdverseEvent@sjm.com. 
 
5.8 Subject Death 
5.8.1 Procedure for recording and reporting Subject Death 
The investigator will document and report all subject deaths to the sponsor immediately but no 
later than 72 hours after becoming aware of the event. 
 
Should death occur, the investigator should record the information in the hospital records and 
immediately document the information on the Death Form. By completing the form the sponsor 
will be notified. 
 
Note: Refer to Table 1 ‘Data Collection’ and Appendix G ‘Data Collection Method’ 
In case of EDC failure, notify Sponsor via Fax or via E2AdverseEvent@sjm.com. 
 
Subject Death is an outcome of a serious adverse event (SAE).  Death is therefore related to an 
SAE and all efforts to obtain the SAE details should be made and the Adverse Event form must 
be completed.  Any supporting documentation (autopsy records, death certificates, 
hospitalization records) must be sent to SJM with the corresponding SAE and Death CRFs. 
 
The subject’s death is an Early Conclusion of the subject’s participation in the investigation. 
Therefore, the investigator is requested to complete the Termination form.  
 
The investigator must notify the EC, if appropriate, in accordance with national and local laws 
and regulations. 
 
5.9 Document and data control 
5.9.1 Traceability of documents and data 
The investigator shall ensure accuracy, completeness, legibility and timeliness of the data 
reported to the sponsor on the electronic case report forms (eCRFs) and in all required reports. 
When copies of the original source document as well as print outs of original electronic source 
documents are retained, these shall be signed and dated by a member of the investigational site 
team with a statement that it is a true reproduction of the original source document. 
 

           
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5.9.2 Recording data 
Source documents shall be created and maintained by the investigational site team throughout 
the clinical investigation. 
 
The data reported on the eCRFs shall be derived from, and be consistent with, source 
documents, and any discrepancies shall be explained in writing. 
 
The eCRFs shall be validated by the Principal Investigator or a delegated investigator. Any 
change or correction to data reported shall be dated and explained if necessary. The original 
entry will remain available by audit trail. 
 
5.9.3 Review of data 
 
The clinical investigation will be monitored by reviewing the eCRF approved by the investigators.  
 
The following activities will occur: 
 
 
All eCRFs will be reviewed for completeness and accuracy after being uploaded into the 
database. 
 
The investigator (co-investigator) and/or delegate is notified regarding any missing or 
unclear/inconsistent data. 
 
5.10 Monitoring  
On site-monitoring shall be performed during the clinical investigation in order to guarantee 
adherence to all applicable regulations, the Clinical Investigation Plan and the signed Clinical 
Study Agreement. By monitoring, the Sponsor can also verify the accuracy of data collected on 
the accompanying eCRFs throughout the duration of the clinical investigation.   
Monitoring is necessary to ensure adequate protection of the rights and safety of human 
subjects involved in the clinical investigation and the quality and integrity of the data obtained 
during the investigation. The sponsor will at the same time assess the investigational site and 
study team on staffing and facilities to ensure the investigation can continue in a safe and 
effective fashion. 
During the monitoring visits, data reported on the eCRF shall be reviewed as specified in the 
monitoring plan.  
  
5.10.1 Designated Monitors 
Only monitors qualified by education, training and experience, which have been trained on the 
Clinical Investigation Plan, eCRF content, Monitoring Plan, relevant requirements and informed 
consent process will be allowed to perform monitoring activities during this clinical investigation. 
The monitor’s qualifications and training will be documented by the sponsor.  A list of monitors is 
available upon request. 
5.10.2 Monitoring Plan 
Prior to the start of the site monitoring activities for this clinical investigation, a project specific 
Monitoring Plan (MP) will be created. 

           
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At a minimum, the Monitoring Plan will include the following: 
 
 
Required activities 
 
Frequency of monitoring visits 
 
Visit Requirements 
 
Procedures for securing site compliance 
 
Monitoring report content and timelines  
 
Close-out procedures 
 
The Monitoring Plan may be updated as appropriate.  All revisions will be tracked.  
5.11 Competent Authority (CA) Inspections 
The investigator and/or delegate should contact SJM immediately upon notification of a CA 
inspection at the site. A clinical monitor will assist the investigator and/or delegate in preparing 
for the inspection. 
 
An investigator who has authority to grant access shall permit authorized CA employees, at 
reasonable times and in reasonable manner, to enter and inspect any establishment where 
devices are held (including any establishment where devices are used or where records or 
results are kept). 
 
An investigator, or any person acting on behalf of such a person with respect to the 
investigation, shall permit authorized CA employees, at reasonable times and in reasonable 
manner, to inspect and copy all records relating to the investigation. 
 
An investigator shall permit authorized CA employees to inspect and copy records that identify 
subjects, upon notice that CA has reason to suspect that adequate informed consent was not 
obtained, or that reports required to be submitted by the investigator, to the Sponsor or EC have 
not been submitted or are incomplete, inaccurate, false or misleading. 
 
5.12 Investigation Termination 
The Sponsor reserves the right to suspend or terminate the investigation in an individual site or 
the entire clinical investigation for significant and documented reasons, at any stage, with 
appropriate written notice to the investigator.  
 
The investigation will be terminated according to applicable regulations. 
 
The investigator shall return all documents to the sponsor;  and notify the Ethics Committee and 
the Competent Authority (if applicable). Follow-up for all enrolled subjects will be as per standard 
of care. 
 
5.12.1 Resuming the Clinical Investigation after Suspension 
The sponsor shall conclude an analysis of the reason(s) for the suspension, implement the 
necessary corrective actions, and decide to lift the temporary suspension. The sponsor shall 
inform the Principal Investigators, EC/Head of Medical Institution or regulatory authority, where 

           
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Page 37 of 78 
appropriate, and the regulatory authority of the rationale, providing them with the relevant data 
supporting this decision.  
Concurrence shall be obtained from the, EC/Head of Medical Institution or regulatory authority 
where appropriate, before the clinical investigation resumes. 
If subjects have been informed of the suspension, the Principal Investigator or authorized 
designee shall inform them of the reasons for resumption. 
5.12.2 Investigation Conclusion 
The investigation will be concluded at an individual study site when: 
 
 
A Close Out visit has been performed by the Sponsor AND 
 
The Final report has been provided 
 
The final report/close-out is acknowledged by the study site’s EC 
 
6  Risks and Benefits of the Clinical Investigation 
6.1 Anticipated Adverse Events and Adverse Device Effects 
 
Possible adverse events associated with the renal denervation procedure include, but are not 
limited to: 
 
Acute renal injury (renal infarction, renal hematoma) 
 
Renal vascular injury (renal artery dissection, renal artery thrombosis, renal artery 
stenosis) 
 
Collateral tissue injury 
 
Malignant or accelerated hypertension 
 
Symptomatic hypotension 
 
Access site complications (arteriovenous fistula, access site thrombosis, embolisation, 
pseudo-aneurysm, hematoma, limb ischemia, femoral nerve injury, or seroma) 
 
Disseminated intravascular coagulation 
 
Infection (access site infection or systemic infection) 
 
Renal failure 
 
Decompensated heart failure 
 
Myocardial infarction 
 
Neurologic event (acute ischemic or hemorrhagic brain injury) 
 
Respiratory compromise 
 
Pain, including Back Pain 
 
Death 
 
Drug reactions 
 
Contrast allergies etc 
 
Bradycardia 
 
Vasospasms 
 
Vasovagal episodes 
6.2 Steps that will be taken to control or mitigate the risks 
 
Every possible effort will be taken to minimize the risks, including: 

           
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 
Careful selection of experienced investigators for the clinical investigation  
 
Regular clinical investigation monitoring visits for each clinical investigation center 
 
Conduction of the clinical investigation in accordance with the Clinical Investigational 
Plan (CIP), all applicable laws and regulations (e.g. ISO14155:2011) and any conditions 
of approval imposed by the appropriate EC or applicable regulatory authorities where the 
clinical investigation is performed 
 
Preparation of the catheter and performance of the renal denervation procedure in 
accordance with the device IFUs. 
 
Catheter advancement under fluoroscopic imaging to minimize the risk of arterial 
damage. 
 
Training of Investigators both on the CIP and EnligHTN Renal Denervation procedure 
 
7 Statistical Analysis 
 
7.1 Study design 
 
This is a post market, prospective, international, multicenter, non-randomized, single arm study 
of the EnligHTN™ Renal Denervation System.  Approximately 500 subjects with uncontrolled 
hypertension will undergo renal artery ablation at approximately 40 investigational sites located 
internationally and will be followed up to five (5) years post procedure. Subjects will be included 
in one of three groups: Group A, Group B and Group C (Refer to Section 4.1 for detailed criteria 
for each group).  
 
The primary objective is to evaluate a mean reduction of office Systolic Blood Pressure at six (6) 
months post renal denervation. 
 
7.2 Sample size estimation 
 
The sample size of approximately 500 patients is used considering the study objectives; to 
observe the proportion of patients with a mean reduction of systolic blood pressure at 6 months, 
and peri-procedural events within 30 days post procedure. Approximately 40 Investigational 
sites will be invited to participate.  A sample size of 500 patients will allow for each site to 
contribute a reasonable number of patients for this multicenter study. No formal power analysis 
or hypothesis test will be performed. However the data collected will be analyzed and presented 
using the descriptive or appropriate summary statistics. 
 
7.3 Analysis Population 
 
All patients who have signed a Patient Informed Consent (PIC) will be considered enrolled in the 
study. However, Primary Analysis population will include those patients that have signed a PIC, 
and had the EnligHTN™ Renal Denervation System enter his/her body. The sample size of 500 
are those subjects in the Primary Analysis population. 
 

           
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As Treated population will include all subjects in whom renal denervation was performed in a 
minimum of one renal artery per kidney (according to the Instructions for Use). 
 
It is anticipated that there may be subjects who have enrolled in the study but are not included in 
the Primary Analysis population or As Treated population, such as:  
 
 
Subjects who are enrolled but do not meet baseline inclusion or exclusion criteria before 
the procedure; these are considered the screen failure population. 
 
Procedurally excluded populations will include subjects who have enrolled in the study 
and start the procedure, but do not have the EnligHTN™ Renal Denervation System 
enter his/her body, due to their anatomy, circumstances related to the procedure, or 
physician judgment.  
Subjects that withdraw from the investigation will not be replaced in any analysis 
population. 
 
7.4 Data Analysis and Reporting 
 
In general data analysis will be performed across all subjects, as well as within each of three 
groups (Group A, B and C), based on Primary Analysis population unless otherwise specified.   
 
The data collected will be presented using the appropriate summary statistics. Continuous data 
will be summarized using descriptive statistics (mean, number of observations, standard 
deviation, minimum and/or maximum values) and categorical data will be summarized using 
frequencies and percentages. 
 
 
7.4.1 Primary objective 
 
The mean reduction of office SBP at six (6) months of the study will be analyzed by: 
 
1.  Computing the reduction of SBP measurements at 6 months compared to baseline for each 
patient with data available in both time points. 
 
2. Calculating the mean and standard deviation of the SBP reduction at 6 months  
 
 
7.4.2 The Secondary objectives 
7.4.2.1 Safety Acute data (30 days post procedure) 
 
 
The peri-procedural events within 30 days post procedure will be summarized as 
percentage of patients defined as:    
 

           
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7.4.2.2 Safety Midterm (6 months) and Long term (2 and 5 years) data 
 
The new renal artery stenosis (>50%) and/or aneurysm at the site of ablation per Renal 
Artery Imaging (CT/MR) will be summarized at 6 months, 2 and 5 years as percentage of 
patients who have stenosis and/or aneurysm.   Kaplan-meier analysis may be performed 
on the time to the first new renal artery stenosis and/or aneurysm at the site of ablation, 
as appropriate.  
 
Renal function change based on  eGFR will be summarized by:  
1.  Computing the change of the eGFR at 6 months, 2 years and 5 years compared to 
baseline for each patient with data available in both time points. 
 
2. Calculating the mean and standard deviation of the eGFR change at those interval 
 
7.4.2.3 
BP reduction 
 
The data of  
 
Change in Ambulatory Blood Pressure parameters at 6 months, 
 
Change in Office Diastolic Blood Pressure at 6 months,  
 
Change in Office and Ambulatory Blood Pressure parameters  
at 12, 24, 36, 48, 60 months post denervation will be calculated in the same way as described in 
the calculation of SBP reduction at 6 month (Section 7.4.1)   
 
 
The percentage of subjects achieving office SBP < 140 at 6 months visit will be 
computed as follows: 
 
                                                                
                                                          
      
 
7.4.3 Other Analyses  
 
In addition, subgroup analyses may be performed as needed such as for subjects that have the 
renal denervation procedure performed on one side but not the other, due to their anatomy, 
circumstances related to the procedure, or physician judgment; and by the patient’s primary 
disease states/conditions.   

           
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Ad Hoc analyses may be performed as needed.  Analysis may be performed based on As 
Treated population as appropriated.  In general, data analysis will be performed on a per subject 
basis. But the data analysis may be presented per kidney, or on renal artery basis, as 
appropriate. 
 
7.4.4 Analysis Software  
The statistical analyses will be performed using SAS™ software version 9.2, or as specified and 
appropriate.  

           
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8 Data Management 
 
All documents and data shall be produced and maintained in a way that assures control and 
traceability. Where relevant, the accuracy of translations shall be guaranteed and documented. 
All documents, and subsequent versions, related to a clinical investigation shall be identifiable, 
traceable and appropriately stored to provide a complete history of the clinical investigation.  
eCRFs shall be developed by Sponsor to capture the data for each enrolled subject as required 
by the CIP. The eCRFs shall include information on the condition of each subject upon entering, 
and during the course of the clinical investigation, exposure to the device and any other 
therapies.  
The Sponsor will be responsible for the data handling. 
 
Data will be analyzed by the Sponsor and may be transferred to the Sponsor’s locations 
worldwide  and/or any other worldwide regulatory authorities in support of a market-approval 
application. 
 
8.1 Data Management Plan 
 
eCRF data will be entered by authorized investigative site personnel in a validated electronic 
database.  
 
The Data Validation Procedure (DVP), will be part of the Data Management Plan (DMP), and 
describes all the computerized data cleaning checks (validation rules) as programmed at the 
time of database set-up. These validation rules may change and be updated throughout the 
course of the investigation. 
 
Manual review and Data Cleaning Convention (DCC) will be used in addition to computerized 
data cleaning checks, to check for discrepancies and to ensure consistency of the data. 
 
All revisions of the DMP will be tracked and include an effective date. 
 
8.2 Source Documents 
Source documents shall be maintained by the investigation site team throughout the clinical 
study.  All findings in this clinical study must be documented as source data, and therefore can 
be verified (and audited).  Source documentation may be paper or electronic, and is defined as 
the first time the data appears and may include for example; all clinical records, hospital records, 
surgery reports, autopsy reports, and any other material that contains original information used 
for clinical study data collection or adverse event reporting.  
 
8.3 Source Data and Subject Files 
The investigator shall keep written or electronic subject files for every subject participating in the 
clinical investigation. In this file, the available demographic and medical information of a subject 
shall be documented, in particular the following:  
 

           
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Name 
Age  
Weight 
Gender 
Height 
Concomitant Medication 
Subject History 
Concomitant diseases 
Scheduled follow ups 
PIC process  
Date of PIC 
Observed AEs 
CIP required examination 
Clinical findings 
Procedure Notes 
 
 
 
 
It should be possible to verify the inclusion and exclusion criteria for the investigation from the 
available data in this file. It must be possible to identify each subject by using this subject file.  
Additionally, any other documents with source data have to bear at least the subject 
identification and the printing date printed by the recording device to indicate to which subject 
and to which procedure the document belongs. The medical evaluation of such records should 
be documented as necessary and signed/dated by the investigator. All data recorded on the 
eCRF must also be part of the subject’s source data. 
 
 
8.4 Confidentiality of Data    
All subject information collected during the course of this study will be kept strictly confidential 
according to applicable country-specific laws and regulations.  All data and information 
concerning subjects and their participation in this study are considered confidential by St. Jude 
Medical, Cardiology Division, Inc., d/b/a St. Jude Medical, Cardiovascular Division, Inc., a U.S. 
company, and its affiliates (located in the U.S.A. and European Economic Area (EEA), Canada, 
and other countries), and other people who work for SJM to provide services related to the 
device and this study (collectively referred to as “SJM”).  All public reporting of the results of the 
study will eliminate identifiable references to the subjects. Information on paper will be kept in 
secured locations. Electronic information will be kept on password-protected computers.  
 
Personal data, including medical and health information, will be processed both by computer 
and manually, during and after the study by SJM, and its affiliates, its designated third party data 
processors, the EC, the institution conducting the study, the study doctors and other healthcare 
personnel involved in the study for the purposes of this study. The electronic data stored for this 
study will be kept in an SJM database, in compliance with applicable law.  Subject data will not 
contain details of study subject identity.  The data will be stored on a secure server and backed 
up routinely.  Personal data will be key-coded to prevent subject identification, except by the 
institution, study doctors and other healthcare personnel involved in the study, if necessary for 
the purpose of the study, for regulatory inspections, and to comply with SJM reporting 
obligations. 
 
Study subjects have a right to gain access and to correct inaccuracies in information about them 
as permitted by applicable law. 
 
In order to help keep subject medical records and personal information confidential only certain 
authorized investigators and SJM personnel, or approved contracted agents of SJM, will have 
access to confidential records.  These include researchers in the hospital who are part of this 
study, SJM and its affiliates and representatives that perform study-related services who may be 
located in the U.S.A., Canada, European Economic Area (EEA) and other countries. The Ethics 
Committee (EC) and other regulatory authorities also have the right to inspect and copy records 
pertinent to this study. It is necessary for them to review study data, portions of study subject 
records and information so that they can follow the study progress, which may include without 
limitation: 

           
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Page 44 of 78 
 
Monitor the accuracy and completeness of the study 
 
Perform scientific analysis and develop the medical product  
 
And/or obtain approval to market the medical products in the USA, Canada, EEA, and 
other countries. 
Any information about subjects that leaves the institution conducting the study will be modified to 
remove certain information that could identify the subject (e.g., subject’s name, age on the day 
of enrollment, address, and hospital number) and only be identifiable by a study ID code.  Study 
data provided to SJM that is published in medical journals and/or presented at scientific 
conferences will not allow the identification of study subjects.  
 
The results of the study will be made available to SJM and its affiliates (located in the U.S.A., 
EEA, Canada, and other countries) and other people who work for SJM to provide services 
related to the device and this study and study center. 
 
A summary of the information on all subjects may be provided to governmental agencies 
(including regulatory agencies), regulatory authorities in the U.S.A., Canada, EEA and other 
countries who may also need to review study data and portions of medical records. Results from 
this study may also be published in scientific journals or presented at conferences as an oral or 
poster presentation; however, the identity of a study subject will not be disclosed. 
 
 

           
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Page 45 of 78 
9 Document Retention 
The Principal Investigator (PI) shall maintain all essential clinical investigation documents from 
prior, during and (as specified) after the clinical investigation on file at the site for a minimum of 
15 years after the termination of this investigation, or longer as per local laws, or when it is no 
longer needed to support a marketing application, whichever is later.   
The PI must contact the sponsor prior to destroying or archiving off-site any records and reports 
pertaining to this investigation to ensure that they no longer need to be retained on-site. 
All original subject files must be stored for the longest possible time permitted by the regulations 
at the hospital, research institute, or practice in question. If archiving can no longer be 
maintained at the site, the investigator will notify the sponsor.  
 
All data and documents shall be made available on request of the relevant authorities in case of 
an audit. 
 
The sponsor will archive and retain all essential clinical investigation documents from prior, 
during and (as specified) after the clinical investigation as per requirements.  
 
10 Amendments to the Clinical Investigational Plan   
The CIP, eCRFs, Patient Informed Consent form and other subject information, or other clinical 
investigation documents shall be amended as needed throughout the clinical investigation, and 
a justification statement shall be included with each amended section of a document. Proposed 
amendments to the CIP shall be agreed upon between the Sponsor and Principal Investigator, 
or the Coordinating Investigator.  
 
The amendments to the CIP and the Patient Informed Consent shall be notified to, or approved 
by, the EC and regulatory authorities, if required. The version number and date of amendments 
shall be documented. 
 
The amendment will identify the changes made, the reason for the changes and if it is 
mandatory or optional to implement the amendment. 
 
Any amendment affecting the subject requires that the subject be informed of the changes and a 
new Patient Informed Consent be signed and dated by the investigator and subject prior to the 
subject’s next follow up. 
 
Changes to, or formal clarifications of, the CIP will be documented in writing and provided to the 
investigators by the Sponsor. This information will be incorporated by the Sponsor when an 
amendment occurs. 
 
 
 

           
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Page 46 of 78 
11 Publication Policy 
 
The results of the clinical investigation will be submitted, whether positive or negative for 
publication.  
 
A ‘Publication Agreement’ will be signed between the Principal Investigator and the Sponsor (if 
applicable). 
 
If such a Publication Agreement is not signed by both parties as a separate agreement but as 
part of an overall Clinical Trial Agreement, the publication policy should be part of the Clinical 
Trial Agreement.   
 
For more information on publication guidelines, please refer to the International Committee of 
Medical Journal Editors (ICMJE) on www.icmje.org. 

           
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12 Investigation Organization 
12.1 Investigation Management / Sponsor 
The organization, which takes responsibility for the initiation and/or implementation and 
coordination for the investigation is St. Jude Medical Cardiology Division Inc. d/b/a St. Jude 
Medical, Cardiovascular Division, Inc. with a principal place of business at 177 East County 
Road B, St. Paul, MN 55117 and with offices associated with the operation of this investigation 
located at: 5050 Nathan Lane Plymouth, MN 55442.   
 
SJM will delegate responsibilities to the local SJM clinical entities in each country, as defined by 
the Power of Attorney.  
Sponsor Responsibilities 
Sponsor’s responsibilities are in accordance with applicable guidelines. This includes but is not 
limited to the following activities: 
 
 
the design, overall conduct, analysis, and reporting of the results from this study 
 
Performing those actions necessary to protect the rights of subjects and the scientific 
credibility of the manner in which this study is conducted 
 
Selecting qualified study Investigators, study monitors and research staff   
 
Sign off the clinical investigational plan before the start of the investigation or after 
modifications to the CIP;  
 
Development of database; 
 
Selection of clinical investigators; 
 
Training of the clinical investigational sites; 
 
Activate the sites after receipt of the required documentation; 
 
Monitor the participating centers by reviewing collected data and investigation 
documentation for completeness and accuracy;  
 
Perform data analysis; 
 
Ensure that all adverse events and adverse device effects are reported and reviewed 
with the clinical investigator(s) and where appropriate that all serious adverse events and 
serious adverse device effects are reported to the relevant authorities and Ethics 
Committee(s) and/or safety monitoring committee(s); 
 
Maintain an updated list of principal investigators, investigational sites and institutions. 
This list shall be available upon request. 
 
SJM reserves the right to obtain data clarification and/or additional medical 
documentation on subjects enrolled in this study at any time during the subject 
participation and until the study is terminated or closed by study final report.  An interim 
analysis may be completed at the discretion of the Sponsor. 
 
Blank, revision controlled CRFs and patient information sheet/patient consent form 
template 
 
Signed Study Agreements and completed Investigator Financial Disclosure information  
 
EC approval letters, including a copy of the approved information sheet and consent 
forms 
 
All correspondences relating to the conduct of this study between SJM and the study 
site, ECs, and Study Monitors 
 
CVs and professional licenses for all study personnel, if applicable 

           
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Page 48 of 78 
 
Protocol/device related training records for all applicable study personnel 
 
Site personnel signatures and documentation of the Investigator’s delegation of study 
related responsibilities 
 
List of EC voting members 
 
Investigator’s Brochure 
 
Insurance certificate 
 
12.2 Clinical Investigators 
All parties participating in the conduct of the clinical investigation shall be qualified by education, 
training or experience to perform their tasks and this shall be documented appropriately.  
 
The role of the Principal Investigator is to implement, supervise, and manage the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and the rights, safety, and 
well-being of the subjects involved in the clinical investigation.  
All investigators shall avoid improper influence on or inducement of the subject, sponsor, 
monitor, other investigator(s) or other parties participating in or contributing to the clinical 
investigation. 
The Principal Investigator shall; 
1. Be qualified by education, training and experience to assume responsibility for the 
proper conduct of the clinical investigation.  
2. Principal investigator and investigation team members shall provide signed and 
dated  CVs and other relevant documentation, 
3. Be experienced in the field of application and documented training of 
investigational device use under consideration, 
4. Disclose potential conflicts of interest, including financial disclosure, 
5. Be knowledgeable with the method of obtaining informed consent.  
 
Investigator’s responsibilities 
By agreeing to this Clinical Investigation Plan, the investigators accept to allow monitoring, 
audits, Ethics Committee review, and regulatory inspections that are related to the investigation. 
They also agree to provide authorized individuals with direct access to source data and 
documentation as well as the right to copy records, provided such activities do not violate 
subject consent and subject data confidentiality.  
 
A Principal Investigator should have experience in and/or will be responsible for: 
 
 
Providing signed Clinical Trial Agreement and appropriate appendices; as wll as other 
study specific agreements; 
 
Providing the Sponsor with copies of any clinical-investigation-related communications 
between the Principal Investigator and the EC; 
 
Screening and selecting appropriate subjects; 
 
Providing appropriate Ethics Committees Approved Patient Informed Consent; 

           
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Page 49 of 78 
 
Conducting the clinical investigation in accordance with the signed agreement with St 
Jude Medical, the investigation plan, all applicable laws and regulations, and any 
conditions of approval imposed by the appropriate Ethics Committees or applicable 
regulatory authorities where the investigation is performed; 
 
Collecting and archiving of source data obtained prior to procedure, during procedure, at 
follow-up examinations and after the investigation has been completed; 
 
Strict adherence to the CIP testing requirements to provide for optimal safety and 
efficacious use of the device under clinical investigation; 
 
Adequate safety reporting; 
 
Supporting the monitor, and auditor, if applicable, in their activities to verify compliance 
with the CIP, to perform source data verification and to correct the case report forms 
where inconsistencies or missing values are identified; 
 
Notifying the Sponsor of any deviations from the protocol 
 
Sign off the final version of the clinical investigation plan and amendments to the CIP 
 
It is acceptable for the Principal Investigator to delegate one or more functions to an associate or 
co-investigator, however, the Principal Investigator remains responsible for the proper conduct 
of the clinical investigation, complying with the investigational plan and collecting all required 
data. This delegation of specific functions shall be documented on the Signature and Delegation 
List (provided by Sponsor). The investigation is not transferable to other centers attended by the 
investigator unless prior approval is obtained from SJM. 
 

           
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Page 50 of 78 
Clinical Coordinating Investigator 
 
In addition to the responsibilities of the investigators, the Clinical Coordinating Investigator will: 
 
 
Sign off the final version of the investigational plan and after modifications to the CIP; 
 
Act as main contact for all investigators in case of medical questions related to the 
conduct of the investigation. 
 
The following investigators have been appointed by the Sponsor as the Clinical Coordinating 
Investigators: 
 
Professor Stephen Worthley, M.B., B.S., Ph.D., 
F.R.A.C.P, R.A.C.C., F.C.S.A.N.Z 
Royal Adelaide Hospital 
The University of Adelaide 
Adelaide, South Australia 
5005 Australia 
 
Tel: +61 08 8222 608 
 
 
 
Dr M Lobo MBChB PhD FRCP 
NIHR Barts Cardiovascular Biomedical Research Unit 
William Harvey Research Institute  
Queen Mary University of London 
London  EC1M  6BQ 
  
Tel: +44 020 7882 3416 
 
 
12.3 Committees 
12.3.1 Steering Committee (SC) 
 
The SC is championed by the Clinical Coordinating Investigator (CCI) Prof. Worthley. This 
committee will be actively involved in the investigation, and review its progress at regular 
intervals. The Steering Committee will serve as a decision making committee and assist with 
decisions along with the sponsor for the medical and scientific conduct of the study.  The 
Steering Committee will operate in accordance with the steering committee charter.  The 
Steering Committee will approve the CIP and any amendments (if applicable).  At any time, this 
committee may recommend that the investigation be put on hold or even terminated for safety, 
ethical or other reasons. The Steering Committee will be composed of medical practitioners who 
are experts in the field of the proposed indication for the study. 
 
 

           
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Page 51 of 78 
12.3.2 Clinical Event Committee (CEC) 
An independent Clinical Event Committee (CEC) will be utilized to regularly review study 
progress with regard to safety. Members of the CEC will include at a minimum, 3 physicians who 
are familiar with hypertension therapies including RF ablation of the renal artery. Physicians on 
the CEC will not participate in the investigation as investigators.  The purpose of the CEC is to:  
 
 
Review and adjudicate all serious adverse events and adverse device effects as they 
occur over the course of the clinical investigation 
 
Determine severity classification and relationship to the device and procedure 
 
Provide oversight for issues affecting general subject welfare  
 
 
The CEC will have a formalized charter that will detail a schedule for meeting times, explicit rules 
outlining the minimum amount of data required, process followed in order to assure appropriate 
and consistent classification of clinical events. CEC members will be provided clinical data and 
source documents to allow adjudication of events without subject, site or investigator identifying 
information. CEC decisions will be documented in meeting minutes, which will be maintained in 
the study master file 
 
12.4 Outsourcing of duties and functions 
The sponsor may transfer any or all of the duties and functions related to the clinical 
investigation, including monitoring, to an external organization (such as a CRO or individual 
contractor), but the ultimate responsibility for the quality and integrity of the clinical investigation 
shall reside with the sponsor. All requirements applying to the sponsor shall also apply to the 
external organization inasmuch as this organization assumes the clinical-investigation-related 
duties and functions of the sponsor. 
 
12.4.1 Power of Attorney (POA) 
The POA delegates sponsor’s responsibility for specified tasks to the country entities, divisions 
or designee, involved in the clinical project. The POA is signed and dated by appropriate parties. 
The POA can consist of, but is not limited to: 
 
1. Ensure that the clinical agreements are prepared appropriately, comply with legal 
obligations and are signed/dated by all parties; 
2. Ensure that essential documents to activate the center are collected and maintained in 
the ISB; 
3. Activate the centers and manage the centers throughout the duration and close of the 
investigation; 
4. Report Adverse Events to relevant authorities 
5. Ensure that subject data relevant to the investigation is referenced in the hospital 
records, collected and provided to Sponsor  
 
 
 

           
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Page 52 of 78 
13 Bibliography  
1. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure 
levels in 6 European countries, Canada, and the United States. JAMA 2003; 289:2363–9. 
 
2. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to 
vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective 
studies. Lancet 360:1903-13. 
 
3. Heart disease and stroke statistics 2010 update: a report from the American Heart 
Association. Circulation 2010; 121:e46-215. 
 
4. World Health Organization. World Health Report 2002: Reducing Risks, Promoting Healthy 
Life. Geneva, Switzerland: World Health Organization, 2002. 
 
5. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of 
worldwide data. Lancet 2005; 365:217-223. 
 
6. Turnbull F, Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different 
blood-pressure-lowering regimens on major cardiovascular events: Results of 
prospectivelydesignedoverviews of randomized trials. Lancet 2003; 362:1527-35. 
 
7. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. 
Part 2. Short-term reductions in blood pressure: overview of randomised drug trials in their 
epidemiological context. Lancet 1990; 335:827-38. 
 
8. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive 
therapies used as first-line agents. JAMA 1997;277:739-45. 
 
9. Papademetriou V, Farsang C, Elmfeldt D, et al for the SCOPE Study Group: Stroke 
Prevention with the AT1-receptor Blocker Candesartan in Elderly Patients with Isolated 
Systolic Hypertension: The Study on COgnition and Prognosis in the Elderly (SCOPE). J Am 
Coll Cardiol 2004; 44:1175-80. 
 
10. Papademetriou V, Doumas M. Treatment strategies to prevent stroke: focus on optimal lipid 
and blood pressure control. Expert Opin Pharmacother 2009; 10:955-66. 
 
11. Lloyd-Jones DM, Evans JC, Larson MG, et al. Differential control of systolic and diastolic 
blood pressure: factors associated with lack of blood pressure control in the community. 
Hypertension 2000; 36:594 –9. 
 
12. Lloyd-Jones DM, Evans JC, Larson MG, et al. Treatment and control of hypertension in the 
community: a prospective analysis. Hypertension 2002; 40:640–6. 
 
13. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation and 
treatment. Hypertension 2008; 117:510-26. 
 
14. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J 
Am Coll Cardiol 2008; 52:1749-57. 
 

           
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Page 53 of 78 
15. Papadopoulos DP, Papademetriou V. Resistant hypertension: diagnosis and management. 
J Cardiovasc Pharmacol Ther 2006; 11:113-8. 
 
16. Garg JP, Elliott WJ, Folker A, et al. Resistant hypertension revisited: a comparison of two 
university-based cohorts. Am J Hypertens 2005; 18:619-26. 
 
17. Epstein M. Resistant hypertension: prevalence and evolving concepts. J Clin Hypertens 
2007; 9(1 Suppl 1):2–6. 
 
18. Kaplan NM. Resistant hypertension. J Hypertens 2005; 23:1441– 4. 
 
19. Moser M, Cushman W, Handler J. Resistant or difficult to treat hypertension. J Clin 
Hypertens 2006; 8:434-40. 
 
20. Doumas M, Guo D, Papademetriou V. Carotid baroreceptor stimulation as a therapeutic 
target in hypertension and other cardiovascular conditions. Expert Opin Ther Targets 2009; 
13:413-25. 
 
21. Guyton AC, Hall, JE. 2006. Guyton and Hall Textbook of Medical Physiology with 
StudentConsult Online Access (11th ed.). Philadelphia: Elsevier Saunders. 
 
22. Joyner MJ, Charkoudian N, Wallin BG. Sympathetic nervous system and blood pressure in 
humans: individualized patterns of regulation and their implications. Hypertension 2010; 
56:10-6. 
 
23. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: 
achievements and perspectives. Hypertension 2009; 54:690-7. 
 
24. Tsioufis C, Kordalis A, Flessas D, Anastasopoulos L, et al. Pathophysiology of resistant 
hypertension: the role of sympathetic nervous system. Int J Hypertens 2011; 642416. 
 
25. Barajas L, Liu L, Powers K. Anatomy of the renal innervation: intrarenal aspects and ganglia 
of origin. Can J Physiol Pharmacol 1992; 70:735-49. 
 
26. Luff SE, Hengstberger SG, McLahlan EM, Anderson WP. Distribution of sympathetic 
neuroeffector junctions in the juxtaglomerular region of the rabbit kidney. J Auton Nerv Syst 
1992; 40:239-53. 
 
27. Barajas L, Powers K, Wang P. Innervation of the renal cortical tubules: a quantitative study. 
Am J Physiol 1984; 247:F50-60. 
 
28. Esler M. The sympathetic system and hypertension. Am J Hypertens 2000; 13:S99-105. 
 
29. Kopp UC, DiBona GF. The neural control of renal function. In: Seldin G, Giebisch G, eds. 
The Kidney: Physiology and Pathophysiology. 3rd ed. New York: Raven Press; 2006:981- 
1006. 
 
30. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997; 77:75-197. 
 
31. Ye S, Zhong H, Yanamandala V, Campese VM. Renal injury caused by intrarenal injection 

           
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Page 54 of 78 
of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens 
2002; 15:717-24. 
 
32. Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with 
chronic renal failure. Hypertension 1995; 25:878-82. 
 
33. Ye S, Gamburd M, Mozayeni P, Koss M, Campese VM. A limited renal injury may cause a 
permanent form of neurogenic hypertension. Am J Hypertens 1998; 11:723–8. 
 
34. Ye S, Ozgur B, Campese VM. Renal afferent impulses, the posterior hypothalamus, and 
hypertension in rats with chronic renal failure. Kidney International 1997; 51:722–7. 
 
35. Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic 
hypertension. Am J Cardiol 2010; 105:570-6.Esler M. The sympathetic system and 
hypertension. Am J Hypertens 2000; 13:S99-105. 
 
36. Page IH, Heuer GJ. A surgical treatment of essential hypertension. J Clin Invest 1935; 
14:22-6. 
 
37. Freyberg RH, Peet MM. The effect on the kidney of bilateral splanchnicectomy in patients 
with hypertension. J Clin Invest 1937; 16:49-65. 
 
38. Isberg EM, Peet MM. The influence of supradiaphragmatic splanchnicectomy on the heart in 
hypertension. Am Heart J 1948; 35:567-83. 
 
39. Smithwick RH. Surgical treatment of hypertension. Am J Med 1948; 4:744-59. 
 
40. Whitelaw GP, Kinsey D, Smithwick RH. Factors influencing the choice of treatment in 
essential hypertension: surgical, medical, or a combination of both. Am J Surgery 1964; 
107:220-31. 
 
41. Allen EV. Sympathectomy for essential hypertension. Circulation 1952; 6:131-40. 
 
42. Smithwick RH. Hypertensive vascular disease: results of and indications for 
splanchnicectomy. J Chron Dis 1955; 1:477-96. 
 
43. White PD, Smithwick RH, Matthews MW, et al. The electrocardiogram in hypertension. The 
effect of radical lumbodorsal sympathectomy. Am Heart J 1945; 30:165-83. 
 
44. Chavez I, Mendez L. Surgical treatment of hypertensive heart disease and of heart failure of 
hypertension. Am Heart J 1949; 37:523-30. 
 
45. Krum H, Schlaich M, Whitburn R, et al. Catheter-based renal sympathetic denervation for 
resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 
373:1275-81. 
 
46. Schlaich M, Krum H, Walton T, et al. Two-year durability of blood pressure reduction with 
catheter-based renal sympathetic denervation. J Hypertens 2010; 28:e-Supplement A:e446 
(Abstract). 
 

           
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Page 55 of 78 
47. Esler MD, Krum H, A Sobotka, P, et al for the Renal sympathetic denervation in patients with 
treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. 
Lancet 2010; 376: 1903-9. 
 
48. Schlaich MP, Sobotka PA, Krum H, et al.: Renal sympathetic nerve ablation for uncontrolled 
hypertension. N Engl J Med 2009; 361:932–4. 
 
49. Bakker J, Goffette PP, Henry M, et al. The Erasme study: a multicenter study on the safety 
and technical results of the Palmaz stent used for the treatment of atherosclerotic ostial 
renal artery stenosis. Cardiovasc Intervent Radiol. 1999; 22:468–474. 
 
50. Beek FJ, Kaatee R, Beutler JJ, et al. Complications during renal artery stent placement for 
atherosclerotic ostial stenosis. Cardiovasc Intervent Radiol 1997; 20:184 –190. 
 
51. Leertouwer TC, Gussenhoven EJ, Bosch JL, et al. Stent placement forrenal arterial 
stenosis: where do we stand? A meta-analysis. Radiology 2000; 216:78–85. 
 
52. Martin LG. Renal revascularization using percutaneous balloon angioplasty for 
fibromuscular dysplasia and atherosclerotic disease. In: Calligaro KD, Doughtery MJ, ed. 
Modern management of renovascular hypertension and renal salvage. Baltimore, MD: 
Williams and Wilkins, 1996; 125–144. 
 
53. Quality Improvement Guideline for Angiography, Angioplasty, and Stent Placement for the 
Diagnosis and Treatment of Renal Artery Stenosis in Adults: J. Vasc Interv Radiol 2010; 
21;421-430, Louis G. Martin, John H Rundback et al.). 
 
54. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and 
Treatment of High Blood Pressure: Hypertension. 2003; 42: 1206–1252 
 
55. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of 
arterial hypertension: the Task Force for the Management of Arterial Hypertension of the 
European Society of Hypertension (ESH) and of the European Society of Cardiologyv(ESC). 
Eur Heart J 2007; 28: 1462 -1536. 
 
56. Krum H, et al. Catheter-based renal sympathetic denervation for 
resistant hypertension: Durability of Blood Pressure Reduction Out to 24 Months. Hypertension 
2011;57:911-917. 
 
57. AHA Medical/Scientific Statement: 1994 revisions to classification of functional capacity and 
objective assessment of patients with diseases of the heart. Circulation. 1994;90:644-645 
 
58. Worthley S, Worthley M, et al. EnligHTN I: Safety and efficacy of a novel multi-electrode 
renal denervation catheter in patients with resistant hypertension: A first-in-man multi-center 
study.Presented at: European Association of Percutaneous Cardiovascular Interventions, 
EuroPCR 2012 Congress, Paris, France, May 15-18, 2012. 
 
 
 
 
 

           
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Page 56 of 78 
Appendix A: Office Blood Pressure Measurement 
 
Office Blood Pressure Visits: Baseline, Discharge, 1M, 6M, 12M, 24M, 36M, 48M, 60M 
 
 
Office blood pressure corresponds to the blood pressure measured by the doctor or the 
nurse/staff in the office or in the clinic during the subject visit. 
 
 
Operating Procedures  
 
 
Subject Instruction: 
 
 
Avoid caffeine, exercise and smoking at least 30 minutes prior to the blood pressure 
measurements 
 
Administrator Instructions: 
 
 
Allow the subject to sit quietly for at least 5 minutes in a chair, with feet on the floor 
before beginning the blood pressure measurements. 
 
The subject’s arm should be supported. 
 
Have the cuff at the heart level of the subject 
 
 Blood pressure measured with a validated device to identify systolic and diastolic BP. 
Take three blood pressure measurements (ESC/ESH minimum of two) spaced by 1 to 2 
minutes and record the measured values into the worksheet.  
 
The average of these three measured values determine the office blood pressure of the 
subject at this visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

           
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Page 57 of 78 
 
 
Appendix B: 24 Hour Ambulatory Blood Pressure 
 
The standard 24-hour ambulatory blood pressure Visits:  Baseline, 6M, 12M, 24M, 36M, 48M, 
60M 
 
In the 24-hour blood pressure monitoring, the blood pressure of patient will be measured every 
30 minutes during the daytime and every 60 minutes during the night time. 
 
Operating Procedures (ESC and ESH Guidelines)55 
 
Patient Instructions: 
 
 
Engage in normal activities, but to refrain from strenuous exercise during the 
measurements 
 
Keep the arm extended and still during cuff inflations 
 
Record into the 24-Hour Ambulatory Blood Pressure Recording Log  any unusual events 
that may occur during the 24-hour monitoring  
 
 
Administrator Instructions: 
 
 
Set-up the time interval of automatic blood pressure measurement for patient during the 
visit 
 
 Ensure that at least two measurements per hour are taken during the person’s usual 
waking hours (for example, between 08:00 and 22:00).  
 
The average value of at least 14 measurements taken during the person’s usual waking 
hours should be used for calculation of mean.  
 
Ensure that at least one measurement per hour is taken during the person’s usual 
sleeping hours (for example, between 22:00 and 8:00).  
 
The average value of at least 8 measurements taken during the person’s usual sleeping 
hours should be used for calculation of mean.  
 
 
 
 

           
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Page 58 of 78 
Appendix C: NYHA Assessment Classifications57  
 
NYHA Assessment will be evaluated at baseline, 1M, 6M, 24M, and 60M follow-up visit and 
should be classified based on the following definitions:  
 
Class Functional Capacity: How a patient with cardiac disease feels 
during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  
If any physical activity is undertaken, discomfort increases. 
 
 
 

           
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Appendix D: Patient Information Sheet and Consent Form 
Template 
 
PATIENT INFORMATION SHEET AND CONSENT FORM 
 
Full title: EnligHTN II - IntErnational non-randomized, single-arm, long-term follow-up study of 
patients with uncontrolled HyperTensioN 
Study Location:  
Principal Investigator: 
Sponsor:  St. Jude Medical Cardiology Division, Inc. d/b/a St Jude Medical Cardiovascular 
Division, Inc.  
 
 
1. Introduction 
 
You are invited to take part in a research study because you have high blood pressure that is 
difficult to treat with medication.  The research project is testing a device and a treatment for 
high blood pressure.  The treatment is called renal denervation.  
This Patient Information Sheet and Consent Form tells you about the research study. It will 
explain the tests and treatments involved. Knowing what is involved will help you decide if you 
want to take part in the research. 
 
Please read this information carefully and ask questions about anything that you don’t 
understand or want to know more about. Before deciding whether or not to take part, you might 
want to talk about it with a relative, friend or your local doctor. 
 
Participation in this study is voluntary. If you don’t wish to take part, you don’t have to. You will 
receive the best possible care whether you take part or not. 
 
If you decide you want to take part in the research project, you will be asked to sign the consent 
section. By signing it you are telling us that you: 
 
 
understand what you have read;  
 
consent to take part in the research project; 
 
consent to have the tests and treatments that are described; 
 
consent to the use of your personal and health information as described. 
 
You will be given a copy of this Patient Information Sheet and Consent Form to keep. 
 
 
 

           
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2. Purpose and Description of the Research 
 
The purpose of this study is to collect information regarding the effectiveness of a procedure 
used to treat high blood pressure. The procedure is called renal denervation.  It involves placing 
a catheter (long thin round solid tube capable of conducting radiofrequency energy) in your renal 
(kidney) artery and heating the tip of the catheter to damage the tissue in particular areas of the 
artery. This tissue is known to contribute to high blood pressure.  Previous studies have shown 
that this treatment was effective in lowering blood pressure. However, more clinical data is 
required to confirm these results.   
 
The sponsor of the study is the maker of the device.  The EnligHTN Renal Denervation System, 
has been approved for use, and is commercially available. None of the tests and procedures in 
this study are experimental.  
 
Approximately 500 patients will take part in the project at up to 40 centers located in about 17 
different countries.  All patients who are eligible and have the appropriate artery anatomy will 
have the renal denervation procedure.  
 
Your participation in this study will be approximately 5 years.  This study will collect data from 
you medical history including past treatment for your high blood pressure, the renal denervation 
procedure, and follow-up study visits.   
 
3. Study Tests and Procedures 
 
If you agree to participate, the investigator will record your current medications and blood 
pressure measurements, demographics, and physical assessment for height and weight. The 
doctor will also complete a NYHA assessment, which is an evaluation to rank the limitations in 
your daily activities based on shortness of breath and chest pain.   
 
 
Your doctor will need to confirm your blood pressure.  You may be asked to wear a 24 hour 
blood pressure recording device. This test involves taking your blood pressure at 30 minute 
intervals throughout the day and at 60 minute intervals during the night using a portable monitor. 
The monitor itself is a small box approximately 3cm x 11cm x 9cm in dimension.  The monitor is 
worn on a belt around your waist and there will be a tube connecting the box to a cuff which is 
worn on your arm.  The monitor automatically inflates every 30 minutes during the day (or every 
60 minutes during the night) over 24 hours. When the cuff begins to inflate you are required to 
keep your arm extended and still until the cuff deflates. You will also be asked to record unusual 
events during these 24 hours on a log.  It is advisable that you arrange to wear the monitor on a 
day when you can go about your usual activities, including attending work but refrain from doing 
strenuous exercise. You will not be able to shower or bathe until the monitor is removed the 
following day.  It is important to return the monitor at this time. 
 
You will be asked to record your medication use for 2 weeks prior to the renal denervation 
procedure. This will require you to come back to see your doctor for a confirmatory visit to make 
sure you are eligible for the procedure. 
 
During this visit, you will also be asked to complete a Quality of Life Questionnaire to assess 
your general wellbeing, and to provide a blood sample (about 10-15mL) and urine sample to 

           
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Page 61 of 78 
measure how well your kidneys are working. You will be asked not to eat or drink anything 
except water after 10 pm the night prior to the visit.  
 
[Only applicable at 6 selected centers. Please remove section in italics if center won’t perform 
TTE.]  
 
You will have an echocardiogram (TTE) and may experience some discomfort from the 
echo transponder (wand) pushing on your chest during the echocardiogram test.  You 
may be asked to hold very still, breathe in and out very slowly, hold your breath, or lie on 
your left side during an echocardiogram.  You will not have pain during this procedure; 
however, you may feel uncomfortable from lying still or from the transducer (a small 
instrument that looks like a microphone) being pressed firmly against your chest to 
obtain pictures of your heart.  Although most people do not experience any discomfort 
from ultrasound tests, if you have severe difficulty breathing or cannot lie flat for a long 
examination, please talk to your doctor or the technician performing your procedure 
about any concerns you have 
 
You will have a test to assess the structure of your renal arteries. You may have a painless 
Abdominal Ultrasound, a Computed Axial Tomography (CT) scan, a Magnetic Resonance 
Angiogram (MRA) or an Angiogram to assess your renal arteries.   The following helps explain 
each test:  
 
 
If you have an Abdominal Ultrasound you will be lying down for the procedure. A clear, 
water-based conducting gel is applied to the skin over the abdomen. This helps with the 
transmission of the sound waves. A handheld probe called a transducer is then moved 
over the abdomen. You may be asked to change position so that the health care provider 
can examine different areas. You may also be asked to hold your breath for short periods 
of time during the examination. The procedure usually takes less than 30 minutes 
 
A CT scan combines special x-ray equipment to produce multiple images or pictures of 
the inside of the body. These images of the area being studied can then be examined on 
a computer monitor. During the test, you will lie on a table that is attached to the CT 
scanner, which is a large doughnut-shaped machine. The CT scanner sends X-rays 
through the body area being studied. Each rotation of the scanner provides a picture of 
the area being studied. In some cases, a dye called contrast material may be used. It 
may be put in a vein in your arm to see the area better. For some types of CT scans you 
drink the dye. The dye makes structures and organs easier to see on the CT pictures. 
This procedure can take 15 to 30 minutes.  
 
Most Magnetic Resonance Angiograms (MRA) exams are typically painless. You will be 
positioned on the moveable examination table. Straps may be used to help you stay still 
and maintain the correct position during imaging. It is normal for the area of your body 
being imaged to feel slightly warm, but if it bothers you, notify the radiologist or 
technologist. It is important that you remain perfectly still while the images are being 
recorded. MRA exams generally include multiple runs (sequences), each typically a few 
seconds to a few minutes at a time. The entire examination is usually completed within 
one hour. If a contrast material will be used in the MRA exam, a nurse or technologist will 
insert an intravenous (IV) line into a vein in your hand or arm. It is normal to feel coolness 
and a flushing for a minute or two when the contrast material is injected. 

           
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 
An Angiogram is a special kind of x-ray.  You will receive a local anaesthetic and then a 
small puncture will be made through the skin into the femoral artery on your upper thigh 
(groin).With the aid of fluoroscopy (x-ray that uses a fluorescent screen) a thin, flexible 
tube called a catheter will be threaded to the renal artery.  A special dye will be injected 
through the catheter so the renal artery will show up clearer on the x-ray.  You may be 
presented with a separate consent form that describes the renal artery angiogram 
procedure in greater detail.  
 
 
If the structure of your renal arteries is appropriate for the study, you will continue to have the 
renal denervation procedure.  If the structure of your renal arteries is not appropriate, you will not 
have the renal denervation procedure. However, you will still need to attend a 1 month follow-up 
visit. At this visit a physical assessment and office blood pressure will be performed.  
 
The renal denervation procedure will create a small opening (puncture) in an artery in your leg 
near the groin so that tubes, called catheters, can be introduced into your renal arteries.  The 
catheter will deliver heat (using radiofrequency energy) and ablate (damage) the nerves from 
inside the artery.  The investigator will repeat the ablation until he/she feels appropriate. After 
ablation, the catheter will be placed in the second renal artery to ablate the nerves there.   
 
Once the renal angiogram and renal denervation procedure are complete, the catheter will be 
slowly and carefully removed and pressure will be applied or a device used in order to help the 
arterial puncture to reseal itself.   
 
After the procedure you will be transferred for observation and you may stay in the hospital 
overnight. While you are in hospital your vital signs will be recorded continuously and your blood 
pressure will be recorded every 4 hours after the procedure until discharge or for a maximum of 
24 hours.   Also, any unfavorable or unintended symptoms or findings you may have (adverse 
events) will be recorded and treated as appropriate.   
 
Prior to discharge from hospital your blood pressure and the medications you are taking will be 
recorded.   
 
After the renal denervation procedure, you will return for a follow-up visit at 1 month, 6 months, 
12 months (1 year), 24 months (2 year), 36 months (3 year), 48 months (4 year) and at 60 
months (5 year).   
During your follow up visits the following tests/assessments will be performed: 
 
Physical Assessment and medication review at every visit 
 
Office blood pressure measurements at every visit 
 
24 hour Ambulatory Blood Pressure  at 6, 12, 24, 36, 48 and 60 month visits 
 
Blood and urine samples will be collected at 6, 12, 24 and 60 month visits. You will be 
asked to not to eat or drink anything except water after 10pm the night prior to the 6 
month visit.     
 
[Only applicable at 6 selected centers. Please remove this point if center won’t perform 
TTE.]  Echocardiogram (TTE) at the 1, 6, 24 and 60 month visits 
 
NYHA Assessment at the 1, 6, 24 and 60 month visits 
 
Quality of Life Questionnaire at 1, 6, 24 and 60 month visits 

           
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 
Renal artery evaluation at 6, 24 and 60 month visits 
 
4. Study Related  Risks 
 
There are risks, discomforts, and inconveniences associated with any research study that you 
should consider before deciding to participate in this study.  You should talk with the investigator 
if you have any questions. 
Precautions will be taken to ensure that side effects, should they occur, will be acted upon 
immediately. 
 
Many side effects go away shortly after treatment ends.  However, sometimes side effects can 
be serious, long lasting or permanent.  Tell your doctor if you have any problems.  Your doctor 
will discuss the best way of managing any side effects with you. 
 
Having blood taken may cause some discomfort or bruising.  Sometimes, the blood vessel may 
swell, or blood may clot in the blood vessel, or the spot from which blood is taken could become 
inflamed.  Rarely, there could be a minor infection or bleeding.  If this happens, it can be easily 
treated. 
 
The renal denervation is an interventional approach, and as such carries some potential risks, 
which may include but are not limited to the following: 
 Acute renal injury (renal infarction, renal hematoma) 
 Renal vascular injury (renal artery dissection, renal artery thrombosis, renal artery stenosis) 
 Collateral tissue injury 
 Malignant or accelerated hypertension 
 Symptomatic hypotension 
 Access site complications (arteriovenous fistula, access site thrombosis, embolisation, 
pseudo-aneurysm, hematoma, limb ischemia, femoral nerve injury, or seroma) 
 Disseminated intravascular coagulation 
 Infection (access site infection or systemic infection) 
 Renal failure 
 Decompensated heart failure 
 Myocardial infarction 
 Neurologic event (acute ischemic or hemorrhagic brain injury) 
 Respiratory compromise 
 Pain, including Back Pain 
 Death 
 Drug reactions 
 Contrast allergies etc 
 Bradycardia 
 Vasospasms 
 Vasovagal episodes 
 
When you have CT scan or renal artery angiogram, you will be exposed to radiation.  This 
research study involves exposure to a small amount of radiation. As part of everyday living, 
everyone is exposed to naturally occurring background radiation and receives a dose of about 2 
millisieverts (mSv) each year. The effective dose from this study is about 25 mSv. The dose from 

           
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Page 64 of 78 
this study is comparable to that received from several computed tomography x-ray (CT) and 
nuclear medicine procedures. The benefits from the study should be weighed against the 
possible detrimental effects of radiation, including an increased risk of fatal cancer. In this 
particular study, the risk is moderate and the estimated risk of such harm is about 1 in 800. For 
comparison, this risk is about 200 times lower than the cancer mortality rate in the general 
population of about one case in every four people. 
 
The effects of renal denervation procedure on the unborn child and on the newborn baby are not 
known. Because of this, it is important that study participants are not pregnant or breast-feeding 
and do not become pregnant during the course of the research project.  You must not participate 
in the research if you are pregnant or trying to become pregnant, or breast-feeding.  If you are 
female and child-bearing is a possibility, you may be required to undergo a pregnancy test prior 
to commencing the research project.  
 
If you do become pregnant whilst participating in the study, you should advise your treating 
doctor immediately.  
 
There may be other risks that are not known at this time. Tell your doctor immediately about any 
new or unusual symptoms that you get.  
 
5. Potential Benefits 
 
We cannot guarantee or promise that you will receive any benefits from this research.  However, 
possible benefits may include a decrease in your blood pressure, which may also have 
beneficial effects on your heart.  It should be noted that less than 20% of patients in previous 
studies had no significant reduction in blood pressure. The information gathered from the study 
will add to the understanding of the treatment options for patients with high blood pressure. This 
knowledge may advance medical science and may, in turn, benefit other patients with high blood 
pressure.  
 
6. Alternative Therapy 
 
Participation in this study is not your only option.  Your other options may include changing your 
blood pressure medications.  Discuss these options with your doctor before deciding whether or 
not to take part in this study.  This treatment differs from standard treatment as it involves a 
procedure rather than the use of medications. 
 
While you are participating in this research project, you may not be able to take some or all of 
the medications or treatments that you have been taking for your condition or for other reasons.  
It is important to tell your doctor and the research staff about any treatments or medications you 
may be taking, including over-the-counter medications, vitamins or herbal remedies, 
acupuncture or other alternative treatments.  You should also tell your doctor about any changes 
to these during your participation in the research.  Also ask your doctor to explain to you which 
treatments or medications may be taken while you are participating in this research project.  
 
7. Study Related Injuries 
 
Your study doctor and St. Jude Medical will take all reasonable measures to prevent any injury 
or illness that might result from your participation in this research. In the event you are injured or 

           
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become ill as a direct result of your participation, medical care and treatment will be available at 
this hospital.  
 
Should physical injury with a link to the study occur, medical care, including first aid, emergency 
treatment, and follow-up care will be available as needed.  You may be expected to pay for such 
treatment or seek reimbursement from your health care coverage. 
 
      If you followed all the instructions of the study and are injured during the study as a direct result 
of your participation in the study, SJM agrees to pay for reasonable and necessary, and 
otherwise non-covered treatment of injuries or adverse reactions which are a direct result of 
protocol-related procedures, which you would not have received as part of routine medical care, 
or that are caused by a defect or malfunction of the device during the study.  SJM is not 
responsible for medical risks or conditions (including the natural progression or manifestation of 
your coronary disease or any underlying illness, whether previously diagnosed or not) that you 
would face if you were not participating in the study.  SJM is not responsible for the wrongdoing 
or action of any other party other than including any illness or injuries resulting from your failure 
to follow the study’s instructions, including participation in all follow-up visits.  The sponsor will 
maintain insurance in accordance with the applicable local laws. 
 
 
8. Confidentiality 
 
To help keep your medical records and personal information confidential only certain authorized 
people will have access to your records.  These include without limitation researchers in your 
hospital who are part of this study, Sponsor and its affiliates and representatives of SJM that 
perform study-related services located in the U.S., European Economic Area and other 
countries.  It is necessary for them to review your records so that they can follow the study 
progress.  A summary of the information on all patients may be provided to governmental 
agencies (including regulatory agencies); regulatory authorities in the U.S., European Economic 
Area and other countries who may also need to review your medical records. Information from 
this study may also be published in medical journals.  However, your name and any other 
information that could identify you will never be used. 
Your personal data, including medical and health information, will be processed both by 
computer and manually, during and after the study by SJM, and its affiliates, its designated third 
party data processors, the Ethics Committee, the institution, the Investigators and other health 
personnel involved in the study for the purposes of this Trial. Personal data about you will be 
key-coded so as not to permit your identification, except if necessary for the purpose of the trial, 
for regulatory inspections, and to comply with reporting obligations. 
The data may be used for additional medical or scientific research projects in the future, 
publication in scientific journals, and obtaining regulatory approvals for the studied device.  Data 
may, if necessary for the above purposes, be communicated to the processors, regulatory 
authorities and Ethics Committees located countries of the European Economic Area (“EEA”), in 
the United States of America (“US”) and governmental agencies (including regulatory agencies) 
in other countries.  Some of the non-EEA countries to which your data may be transferred may 
not offer an adequate level of protection of privacy of personal data. SJM has taken security 
measures to ensure your personal data will be processed and used in a confidential way. 
 

           
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Page 66 of 78 
You understand that your personal data, including but not limited to medical findings, is to be 
collected, stored and analyzed in the scope of this clinical trial.  The information on your state of 
health will be used in accordance with the applicable statutory provisions and the use requires 
the following freely given declaration of consent prior to the participation in the clinical trial, i.e. 
without your below consent, you cannot participate in the clinical trial. 
 
• You agree that, in the scope of this clinical trial, your personal data, including but not limited to 
information on your state of health, is collected and stored both in paper form and on electronic 
data carriers at the clinic in charge.  If necessary, the collected data may be transmitted in 
anonymous form: 
 
a) to the clinic, the sponsor or its designee for scientific evaluation purposes, 
 
b) in case of adverse events: to the clinic, the sponsor and the competent  
regional authority.  
 
• You understand and agree that your personal data may be transferred outside of the European 
Economic Area, including the United States for purposes that include, without limitation, 
processing monitoring, auditing and control of the study or the conduct of inspections by the 
relevant authorities, medical product development, additional scientific analysis of the study 
data, obtaining approval to use and market medical products resulting from, or related to the 
study.  You understand that the data protection laws outside the European Economic Area may 
not be as strict as in your own country. 
 
• You further agree that authorized representatives of the sponsor bound to secrecy as well as 
the competent supervisory authorities may access your personal data, including but not limited 
to your health data, kept by the investigator to the extent that this is required for the verification 
of the proper performance of the study.  For this purpose, you hereby release the investigator 
from your medical confidentiality obligation.  
 
• You have been advised of your right to terminate your participation in the clinical trial at any 
time.  In the event that you revoke your consent to participate in the study, you are entitled to 
request the deletion of all your personal data stored until such point in time.  
 
• You agree that your data will be retained for a period of at least fifteen years (or longer if 
required by local country laws) following the termination or discontinuation of the trial.  After that, 
your personal data will be deleted unless required otherwise by statutory, by-law or contractual 
provisions. 
 
You have a right to gain access and to correct inaccuracies in information about you held by 
SJM. 
By signing the Patient Consent Form, you expressly consent to the collection, use, review and 
disclosure of such information. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
US Law.  This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
 
9. Compensation (medical/financial) 
 

           
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Page 67 of 78 
You will not be paid for taking part in the study. However, you will not be charged the costs 
specifically related to the study. The costs not specifically related to the study will be charged 
and reimbursed as usually by your health care coverage. .   
 
10. Study Questions  
 
We hope this answers your questions concerning the proposed evaluation, but if you have any 
questions about this research you should contact your doctor (“the Investigator”) 
(tel:________________________) or the Hospital department.  If you have questions about your 
rights as a research subject you should contact the Ethics Committee at [telephone #].  You can 
also write to the Ethics Committee at [address]. 
 
11. Study Withdrawal  
 
Your participation in the study is entirely voluntary.  If you decide to participate, you may quit the 
study at any time without a reason.  Just tell your doctor you do not wish to continue your 
participation.  If you leave the study before the final regularly scheduled visit, you may be asked 
by the study doctor to make a final visit.  It is recommended you continue to see your regular 
doctor.  There will be no penalty or loss of any benefits to which you are otherwise entitled if you 
decide not to continue with the study.  When you withdraw from the study, no new health 
information which might identify you will be gathered after that date. Information that has already 
been gathered may still be used and given to others as described in this form  Your doctor or 
SJM may also stop your participation at any time, without your consent, due to medical 
conditions or other factors that affect your study eligibility.   
 
 
12. New Findings 
 
During the research project, new information about the risks and benefits of the project may 
become known to the researchers.  If this occurs, you will be told about this new information and 
your doctor will discuss whether this new information affects you. 
 
 

           
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Patient Informed Consent (PIC) Template 
 
Full title: EnligHTN II - IntErnational non-randomized, single-arm, long-term follow-up study of 
patients with uncontrolled HyperTensioN 
Study Location: 
Principal Investigator: 
Sponsor:  St. Jude Medical Medical Cardiology Division, Inc. d/b/a St Jude Medical 
Cardiovascular Division, Inc.  
 
Are you currently participating in other research studies?   ___Yes  ___No  
 
Statement of Informed Consent: 
 
 
I understand that my participation in this study is voluntary 
 
I understand that I am free to refuse to participate in this study without giving reason and 
without my medical or legal rights being affected 
 
I understand that I am free to withdraw from this study at any time without giving reason 
and without my medical care or legal rights being affected. 
 
I understand that data collected during this study prior to the withdrawal will be used in 
the analysis and communicated in publication.  
 
I understand that information gained during the study maybe published, and I will not be 
identified and personal data will remain confidential. 
 
I understand that my health information may be stored in a database and study results 
may be looked at, used, and disclosed by the investigators, St. Jude Medical, Cardiology 
Division, Inc. d/b/a (doing business as) St. Jude Medical, Cardiovascular Division, Inc.,  a 
U.S. company, and its affiliates (located in the USA and EEA and other countries, and 
other people who work for St. Jude Medical to provide services related to the device and 
this study (SJM) regulatory authorities, and the Ethics Committee,  when it is relevant to 
my taking part in this research. I give permission for these individuals to have access and 
use to my medical information for this study.  
 
I understand that photograph and video recordings (after being anoymised) may be 
taken during the operation of the device during the study and used for this study and 
future research. 
 
I understand that my information will not be used for any mailing lists or sold to anyone 
for marketing purposes. 
 
I understand I have a right of access and a right to correct any inaccuracies in 
information about me . 
 
I understand the risks associated with this study. 
 
I understand that I may not benefit from taking part in the study. 
 
I understand that this study was reviewed by the Ethics Committee. 
 
I understand how to contact the research team if I have concerns about the study 
Acknowledgement of the information provided: 
 
I confirm that I have read and understand the information presented for this study. 
 
I have had the opportunity to discuss participation in the study and have had the 
opportunity to ask questions and have them answered. 

           
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Page 69 of 78 
 
Informed Consent Agreement: 
 
I agree to participate in this study and to comply with the procedures related to it. 
 
I give my permission to have my general practitioner  informed of my participation in this 
study. 
 
I give my permission to access my records by the investigator, sponsor(and its 
designees), ethics committee, and regulatory authorities for data for the purpose of this 
study. 
 
Subject Signature 
 
Subject Signature _______________________________  Date________________ 
   
Printed Name of Subject ____________________________________________ 
 
Subject’s Legal Representative (if necessary) Signature 
 
Signature _______________________________  Date________________   
 
Printed Name of Legal Representative____________________________________ 
 
 
Person Conducting Informed Consent Discussion 
 
Signature ____________________________________ 
Date ________________ 
 
Printed Name ____________________________________ 
 
 
 
 

           
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Clinical Investigational Plan: EnligHTN II 
 
 
Page 70 of 78 
 
Appendix E: Abbreviations 
 
Abbreviation 
Term 
ABP 
ADE 
AE 
ANZ 
ASADE 
BP 
CA 
CCI 
CIP 
CRF 
CPRB 
CT 
DCC 
DD 
DMP 
DVP 
EC 
eCRF 
EDC 
eGFR 
EMEAC 
ESC 
ESH 
GP 
ICMJE 
IFU 
ISB 
ISO 
MDRD 
MP 
MR 
NAP 
PI 
POA 
RDC 
RF 
SADE 
SAE 
SC  
SJM 
USADE 
WMA 
Ambulatory Blood Pressure 
Adverse Device Effect 
Adverse Event 
Australia – New Zealand 
Anticipated Serious Adverse Device Effect 
Blood Pressure 
Competent Authority 
Clinical Coordination Investigator 
Clinical Investigational Plan 
Case Report Form 
Clinical Project Review Board 
Computed Axial Tomography 
Data Cleaning Convention 
Device Deficiency 
Data Management Plan 
Data Validation Procedure 
Ethics Committee 
Electronic Case Report Form 
Electronic Data Capture 
Estimated Glomerular Filtration Rate 
Europe, Middle East, Africa, Canada 
European Society of Cardiology 
European Society of Hypertension 
General Practitioner 
International Committee of Medical Journal Editors 
Instructions for Use 
Investigator Site Binder 
International Organization for Standardization 
Modification of Diet in Renal Disease 
Monitoring Plan 
Magnetic Resonance 
Not Applicable 
Principal Investigator 
Power of Attorney 
Remote Data Capture 
Radiofrequency 
Serious Adverse Device Effect 
Serious Adverse Event 
Steering Committee 
St. Jude Medical 
Unanticipated Serious Adverse Device Effect 
World Medical Association 
 

           
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Appendix F: Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION 
 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
 
Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles. 
 
 
It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
 
 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
 
 
Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
 
 
In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
 

           
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 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
 
In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
 
Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue 
influence. 
 
Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
 
It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
 
 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
 
Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
 
 
The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 

           
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sponsors, institutional affiliations, and other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
 
 
The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must 
be independent of the researcher, the sponsor and any other undue influence. It must 
take into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee. 
 
 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professional and never 
the research subjects, even though they have given consent. 
 
 
Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
 
 
Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals 
or communities affected by the condition under investigation. 
 
 
Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
 

           
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 
Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
 
 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
 
 
Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
 
 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
 
 
In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
 
 
For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
 
When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 

           
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physician or may consent under duress. In such situations the informed consent should 
be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
 
 
For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is 
intended to promote the health of the population represented by the potential subject, the 
research cannot instead be performed with competent persons, and the research entails 
only minimal risk and minimal burden. 
 
 
When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
 
 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable 
to give informed consent have been stated in the research protocol and the study has 
been approved by a research ethics committee. Consent to remain in the research 
should be obtained as soon as possible from the subject or a legally authorized 
representative. 
 
 
Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and 
accuracy of their reports. They should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results should be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
 

           
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 
The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
 
 
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances: 
 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
 
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
 
 
At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
 
 
The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
 
 
In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 
 
 

           
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Appendix G: Data Collection Method (EDC) 
 
Sponsor/Investigators are required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on 
each subject. Source documents include all original records from which eCRFs derive their data. 
 
 
Access to eCRF application 
 
The eCRF application is accessed through the internet and requires the use of a personal user 
account and password. 
 
The following documents and information are required prior to receipt of personnel user account 
and password: 
 
 
Current signed and dated CV 
 
Completed Signature and Delegation List 
 
Documented training 
 
Email address and telephone 
 
Personal user account and password are provided via email. User account and password are 
confidential and personal. They are not to be shared with other people. 
 
The first time the application is accessed, the password will need to be changed. 
If the password is forgotten and/or lost, a new password can be provided via email by following 
the instructions on the webpage. 
 
Each center must be authorized to start enrolling patients in the investigation before access 
privileges to the application is made available. 
 
Access privileges are based on the tasks assigned on the Signature and Delegation List and will 
be either: 
 
 
Data entry and review 
 
Data entry, review and sign off 
 
All eCRFs are completed, saved (‘save complete’) and approved by an investigator in a timely 
manner. 
 
 
 
 

           
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Appendix H: List of Case Report Forms 
 
Data Points Provided Under Separate Cover 
 
 
Screening: Inclusion/Exclusion Criteria 
 
Baseline/Medical History Form 
 
Confirmatory Visit Form 
 
Physical Assessment/Office Blood Pressure Form 
 
24 Hour Ambulatory Blood Pressure Form 
 
Echocardiography Form 
 
Blood/Urine Lab Form: Serum Creatinine, eGFR, Hemoglobin A1c, Fasting Glucose, 
Fasting Insulin and Albumin-Creatinine Ratio 
 
Medications Log 
 
Renal Artery Evaluation Form 
 
Renal Denervation Procedure Form 
 
Additional Arteries From 
 
Post Procedure and Discharge Form 
 
Adverse Event Form 
 
Death Form 
 
Deviation Form 
 
Termination Form