EnligHTN European Observational Study
Conditions: Uncontrolled Hypertension
Sponsor: Abbott Medical Devices

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
©2014 – SJM International, Inc.: All rights reserved. No portion of this work may be reproduced in whole 
or in part without the express written permission of SJM International, Inc. 
 
 
Page 1 of 60 
CPRB Code 
: CV-12-064-EU-HT 
Project Acronym 
: EnligHTN European Obs Study 
Project Version 
: 2.0 final 
Version Date 
: 25Mar2014 
 
 
EnligHTN European Observational Study 
 
Clinical Investigation Plan (CIP) 
Amendment 1  
 
 
Sponsor 
SJM International, Inc. 
Da Vincilaan 11 – box F1 
1935 Zaventem 
Belgium 
Tel: +32 2 774 69 37 
Fax: +32 2 774 69 46 
 
 
Clinical Director 
 
Signature 
 
 
 
Angie Roach 
 
 
Date 
 
 
 
Clinical Coordinating 
Investigator 
Dr. José Diaz 
Hospital Juan Ramon Jimenez 
Ronda Norte 
21005 Huelva 
Spain 
Tel: +34 616 67 6095 
 
Signature 
 
 
Date 
 
 
 
 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
©2014 – SJM International, Inc.: All rights reserved. No portion of this work may be reproduced in whole 
or in part without the express written permission of SJM International, Inc. 
 
 
Page 2 of 60 
 
Revision History 
Amendment N° 
Project 
Version 
Date 
Rationale 
Details 
NAP 
V1.0 
03May2013 First release of CIP 
NAP 
1 
V2.0 
25Mar2014 
Main Changes to the CIP: 
 
 To adapt the indication 
according to the updated 
Instructions for EnligHTN 
ablation catheter 
 
 To remove the need for a 
Clinical Event Committee 
(CEC) 
See 
Summary of 
Changes 
 
 
 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
©2014 – SJM International, Inc.: All rights reserved. No portion of this work may be reproduced in whole 
or in part without the express written permission of SJM International, Inc. 
 
 
Page 3 of 60 
 
 
Table of Contents 
 
1 
Summary of Changes .......................................................................................................... 6 
2 
Synopsis ............................................................................................................................ 10 
3 
Background ....................................................................................................................... 14 
4 
Investigational Design........................................................................................................ 16 
4.1 
Purpose ...................................................................................................................... 16 
4.2 
Objectives ................................................................................................................... 16 
4.3 
Investigational Type .................................................................................................... 17 
4.4 
Patient Population ....................................................................................................... 17 
4.5 
Inclusion and Exclusion Criteria / Point of Enrollment .................................................. 17 
4.6 
Expected duration of the Investigation ......................................................................... 18 
4.7 
Expected duration of each subject’s participation ........................................................ 18 
4.8 
Number of Subjects required to be included in the Investigation ................................. 18 
4.9 
Estimated time needed to select this subject population .............................................. 18 
4.10 Devices Used .............................................................................................................. 19 
4.10.1 
EnligHTN™ Renal Artery Ablation Catheter ......................................................... 19 
4.10.2 
EnligHTN™ RF Ablation Generator ...................................................................... 19 
4.10.3 
EnligHTN™ Guiding Catheter (optional) ............................................................... 19 
4.11 Intended Use ............................................................................................................... 19 
5 
Procedures ........................................................................................................................ 20 
5.1 
Enrollment/Baseline Visit ............................................................................................. 20 
5.1.1 
Medical History .................................................................................................... 21 
5.1.2 
Physical Assessment ........................................................................................... 21 
5.1.3 
Office Blood Pressure .......................................................................................... 21 
5.1.4 
Ambulatory Blood Pressure .................................................................................. 22 
5.1.5 
Medication............................................................................................................ 22 
5.1.6 
Blood/Urine Analysis ............................................................................................ 22 
5.1.7 
NYHA Assessment ............................................................................................... 22 
5.1.8 
Renal artery evaluation ........................................................................................ 22 
5.2 
Renal Denervation Procedure ..................................................................................... 23 
5.3 
Discharge .................................................................................................................... 23 
5.4 
Follow-up visits ........................................................................................................... 24 
5.4.1 
Medications .......................................................................................................... 24 
5.4.2 
Office Blood Pressure .......................................................................................... 24 
5.4.3 
Ambulatory Blood Pressure .................................................................................. 24 
5.4.4 
Blood and Urine Analysis ..................................................................................... 24 
5.4.5 
NYHA Assessment ............................................................................................... 24 
5.4.6 
Renal artery evaluation ........................................................................................ 24 
5.4.7 
Adverse Events .................................................................................................... 25 
5.5 
Clinical Investigation Termination ................................................................................ 25 
5.6 
Description of activities performed by Sponsor Representatives ................................. 26 
5.7 
Description of post investigational provision of medical care ....................................... 26 
6 
Clinical Investigation Conduct ............................................................................................ 26 
6.1 
Ethics Committee ........................................................................................................ 26 
6.2 
Ethical Basis ............................................................................................................... 26 
6.3 
Insurance .................................................................................................................... 27 
6.4 
Statements of Compliance .......................................................................................... 27 
6.5 
Adherence to the Clinical Investigation Plan ................................................................ 27 
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CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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6.5.1 
Repeated non-compliance ................................................................................... 28 
6.6 
Informed Consent Process .......................................................................................... 28 
6.6.1 
General Process .................................................................................................. 28 
6.7 
Adverse Event, Adverse Device Effect ........................................................................ 29 
6.7.1 
Medical device ..................................................................................................... 29 
6.7.2 
Adverse Event (AE) .............................................................................................. 30 
6.7.3 
Serious Adverse Event (SAE) .............................................................................. 30 
6.7.4 
Adverse Device Effect (ADE) ............................................................................... 30 
6.7.5 
Serious Adverse Device Effect (SADE) ................................................................ 30 
6.7.6 
Unanticipated Serious Adverse Device Effect (USADE) ....................................... 30 
6.7.7 
Anticipated Serious Adverse Device Effect (ASADE) ........................................... 30 
6.7.8 
Procedure for assessing, recording and reporting adverse events, adverse device 
effects, serious adverse events and serious adverse device effects ..................... 31 
6.8 
Subject Death ............................................................................................................. 31 
6.8.1 
Procedure for recording and reporting Subject Death ........................................... 31 
6.9 
Document and data control ......................................................................................... 32 
6.9.1 
Traceability of documents and data ...................................................................... 32 
6.9.2 
Recording data ..................................................................................................... 32 
6.9.3 
Review of data ..................................................................................................... 32 
6.10 Monitoring ................................................................................................................... 32 
6.10.1 Designated Monitors ............................................................................................ 33 
6.10.2 Monitoring Plan .................................................................................................... 33 
6.11 Competent Authority (CA) Inspections ........................................................................ 33 
6.12 Investigation Termination ............................................................................................ 33 
6.12.1 Resuming the Clinical Investigation after Suspension .......................................... 34 
6.12.2 Investigation Conclusion ...................................................................................... 34 
7 
Risks and Benefits of the clinical investigation ................................................................... 34 
7.1 
Anticipated clinical benefits ......................................................................................... 34 
7.2 
Anticipated Adverse Events and Adverse Device Effects ............................................ 34 
7.3 
Steps that will be taken to control or mitigate the risks ................................................ 34 
7.4 
Risk-to-benefit rationale .............................................................................................. 35 
8 
Statistical considerations ................................................................................................... 36 
8.1 
Study design ............................................................................................................... 36 
8.2 
Sample size estimation ............................................................................................... 36 
8.3 
Analysis Population ..................................................................................................... 36 
8.4 
Data Analysis and Reporting ....................................................................................... 36 
8.4.1 
Primary objective analysis .................................................................................... 37 
8.4.2 
Secondary objectives analysis ............................................................................. 37 
8.4.3 
Other Analyses .................................................................................................... 38 
8.4.4 
Analysis Software................................................................................................. 38 
9 
Data Management ............................................................................................................. 39 
9.1 
Data Management Plan ............................................................................................... 39 
9.2 
Source Documents ...................................................................................................... 39 
9.3 
Source Data and Subject Files .................................................................................... 39 
9.4 
Confidentiality of Data ................................................................................................. 40 
10 
Document Retention .......................................................................................................... 41 
11 
Amendments to the Clinical Investigational Plan................................................................ 41 
12 
Publication Policy .............................................................................................................. 42 
13 
Investigation Organization ................................................................................................. 43 
13.1 Investigation Management / Sponsor .......................................................................... 43 
13.2 Clinical Investigators ................................................................................................... 44 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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13.3 Outsourcing of duties and functions ............................................................................ 46 
13.3.1 Power of Attorney (POA) ...................................................................................... 46 
14 
Bibliography ....................................................................................................................... 47 
Appendix A: Abbreviations ........................................................................................................ 51 
Appendix B: Declaration of Helsinki ........................................................................................... 53 
Appendix C: Device Manual ...................................................................................................... 57 
Appendix D: Data Collection Method ......................................................................................... 58 
 
 
 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
©2014 – SJM International, Inc.: All rights reserved. No portion of this work may be reproduced in whole 
or in part without the express written permission of SJM International, Inc. 
 
 
Page 6 of 60 
1 
Summary of Changes 
 
Change 1:  
Modification of the Inclusion and Exclusion Criteria following the change of indication from 
‘hypertension’ to ‘resistant hypertension’ in the Instructions for Use. Patients unable to take 3 
anti-hypertensive 
medications 
because 
of intolerance 
cannot 
be 
enrolled following 
implementation of this amendment. 
 
Change 2:  
Update of the intended use of the ablation catheter from ‘hypertension’ to ‘resistant 
hypertension’ 
 
Change 3:  
Clarification of tests and assessments performed per standard of care before the baseline visit, 
which can be used for the study.  
 
Change 4:  
Modification of need to collect the Urine albumin-creatinine ratio. Will only be collected if lab test 
was performed per standard of care. 
 
Change 5: 
Removal of reference of an Investigator Brochure, as the device has been marketed and the 
Instructions for Use should do. 
 
Change 6:  
Removal of the Clinical Event Committee (CEC) as usually not required for an Observational 
Study. The safety oversight including classification of events and determination of relationship of 
events to device and procedure will be done by SJM. 
 
Change 7: 
Replacement of Appendix B: Declaration of Helsinki with the version of the 64th  WMA General 
Assembly, Oct 2013. 
 
Other changes: 
Corrections of typos and grammatical errors having no impact on the content of the protocol; 
Updates to section numbers. 
 
 
SJM-CIP-10060A

 
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CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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Page 7 of 60 
 
Change 
number, 
Paragraph(s) 
& Page(s) 
(referring to CIP 
v2.0) 
CIP V1.0 
CIP V2.0 
Amendment 1 
Change 1: 
Synopsis 
(p.11) and 
Inclusion and 
Exclusion 
criteria (p.18)  
 
Subject has established hypertension 
(diagnosed ≥12 months prior to 
baseline) and is on a guideline based 
drug regimen at a stable (≥ 14 days) 
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-I/ARB, Calcium 
Channel Blockers, Beta Blockers, or 
diuretic) and is unable to take 3 anti-
hypertensive drugs  
 
Subject has established hypertension 
(diagnosed ≥12 months prior to 
baseline) and is on a guideline based 
drug regimen at a stable (≥ 14 days) 
and a fully tolerated dose consisting of 
≥3 anti-hypertensive medications 
(including 1 diuretic) 
Change 2: 
Intended Use 
(p.19) 
The ablation catheter is indicated for 
use in renal denervation procedures 
for the treatment of hypertension.   
 
The ablation catheter is indicated for 
use in renal denervation procedures 
for the treatment of resistant 
hypertension.   
 
Change 3: 
Enrollment/ 
Baseline 
Visit (p.21) 
All baseline activities are performed 
after the patient is enrolled in the 
investigation. Tests and other required 
assessments performed as standard 
of care before the baseline visit can 
be used if done within 90 days prior to 
procedure. 
All baseline activities are performed 
after the patient is enrolled in the 
investigation. Ambulatory Blood 
Pressure Recordings performed as 
standard of care within 2 weeks 
before the baseline visit can be used. 
Other tests and required assessments 
performed as standard of care before 
the baseline visit can be used if done 
within 90 days prior to procedure. 
SJM-CIP-10060A

 
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CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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Change 4: 
Procedures 
(p.22) and 
Blood/Urine 
Analysis 
(p.24) 
Urine albumin-creatinine ratios are 
required per Table 1 Data/CRF 
collection.   
 
 
Blood and urine samples will be 
drawn and analyzed. The following 
results will be collected:   
 
Serum Creatinine  
 
eGFR 
 
Urine albumin-creatinine ratio  
 
Pregnancy test (if applicable) 
 
Updated Table 1 Data/CRF collection 
to clarify that Urine albumin-creatinine 
ratios will only be collected if done per 
clinical routine. 
 
Blood and urine samples will be 
drawn and analyzed. The following 
results will be collected:   
 
Serum Creatinine  
 
eGFR 
 
Urine albumin-creatinine ratio 
(if available per standard of 
care) 
 
Pregnancy test (if applicable) 
 
Change 5: 
Anticipated 
Adverse 
Events and 
Adverse 
Device 
Effects (p.34) 
Adverse events potentially associated 
with the use of the EnligHTN Renal 
Denervation 
System 
and 
their 
potential 
complications 
are 
documented in the Instructions for 
Use 
(IFU) 
and 
the 
Investigator 
Brochure (IB). Both documents are 
available upon request. 
 
Adverse events potentially associated 
with the use of the EnligHTN Renal 
Denervation 
System 
and 
their 
potential 
complications 
are 
documented in the Instructions for 
Use (IFU) which is available upon 
request. 
 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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Change 6: 
Clinical 
Event 
Committee 
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 serious 
adverse events and adverse 
device effects as specified in 
the CEC charter 
 
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 
and processes 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. 
 
Section has been removed. 
 
 
SJM-CIP-10060A

 
CIP – EnligHTN European Observational study 
CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
©2014 – SJM International, Inc.: All rights reserved. No portion of this work may be reproduced in whole 
or in part without the express written permission of SJM International, Inc. 
 
 
Page 10 of 60 
2 
Synopsis 
 
Title: 
EnligHTN European Observational Study 
Acronym: 
EnligHTN European Obs Study 
Purpose: 
The purpose of this observational study is to further evaluate the safety and 
performance of the EnligHTN™ Renal Denervation System in the treatment of 
patients with uncontrolled hypertension in clinical routine practice. 
Objectives: 
Primary: 
Mean reduction in office Systolic Blood Pressure at 6 months 
 
Secondary: 
o Acute (30 days) 
o Safety: 
 
Assessment of peri-procedural adverse events up until 
30 days post procedure 
o Performance: 
 
Mean reduction in office Systolic and Diastolic Blood 
Pressure at 1 month 
 
Mean reduction in ambulatory Systolic and Diastolic 
Blood Pressure at 1 month 
 
Percentage of subjects achieving office Systolic Blood 
Pressure < 140 mmHg at 1 month 
o Mid to long term (6 and 12 months) 
o Safety: 
 
Renal function change based on eGFR at 6 and 12 
months 
 
Assessment of renovascular safety as measured by new 
renal artery stenosis and aneurysm at the site of ablation 
at 6 months 
o Performance: 
 
Mean reduction in office Systolic Blood Pressure at 12 
months 
 
Mean reduction in office Diastolic Blood Pressure at 6 
and 12 months 
 
Mean reduction in ambulatory Systolic and Diastolic 
Blood Pressure at 6 and 12 months 
 
Percentage of subjects achieving office Systolic Blood 
Pressure < 140 mmHg at 6 and at 12 months 
Design: 
This is a post market, multi-center, open label, observational study.  
Approximately 500 subjects with uncontrolled hypertension will undergo renal 
artery ablation at approximately 50 investigational sites located in Europe and 
the Middle-East, and will be followed for 1 year post procedure.   
 
The expected duration of the investigation will be approximately 4 years. 
 
 
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CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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or in part without the express written permission of SJM International, Inc. 
 
 
Page 11 of 60 
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 participating countries. 
Further CE marked released devices for renal denervation will be used in this 
investigation as they become available on the market. 
Patient 
Population:  
The patient population enrolled in this investigation will consist of males and 
females with uncontrolled hypertension who meet all inclusion criteria, and 
none of the exclusion criteria. 
Patient 
Screening: 
Patient Screening: 
Patients who do meet all inclusion criteria and don’t meet any of the exclusion 
criteria are eligible to participate. 
 
Eligible patients 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 of the investigation once he/she has been fully 
informed about the investigation, has agreed to participate, and signed & dated 
the Patient Informed Consent (PIC) form.  
 
Inclusion Criteria 
o Subject is planned to undergo a renal denervation procedure for the 
treatment of hypertension 
o Subject is ≥18 years of age at time of consent 
o Subject must be able and willing to provide written informed consent  
o Subject must be able and willing to comply with the required follow-up 
schedule 
o Subject has office SBP ≥ 140 mmHg 
o Subject has established hypertension (diagnosed ≥12 months prior to 
baseline) and is on a guideline based drug regimen at a stable (≥ 14 
days) and a fully tolerated dose consisting of ≥3 anti-hypertensive 
medications (including 1 diuretic)  
 
Exclusion Criteria 
o Subject has known significant renovascular abnormalities such as renal  
artery stenosis > 30%  
o Subject has undergone prior renal angioplasty, renal denervation,  
indwelling renal stents, and/or abdominal aortic stent grafts   
o Subject has a history of hemodynamically significant valvular heart 
disease 
o Subject has blood clotting abnormalities 
o Subject life expectancy is < 12 months, as determined by the Study 
Investigator 
o Subject is participating in another clinical study which has the potential 
to impact his/her hypertension management (pharmaceutical/ device/ 
homeopathic) 
o Subject is pregnant, nursing, or of childbearing potential and is not 
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Page 12 of 60 
using adequate contraceptive methods 
o Subject has active systemic infection 
o Subject has known  renal arteries with diameter(s) < 4 mm  
o Subject has an estimated GFR <45 mL/min per 1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) formula  
o Subject had a renal transplant or is awaiting a renal transplant 
 
 
 
 
 
 
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CV-12-064-EU-HT_CIP_V2.0_final_25Mar2014 EnligHTN European Observational Study 
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Page 13 of 60 
Figure 1: Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure: 
 
Renal Denervation Procedure 
possible? 
Follow-up: 1-, 6- and 12-Month: 
 
 
Office Blood Pressure 
 
Physical Assessment and NYHA Assessment 
 
Ambulatory Blood Pressure (if done per clinical routine) 
 
Blood and Urine Lab Collection (at 6 and 12 months) 
 
Renal artery evaluation at 6 months (if clinically indicated or done per clinical 
routine) 
 
Medications 
Procedural Exclusion:  
 
Subjects in which the 
procedure was started but do 
not have the EnligHTN Renal 
Artery Ablation Catheter 
enter their body will be 
followed for 30 days post 
procedure and then 
discontinued. 
Enrollment/Baseline: 
 
 
Patient Informed Consent (point of enrollment) 
 
Review of INCL/EXCL criteria 
 
Medical History 
 
Office Blood Pressure 
 
Physical Assessment and NYHA Assessment 
 
Ambulatory Blood Pressure (if done per clinical routine) 
 
Blood and Urine Lab Collection 
 
Medications 
 
Renal Artery Anatomy Evaluation (if done per clinical routine) 
Discharge: 
 
 
Office Blood Pressure  
 
Physical Assessment 
 
Medications 
 
No 
Yes 
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Page 14 of 60 
 
3 
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, the blood pressure in these 
patients remained 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 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. 
 
 
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Page 15 of 60 
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 resistant hypertension.  
 
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).45-47,51  
 
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) is 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 1 March 2012 with a total of 46 patients 
having undergone the renal denervation procedure.  Subjects will be followed for 24 months post 
procedure.   
 
The 1 month clinical results from EnligHTN I were presented at the European Association of 
Percutaneous Cardiovascular Interventions, EuroPCR 2012 Congress 15-18 May 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 min. 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 ≥ 10 mmHg reduction in systolic Blood Pressure. 
 
The 3 months 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 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 between baseline and 3 
months was -9.9/-5.4 mmHg52. 
 
The 6 months primary endpoint results from EnligHTN I were presented at the American Heart 
Association meeting on 5 November 2012. Compared to baseline, Office and 24-hour 
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Ambulatory Systolic BP of the 45 subjects with available data (one subject had a missed visit) 
significantly decreased at all-time points (p value <0.0001).  The average Office BP (mmHg) at 
baseline, 1 month, 3 months  and 6 months post denervation procedure were 176/96, 148/87, 
149/87, and 150/86 respectively.  The resulting average Office BP (mmHg) reductions from 
baseline at 1 month, 3 months, and 6 months were -28/-10, -27/-10, and -26/-10.  Over the 
follow-up period, as many as 80% of subjects had a reduction in office systolic BP of at least 10 
mmHg or greater and up to 41% had an office BP of less than 140 mmHg.  The average 24-hour 
Ambulatory BP (mmHg) reduction from baseline to 1 month, 3 months, and 6 months was -10/-
5, -10/-5, and -10/-6 respectively.  No serious vascular adverse events occurred during the 
procedure, including no renal artery damage (i.e. no renal artery dissections, aneurysms, new 
stenoses, or flow limiting renal artery vasospasms) or other vascular access complications.  
Minor peri-procedural events which were attributed to either the device or procedure were 
reported, including: non-flow limiting vasospasms, site hematomas, and vasovagal episodes.  All 
minor events attributed to the device and/or procedure have resolved without further clinical 
sequelae. 
 
Due to promising clinical evidence, this new therapeutic approach is likely to find a quick 
adoption. This EnligHTN observational study is designed to collect more data, critical to the 
benefit of the therapy, within a routine clinical setting. 
4 
Investigational Design 
4.1 Purpose 
The purpose of this observational study is to further evaluate the performance and safety of the 
EnligHTN™ Renal Denervation System in the treatment of patients with uncontrolled 
hypertension in clinical routine practice. 
4.2 Objectives 
Primary Objective 
The primary objective will be to describe the mean reduction in office Systolic Blood Pressure at 
6 months. 
 
Secondary Objectives 
The secondary objectives are: 
 
o Acute (30 days) 
o Safety: 
 
Assessment of peri-procedural adverse events up until 30 days post 
procedure 
o Performance: 
 
Mean reduction in office Systolic and Diastolic Blood Pressure at 1 month 
 
Mean reduction in ambulatory Systolic and Diastolic Blood Pressure at 1 
month 
 
Percentage of subjects achieving office Systolic Blood Pressure < 140 
mmHg at 1 month 
o Mid to long term (6 and 12 months) 
o Safety: 
 
Renal function change based on eGFR at 6 and 12 months 
 
Assessment of renovascular safety as measured by new renal artery 
stenosis or aneurysm at the site of ablation at 6 months 
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o Performance: 
 
Mean reduction in office Systolic Blood Pressure at 12 months 
 
Mean reduction in office Diastolic Blood Pressure at 6 and 12 months 
 
Mean reduction in Ambulatory Systolic and Diastolic Blood Pressure at 6 
and 12 months 
 
Percentage of subjects achieving office Systolic Blood Pressure < 140 
mmHg at 6 and at 12 months 
4.3 Investigational Type 
This is a prospective, multicenter, observational study of the EnligHTN™ Renal Denervation 
System.  Approximately 500 subjects with uncontrolled hypertension will undergo renal artery 
ablation at approximately 50 investigational sites located in Europe and the Middle-East, and will 
be followed for 1 year post procedure.   
4.4 Patient Population 
The patient population enrolled in this investigation will consist of male and female patients, 18 
years of age or older, who meet all specified inclusion criteria and none of the exclusion criteria 
(Section 4.5).   
 
The patient will be given ample time to ask questions and to understand the risks of taking part 
in this investigation. In case the patient agrees to participate, a duly signed and dated Patient 
Informed Consent (PIC) will be obtained. 
4.5 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 and signed & dated the PIC form 
(Refer to section 6.6 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 enrollment.  
All subjects enrolled in the study (including those withdrawn from the study 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. 
 
Inclusion Criteria 
 
Subject is planned to undergo a renal denervation procedure for the treatment of 
hypertension 
 
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 SBP ≥ 140 mmHg  
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 
Subject has established hypertension (diagnosed ≥12 months prior to baseline) and is on 
a guideline based drug regimen at a stable (≥ 14 days) and a fully tolerated dose 
consisting of ≥3 anti-hypertensive medications (including 1 diuretic) 
 
Exclusion Criteria 
 
Subject has known 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 a history of hemodynamically significant valvular heart disease 
 
Subject has blood clotting abnormalities  
 
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 his/her 
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 known renal arteries with diameter(s) < 4 mm 
 
Subject has an estimated GFR <45 mL/min per 1.73 m2 using the MDRD formula 
 
Subject had a renal transplant or is awaiting a renal transplant 
 
Procedural Exclusions: 
Subjects who have been enrolled in the study, and in whom 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.  These subjects will be followed for 30 days post procedure.  The reason for the 
procedural exclusion will be documented on the Procedural CRF.   
4.6 Expected duration of the Investigation 
The expected duration of the investigation will be approximately 4 years. 
4.7 Expected duration of each subject’s participation 
The expected duration of each subject’s participation will be approximately 1 year. 
4.8 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.  
4.9 Estimated time needed to select this subject population 
The estimated time needed to enroll the number of subjects will be approximately 24-36  
months. 
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4.10 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 manufacturer of the EnligHTN™ Renal Denervation System is St. Jude Medical, 
Cardiovascular Division, 14901 DeVeau Place, Minnetonka, MN 55345-2126, USA 
 
The following market approved St. Jude Medical devices to be initially used in this investigation 
are:   
 
4.10.1 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. 
 
4.10.2 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. 
 
4.10.3 EnligHTN™ Guiding Catheter (optional) 
The EnligHTN™ Guiding Catheter system is comprised of two components: a guiding catheter 
and 
a 
dilator. 
 
The 
guiding 
catheter 
is 
constructed 
of 
three 
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. 
 
Upon receiving CE mark, new generations of SJM devices for renal denervation may be used in 
this clinical investigation as they become available on the market.  
4.11 Intended Use  
The ablation catheter is indicated for use in renal denervation procedures for the treatment of 
resistant hypertension.   
 
 
 
 
 
 
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Page 20 of 60 
5 
Procedures 
Table 1: Data/CRF Collection 
 
5.1 Enrollment/Baseline Visit  
Prior to enrollment in the study, 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. 
 
Visit 
Activity 
Enrollment 
/ Baseline 
Procedure 
Discharge 
<72 hrs 
 
1M 
±14d 
 
6M 
±30d 
 
12M 
±60d 
PIS & PIC 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Medical  History 
X 
 
 
 
 
 
Office Blood Pressure 
X 
 
X 
X 
X 
X 
Physical Assessment 
X 
 
X 
X 
X 
X 
Ambulatory Blood 
Pressure 
X1,2 
 
 
X1 
X1 
X1 
NYHA Assessment 
X 
 
 
X 
X 
X 
Serum creatinine 
X 
 
 
 
X 
X 
Estimated GFR 
X 
 
 
 
X 
X 
Urine albumin-to-
creatinine ratio 
X1 
 
 
 
X1 
X1 
Medications 
X 
 
X 
X 
X 
X 
Renal Artery Anatomy 
Evaluation 
X1 
X 
 
 
X1 
 
Pregnancy Test (urine / 
blood) 
X** 
 
 
 
 
 
Renal Denervation 
Procedure 
 
X 
 
 
 
 
Adverse Event 
Assessment 
** 
** 
** 
** 
** 
** 
CIP Deviation 
** 
** 
** 
** 
** 
** 
Withdrawal/ 
Termination 
 
** 
** 
** 
** 
** 
(**)  As applicable 
(1) If done per clinical routine 
(2) Ambulatory Blood Pressure Recordings of the last 2 weeks can be used 
 
 
 
 
 
 
 
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Page 21 of 60 
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 6.6 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) form, 
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 form and therefore has been enrolled in the 
investigation.    
 
NOTE: As soon as the subject signs the Patient Informed Consent form, adverse events need to 
be reported according to the guidelines mentioned in Section 6.7.8. 
 
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. Ambulatory Blood Pressure (ABP) 
recordings performed as standard of care within 2 weeks before the baseline visit can be used. 
Other tests and required assessments performed as standard of care before the baseline visit 
can be used if done within 90 days prior to procedure. 
 
5.1.1 Medical History 
A complete medical history of the subject will be reviewed and recorded including: 
 
Hypertension, renal disease, cardiovascular disease, neurological disease, obstructive 
sleep apnea, hyperlipidemia, diabetes (Type I and II), smoking, thyroid disease, liver 
disease, chronic obstructive pulmonary disease, and alcohol consumption. 
    
5.1.2 Physical Assessment 
The subject will have a physical assessment recording at the baseline visit to capture the 
following: 
 
Age  
 
Gender 
 
Height  
 
Weight 
5.1.3 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.   
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Measurements should be taken according to Standard Joint National Committee VII Guidelines / 
ESC and ESH Guidelines49, 50. 
5.1.4 Ambulatory Blood Pressure 
When performed per standard of care, daytime mean ABP, night time mean ABP and 24 hour 
average ABP values will be collected. Recordings of the last two weeks can be used. 
5.1.5 Medication 
The subject’s baseline medication regimen, including medication name, dose, and frequency will 
be reviewed and recorded, making note of those medications taken specific to the subject’s 
hypertension therapy. 
 
The investigator will assess that the subject was on a stable anti-hypertensive medication 
regimen for a period of at least 14 days prior to enrollment. This assessment will be left at 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 deemed clinically necessary.  
 
Investigators will urge subject compliance to prescribed medical regimen throughout the trial.  If 
the subject is non-compliant without medical rationale, the subject may be excluded. 
5.1.6 Blood/Urine Analysis  
Blood and urine samples will be drawn and analyzed. The following results will be collected:   
 
Serum Creatinine  
 
eGFR 
 
Urine albumin-creatinine ratio (if available per standard of care) 
 
Pregnancy test (if applicable) 
5.1.7 NYHA Assessment 
NYHA Assessment53 will be evaluated at baseline and will be classified as the following: 
 
Class I:  No limitations of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea or anginal pain. 
 
Class II:  Slight limitation of physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea or anginal pain. 
 
Class III:  Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary physical activity causes fatigue, palpitation, dyspnea or anginal pain. 
 
Class IV:  Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest.  If any physical activity is undertaken, discomfort is 
increased. 
5.1.8 Renal artery evaluation  
Renal artery evaluation results from either computed axial tomography (CT scan), duplex 
ultrasonography, angiography, or magnetic resonance (MR) angiography will be collected if 
available.   
 
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5.2 Renal Denervation Procedure 
The renal denervation procedure should always be done with the aid of fluoroscopy. After 
confirming subject renal artery anatomy and inclusion and exclusion criteria the site will prepare 
and perform the renal nerve ablation according to the EnligHTN™ Renal Denervation System 
Instructions for Use (IFU). 
 
The investigator will select the appropriate basket size of the EnligHTN™ Renal Artery Ablation 
Catheter (small size for a renal artery diameter between 4mm and 6mm and large size for a 
renal artery diameter between 5.5mm and 8mm). The EnligHTN™ Renal Artery Ablation 
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 
EnligHTN™ Renal Artery Ablation 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 lesions are recommended) in the main renal artery. When 
the ablation procedure is completed in this main renal artery, the EnligHTN™ Renal Artery 
Ablation Catheter will be withdrawn from the artery with the basket fully closed. Images of the 
renal artery using a 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 contra-lateral main renal 
artery. When the ablation procedure for the contra-lateral main renal artery is also completed, 
the EnligHTN™ Renal Artery Ablation Catheter will be withdrawn from the artery with the basket 
fully closed and the catheter will be visually inspected and flushed with heparinized saline. 
Finally, the sheath will be removed according to the institution’s standard of care.  
 
Procedural data collected will include but is not limited to: 
 
 
EnligHTN™ Renal Denervation System device information  
 
Guiding catheter used – manufacturer  
 
Number of arteries ablated 
 
Number of ablations performed 
 
Device settings 
 
Procedure time 
 
Ablation time 
 
Fluoroscopy time 
 
Volume of contrast media 
 
Adverse events (check if any adverse events or adverse device effects occurred since 
enrollment of the patient into the study, and document the event in the hospital records 
and report the adverse event according to specifications in section 6.7.8.) 
5.3 Discharge  
Discharge is expected to occur within 72 hours post procedure. The following information will be 
collected: 
 
 
Weight (as part of the Physical assessment) 
 
Office Blood Pressure (as the average of three measurements) 
 
Anti-hypertensive medication  
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 
Adverse events (check if any adverse events or adverse device effects occurred since 
enrollment of the patient into the study, and document the event in the hospital records 
and report the adverse event according to specifications in section 6.7.8.) 
5.4 Follow-up visits 
Subjects will return for follow-up at 1 month (±14 days), 6 months (± 30 days) and at 12 months 
(± 60 days) post-procedure.   
 
The following will be evaluated / reviewed according to Table 1: 
 
5.4.1 Medications 
Anti-hypertensive medication will be collected at each follow-up visit.  
 
5.4.2 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 Guidelines49, 50. 
 
5.4.3 Ambulatory Blood Pressure 
When performed per standard of care, daytime mean ABP, night time mean ABP and 24 hour 
average ABP values will be collected. 
 
5.4.4 Blood and Urine Analysis 
Blood and urine samples will be drawn and analyzed, and the following results will be collected 
at both the 6 months and 12 months follow-up visit:   
 
Serum Creatinine  
 
eGFR  
 
Urine albumin to creatinine ratio (if available per standard of care)    
 
5.4.5 NYHA Assessment 
NYHA Assessment53 will be evaluated at the 1 month, 6 months and 12 months follow-up visits 
and will be classified as the following: 
 
 
Class I:  No limitations of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea or anginal pain. 
 
Class II:  Slight limitation of physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea or anginal pain. 
 
Class III:  Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary physical activity causes fatigue, palpitation, dyspnea or anginal pain. 
 
Class IV:  Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest.  If any physical activity is undertaken, discomfort is 
increased. 
 
5.4.6 Renal artery evaluation  
At 6 months, renal artery evaluation results from either computed axial tomography (CT scan), 
duplex ultrasonography, angiography, or magnetic resonance (MR) angiography will be 
collected if available.  
 
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Page 25 of 60 
5.4.7 Adverse Events  
Confirm if any adverse events or adverse device effects occurred since the last visit and 
document in the hospital records. Report the adverse events according to specifications in 
section 6.7.8. 
 
5.5 Clinical Investigation Termination  
Each subject will be followed for 1 year 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.  A Clinical investigation Termination CRF 
should be completed by the site and provided to the Sponsor.  
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  
 
Subject death (in case of subject death, the 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.   
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5.6 Description of activities performed by Sponsor Representatives 
Trained sponsor personnel may perform certain activities to ensure compliance to the 
investigational plan and may provide technical expertise. 
 
Sponsor personnel will not: 
 
Perform the informed consent process 
 
Practice medicine 
 
Provide medical diagnosis or treatment to subjects 
 
Discuss a subject’s condition  or treatment with a subject 
 
Independently collect clinical investigational data or complete study documentation 
5.7 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. 
6 
Clinical Investigation Conduct 
6.1 Ethics Committee 
A duly constituted EC representing the prospective study site must review and approve the 
subject informed consent and research authorization document, the Clinical Investigation Plan, 
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 Patient Informed Consent 
form 
 
the approved version of any other submitted document (e.g. 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. 
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.   
6.2 Ethical Basis 
This clinical investigation will be performed in accordance with the most current versions of the 
World Medical Association Declaration of Helsinki and any applicable regional and national 
regulations. Prior to starting the investigation, the Clinical Investigation Plan will be submitted 
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together with associated documents including Patient Information Sheets, and subject Informed 
Consent Forms in the local language to the relevant EC for review. 
6.3 Insurance 
As sponsor, SJM has taken up general liability insurance in accordance with the requirements of 
the applicable local laws. If required, additional subject coverage or an investigation specific 
insurance shall be provided by the Sponsor as well. 
6.4 Statements of Compliance 
ISO14155 shall be used as a guideline with following exceptions: 
 
Limited AE reporting -> refer to section 6.7.8 
 
Device Deficiencies 
 
Device Accountability 
 
The investigator shall not start enrolling subjects or requesting informed consent prior to 
obtaining Ethics Committee approval and Competent Authority approval, if applicable, 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. 
6.5 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.  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 
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 affect 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.  
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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. 
 
6.5.1 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: 
 
 
Contacting the investigator by telephone 
 
Contacting the investigator in writing 
 
Visiting the investigator 
 
Retraining of the investigator 
 
Site “for-cause” audit 
 
Implementation of corrective action preventive action plan  
 
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. 
6.6 Informed Consent Process 
6.6.1 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). 
 
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 and the study center’s EC.  Prior to the patient signing the 
PIC, 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.    
  
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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 personally 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. 
 
6.7 Adverse Event, Adverse Device Effect 
The definitions provided below are in accordance to ISO 14155:2011 (E). 
 
6.7.1 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, 
 
Desinfection of medical devices  
 
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 
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 
 
6.7.2 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. 
 
6.7.3 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. 
 
6.7.4 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. 
 
6.7.5 Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
6.7.6 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. 
 
6.7.7 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. 
 
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6.7.8 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 form). 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 Adverse Events and all Adverse Device Effects 
(regardless of severity) are to be documented and reported to the sponsor immediately and 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. 
 
 
Procedure related: The AE is deemed related to the procedure if it occurred during the 
procedure or is directly linked to 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 in the eCRF. All unresolved AEs should be followed by the 
investigator until resolution is reached.  
 
Note: Refer to Table 1 ‘Data Collection’ and Appendix D ‘Data Collection Method’. 
In 
case 
of 
EDC failure, 
notify 
Sponsor 
via 
fax 
(+800 
2546 
2546) 
or 
e-mail 
(AdverseEvent@sjm.com). 
6.8 Subject Death 
6.8.1 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 D ‘Data Collection Method’ 
In 
case 
of 
EDC failure, 
notify 
Sponsor 
via 
fax 
(+800 
2546 
2546) 
or 
e-mail 
(AdverseEvent@sjm.com). 
 
Subject Death is the outcome of a serious adverse event (SAE).  Death can therefore be 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. Prior 
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to sending such documentation, personal identifiers will be redacted and replaced by the study-
specific subject ID. 
 
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. 
6.9 Document and data control 
6.9.1 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. 
6.9.2 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 and signed 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. 
6.9.3 Review of data 
The clinical investigation will be monitored by reviewing the eCRF approved by the investigators.  
 
The following activities will occur: 
 
 
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. 
6.10 Monitoring  
Risk-based 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. 
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During the monitoring visits, data reported on the eCRF shall be reviewed as specified in the 
monitoring plan.  
6.10.1 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. 
6.10.2 Monitoring Plan 
Prior to the start of the site monitoring activities for this clinical investigation, a project specific 
Monitoring Plan (MP) will be created. 
 
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.  
6.11 Competent Authority (CA) Inspections 
The investigator and/or delegate should contact SJM immediately upon notification of a CA 
inspection at the site. A clinical representative 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. 
6.12 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.  
 
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The investigation will be terminated according to applicable regulations. 
 
At termination, the investigator shall return all documents to the sponsor, and notify the Ethics 
Committee and the Competent Authority (where applicable). Follow-up for all enrolled subjects 
will be continued as per standard of care. 
6.12.1 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 
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. 
6.12.2 Investigation Conclusion 
The investigation will be concluded when: 
 
 
A Close Out visit has been performed at each participating site AND 
 
The final report has been provided by the sponsor. 
 
7 
 Risks and Benefits of the clinical investigation 
7.1 Anticipated clinical benefits 
It is expected that subjects undergoing a renal denervation procedure with the EnligHTN Renal 
Denervation System will experience additional and sustainable blood pressure lowering effects 
compared to drug treatment alone. 
The information collected in this clinical investigation will be added to the current knowledge and 
understanding of treatment options for patients with uncontrolled hypertension.  
7.2 Anticipated Adverse Events and Adverse Device Effects 
Adverse events potentially associated with the use of the EnligHTN Renal Denervation System 
and their potential complications are documented in the Instructions for Use (IFU) which is 
available upon request. 
7.3 Steps that will be taken to control or mitigate the risks 
No additional risks above those known for the device are to be expected in this observational 
study. Following efforts to minimize risks will be taken: 
 
Regular clinical investigation monitoring visits with risk-based monitoring of collected 
patient data across all centers. 
 
Conduction of the clinical investigation in accordance with the Clinical Investigational 
Plan (CIP), all applicable laws and regulations and any conditions of approval imposed 
by the appropriate EC or applicable regulatory authorities where the clinical investigation 
is performed. 
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 
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 the EnligHTN Renal Denervation 
procedure. 
7.4 Risk-to-benefit rationale 
The risks associated with the EnligHTN Renal System are comparable to those associated with 
the use of other currently available renal denervation systems. Patients participating in this 
clinical investigation are indicated for a renal denervation procedure as part of their standard 
medical management and are subject to the risks associated with these devices. It is considered 
that renal denervation offers a better long-term prognosis which should fairly outweigh the 
potential risk associated with such procedure. 
 
 
 
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8 
Statistical considerations 
8.1 Study design 
This is a post market, prospective, observational study of the EnligHTN™ Renal Denervation 
System.  Approximately 500 subjects with uncontrolled hypertension will undergo renal artery 
ablation at approximately 50 investigational sites located in Europe and the Middle-East and will 
be followed up to 1 year post procedure.  
 
The primary objective is to evaluate a mean reduction of office Systolic Blood Pressure at 6 
months post renal denervation. 
8.2 Sample size estimation 
The sample size estimation is based on the primary objective of this study. The aim is to define 
a precise two sided 95% confidence interval with a half width of 2.35mmHg for the mean 
reduction of office SBP at 6 Months. Using estimates from the EnligHTN 1 study, the mean ±SD 
for reduction of office SBP at 6 Months was -26 ±24.7mmHg. In order to achieve the desired 
level of precision a total of 425 patients is needed. Assuming a 15% attrition rate the study will 
aim to enroll approximately 500 patients.  
8.3 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 
form, and had the EnligHTN™ Renal Denervation System enter his/her body. The sample size 
of 500 subjects refers to those subjects in the Primary Analysis population. 
 
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 been 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 who withdraw from the investigation will not be replaced in any analysis population. 
8.4 Data Analysis and Reporting 
Data analysis will be performed across all subjects, 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 (number of observations, mean, standard 
deviation, minimum and maximum values).  
Continuous primary and secondary outcomes between time points will be compared as follows: 
normality of data will be verified with the use of box plots and Kolmogorov-Smirnov normality 
tests. For normally distributed data, comparisons will be performed using paired t-tests. In cases 
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where the data is not normally distributed, the non parametric Wilcoxon-Signed-Rank test will be 
used to analyze the data. Results will be expressed in terms of p-values. 
Categorical data will be summarized using frequencies and percentages. 
8.4.1 Primary objective analysis 
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  
8.4.2 Secondary objectives analysis 
 
Acute (30 days post procedure) 
 
 
Safety 
The percentage of subjects with peri-procedural events within 30 days post 
procedure will be computed as follows:    
                                                                             
                                               
     
 
Performance 
The mean reduction in office Systolic and Diastolic Blood Pressure at 1 month and 
the mean reduction in ambulatory Systolic and Diastolic Blood Pressure at 1 month 
will be calculated in a similar way as described for the primary objective (Section 
8.4.1).The percentage of subjects achieving office Systolic Blood Pressure < 140 
mmHg at 1 month will be computed as follows: 
 
                                                       
                                                 
     
 
Mid to long term (6 and 12 months) 
 
 
Safety 
Renal function change based on  eGFR will be summarized by:  
 
1. Computing the change of the eGFR at 6 and 12 months, compared to baseline 
for each patient with data available at both time points. 
2. Calculating the mean and standard deviation of the eGFR change at those 
intervals 
 
Assessment of renovascular safety as measured by occurrence of new renal artery 
stenosis (> 50%) and aneurysm at the site of ablation per Renal Artery Imaging will 
be summarized at 6 months as a percentage of subjects who have stenosis (> 50 
%) or aneurysm.  
 
 
Performance 
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The mean reduction in office Systolic Blood Pressure at 12 months, the mean 
reduction in office Diastolic Blood Pressure at 6 and 12 months and the mean 
reduction in ambulatory Systolic and Diastolic Blood Pressure at 6 and 12 months 
post denervation will be calculated in a similar way as described for the primary 
objective (Section 8.4.1). 
Percentage of subjects achieving office Systolic Blood Pressure < 140 mmHg at 6 
and at 12 month will be computed as follows: 
 
                                                        
                                                  
     
                                                         
                                                   
     
 
8.4.3 Other Analyses  
Summary statistics for medications being used by subjects and changes to them will be 
presented for each follow-up visit. 
 
In addition, subgroup analyses may be performed as needed, e.g.: 
 
 
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) 
 
based on the number of ablation points performed 
 
by the subject’s primary disease conditions.   
 
Ad hoc analyses may be performed as needed.  Analysis may be performed based on As 
Treated population as deemed appropriate.  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. 
8.4.4 Analysis Software  
The statistical analyses will be performed using SAS™ software version 9.2, or as specified and 
appropriate.  
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9 
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. 
9.1 Data Management Plan 
eCRF data will be entered by authorized investigative site personnel in a validated electronic 
database using Oracle Clinical.  
 
The Data Management Plan (DMP) 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) when applicable 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. 
9.2 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.  
9.3 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, which will be kept on the site, the available demographic and 
medical information of a subject shall be documented, in particular the following:  
 
Name 
Date of Birth 
Weight 
Gender 
Height 
Concomitant Medication 
Subject History 
Concomitant diseases 
Scheduled follow ups 
PIC process  
Date of PIC 
Observed AEs 
CIP required examinations 
Clinical findings 
Procedure Notes 
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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 be part of the subject’s source data. 
 
9.4 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 SJM 
International, Inc. and its affiliates, 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: 
 
 
Monitoring the accuracy and completeness of the study 
 
Performing scientific analysis and developing the medical product  
 
And/or obtaining 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, address, and 
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Page 41 of 60 
hospital number) and only be identifiable by a study-specific subject 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, the European 
Economic Area 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. 
10 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.  
11 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 the Coordinating 
Investigators.  
 
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. 
 
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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. This information will be incorporated when an amendment occurs. 
12 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 such a 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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13 Investigation Organization 
13.1 Investigation Management / Sponsor 
The organization, which takes responsibility for the initiation and/or implementation and 
coordination for the investigation is SJM International, Inc., with offices located at: 
 
SJM International, Inc. 
Corporate Village, Building Figueras 
Da Vincilaan 11, Box F1 
B-1935 Zaventem 
Belgium 
Tel: +32 2 774 69 37 
Fax: +32 2 774 69 46 
 
As defined in the Power of Attorney (PoA), SJM International will delegate responsibilities to the 
local SJM clinical entity in each participating country or region.  
 
Sponsor Responsibilities 
Sponsor’s responsibilities are in accordance with applicable guidelines, covering the design, 
overall conduct, analysis and reporting of the results of the study. This includes but is not limited 
to the following activities: 
 
 
Perform those actions necessary to protect the rights of subjects and the scientific 
credibility of the manner in which this study is conducted; 
 
Select 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;  
 
Develop the study database; 
 
Train 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 (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); 
 
Review the investigator´s assessment of all adverse events and determine and 
document in writing their seriousness and relationship to the investigational device; 
 
Report or ensure reporting of all serious adverse events to the EC by the Principal 
Investigator(s), if required by the EC, by national regulations or by the CIP; 
 
Report all serious adverse events to regulatory authorities within the required time 
period, if required by national regulations or by the CIP; 
 
Maintain an updated list of principal investigators, investigational sites and institutions. 
This list shall be available upon request; 
 
Design revision controlled CRFs and Patient Information Sheet / Patient Informed 
Consent form templates; 
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Page 44 of 60 
 
Obtain signed Study Agreements and completed Investigator Financial Disclosure 
information; 
 
Collect EC approval letters, including a copy of the approved information sheet and 
consent forms; 
 
Archive all correspondences relating to the conduct of this study between SJM and the 
study site, ECs, and Study Monitors; 
 
Collect CVs and professional licenses for all study personnel, if applicable; 
 
Obtain protocol/device related training records for all applicable study personnel; 
 
Collect site personnel signatures and documentation of the Investigator’s delegation of 
study related responsibilities; 
 
Collect a list of EC voting members; 
 
Provide insurance certificates. 
 
13.2 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. Provide signed and dated  CVs (for all members of the investigational team) and 
other relevant documentation, 
3. Be experienced in the field of application and have documented training of 
investigational device use under evaluation, 
4. Disclose potential conflicts of interest, including financial disclosure, 
5. Be knowledgeable in 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 well as other 
study specific agreements; 
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 
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; 
 
Conducting the clinical investigation in accordance with the signed agreement with St. 
Jude Medical, the Clinical 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; 
 
Assuring strict adherence to the CIP testing requirements to provide for optimal safety 
and efficacious use of the device under clinical investigation; 
 
Performing adequate safety reporting (including complete AE source documentation (e.g. 
to allow for accurate adjudication of events by the sponsor); 
 
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; 
 
Signing off the signature page for each final version of the clinical investigation plan 
(including 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 
Log (provided by Sponsor). The investigation is not transferable to other centers attended by the 
investigator unless prior approval is obtained from SJM. 
 
Clinical Coordinating Investigator (CCI) 
In addition to the responsibilities of the Principal Investigators, the Clinical Coordinating 
Investigator will: 
 
 
Sign off all final versions of the investigational plan; 
 
Act as main contact for all investigators in case of medical questions related to the 
conduct of the investigation. 
 
The following investigator has been appointed by the Sponsor as the Clinical Coordinating 
Investigator: 
 
Dr. José Diaz 
Hospital Juan Ramon Jimenez 
Ronda Norte 
21005 Huelva 
Spain 
Tel: +34 616 67 6095 
 
 
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13.3 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 Clinical Research 
Organization 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. 
13.3.1 Power of Attorney (POA) 
The POA delegates sponsor’s responsibility for specified tasks to the country entities, divisions 
or designees, 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 47 of 60 
14 Bibliography  
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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). 
 
47. Esler MD, Krum H, A Sobotka, P, et al for the Renal sympathetic denervation in patients with 
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treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized 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. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and 
Treatment of High Blood Pressure: Hypertension. 2003; 42: 1206–1252 
 
50. 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. 
 
51. 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. 
 
52. Worthley, S. et al. TCT-213 Safety And Efficacy Of A Novel Multi-Electrode Renal 
Denervation Catheter In Resistant Hypertension: 3 Month Data From The EnligHTN I Trial. 
Journal of the American College of Cardiology 60: 17 (suppl), B62 (2012). 
 
53. 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 
 
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Appendix A: Abbreviations 
 
Abbreviation 
Term 
ABP 
ACE-I 
ADE 
AE 
ARB 
ASADE 
BP 
CA 
CCI 
CIP 
CRA 
CRF 
CPRB 
CT 
CV 
DCC 
DMP 
EC 
eCRF 
EDC 
EEA 
eGFR 
ESC 
ESH 
ICMJE 
IFU 
Ir 
ISB 
ISO 
MDRD 
MP 
MR 
NYHA 
PI 
PIS 
PIC 
POA 
PTFE 
Pt 
RDC 
RF 
SADE 
SAE 
SBP 
SJM 
UADE 
Ambulatory Blood Pressure 
Angiotensin Converting Enzyme Inhibitor 
Adverse Device Effect 
Adverse Event 
Angiotensin II Receptor Blocker 
Anticipated Serious Adverse Device Effect 
Blood Pressure 
Competent Authority 
Clinical Coordinating Investigator 
Clinical Investigational Plan 
Clinical Research Associate 
Case Report Form 
Clinical Project Review Board 
Computed axial Tomography 
Curriculum vitae 
Data Cleaning Convention 
Data Management Plan 
Ethics Committee 
electronic Case Report Form 
Electronic Data Capture 
European Economic Area 
estimated Glomerular Filtration Rate 
European Society of Cardiology 
European Society of Hypertension 
International Committee of Medical Journal Editors 
Instructions For Use 
Iridium 
Investigator Site Binder 
International Organization for Standardization 
Modification of Diet in Renal Disease 
Monitoring Plan 
Magnetic Resonance 
New York Heart Association 
Principal Investigator 
Patient Information Sheet 
Patient Informed Consent 
Power of Attorney 
Polytetrafluoroethylene 
Platinum 
Remote Data Capture 
Radiofrequency 
Serious Adverse Device Effect 
Serious Adverse Event 
Systolic Blood Pressure 
St. Jude Medical 
Unanticipated Adverse Device Effect 
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USA 
USADE 
WMA 
United States of America 
Unanticipated Serious Adverse Device Effect 
World Medical Association 
 
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Appendix B: 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 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. 
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 be applied with 
consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt these 
principles.                                                                                                           
General Principles 
3. 
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.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
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 proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects 
and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must 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. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional. 
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13.  Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this 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.  
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. Medical 
research involving human subjects may only be conducted if the importance of the objective outweighs 
the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with foreseeable 
benefits to them and to other individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed. When the risks are 
found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, 
physicians must assess whether to continue, modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. All vulnerable groups and individuals should receive specifically 
considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. 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. 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified 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, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research study. In 
clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. 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 amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
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Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
Informed Consent                                                                                                              
25. Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual 
capable of giving informed consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 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, post-study provisions 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. All medical research subjects should be given the option of being 
informed about the general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised 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 
group represented by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent 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 authorised representative. The potential subject’s dissent should be respected. 
30. 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  group. In such circumstances the physician must 
seek informed consent from the legally authorised 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 must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their 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 adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best proven intervention(s), except in the following circumstances: Where no proven intervention exists, 
the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound 
methodological reasons the use of any intervention less effective than the best proven one, the use of 
placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the 
patients who receive any intervention less effective than the best proven one, placebo, or no intervention 
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will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention. Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial in 
the trial. This information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers 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. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication.  
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 
 
 
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Appendix C: Device Manual 
The EnligHTN RF ablation generator, the EnligHTN Renal Artery Ablation Catheter and the 
EnligHTN Guiding cathether (optional) will be used according to the Instructions For Use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D: Data Collection Method  
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 1:1.  
Source documents include all original records from which CRFs derive their data. All 
documentation pertaining to clinical assessments and medical evaluations should be signed and 
dated by the appropriate clinical personnel. 
 
Electronic Data Capture (EDC) will be used for this investigation, therefore, please find below 
instructions on how to access and use the eCRF application. 
 
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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