Global Clinical Study of Renal Denervation in the Distal Main and First Order Branch Renal Arteries Using the Symplicity Spyral™ Multi-electrode Renal Denervation System (SPYRAL DYSTAL)
Phase: NA
Conditions: Hypertension, Vascular Diseases, Cardiovascular Diseases
Sponsor: Medtronic Vascular

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Clinical Investigation Plan 
Title 
Global Clinical Study of Renal Denervation in the distal main and first 
order branch renal arteries using the Symplicity Spyral™ multi- 
electrode renal denervation system (SPYRAL DYSTAL) 
Product Name 
The Symplicity Spyral™ multi-electrode renal denervation catheter 
(Symplicity Spyral™ catheter) and the Symplicity G3™ renal 
denervation RF generator (Symplicity G3™ generator) 
Sponsor/ Funding Source 
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, CA United States 
Regional sponsor: 
Medtronic Bakken Research Center (BRC) B.V. 
Endepolsdomein 5 
6229 GW Maastricht, The Netherlands 
Document version 
5.0 – 14 Mar 2022 
NCT # 
NCT04311086 
Coordinating Investigators 
Prof. Dr. David Lee 
Stanford University Medical Center 
300 Pasteur Drive 
Stanford, California 94305 
US 
Prof. Dr. Andrew Sharp 
Department of Cardiology 
University Hospital of Wales 
Heath Park Way 
Cardiff, Wales 
CF14 4CX 
UK 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 

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Title Page .................................................................................................................................. 1 
Table of Contents ...................................................................................................................... 2 
1. 
Glossary.............................................................................................................................. 7 
2. 
Synopsis ............................................................................................................................. 9 
3. 
Introduction ..................................................................................................................... 17 
3.1. Background ........................................................................................................................ 17 
3.2. Purpose .............................................................................................................................. 21 
4. 
Objectives and Endpoints ................................................................................................ 22 
4.1. Objectives .......................................................................................................................... 22 
4.2. Endpoints ........................................................................................................................... 22 
4.2.1. 
Efficacy endpoints ................................................................................................................. 22 
4.2.2. 
Safety endpoints ................................................................................................................... 22 
4.2.3. 
Additional analysis ................................................................................................................ 23 
5. 
Study Design .................................................................................................................... 24 
5.1. Duration ............................................................................................................................. 25 
5.2. Rationale ............................................................................................................................ 25 
5.2.1. 
Rationale for duration of period off medications ................................................................. 25 
5.2.2. 
Rationale for comparator ...................................................................................................... 25 
6. 
Product Description ......................................................................................................... 27 
6.1. The Symplicity Spyral™ multi-electrode renal denervation system ............................................ 27 
6.2. The Symplicity Spyral™ Catheter .......................................................................................... 27 
6.3. Symplicity G3™ Generator ................................................................................................... 29 
6.4. Manufacturer ...................................................................................................................... 30 
6.5. Packaging ........................................................................................................................... 30 
6.6. Intended Population ............................................................................................................ 31 
6.7. Equipment .......................................................................................................................... 31 
6.8. Product Use ........................................................................................................................ 31 
6.9. Product Training Requirements ............................................................................................. 33 
6.10. 
Product Receipt and Tracking ......................................................................................... 33 
6.11. 
Product Storage............................................................................................................. 34 
6.12. 
Product Return .............................................................................................................. 34 
7. 
Ethics ................................................................................................................................ 36 
7.1. Statement(s) of Compliance ................................................................................................. 36 
7.1.1. 
Ethics Committee/Institutional Review Board Approval ...................................................... 37 
7.1.2. 
Regulatory Submission .......................................................................................................... 38 
8. 
Selection of Subjects ........................................................................................................ 39 
Table of Contents 

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8.1. Study Population ................................................................................................................. 39 
8.2. Subject Enrollment .............................................................................................................. 39 
8.3. Inclusion Criteria ................................................................................................................. 39 
8.4. Exclusion Criteria ................................................................................................................. 40 
8.5. Subject Consent .................................................................................................................. 42 
8.5.1. 
Revisions in the Patient Information and Informed Consent form ....................................... 42 
9. 
Study Procedures ............................................................................................................. 44 
9.1. Schedule of Events .............................................................................................................. 44 
9.1.1. 
Screening Visit 1 .................................................................................................................... 44 
9.1.2. 
Medication Washout Period ................................................................................................. 45 
9.1.3. 
Two Week Screening Visit ..................................................................................................... 45 
9.1.4. 
Screening Visit 2 .................................................................................................................... 45 
9.1.5. 
Procedure Visit ...................................................................................................................... 47 
9.1.6. 
Follow-up Visits ..................................................................................................................... 49 
9.1.7. 
Unscheduled Follow-up Visits ............................................................................................... 52 
9.1.8. 
Confirmatory Blood Draws to Assess Renal Function ........................................................... 52 
9.1.9. 
Anti-hypertensive medication escape criteria ...................................................................... 52 
9.1.10. Medication Re-Introduction for Subjects with 3M Systolic OBP ≥ 140 mmHg ................... 53 
9.2. Assessment of Safety .......................................................................................................... 56 
9.3. Recording Data ................................................................................................................... 56 
9.3.1. 
Database/Case Report Forms ............................................................................................... 56 
9.3.2. 
Blood Pressure Monitors ....................................................................................................... 57 
9.4. Deviation Handling .............................................................................................................. 57 
9.5. Reporting Requirements ...................................................................................................... 59 
9.5.1. 
Investigator Reporting Responsibilities ................................................................................. 59 
9.5.2. 
Sponsor Reporting Responsibilities ....................................................................................... 60 
9.6. Subject Withdrawal or Discontinuation .................................................................................. 62 
9.6.1. 
Subject Exit from Study ......................................................................................................... 62 
9.6.2. 
Missed Follow-up Visits ......................................................................................................... 63 
10. Risks and Benefits ............................................................................................................ 64 
10.1. 
Potential Risks ............................................................................................................... 64 
10.2. 
Potential Benefits ........................................................................................................... 67 
10.3. 
Risk-Benefit Rationale .................................................................................................... 68 
11. Adverse Events and Device Deficiencies .......................................................................... 70 
11.1. 
Definitions/Classifications ............................................................................................... 70 
11.2. 
Reporting of Adverse Events and Device Deficiencies ........................................................ 73 
11.2.1. Reporting Process .................................................................................................................. 74 
11.2.2. Non-reportable and Unavoidable Adverse Events ................................................................ 75 
11.2.3. Unanticipated Adverse Device Effect .................................................................................... 76 

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11.2.4. Device Deficiencies ................................................................................................................ 76 
11.2.5. Product Complaint Reporting ................................................................................................ 77 
11.2.6. Emergency Contact ............................................................................................................... 77 
12. Data Review Committees ................................................................................................. 78 
12.1. 
Clinical Event Committee ................................................................................................ 78 
12.2. 
Data Safety Monitoring Board ......................................................................................... 78 
12.3. 
Study Coordinating Investigators ..................................................................................... 78 
13. Statistical Design and Methods ........................................................................................ 79 
13.1. 
General Methods ........................................................................................................... 79 
13.2. 
Analysis Sets ................................................................................................................. 79 
13.2.1. Intention-To-Treat Population .............................................................................................. 79 
13.2.2. Modified Intention-To-Treat Population ............................................................................... 79 
13.2.3. Per Protocol Population ........................................................................................................ 79 
13.3. 
Sample Size Justification ................................................................................................ 80 
13.4. 
Efficacy Endpoints – Propensity Score Adjustment ............................................................ 80 
13.5. 
Safety Endpoint Analysis ................................................................................................ 81 
13.6. 
Analysis of Baseline Characteristics .................................................................................. 81 
13.7. 
Missing Data ................................................................................................................. 81 
14. Study Administration ....................................................................................................... 82 
14.1. 
Monitoring .................................................................................................................... 82 
14.2. 
Data Management ......................................................................................................... 83 
14.2.1. Electronic Data Capture ........................................................................................................ 83 
14.2.2. Source data on Case Report Forms ....................................................................................... 84 
14.2.3. Time windows for completion and submission of Case Report Forms ................................. 84 
14.2.4. Data review and processing .................................................................................................. 84 
14.3. 
Direct Access to Source Data/Documents ......................................................................... 84 
14.3.1. Accessibility of investigational site staff and study materials ............................................... 84 
14.3.2. Audits and investigation site inspections .............................................................................. 84 
14.4. 
Confidentiality ............................................................................................................... 85 
14.5. 
Liability ......................................................................................................................... 85 
14.5.1. Insurance ............................................................................................................................... 85 
14.5.2. Subject compensation and indemnification ......................................................................... 85 
14.6. 
Clinical Investigation Plan Amendments ........................................................................... 86 
14.7. 
Record Retention ........................................................................................................... 86 
14.7.1. Investigator Records .............................................................................................................. 86 
14.7.2. Sponsor Records .................................................................................................................... 87 
14.7.3. Source Documents ................................................................................................................ 88 
14.8. 
Publication and Use of Information .................................................................................. 89 
14.9. 
Suspension or Early Termination ..................................................................................... 90 

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14.9.1. Study-wide termination or suspension ................................................................................. 90 
14.9.2. Investigator/study site termination or suspension ............................................................... 91 
14.9.3. Procedures for planned study closure, termination, or suspension ..................................... 91 
14.10. 
Role of Sponsor Representatives ..................................................................................... 92 
14.11. 
Site Selection ................................................................................................................ 93 
14.12. 
Site Activation ............................................................................................................... 94 
14.12.1. Curriculum Vitae.................................................................................................................... 96 
14.12.2. Clinical Trial Agreement ........................................................................................................ 96 
15. References ....................................................................................................................... 97 
16. Appendices ....................................................................................................................... 99 
16.1. 
Contact Information ....................................................................................................... 99 
16.1.1. Coordinating Investigators .................................................................................................... 99 
16.1.2. Other contacts ....................................................................................................................... 99 
16.1.3. List of participating investigational sites and investigators ................................................ 101 
16.2. 
Case Report Forms ...................................................................................................... 101 
16.3. 
Sample Investigator Agreement .................................................................................... 101 
16.4. 
Event Definitions ......................................................................................................... 101 
16.5. 
Blood Pressure Measurement Procedures ....................................................................... 105 
16.5.1. Office Blood Pressure .......................................................................................................... 105 
16.5.2. Orthostatic Hypotension Evaluation (SV2 ONLY) ................................................................ 107 
16.5.3. Ambulatory Blood Pressure Monitoring ............................................................................. 107 
17. Version History ............................................................................................................... 109 
 
Table of Tables 
Table 1: Schedule of Treatments and Assessments .................................................................................... 15 
Table 2: Schedule of testing through 12 months for subjects with office SBP ≥180 mmHg (confirmed via 
2 sets of measurements) or escape via investigator discretion during off-medication period post- 
procedure .................................................................................................................................................... 16 
Table 3: Schedule of Treatments and Assessments .................................................................................... 54 
Table 4: Schedule of testing through 12 months for subjects with office SBP ≥180 mmHg (confirmed via 
2 sets of measurements) or escape via investigator discretion during off-medication period post- 
procedure .................................................................................................................................................... 55 
Table 5: Scenarios for Subject Exit from Study ........................................................................................... 62 
Table 6: Required Timeframes for Adverse Event and Device Deficiency reporting from Investigator to 
Medtronic ................................................................................................................................................... 73 
Table 7: Sponsor Adverse Events Reporting Requirements to National Competent Authority in EU/EEA 74 
Table 8: Adverse Event Classification Responsibilities ................................................................................ 75 

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Table 9: Unavoidable Adverse Events ......................................................................................................... 76 
Table 10: Other Contacts ............................................................................................................................ 99 
Table 11: BP Cuff Size Chart ...................................................................................................................... 106 
 
 
Table of Figures 
Figure 1: Spiral Configuration of Four Gold Electrodes ............................................................................... 28 
Figure 2: Overview of Symplicity Spyral™ Catheter .................................................................................... 28 
Figure 3: Symplicity G3™ Generator ........................................................................................................... 29 
Figure 4: RF on Screen ................................................................................................................................. 30 
Figure 5: Illustration of peri-arterial renal nerve location .......................................................................... 32 
Figure 6: Illustration of renal artery anatomy ............................................................................................. 32 
Figure 7: Schematic representation of positioning of Symplicity Spyral catheter. ..................................... 48 

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Term 
Definition 
1M, 3M, 4M, 6M, 12M 
1-month, etc. used with follow-up visit windows 
2 wk, 6 wk, 8 wk, 10 wk 
2-week, etc. used with follow-up visit windows 
ABPM 
ambulatory blood pressure monitoring 
ADE 
adverse device effect 
AE 
adverse event 
AH 
antihypertensive 
BP 
blood pressure 
CEC 
clinical events committee 
CIN 
contrast-induced nephropathy 
CIP 
clinical investigation plan 
CKD 
chronic kidney disease 
CRF 
case report form 
CTA 
clinical trial agreement 
DC 
discharge 
DD 
device deficiency 
DUS 
duplex ultrasound 
eGFR 
estimated glomerular filtration rate 
EC 
ethics committee 
EDC 
electronic data capture 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
FMD 
fibromuscular dysplasia 
GCP 
good clinical practice 
IC 
informed consent 
IFU 
instructions for use 
IRB 
institutional review board 
ITT 
intention-to-treat 
1. Glossary 

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Term 
Definition 
MRA 
magnetic resonance angiography 
OBP 
office blood pressure 
RDC 
remote data capture 
RDN 
renal denervation 
RF 
radiofrequency 
RX 
rapid exchange 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SIV 
site initiation visit 
SNS 
sympathetic nervous system 
SV1, SV2 
Screening Visit 1, Screening Visit 2 
UADE 
unanticipated adverse device effect 

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Title 
Global Clinical Study of Renal Denervation in the distal main and first order 
branch renal arteries using the Symplicity Spyral™ multi-electrode renal 
denervation system (SPYRAL DYSTAL) 
Clinical Study Type 
Multi-center, international, prospective, interventional, single arm study 
Product Name 
The Symplicity Spyral™ multi-electrode renal denervation catheter 
(Symplicity Spyral™ catheter) and the Symplicity G3™ renal denervation RF 
generator (Symplicity G3™ generator) 
EUDAMED number 
CIV-19-12-031165 
Sponsor 
Global sponsor: 
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, CA United States 
Regional sponsor: 
Medtronic Bakken Research Center (BRC) B.V. 
Endepolsdomein 5 
6229 GW Maastricht, The Netherlands 
Note: this clinical study is funded by the Global sponsor. 
Objective 
The objective of this single arm interventional study is to determine if renal 
denervation performed in the distal main and first order branch renal 
arteries is as effective in reducing blood pressure as the procedural approach 
used in the SPYRAL HTN-OFF MED clinical study. 
Product Status 
Investigational in the United States. Commercially approved in countries that 
accept CE-mark. (Device will be used in accordance with the Instructions for 
Use.) 
Endpoints 
Efficacy endpoints 
The efficacy endpoints will be compared to the SPYRAL HTN-OFF MED 
efficacy endpoints using a propensity score stratified analysis at 3 months. 
At 6 months and 12 months, the endpoints will be analyzed within the 
SPYRAL DYSTAL study only. 
• Change in systolic blood pressure (SBP) from baseline (Screening Visit 2) 
to 3, 6 and 12 months post-procedure as measured by 24-hour ambulatory 
blood pressure monitoring (ABPM). 
2. Synopsis 

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• Change in office SBP from baseline (Screening Visit 2) to 3, 6, and 12 
months post-procedure. 
• Change in diastolic blood pressure (DBP) from baseline (Screening Visit 2) 
to 3, 6, and 12 months post-procedure as measured by 24-hour ABPM. 
• Change in office DBP from baseline (Screening Visit 2) to 3, 6, and 12 
months post-procedure. 
• Incidence of achieving target office SBP (SBP<140 mmHg) at 3, 6, and 12 
months post-procedure. 
• Comparison of the pattern of BP reduction over 24 hours of ABPM 
between this study and the SPYRAL HTN-OFF MED study. 
Safety endpoints 
• Safety composite at 1, 3, 6 and 12-months post-procedure: 
Incidence of the following events: 
- All-cause mortality 
- End-stage renal disease (ESRD) 
- Significant embolic event resulting in end-organ damage 
- Renal artery perforation requiring intervention 
- Renal artery dissection requiring intervention 
- Vascular complications 
- Hospitalization for hypertensive crisis not related to confirmed 
non-adherence with medications or the protocol 
- New renal artery stenosis >70%, confirmed by angiography and as 
determined by the angiographic core lab at 6 months follow up 
• Myocardial infarction 
• Stroke 
• Renal artery re-intervention 
• Major bleeding according to TIMI definition (i.e., intracranial hemorrhage, 
≥5 g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease 
in hematocrit, or death due to bleeding within seven days of the 
procedure) 
• Increase in serum creatinine >50% from Screening Visit 2 
The following additional analyses will be conducted: 
• Procedural characteristics 
Study Design 
Multi-center, international, prospective, interventional, single arm study 
treating approximately 50 subjects who will undergo the renal denervation 
procedure. 

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Study Population 
Subjects with uncontrolled hypertension will be enrolled in accordance with 
the inclusion and exclusion criteria specified in the protocol. Approximately 
350 subjects will be enrolled in order to treat approximately 50 subjects at 
up to 15 study centers. 
Study Duration 
Total study duration will be approximately 2.5 years, including enrollment up 
to minimally 12 months follow up (subjects will be consented for a maximum 
follow up of 5 years in case there are reasons that would require the follow 
up to be extended beyond the currently planned 12 months follow up). 
Inclusion Criteria 
1. Individual is ≥20 and ≤80 years old at time of enrollment (consent). 
2. Individual has an office systolic blood pressure (SBP) ≥ 150 mmHg and 
<180 mmHg and an office diastolic blood pressure (DBP) ≥90 mmHg 
measured at Screening Visit 2, according to the guidelines in Appendix 
16.5. 
3. Individual has a valid 24-hour ABPM average SBP ≥140 mmHg and 
<170 mmHg measured at Screening Visit 2, according to guidelines in 
Appendix 16.5. 
ABPM is considered valid if the number of successful daytime readings 
captured is ≥ 21 and the number of successful nighttime readings 
captured ≥12. 
4. Individual agrees to have all study procedures performed, and is 
competent and willing to provide written, informed consent to 
participate in this clinical study. 
5. Individual is willing to discontinue current antihypertensive 
medications at Screening Visit 1 through the 3-month post-procedure 
visit. 
Exclusion Criteria 
1. Individual has one or more of the following conditions: stable or 
unstable angina within three months of enrollment, myocardial 
infarction within three months of enrollment; heart failure, 
cerebrovascular accident or transient ischemic attack, or atrial 
fibrillation at any time. Subjects are permitted to take aspirin or 
clopidogrel for cardiovascular risk reduction. Subjects who received 
catheter or surgical treatment for atrial fibrillation and are in sinus 
rhythm are not excluded. 
2. Individual has undergone prior renal denervation. 
3. Individual has at least one main renal artery with a diameter of less 
than 3 mm or greater than 8 mm. 

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4. Individual has presence of FMD (defined as visible beading of the 
artery on angiography). 
5. Individual has >50% stenosis in any treatable vessel. 
6. Individual has a renal artery stent placed <3 months prior to the 
denervation procedure. 
7. Individual has presence of a renal artery aneurysm defined as any 
localized increase in the diameter of the vessel. 
8. Individual has disease not allowing any treatment in the main renal 
artery. 
9. Individual has an estimated glomerular filtration rate (eGFR) of <45 
mL/min/1.73m2, using the 4-variable MDRD calculation (in mL/min per 
1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if subject is black) x 
0.742 (if female)). 
10. Individual has documented type 1 diabetes mellitus or poorly- 
controlled type 2 diabetes mellitus with glycosylated hemoglobin 
greater than 8.0%. (If the glycosylated hemoglobin in the subject’s 
records is >3 months old (from the date of Screening Visit 2), or history 
of uncontrolled blood sugars raises concern, it is required to analyze 
glycosylated hemoglobin as part of Screening Visit 2 labs). 
11. Individual is taking SGLT2 inhibitor or GLP-1 agonists that have 
been prescribed <90 days prior to Screening Visit 1 or does not plan on 
remaining on these drugs for the duration of the trial. 
12. Individual has had ³1 episode(s) of orthostatic hypotension not 
related to medication changes within the past year or has had a 
reduction of SBP ≥20 mmHg or DBP ≥10 mmHg within three minutes of 
standing coupled with symptoms during the screening process (at 
SV2). 
13. Individual requires chronic oxygen support or mechanical 
ventilation other than nocturnal respiratory support for sleep apnea 
(e.g., CPAP, BiPAP). 
14. Individual with a history of narcotic drug abuse, is currently on 
methadone, or who has used narcotic drugs more than once in the 
month prior to Screening Visit 1. 
15. Individual had documented primary pulmonary hypertension. 

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16. Individual has untreated secondary cause of hypertension (either 
known or suspected) or is taking drugs that increase sympathetic tone 
that could contribute to hypertension. 
17. Individual has frequent intermittent or chronic pain that results in 
treatment with non-steroidal anti-inflammatory drugs (NSAIDs) for 
two or more days per week over the month prior to Screening Visit 2. 
18. Individual with HIV on anti-retroviral drug therapy without 
documentation that hypertension preceded initiation of anti-retroviral 
drug treatment. 
19. Individual has a scheduled or planned surgery that, in the opinion 
of the Investigator, may affect study endpoints. 
20. Individual has a documented condition that would prohibit or 
interfere with ability to obtain an accurate blood pressure 
measurement using the protocol-specified automatic/office blood 
pressure monitor (e.g., upper arm circumference outside cuff size 
ranges available by geography or arrhythmia such as atrial fibrillation 
that interferes with automatic monitor’s pulse sensing and prohibits 
an accurate measurement). 
21. Individual works night shifts. 
22. Individual has severe cardiac valve stenosis for which, in the 
opinion of the investigator, a significant reduction of blood pressure is 
contraindicated. 
23. Individual has a documented confounding medical condition, which 
in the opinion of the investigator, may adversely affect the safety of 
the participant (e.g., has clinically significant peripheral vascular 
disease, aortic aneurysm, bleeding disorders such as 
thrombocytopenia, hemophilia, or significant anemia). 
24. Individual is pregnant, nursing or planning to become pregnant 
during the course of the study follow up. (Note: Pre-menopausal 
female participants must have a negative serum or urine human 
chorionic gonadotropin (hCG) pregnancy test prior to angiography). 
25. Individual has a known unresolved history of drug use or alcohol 
dependency, lacks the ability to comprehend or follow instructions, or 
would be unlikely or unable, in the opinion of the investigator, to 
comply with study follow-up requirements. 

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26. Individual is currently enrolled in a concurrent investigational drug 
or device study, unless approved by the study sponsor. (Note: For the 
purpose of this protocol, participants involved in extended follow-up 
studies for products that were investigational but are currently 
commercially available are not considered enrolled in an 
investigational study). 
27. Individual is currently taking anti-mineralocorticoid drugs. (Note: 
Subjects may be enrolled as long as anti-mineralocorticoid drugs are 
weaned off at least 8 weeks prior to Screening Visit 1). 
28. Individual has an active peptic ulcer or gastrointestinal (GI) 
bleeding within the prior six months from consent. 
29. Individual has a history of bleeding diathesis or coagulopathy or will 
refuse blood transfusions. 
30. Individual has polycystic kidney disease, unilateral kidney, atrophic 
kidney, or history of renal transplant. 
Follow up 
Subjects will be followed up for a minimum of 12 months post-procedure 
(Subjects will be consented for a maximum of 5 years follow up). 

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Table 1: Schedule of Treatments and Assessments 
 
Screening 
Procedure 
Post-procedure follow up 
Required Assessments 
SV1 
2Wk 
SV2 
Proced 
ure 
DC 
2Wk 
1M 
6Wk 
8Wk 
10Wk 
3M 
4M1 
6M 
12M 
Mode (O- in office, P-phone) 
O 
O 
O 
O 
O 
P2 
P2 
P2 
O 
O 
O 
O 
Window (M-month, Wk-week, d-days) 
-- 
±3 d 
-- 
±3 d 
±7 d 
±3 d 
±7 d 
±3 d 
±14 d 
±7 d 
±14 d 
±30 d 
Medical history 
X 
Clinical assessment 
X 
X 
X 
X 
X 
X8 
X8 
X8 
Renal denervation procedure 
X 
OBP per study guidelines 
X 
X 
X 
X 
X 
X 
X4 
X4 
X4 
X 
X 
X 
X 
24h ABPM per study guidelines 
X 
X 
X 
X 
Witnessed pill intake3 
X 
X 
Medications prescribed1 
X1 
Blood tests (Chem7)4 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancy test 
X 
Drug testing 
X 
X 
Renal artery imaging– angiogram 
X 
Renal artery imaging-DUS5 
X 
Mortality assessment6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication and event review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
1: 4M follow-up is only required if 3M systolic OBP≥140 mmHg, prescribe AH medications according to section 9.1.9 if SBP ≥ 140 mmHg 
2: If medically necessary, phone contact may be replaced with office visit. OBP (per Appendix 16.5) to be obtained for an office visit or following alternative methods of data collection as described in section 9.1.6. 
3: Witnessed pill intake (if subject is taking AH medications), complete after OBP measurements 
4: Bicarbonate will not be measured for subjects enrolled in Europe. 
5: DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CT or angiogram to be used if DUS is nondiagnostic. Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic or stenosis >60- 
70% is suspected. If renal imaging is not captured at the 6M follow-up visit due to extenuating circumstances, renal imaging is required at the next scheduled study visit. 
6: Mortality assessment will be completed by the investigational site when a subject cannot be reached after each of the protocol required follow-up visits 
7: SAE only review required at 12M visit 
8: Clinical assessment of weight only 
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Table 2: Schedule of testing through 12 months for subjects with office SBP ≥180 mmHg (confirmed via 2 sets of measurements) or 
escape via investigator discretion during off-medication period post-procedure 
 
Procedure 
Post-Procedure 
Required Assessments 
Procedure 
DC 
2Wk 
1M 
6Wk 
10Wk 
3M 
6M 
12M 
Mode (O- in office, P-phone) 
O 
O 
O 
O 
O 
O 
O 
Window (M-month, Wk-week, d-days) 
-- 
-- 
± 3 d 
±7 d 
± 3 d 
± 3 d 
± 14 d 
± 14 d 
± 30 d 
OBP per study guidelines 
X 
X 
X 
X 
X 
X 
X 
X 
Renal artery imaging1 
X1 
Mortality assessment2 
X 
X 
X 
X 
X 
X 
X 
Medication and event review 
X 
X 
X 
X 
X 
X 
X 
X3 
1: DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CT or angiogram to be used if DUS is nondiagnostic. Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic 
or stenosis >60-70% is suspected. If renal imaging is not captured at the 6M follow-up visit due to extenuating circumstances, renal imaging is required at the next scheduled study visit. 
2: Mortality assessment will be completed by the investigational site when a subject cannot be reached after each of the protocol required follow-up visits 
3: SAE only review required at 12M visit 
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3.1. 
Background 
Chronic activation of the sympathetic nervous system (SNS) has been identified by preclinical and clinical 
literature as a common and key factor in disease states such as hypertension, heart failure, and chronic 
kidney disease.1-3 The renal sympathetic nerves are a major contributor to the complex pathophysiology 
of elevated SNS activity and hypertension. Therapeutic renal denervation, the deliberate disruption of the 
sympathetic nerves connecting the kidneys with the central nervous system, has been shown to be an 
effective means of modulating elevated SNS activity - both by reducing the sympathetic control of renal 
function (renin release, sodium excretion and renal blood flow) and by removing the renal afferent 
sympathetic contribution to central sympathetic elevation.4 It is important to note that the kidneys 
maintain appropriate electrolyte and volume homeostasis, despite being denervated, as demonstrated 
by the human kidney transplant experience.5 Prior to pharmacological treatment, hypertension was 
sometimes treated with complex invasive procedures, such as surgical nephrectomy and even radical 
surgical sympathectomy. 
 
Medtronic has developed a radiofrequency catheter with multiple electrodes, as a minimally invasive 
means of achieving renal sympathetic denervation. Bilateral renal denervation will be performed using a 
percutaneous, catheter-based system that delivers radiofrequency (RF) energy through the luminal 
surface of each renal artery at four locations simultaneously. In comparison to the previous single- 
electrode Symplicity™ renal denervation system, the multi-electrode catheter provides the physician with 
a pre-defined and consistent ablation pattern that is intended to improve the accuracy of treatment. The 
RF energy may be delivered to up to 4 electrodes simultaneously. If the physician elects to complete 
multiple treatments in one artery, subsequent treatments are easily accommodated by re-positioning the 
catheter proximally (at least 5 mm) and de-selecting electrodes via the graphical user interface on the 
Symplicity G3 generator. The electrodes are mounted on to a self-expanding Nitinol shaft that takes a 
spiral configuration allowing electrode contact with the vessel wall. An evaluation of the results of pre- 
clinical (in-vivo) and in-vitro testing supporting the use of the Symplicity Spyral catheter and Symplicity G3 
generator as investigational devices in human subjects is included in the Investigator’s Brochure. 
Medtronic has performed a comprehensive set of bench testing and preclinical studies that have shown 
that this manner of low-power ablation produces distinct, focal, sterile lesions that subsequently heal, 
resulting in no clinically relevant long-term sequelae to either the vessel or the kidney. 
 
The currently ongoing SPYRAL PIVOTAL – SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED studies are 
multi-center, international, single blind, randomized, sham-controlled studies designed to evaluate the 
effect of renal denervation on blood pressure. The SPYRAL PIVOTAL – SPYRAL HTN-OFF MED study is 
evaluating the effect of renal denervation in the absence of antihypertensive medications, whereas the 
SPYRAL HTN-ON MED study is evaluating the effect of renal denervation on standard medical therapy. 
3. Introduction 

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Preliminary data on the first 80 randomized subjects with three months follow up within the SPYRAL HTN- 
OFF MED study were published in August 2017 in The Lancet.6 The mean difference between the groups 
favored renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h 
SBP –5·0 mm Hg (95% CI –9·9 to –0·2; p=0·0414), 24-h DBP –4·4 mm Hg (–7·2 to –1·6; p=0·0024), office 
SBP –7·7 mm Hg (–14·0 to –1·5; p=0·0155), and office DBP –4·9 mm Hg (–8·5 to –1·4; p=0·0077). Baseline- 
adjusted analyses showed similar findings. There were no major adverse events in either group. 
Additionally, preliminary data on the first 80 randomized SPYRAL HTN-ON MED subjects with six months 
follow-up were published in May 2018 in The Lancet.7 Office and 24-h ambulatory blood pressure 
decreased significantly from baseline to six months in the renal denervation group: 24-h SBP –7·0 mm Hg, 
95% CI –12·0 to –2·1; p=0·0059, 24-h DBP –4·3 mm Hg, –7·8 to –0·8; p=0.0174, office SBP –6·6 mm Hg, – 
12·4 to –0·9; p=0·0250, and office DBP –4·2 mm Hg, –7·7 to –0·7; p=0·0190). The change in blood pressure 
was significantly greater at six months in the renal denervation group than the sham-control group for 
office SBP (difference –6·8 mm Hg, 95% CI –12·5 to –1·1; p=0·0205), 24-h SBP (difference –7·4 mm Hg, – 
12·5 to –2·3; p=0·0051), office DBP (difference –3·5 mm Hg, –7·0 to –0·0; p=0·0478), and 24-h DBP 
(difference –4·1 mm Hg, –7·8 to –0·4; p=0·0292). 
 
These initial results from both studies provided biological proof of principle for the blood-pressure- 
lowering efficacy of renal denervation. The safety profile within these published cohorts showed no major 
adverse events. 
 
In order to test the hypothesis in the SPYRAL PIVOTAL - SPYRAL HTN-OFF MED study that renal denervation 
decreases blood pressure and is safe when studied in the absence of antihypertensive medications, study 
subjects were randomized to the Denervation or Control group in a 1:1 fashion. In addition to subjects 
being blinded to their randomization assignment, site personnel involved in the measurement of office 
blood pressure were also blinded to study subjects’ randomization assignment through the primary 
endpoint to prevent potential bias of results. Subjects were studied in the absence of antihypertensive 
medications to assess the impact of renal denervation on systolic blood pressure in the absence of 
medication. 
 
Study enrollment was stopped for efficacy after the first interim analysis in February 2020. Data from the 
initial 80 patients with three months follow up from the SPYRAL HTN-OFF MED study was combined with 
data from the initial 251 patients with three months follow up from the SPYRAL PIVOTAL-SPYRAL HTN- 
OFF MED study and was presented at ACC World Congress of Cardiology in March 2020. Concurrently, an 
article presenting the data was published in The Lancet. A brief summary of the SPYRAL PIVOTAL-SPYRAL 
HTN-OFF MED data is provided below. 
 
The primary endpoint, change in 24-h blood pressure at three months, was compared between groups. 
Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. 
The primary analysis was done in the intention-to-treat population. Safety events were assessed to three 
months. 

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From June 25, 2015, to Oct 15, 2019, 1519 patients were enrolled, of whom 1188 were excluded because 
they did not meet inclusion criteria. 166 were randomly assigned to renal denervation and 165 to the 
sham procedure (80 were included in the pilot and 251 in Pivotal). 
 
There were no major safety events reported at one month. There was one major safety event in each 
treatment group up to three months (one admission to hospital for hypertensive crisis or emergency in 
the renal denervation group and one new stroke in the sham procedure group), and neither was 
attributed to the device or trial procedures. 
 
For the primary efficacy endpoint of changes from baseline in 24-h systolic blood pressure at three 
months, there was a significant difference between the renal denervation and sham procedure groups. 
This endpoint was met with a posterior probability of superiority greater than 0.999 and a treatment 
difference of -3.9 mm Hg (95% BCI -6.2 to -1.6). For the secondary efficacy endpoint of difference in three- 
month changes in office systolic blood pressure between the two groups, the difference was significant, 
and the endpoint was met (difference -6.5 mm Hg (95% BCI -9.6 to -3.5), with posterior probability of 
superiority of more than 0.999. The blood pressure changes analyzed using the prespecified ANCOVA- 
adjusted frequentist analysis of the overall population show similar changes in blood pressure to Bayesian 
results. 
 
Besides the “confounding factors” analysis of SYMPLICITY HTN-38 indicating that the blood pressure 
response to renal denervation may depend on the number of lesions applied, few studies have shown a 
strong relationship between the number of lesions delivered and subsequent blood pressure reduction. 
These new results indicate that the location of the lesion, i.e., the distal main and branches, may be an 
important factor in blood pressure reduction. 
 
Both SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials used the same RDN technique, applying 
treatments in eligible renal arteries and the branches, and presented similar results in three and six 
months follow-up, respectively. In the SPYRAL HTN-OFF MED6 trial, on average 17.9 ± 10.5 ablations were 
performed in the main renal arteries, and an additional 25.9 ± 12.8 ablations were performed in branch 
vessels. 
 
Recently Petrov and colleagues9 evaluated renal denervation therapy beyond the proximal main renal 
artery (Y-pattern), including the primary branches, and compared it to the standard procedure applied 
only within the main vessel. In 80 patients treated with the standard ablation using the first generation 
Symplicity “Flex” catheter, 12.0± 3.0 total ablations (both sides) were applied while 20.4±3.9 total 
ablations were delivered for the group of 39 patients with Y-pattern denervation (P < 0.001). Renal 
denervation was associated with significant decreases in both office and ambulatory systolic and diastolic 
blood pressure in both groups. The reduction in 24-hour mean ambulatory systolic blood pressure at six 
months was significantly greater (P = 0.002) for the Y-Pattern group (−22.1 ± 15.4 mm Hg) compared to 
the Standard group (−11.8 ± 16.2 mm Hg). Changes in diastolic office and ambulatory pressure were also 

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significantly greater at six months in the Y-pattern ablation group. These findings support the benefit of 
improved blood pressure reduction by including denervation of nerves in the renal artery branch vessels. 
 
Similarly, Pekarskiy and colleagues10 compared renal denervation therapy in the distal main vessel and 
the arterial branches to ablation in the proximal main artery in 51 randomized hypertensive subjects. The 
magnitude of the 24-hour pressure drops at six months post-procedure for the “distal” approach was 
significantly higher than the “traditional” approach achieved using the Symplicity Flex denervation system 
(22.6 ± 20.0 vs 9.4 ± 18.7 mm Hg; P < 0.05). 
 
In a dual-center prospective analysis, Fengler and colleagues11 reported comparative efficacy and safety 
between a group of 25 treatment resistant hypertension patients treated with ablation of main renal 
artery, side branches, and accessory arteries to a matched control group (N = 25) with only main renal 
artery ablation. Systolic 24-hour mean ABP decreased significantly after three months in the combined 
ablation group (−8.5 ± 9.8/−7.0 ± 10.7 mm Hg, P < 0.001/0.003), but not in patients with main artery 
treatment (−3.5 ± 11.1/−2.0 ± 7.6 mm Hg, P = 0.19/0.20) and systolic daytime BP was significantly lower 
in patients with combined ablation compared to main artery ablation (P = 0.033). 
 
The results of the preclinical IVY study using norepinephrine drop and cortical axon area density as 
alternative indices to blood pressure drop when main vessel ablation was augmented with branch therapy 
treatment in a long-term study in pigs13 also shows a trend towards greater office blood pressure 
reduction. 
 
A post hoc analysis of a previously reported single center non-randomized study from Kiuchi and 
colleagues14 analyzed the correlation between the number of lesions and blood pressure drop according 
to lesion location supporting the concept of targeting the distal part of the main renal artery and the 
branches rather than increasing the number of RF applications in the main renal artery. Thirty patients 
with “resistant” hypertension and CKD received renal denervation with a cardiac EP catheter. Mean 24- 
hour systolic blood pressure decreased by 21 mmHg at two years. An average of 17 total lesions (right 
plus left) were applied, including an average of 5 proximal, 5 mid, 5 distal, and 2 branch lesions. The total 
number of ablations was not correlated with BP drop. However, the number of lesions applied in the 
branches was linearly associated with 24-hour SBP-lowering effect at both 12 and 24 months of follow up. 
The strongest correlation between the number of lesions and blood pressure drop was observed when 
combining distal main plus branch lesions. The results suggest that focusing therapy on the distal main 
and branches may increase blood pressure reduction. 
 
Besides one HTN-3 post hoc analysis,8 no trial (including SPYRAL HTN-ON and -OFF MED) has shown a 
correlation between the total number of lesions and BP reduction. The number of RF lesions did not 
correlate with BP reduction,15-19 unless the lesions were delivered to the branches.14,20 
As compared to the currently recommended procedure specified in the SPYRAL HTN ON and OFF MED 
trials, a procedure focused on the distal main renal arteries and first order branches suggests similar safety 

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and blood pressure reductions but with potential for shorter procedural times, less radiation exposure, 
and less contrast usage. 
 
3.2. 
Purpose 
The objective of this single arm interventional study is to determine if renal denervation performed in the 
distal main renal arteries and first order branches is as effective as the procedural approach in the SPYRAL 
HTN-OFF MED clinical study. 

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4.1. 
Objectives 
The objective of this single arm interventional study is to determine if renal denervation performed in the 
distal main renal arteries and first order branches is as effective as the procedural approach in the SPYRAL 
HTN-OFF MED clinical study. 
 
4.2. 
Endpoints 
The following endpoints will be analyzed in this study: 
 
4.2.1. Efficacy endpoints 
The efficacy endpoints will be compared to the SPYRAL HTN-OFF MED efficacy endpoints using a 
propensity score stratified analysis at 3 months. At 6 months and 12 months, the endpoints will be 
compared and analyzed within the SPYRAL DYSTAL study only. 
 
• 
Change in systolic blood pressure (SBP) from baseline (Screening Visit 2) to 3, 6, and 12 
months post-procedure as measured by 24-hour ABPM. 
• 
Change in office SBP from baseline (Screening Visit 2) to 3, 6, and 12 months post-procedure. 
• 
Change in diastolic blood pressure (DBP) from baseline (Screening Visit 2) to 3, 6, and 12 
months post-procedure as measured by 24-hour ABPM. 
• 
Change in office DBP from baseline (Screening Visit 2) to 3, 6, and 12 months post-procedure. 
• 
Incidence of achieving target office SBP (SBP<140 mmHg) at 3, 6, and 12 months. 
• 
Compare the pattern of BP reduction over 24 hours of ABPM between this study and the 
SPYRAL HTN-OFF MED study. 
 
4.2.2. Safety endpoints 
• 
Composite safety endpoint at 1, 3, 6, and 12 months post-procedure: 
Incidence of the following events: 
- 
All-cause mortality 
- 
End-stage renal disease (ESRD) 
- 
Significant embolic event resulting in end-organ damage 
- 
Renal artery perforation requiring intervention 
- 
Renal artery dissection requiring intervention 
- 
Vascular complications 
4. Objectives and Endpoints 

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- 
Hospitalization for hypertensive crisis not related to confirmed non-adherence with 
medications or the protocol 
- 
New renal artery stenosis > 70%, confirmed by angiography and as determined by the 
angiographic core lab at 6-months follow up 
• 
Myocardial infarction 
• 
Stroke 
• 
Renal artery re-intervention 
• 
Major bleeding according to TIMI definition (i.e., intracranial hemorrhage, ≥5 g/dl decrease 
in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to 
bleeding within seven days of the procedure) 
• 
Increase in serum creatinine >50% from Screening Visit 2 
 
4.2.3. Additional analysis 
The following additional analyses will be conducted: 
 
• 
Comparison of procedural characteristics, such as total procedure duration, denervation time 
but not limited to that, between SPYRAL DYSTAL and SPYRAL HTN-OFF MED 

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The SPYRAL DYSTAL study is a multi-center, international, prospective, interventional, single-arm study 
designed to study renal denervation in the distal portion of the main renal arteries and first-order 
branches. Denervation will be performed using the Symplicity Spyral multi-electrode renal denervation 
catheter (Symplicity Spyral catheter) and the Symplicity G3 renal denervation radio frequency (RF) 
generator in a hypertensive population. Subjects will be studied to assess the impact of this renal 
denervation approach on systolic and diastolic blood pressure. 
 
The Symplicity Spyral catheter and Symplicity G3 generator provide a spiral pattern of denervation, 
ensuring circumferential nerve ablation, which is expected to minimize procedure variability. One 
Symplicity G3 generator is intended to be used with a Symplicity Spyral catheter in enrolled subjects. 
Subjects will be studied in the absence of anti-hypertensive medications through the 3-month visit to 
assess the impact of renal denervation on blood pressure in the absence of medications. 
 
Based on previous experience with the SPYRAL HTN-OFF MED study, it is anticipated that there will be 
subjects who will no longer meet study eligibility during the screening period; therefore, approximately 
350 subjects will be enrolled to ensure approximately 50 hypertensive subjects will undergo the renal 
denervation procedure at up to 15 sites. Once enrolled, subjects will undergo screening visits and if 
eligible, will undergo renal denervation and will be followed for at minimum 12 months post-procedure. 
Follow-up visits will take place at discharge, 2Wk, 1M, 6Wk, 8Wk, 10Wk, 3, 4 (if applicable), 6, and 12 
months (see Table 1 for treatments and assessments that will occur at each visit). Upon completion of all 
follow-up visits, subjects will be exited from the study. Subjects will be consented for a maximum follow- 
up of 5 years in case there are reasons that would require the follow up to be extended beyond the 
currently planned 12-months follow up. 
 
The following procedures are defined as outside of Standard of Care CIP procedure (applicable as of EU 
MDR Date of Application) any time they are conducted as per the schedule of events outlined in the CIP: 
 
• 
Study requirement for subjects to be off antihypertensive medication until the 3-month visit. 
• 
Medication re-introduction 
• 
Office Blood Pressure 
• 
24-hour Ambulatory Blood Pressure Monitoring (ABPM), except in several EU countries 
• 
Blood tests 
• 
Procedural angiogram (renal artery imaging – angiogram) 
• 
Follow-up Duplex Ultrasound imaging (DUS) (renal artery imaging) 
5. Study Design 

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• 
Follow-up Magnetic Resonance imaging (MRA) (renal artery imaging) 
• 
Follow-up Computerized Tomographic imaging (CTA) (renal artery imaging) 
 
5.1. 
Duration 
Subjects will participate in the study from the time of signing consent (defined as enrollment) until study 
exit or the time of completion of at least 12 months of follow up post-procedure (subjects will be 
consented for a maximum follow-up of 5 years in case there are reasons that would require the follow up 
to be extended beyond the currently planned 12-months follow up). 
 
Enrollment is expected to take approximately 12 months. Individual investigational sites may enroll up to 
20% of the total study subjects. Total study duration is expected to take approximately 2.5 years. 
 
5.2. 
Rationale 
 
5.2.1. Rationale for duration of period off medications 
A review of hypertension studies of antihypertensive medications was undertaken in conjunction with a 
thorough review of the SYMPLICITY HTN-3 data. Based on this, Medtronic plans to follow the accepted 
pharmaceutical model for hypertension studies and utilize a washout period. This will involve a three to 
four week washout period free of antihypertensive medications prior to procedure, followed by a 12 week 
post-procedure period off medication. Washout and discontinuation of antihypertensive medications 
during the off-medication period should eliminate medication adherence concerns and address both lack 
of adherence and medication changes as potential confounding factors identified in SYMPLICITY HTN-3. 
 
Inclusion and exclusion criteria traditionally used in pharmaceutical studies18 will be utilized as they have 
historically ensured that only subjects with true hypertension (vs white coat) are included and also ensure 
that these subjects are not borderline hypertensive (ambulatory SBP close to 135 mmHg and office SBP 
close to 140 mmHg). Subjects will undergo regular office visits that include blood pressure measurement 
to ensure safety during the off-medication period. 
 
5.2.2. Rationale for comparator 
The efficacy endpoints in this study will be compared to the SPYRAL HTN-OFF MED efficacy endpoints 
using a propensity score stratified analysis as outlined in section 13.4. 
 
The SPYRAL HTN-OFF MED study was chosen because this study has the same eligibility criteria as the 
SPYRAL DYSTAL study, except for the anatomical exclusion criteria. The studies both evaluate blood 
pressure response after approximately 4-months off medication period (office BP and ABPM) post- 

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procedure. The SPYRAL HTN-OFF MED and the SPYRAL DYSTAL studies have different procedural 
requirements which allows for comparison of blood pressure reductions between the two studies. 

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6.1. 
The Symplicity Spyral™ multi-electrode renal denervation system 
The Symplicity Spyral multi-electrode renal denervation system (Symplicity Spyral catheter and Symplicity 
G3 generator) is comprised of a single use, disposable catheter, and a reusable radiofrequency (RF) 
generator. The intended use is to deliver low-level radiofrequency energy through the wall of the renal 
artery to denervate the human kidney. The Symplicity Spyral catheter and Symplicity G3 generator 
received CE Mark in October 2013 and has been commercially available in selected geographies. 
 
6.2. 
The Symplicity Spyral™ Catheter 
The Symplicity Spyral catheter when used with the Symplicity G3 generator will allow for rapid treatment 
of renal arteries by simultaneously delivering radiofrequency energy to four electrodes. The Symplicity 
Spyral catheter consists of a distal, self-expanding array of four gold electrodes radially spaced by 
approximately 90 degrees in a spiral configuration (Figure 1). To minimize the thermal effects on the renal 
artery wall, the design allows for continuous blood flow throughout the treatment, allowing cooling of the 
artery wall and electrodes during treatment. The catheter is advanced to the treatment site by tracking 
over a 0.014 inch guidewire using a rapid exchange based catheter system (Figure 2). The proximal end of 
the guidewire is inserted through the spiral flexible array via the straightening tool, reducing the system 
into a low-profile straight configuration that is 6F compatible and ready for delivery to the renal artery 
treatment site. A radiopaque marker is embedded in the catheter approximately 1 mm proximal from the 
tip to assist in the positioning of the catheter using fluoroscopic guidance. After the device is placed in a 
desired position for ablation in accordance with the IFU, the guidewire is retracted proximally to allow the 
pre-shaped nitinol spiral electrode array to expand radially and place the electrodes in contact with the 
arterial wall in a spiral pattern. The Symplicity Spyral catheter is designed to attain acceptable electrode- 
vessel positioning and wall contact with less overall manipulation and/or interpretation as compared to 
the single-electrode Symplicity catheter design. After treatment, the guidewire can be advanced distally 
to straighten the electrode array and allow for removal from the vessel into the guide catheter for 
placement into the contra-lateral renal artery where the treatment procedure is repeated. 
6. Product Description 

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Figure 1: Spiral Configuration of Four Gold Electrodes 
 
The self-expanding electrode array consists of nitinol stranded tubing to maintain spiral shape-set and 
guidewire lumen integrity during the procedure. The gold electrodes are placed over a polymer outer 
cover that provides insulation from nitinol tubing and bi-filar wires that deliver the RF energy and measure 
temperature. The proximal end of the self-expanding electrode array assembly is attached to the 
intermediate shaft assembly. The intermediate shaft assembly balances the flexibility between the 
proximal shaft and electrode array assembly. The intermediate shaft assembly contains a guidewire lumen 
that terminates at the rapid exchange (RX) guidewire exit port. The jacketed proximal stainless steel 
hypotube joins the delivery system to the handle and integrated cable. The cable connector connects 
directly into the Symplicity G3 generator. 
 
Figure 2: Overview of Symplicity Spyral™ Catheter 
 
The electrodes in the multi-electrode spiral arrangement are positioned to cover all four quadrants of the 
artery’s circumference. The catheter is for single-use only and is sterilized by E-beam irradiation. It is 
provided in a hooped configuration within a tray sealed with a coated Tyvek® lid. 

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6.3. 
Symplicity G3™ Generator 
The Symplicity G3 generator (see Figure 3) is intended to provide a safe and effective means of delivering 
RF energy to the Symplicity Spyral catheter for controlled ablation of tissue. The Symplicity G3 generator 
has been designed with the following features: 
 
• 
Automated safety algorithms similar in all aspects of safety and energy delivery and stoppage 
to first generation Symplicity RF generator 
• 
Non-adjustable treatment parameters 
• 
System performance self-checks at power on and during system operation 
• 
Simultaneous firing of all four electrodes 
• 
Option to select/deselect electrodes per physician discretion 
• 
Touch-screen interface, which allows the user to individually select or de-select the 
electrodes 
• 
Internal RFID tag within the Symplicity Spyral catheter, to communicate with an RFID antenna 
located inside the Symplicity G3 generator to ensure the catheter cannot be re-used 
• 
Messages and audible indicators to the operator with system status information including 
treatment application, warning indications and error indication 
• 
Universal power supply 
• 
Remote as optional component allowing extension of user interface 
 
Figure 3: Symplicity G3™ Generator 
 
Treatments are initiated by an operator using an optional foot switch, remote control, or a button on the 
front of the generator and may also be manually stopped by the operator using these same methods. 
Default treatment parameters cannot be changed by the operator. 
 
Monopolar RF energy is delivered through each electrode, requiring the use of a dispersive electrode to 
provide a return path for currents exiting the catheter. Temperature and impedance values are monitored 

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at each electrode and used to provide input to an algorithm controlling power delivery for individual 
electrodes (Figure 4). 
 
Figure 4: RF on Screen 
 
The following ancillary components may be used with the Symplicity G3 generator: 
 
• 
Symplicity G3 generator cart - an optional accessory as a convenience to facilitate 
movement of the generator within the operating room. The generator cart may be provided 
as part of the clinical study in applicable geographies. 
• 
Foot switch 
• 
Digital Visual Interface (DVI-D) cable - enables the user to extend the visual display of the 
Symplicity G3 generator user interface to standard monitors within the cath lab 
• 
Wired remote control - enables the user to control the generator from within the sterile 
field 
 
6.4. 
Manufacturer 
The Symplicity Spyral catheter is manufactured at Medtronic Ireland. The Symplicity G3 generator (and 
ancillary components) is manufactured by Plexus Corp. (Pinnacle Hill, Kelso TD5 8XX, UK) for Medtronic. 
 
6.5. 
Packaging 
The Symplicity Spyral catheter and Symplicity G3 generator will include the following labeling information 
in geographies where the product is not commercially available: 
 
• 
That the device is intended for investigational use in geographies where the product is not 
approved. 
• 
Identification Number 
• 
Model number 

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• 
Lot/Serial number 
• 
Storage condition 
• 
Expiration date 
• 
Name and address of sponsor 
 
An Instructions for Use (IFU) document is included with each Symplicity Spyral catheter and a User Manual 
is included with each Symplicity G3 generator. 
 
6.6. 
Intended Population 
The Symplicity Spyral catheter and Symplicity G3 generator are indicated for the treatment of 
uncontrolled hypertension. 
 
6.7. 
Equipment 
Medtronic will be responsible for maintenance of the Symplicity G3 generator. In addition, the calibration 
of the office blood pressure (OBP) machines and ambulatory blood pressure machines (ABPMs) will be 
done by Medtronic according to the manufacturer’s requirements. Documentation of the routine 
maintenance will be provided to the study site upon completion. 
 
6.8. 
Product Use 
The Symplicity Spyral catheter and Symplicity G3 generator should be used as outlined in the IFU. 
 
Medtronic has performed a comprehensive set of bench testing and preclinical studies that have shown 
that the manner of low-power ablation produces distinct, focal, sterile lesions that subsequently heal, 
resulting in no clinically relevant long-term sequelae to either the vessel or the kidney. The ability to 
denervate using this approach has been demonstrated to effectively reduce renal nerve activity. 
 
Preclinical studies and histological analyses8-10 observed that renal nerves may have a positional bias, 
suggesting the distal nerves are closer to the arterial lumen (Figure 5). Targeted renal ablation in the distal 
main and branches of the renal arteries may increase the amount of nerve ablation and decrease the 
variability of denervation response. 

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Nerves 
Lumen 
Endothelium 
Media 
Adventitia 
Fat 
 
 
Figure 5: Illustration of peri-arterial renal nerve location 
 
Initial clinical evidence11 from commercial experience supports the combination of branch and main renal 
artery treatments providing a larger and more consistent decrease in blood pressure while maintaining 
the safety profile of renal denervation that was previously established. Treatment of the distal main renal 
arteries and first-order branches will be evaluated in this clinical study to confirm the safety and efficacy 
of this approach. 
 
The catheter is introduced percutaneously to the renal artery via a commercially available sheath and 6F 
guiding catheter suitable for renal artery intervention, using the femoral artery as the access site. A 6F 
sized commercially available guide catheter and a commercially available hemostatic introducer sheath 
may be used in the placement of the catheter. The treatment involves the delivery of a relatively low- 
power and precisely focused RF energy of up to 6.5W to each electrode, simultaneously through the wall 
of the renal artery to disrupt the surrounding renal nerves. The low-power RF ablation has been shown to 
effectively disrupt the renal nerves (located in the adventitia of the renal artery, as depicted in Figure 6) 
without adversely affecting the wall of the artery or surrounding organs. 
 
Figure 6: Illustration of renal artery anatomy 

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6.9. 
Product Training Requirements 
The training approach for the SPYRAL DYSTAL study is described below. 
 
All participating sites in this study will have previous experience with the Symplicity Spyral multi-electrode 
renal denervation system. 
 
Investigators will be trained on the protocol, the procedural approach (as applicable) and other topics 
related to the procedure prior to starting study-related activities. If a participating proceduralist has prior 
experience with using the Spyral catheter, no further (online) training is required. 
 
An online training will be set up on a dedicated learning website for proceduralists with limited experience 
only and is required to be completed before the interventionalist will attend the investigator training 
meeting. The goal for the online training is to provide investigators with an understanding of the handling 
of the Symplicity catheter and Symplicity G3 generator before coming to the meeting. The progress of 
each investigator will be reviewed and documented in the specific training files (site and sponsor). The 
topics for the online training will include but are not limited to following topics: 
 
• 
Review of Spyral In-service Slide deck 
• 
Review of recorded Spyral cases 
 
In the event of a delay greater than three months between the investigator training and the first case 
performed by an investigator, or more than three months between cases during the trial, a refresher shall 
be performed. This will be accomplished by visiting the online training platform and reviewing a recorded 
case, together with potential other tasks. 
 
6.10. 
Product Receipt and Tracking 
Sites are required to maintain investigational device records that contain the following information on all 
components shipped to the site for the study: 
 
• 
Investigational device name 
• 
Device serial/model number 
• 
Date of receipt of device 
• 
Name of person receiving the device 
• 
Name of person using/opening the device (if applicable) 
• 
Date of use (if applicable)/expiration date 
• 
Subject Identification Number (SID) of subject receiving or using the device (if applicable) 
• 
Disposition (implanted, disposed of, or returned to Medtronic) 

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For devices that are returned to Medtronic or disposed of, sites are required to document the following 
additional information: 
 
• 
The reason for the device being returned to Medtronic or disposed of 
• 
Name of the person who returned or disposed of each device 
• 
Date shipped to Medtronic, if returned 
• 
If device is disposed of, the method of disposal 
 
At the end of study enrollment, all remaining investigational devices must be returned to Medtronic. 
 
The Symplicity Spyral catheter and Symplicity G3 RF generator are commercially available in countries that 
accept CE-mark and will be used within approved labelling for this study. The Symplicity Spyral catheter 
and Symplicity G3 RF generator are investigational in the US. 
 
The following devices will be provided to sites and must also be tracked during the clinical study: 
 
• 
Office blood pressure monitors 
• 
Ambulatory blood pressure monitors 
 
6.11. 
Product Storage 
The Symplicity Spyral catheter and Symplicity G3 generator must be stored as labeled at all sites. 
 
Investigational devices/products or products provided by Medtronic free of charge must be stored in a 
secured area. The method of storage shall prevent the use of investigational devices/products for other 
applications than mentioned in this clinical investigation plan (CIP). In addition, all information for the use, 
storage and handling of the investigational device/product as indicated in the IFU and User Manual must 
be taken into account. 
 
6.12. 
Product Return 
Non-functioning investigational devices must be returned to Medtronic as soon as possible for 
investigation. If a Symplicity G3 generator or Symplicity Spyral catheter needs to be returned (e.g. 
expired), a Medtronic representative will help facilitate the return and provide a return address and local 
procedures that need to be followed. In case a Symplicity G3 generator or Symplicity Spyral catheter needs 
to be returned, it will be returned to the address below, following local procedures: 

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Symplicity G3 generator: 
 
Medtronic CardioVascular 
Service and Repair 
Attn: RMA#  
            
Service & Repairs 
7611 Northland Drive 
Brooklyn Park, MN 55428 
Tel: +1 800-433-4311 
 
Symplicity Spyral catheter: 
 
Medtronic PXM RGI Lab Building 4 
Parkmore Business Park West 
Ballybrit 
Galway 
H91 A2Y5 
Ireland 
At the end of the clinical study, all remaining investigational devices/products must be returned to 
Medtronic in the applicable region. 

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7.1. 
Statement(s) of Compliance 
This study is designed to reflect the good clinical practice (GCP) principles outlined in the latest version of 
ISO 14155. These include the protection of the rights, safety and well-being of human subjects, controls 
to ensure the scientific conduct and credibility of the clinical investigation and the definition of 
responsibilities of the sponsor and investigators. 
 
The study will also be conducted in accordance with the Declaration of Helsinki. The principles of the 
Declaration of Helsinki (2013) are implemented in this study by means of the Patient Information and 
Informed Consent (IC) process, Ethics Committee approval, study training, clinical study registration, pre- 
clinical testing, risk benefit assessment, and publication policy. This clinical study will also be registered 
on clinicaltrials.gov and study results posted based on the posting rules stipulated. 
 
In addition, the study will be conducted in compliance with the latest version of ISO 14155, EU MDR and 
other local regulatory requirements as applicable, will also be followed. As the ISO 14155 adverse event 
requirements are focused on pre-market release studies, the adverse event collection will be focused on 
collecting all adverse events only up to 6-months follow up (after that, only serious adverse events will be 
collected). The USADE assessment will also not be performed as the product is market-released in Europe. 
 
In addition, laws and regulations of the countries in which the SPYRAL DYSTAL study is conducted, 
including data protection laws, will be followed. 
 
21 CFR Part 56 (Institutional Review Boards), Part 50 (Protection of Human Subjects), and Part 812 
(Investigational Device Exemptions) only apply to the US; not to other geographies. 
 
Regulatory authority notification/approval to conduct the study is required in all participating geographies 
(where applicable). Investigational sites will be not be activated, nor begin enrolling subjects until the 
required approval/favorable opinion from the respective regulatory agency has been obtained (as 
appropriate). The clinical investigation shall not begin until the required approval/favorable opinion from 
the ethics committee (EC) / institutional review board (IRB) or notification/approval from a regulatory 
authority have been obtained. Additionally, any requirements imposed by a local regulatory agency or 
EC/IRB shall be followed, as appropriate. 
 
Each site must provide Medtronic with a copy of the investigational site’s EC/IRB approval letter and the 
EC/IRB-approved Patient Information and Informed Consent form. 
 
If applicable, approvals for the continuation of the study at each investigational site must be kept current 
in accordance with the EC/IRB review schedule. All site communications to and from the EC/IRB must be 
forwarded to Medtronic as they are sent/received. 
7. Ethics 

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The sponsor will be informed by the EC/IRB and/or the investigator in case any action is taken by an EC/IRB 
with respect to this investigation. 
 
Study reimbursement is outlined in the clinical trial agreement. Indemnification will be done according to 
local laws. 
 
Medtronic contracts with participating institutions/investigators through a Clinical Trial Agreement that 
defines the scope and responsibilities and associated compensation related to carrying out the obligations 
under a clinical study sponsored by Medtronic 
 
This study will be publicly registered on www.clinicaltrials.gov prior to first enrollment. This study will not 
start enrollment in a geography unless applicable national regulatory approval for the Symplicity Spyral 
catheter and G3 generator have been obtained. The devices should be used within the intended approved 
indication. 
 
7.1.1. 
Ethics Committee/ Institutional Review Board Approval 
Here and throughout the document, “EC/IRB” is the term that will be used collectively in reference to an 
ethics committee (EC), institutional review board (IRB), medical ethics committee (MEC), human research 
ethics committee (HREC), research ethics board (REB) unless otherwise stated. 
 
Prior to enrolling subjects in this clinical study, each investigational site’s EC/IRB will be required to 
approve the current CIP, the Patient Information and Informed Consent form, including any other written 
information to be provided to the subjects and, if applicable, the Investigator’s Brochure. 
 
EC/IRB approval of the clinical study must be received in the form of a letter and provided to Medtronic 
before commencement of the clinical study at an investigational site. The approval letter must contain 
the version or date of the documents approved. If this information is not contained in the approval letter, 
it must be retrievable from the corresponding submission letter. In addition, the approval letter needs to 
be accompanied by an EC/IRB roster or letter of compliance, to allow verification that the investigator, 
other investigational site personnel, and/or Medtronic personnel are not members of the EC/IRB. If they 
are members of the EC/IRB, written documentation is required stating that he/she did not participate in 
the approval process. If the EC/IRB imposes any additional requirements (e.g., safety reports, progress 
reports etc.), Medtronic will prepare the required documents and send them to the investigator for 
reporting to the EC/IRB. Investigators must inform Medtronic of any change in status of EC/IRB approval 
once the investigational site has started enrollment. If any action is taken by an EC/IRB with respect to the 
clinical study, that information will be forwarded to Medtronic by the respective investigator. 
Medtronic may revise the CIP, IB (if applicable), IFU, CRFs, Patient Information and Informed Consent form 
and other study documents during the study when revision(s) is determined necessary. Medtronic will 
submit revisions to the regulatory authorities (if applicable per local regulation) and will also request that 
sites submit to their EC/IRB for review per national and local requirements. 

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7.1.2. 
Regulatory Submission 
In countries where submission to the regulatory authority is required per local law, no subjects will be 
enrolled in the clinical study until the respective regulatory authority has approved the current CIP or 
subsequent amendments for the clinical study and other documents as required according to the local 
requirements. 
 
If the regulatory authority imposes any additional requirements (e.g., safety reports, progress reports 
etc.), Medtronic will prepare the required documents and send them to the respective authority (as 
applicable). 

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8.1. 
Study Population 
The population eligible for inclusion into this study includes subjects with uncontrolled hypertension in 
accordance with the Inclusion and Exclusion criteria specified in the protocol. 
 
8.2. 
Subject Enrollment 
Subjects will be pre-screened for potential enrollment in the clinical study based on prior medical history 
and records of office systolic blood pressure. 
 
A subject is considered enrolled in this clinical study at the time at which the subject and investigator or 
authorized designee have personally signed and dated the Patient Information and Informed Consent 
Form. Written informed consent must be obtained prior to Screening Visit 1. 
 
Investigational sites will maintain a subject identification log; however, this document will not be 
submitted to the sponsor. 
 
It is anticipated to enroll approximately 350 subjects to reach approximately 50 renal denervation treated 
subjects within this study. 
 
Each site will receive a supply of single-use catheters. A minimum of 50 single use catheters will be 
required to treat approximately 50 subjects. It is anticipated that a small number (<10%) of catheters will 
need to be replaced due to damage or contamination. Sites will be expected to return all unused study 
product to Medtronic. 
 
8.3. 
Inclusion Criteria 
1. Individual is ≥20 and ≤80 years old at time of enrollment (consent). 
2. Individual has an office systolic blood pressure (SBP) ≥150 mmHg and <180 mmHg and an office 
diastolic blood pressure (DBP) ≥90 mmHg measured at Screening Visit 2, according to the 
guidelines in Appendix 16.5. 
3. Individual has a valid 24-hour ABPM average SBP ≥140 mmHg and <170 mmHg measured at 
Screening Visit 2, according to guidelines in Appendix 16.5. 
ABPM is considered valid if the number of successful daytime readings captured is ≥21 and 
the number of successful nighttime readings captured ≥12. 
4. Individual agrees to have all study procedures performed, and is competent and willing to provide 
written, informed consent to participate in this clinical study. 
5. Individual is willing to discontinue current antihypertensive medications at Screening Visit 1 
through the 3-month post-procedure visit. 
8. Selection of Subjects 

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8.4. 
Exclusion Criteria 
1. Individual has one or more of the following conditions: stable or unstable angina within 3 months 
of enrollment, myocardial infarction within 3 months of enrollment; heart failure, 
cerebrovascular accident or transient ischemic attack, or atrial fibrillation at any time. Patients 
are permitted to take aspirin or clopidogrel for cardiovascular risk reduction. Patients who 
received catheter or surgical treatment for atrial fibrillation and are in sinus rhythm are not 
excluded. 
2. Individual has undergone prior renal denervation. 
3. Individual has one or more main renal artery with a diameter of less than 3mm or greater than 8 
mm. 
4. Individual has the presence of FMD (defined as visible beading of the artery on angiography). 
5. Individual has >50% stenosis in any treatable vessel. 
6. Individual has a renal artery stent placed <3 months prior to the denervation procedure. 
7. Individual has presence of a renal artery aneurysm defined as any localized increase in the 
diameter of the vessel. 
8. Individual has disease not allowing any treatment in the main renal artery. 
9. Individual has an estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73m2, using the 4 
variable MDRD calculation (in mL/min per 1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if 
patient is black) x 0.742 (if female)). 
10. Individual has documented type 1 diabetes mellitus or poorly-controlled type 2 diabetes mellitus 
with glycosylated hemoglobin greater than 8.0%. (If the glycosylated hemoglobin in the patient’s 
records is >3 months old (from the date of Screening Visit 2), or history of uncontrolled blood 
sugars raises concern, it is required to analyze glycosylated hemoglobin as part of Screening Visit 
2 labs.) 
11. Individual is taking SGLT2 inhibitor or GLP-1 agonists that have been prescribed <90 days prior to 
SV1 or who does not plan on remaining on these drugs for the duration of the trial. 
12. Individual has had ≥1 episode(s) of orthostatic hypotension not related to medication changes 
within the past year or has a reduction of SBP ≥20 mmHg or DBP ≥10 mmHg within 3 minutes of 
standing coupled with symptoms during the screening process (at SV2). 
13. Individual requires chronic oxygen support or mechanical ventilation other than nocturnal 
respiratory support for sleep apnea (e.g. CPAP, BiPAP). 
14. Individual with a history of narcotic drug abuse, is currently on methadone, or who has used 
narcotic drugs more than once in the month prior to Screening Visit 1. 
15. Individual had documented primary pulmonary hypertension. 
16. Individual has untreated secondary cause of hypertension (either known or suspected) or is 
taking drugs that increase sympathetic tone that could contribute to hypertension. 
17. Individual has frequent intermittent or chronic pain that results in treatment with non-steroidal 
anti-inflammatory drugs (NSAIDs) for two or more days per week over the month prior to 
Screening Visit 2. 

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18. Individual with HIV on anti-retroviral drug therapy without documentation that hypertension 
preceded initiation of anti-retroviral drug treatment. 
19. Individual has a scheduled or planned surgery that, in the opinion of the Investigator, may affect 
study endpoints. 
20. Individual has a documented condition that would prohibit or interfere with ability to obtain an 
accurate blood pressure measurement using the protocol-specified automatic/office blood 
pressure monitor (e.g., upper arm circumference outside cuff size ranges available by geography 
or arrhythmia such as atrial fibrillation that interferes with automatic monitor’s pulse sensing 
and prohibits an accurate measurement). 
21. Individual works night shifts. 
22. Individual has severe cardiac valve stenosis for which, in the opinion of the investigator, a 
significant reduction of blood pressure is contraindicated. 
23. Individual has a documented confounding medical condition, which in the opinion of the 
investigator, may adversely affect the safety of the participant (e.g. patients with clinically 
significant peripheral vascular disease, aortic aneurysm, bleeding disorders such as 
thrombocytopenia, hemophilia, or significant anemia). 
24. Individual is pregnant, nursing or planning to become pregnant during the course of the study 
follow-up. (Note: Pre-menopausal female participants must have a negative serum or urine 
human chorionic gonadotropin (hCG) pregnancy test prior to angiography). 
25. Individual has a known unresolved history of drug use or alcohol dependency, lacks the ability to 
comprehend or follow instructions, or would be unlikely or unable, in the opinion of the 
investigator, to comply with study follow-up requirements. 
26. Individual is currently enrolled in a concurrent investigational drug or device study, unless 
approved by the study sponsor. (Note: For the purpose of this protocol, participants involved in 
extended follow-up studies for products that were investigational but are currently commercially 
available are not considered enrolled in an investigational study). 
27. Individual is currently taking anti-mineralocorticoid drugs. (Note: Subjects may be enrolled as 
long as anti-mineralocorticoid drugs are weaned off at least 8 weeks prior to Screening Visit 1). 
28. Individual has an active peptic ulcer or gastrointestinal (GI) bleeding within the prior six months 
from consent. 
29. Individual has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions. 
30. Individual has polycystic kidney disease, unilateral kidney, atrophic kidney, or history of renal 
transplant. 

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8.5. 
Subject Consent 
All subjects must complete a Patient Information and Informed Consent form prior to undergoing any 
study-related procedures. Sites must comply with local regulatory requirements (latest version of 
ISO14155) and local EC/IRB policies for obtaining informed consent. The consent form will be provided 
under separate cover. 
 
In advance of the consent discussion, the subject should receive the EC/IRB and Medtronic-approved 
Subject Informed Consent Form. During the consent discussion, the investigator or his/her designee (only 
in geographies where allowed) must fully inform the subject of all pertinent aspects and risks of the study. 
All items discussed in the Subject Informed Consent Form must be explained by research site staff 
designated on the Delegation Task List. The language used shall be as non-technical as possible and must 
be understandable. In the event the subject cannot read and/or write, the consent process shall be 
obtained by reading the consent form aloud to the prospective subject and the impartial witness, where 
applicable. Subject Informed Consent Forms should be made available in subject’s native language. 
 
Neither the investigator nor the investigation site staff shall coerce or unduly influence a subject to 
participate or to continue to participate in the clinical study. The informed consent process shall not waive 
or appear to waive the subject’s rights. The subject will be provided ample time to read and understand 
the Subject Informed Consent Form and to consider participation in the study. 
 
When the subject decides to participate in the clinical study, the site’s current EC/IRB and Medtronic- 
approved Subject Informed Consent Form must be signed and personally dated by the subject and 
investigator or designee. If the subject is not able to read and/or write, an impartial witness shall also sign 
and personally date the consent form to attest that the information in the Subject Informed Consent Form 
was accurately explained and clearly understood by the subject, and that informed consent was freely 
given. 
 
After all required parties have signed and dated the Patient Informed Consent Form, the investigator/or 
designee must provide the subject with a copy of the signed and dated Patient Informed Consent Form. 
The consent process should be documented in the subject’s medical record. 
 
The subject will be informed about the rights to “withdraw from the study at any time”, “withdraw 
without any disadvantage and without having to provide reason.” 
 
8.5.1. Revisions in the Patient Information and Informed Consent form 
Medtronic will inform the investigators whenever information becomes available that may be relevant to 
the subject’s continued participation in the study. The investigator or designee should inform the subject 
in a timely manner. 

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Medtronic will revise the written the Patient Information and Informed Consent form whenever new 
information becomes available that may be relevant to the subject’s continued participation in the study. 
The revised information will be sent to the investigator for approval by the EC/IRB and Competent 
Authority (CA), if required. After approval by the EC/IRB, a copy of this information must be provided to 
the participating subjects, and the information process as described above, in Section 8.5 Subject Consent, 
needs to be repeated. 

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The below section describes the study procedures that the subject will undergo during the clinical study. 
 
9.1. 
Schedule of Events 
 
9.1.1. Screening Visit 1 
After confirmation that the investigator (or authorized delegate) and subject have personally signed and 
dated Patient Information and Informed Consent Form, the following assessments will be performed at 
the Screening Visit: 
 
a) Medical history will be documented from the study subject to evaluate for prior or existing 
medical conditions and/or procedures that would exclude subjects from participation in the 
study. 
b) Office blood pressure measurements will be obtained in accordance with study guidelines in 
Appendix 16.5. This blood pressure measurement will not be used as the baseline BP 
measurement but will be used, in conjunction with the subject’s medical history, to determine 
if, in the investigator’s judgment, the subject’s BP at Screening Visit 2 will qualify for inclusion 
in the study following the antihypertensive drug washout period. However, if the subject’s 
SBP is ≥ 180 mmHg, the subject will be excluded at Screening Visit 1. Subjects with an office 
SBP <180 mmHg and drug naïve subjects with an office DBP ≥ 90 mmHg are eligible to 
continue to the next study visit. Subjects with office SBP ≥ 180 mmHg and drug naïve subjects 
with an office DBP < 90 mmHg will be exited from the trial. 
c) Medication & adverse event reviews will be completed to document baseline medication use 
and adverse events that occur after enrollment. 
Subjects determined to not be eligible for procedure will be exited from the study, as described in the 
Subject Exit from Study (section 9.5.1) of this CIP. 
 
Notification to the primary physician caring for the subject of the subject’s participation in the study will 
be made prior to the next screening visit. The letter should include a brief description of the study, indicate 
that the subject has given permission for the communication, and provide notification that medications 
that affect blood pressure should not be changed without consulting the principal investigator (or 
delegate) from the time of enrollment until after the 6-month follow-up visit as this would impact the 
major endpoint of the study. 
9. Study Procedures 

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9.1.2. Medication Washout Period 
Following completion of Screening Visit 1, subjects on antihypertensive medication must be titrated off 
all antihypertensive medications over a three to four week washout period in a manner specified by the 
investigator. Subjects with an office systolic blood pressure of <180 mmHg after the minimum three week 
washout period (maximum four weeks) will continue to Screening Visit 2 (SV2). Subjects with an office 
systolic blood pressure of ≥180 mmHg at any point during and after the washout until procedure will be 
considered screen failures and will be exited from the study, as described in the Subject Exit from Study 
section 9.5.1. 
 
9.1.3. Tw o Week Screening Visit 
The purpose of this visit is to assess the subject’s office blood pressure two weeks after the 
antihypertensive medication washout period has been started. Drug-naïve subjects do not need this visit. 
The target date is two weeks from Screening Visit 1 ±3 days. 
 
a) Clinical assessment will be conducted to further evaluate for prior or existing medical 
conditions that would exclude subjects from participation in the study and to establish the 
subject’s baseline medical condition. An individual experienced in performing histories and 
physical exams is required to assess subjects for safety assessment during the period of time 
that study subjects are not on antihypertensive medications. 
b) Office blood pressure measurements will be obtained in accordance with Appendix 16.5. This 
blood pressure measurement will not be used as the baseline BP measurement but will be 
used, in conjunction with the subject’s medical history, to determine if, in the investigator’s 
judgment, the subject’s BP at Screening Visit 2 will qualify for inclusion in the study following 
the antihypertensive drug washout period. If the systolic OBP ≥180 mmHg, the subject must 
be exited from the trial. A subject who is drug naïve but still has a two week screening visit 
conducted, should be considered a screen failure if their office diastolic blood pressure is <90 
mmHg when the subject is drug naïve at SV1 through the 2 Week Screening Visit. 
c) Adverse event reviews will be completed to document adverse events that occur after 
enrollment. 
 
9.1.4. Screening Visit 2 
Screening Visit 2 must occur within three to four weeks of completion of SV1. The following assessments 
will be performed at Screening Visit 2: 
 
a) Clinical assessment will be conducted to further evaluate for prior or existing medical 
conditions that would exclude subjects from participation in the study and to establish the 
subject’s baseline medical condition. An individual experienced in performing histories and 

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physical exams is required to assess subjects for safety assessment during the period of time 
that study subjects are not on antihypertensive medications. 
b) Office blood pressure measurements will be obtained in accordance with Appendix 16.5. The 
average office blood pressure value will be used as the baseline value for comparison with 
follow-up visit office blood pressure values. Subjects with an office systolic blood pressure 
≥150 and <180 mmHg and an office DBP ≥90 mmHg are eligible to continue the screening 
process. 
c) Laboratory tests: 
• 
Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, potassium, blood urea 
nitrogen (BUN) or urea, bicarbonate, chloride, and glucose. Bicarbonate will not be 
measured for subjects enrolled in Europe. 
• 
eGFR will be calculated from the serum-creatinine in the Chem-7 panel for eligibility criteria 
by using the 4 variable Modification of Diet in Renal Disease (MDRD) Formula Note: If eGFR 
≥42 and <45 mL/min/1.73m² then subject can be retested after hydration with a single, 
repeat test within two weeks. 
• 
hCG pregnancy test in blood/urine for female subjects who are not postmenopausal. (This 
may also be completed the day of the procedure). 
• 
Drug testing (urine/blood) to ensure medications are no longer present in the subject’s 
system. A urine sample will be collected, preferably using the subject’s first morning urine. 
A blood sample will be collected at the time of the visit. Drug testing samples collected for 
subjects that screen fail after obtaining the sample, must not be sent to the core lab for 
analysis. 
• 
24-hour ABPM will be applied at the conclusion of Screening Visit 2 to confirm subject’s 
baseline blood pressure. This value will be utilized as the baseline value for calculating 
change in 24-hour ABPM at various time points post-procedure. Subjects with a 24-hour 
systolic ABPM of <140 or ≥170 mmHg after completion of the screening visit will be exited 
from the study. Subjects with a 24-hr systolic ABPM of ≥140 and <170 mmHg are eligible to 
continue to the procedure visit. A single repeat measurement is allowed in case of the 
following: 1.) a technical issue with the blood pressure monitor or failure to follow ABPM 
instructions, or 2.) if a valid number of readings is not obtained, or 3.) if the 24-hr systolic 
ABPM measured 135 - <140 mmHg or 170-175 mmHg. ABPM must be conducted according 
to the guidelines in Appendix 16.5. If ABPM is repeated office blood pressure and drug 
testing must be repeated on day the ABPM is applied. 
• 
Adverse event reviews will be completed to document adverse events that occur after 
enrollment. 
Subjects determined to not be eligible for renal angiogram will be exited from the study, as described in 
the Subject Exit from Study section 9.5.1 of this CIP. 

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It is expected that subjects who are eligible to continue to the renal angiogram will be scheduled for a 
procedure date within 14 calendar days of completion of Screening Visit 2. Completion of Screening Visit 2 
is defined as the day the 24-hour ABPM is completed or date of lab results, whichever is later. No subjects 
will be eligible for the renal angiogram more than two weeks following Screening Visit 2. 
 
9.1.5. Procedure Visit 
 
9.1.5.1. 
Renal Angiography 
The denervation procedure will occur once all eligibility criteria have been met as evaluated at Screening 
Visit 2 and during the renal angiogram. 
 
Prior to undergoing renal denervation, the key inclusion/exclusion criteria will be re-confirmed by a renal 
angiography to ensure that subjects still meet previously assessed eligibility criteria. When scheduled, 
subjects will be prepared for a renal angiography according to standard procedures. For subjects with 
chronic kidney disease and/or other risk factors for contrast-induced nephropathy (CIN), the hospital’s 
standard-of-care protocol for CIN prevention will be used. Prior to this procedure, appropriate systemic 
anticoagulation according to IFU requirements (e.g., ACT ≥ 250 sec). Hospital protocol driven or physician 
discretion driven use of short acting antihypertensive medications are permitted to control hypertension 
in order to mitigate bleeding from the arterial access site during the periprocedural period. 
 
An aortogram and selective renal angiography will be performed with all subjects to confirm eligible renal 
artery anatomy. Ensure subject received a minimum aspirin dose of 250 mg intravenous or up to 325 mg 
oral (per local drug dose labelling) prior to procedure (unless subject is already taking aspirin on regular 
basis). If the subject is already taking aspirin daily then at least the usual daily dose should be given on the 
day of the procedure. If the subject has a documented allergy to aspirin, 75 mg per day of clopidogrel can 
be substituted; under these circumstances, a loading dose of at least 150 mg clopidogrel may be 
administered prior to the procedure per physician discretion. 
 
9.1.5.2. 
Denervation Procedure 
The renal artery denervation procedure will be performed according to the supplied Symplicity Spyral 
catheter IFU, Symplicity G3 generator User Manual and associated training provided by Medtronic. Pre- 
treatment with both anxiolytic medications and analgesic medications, such as morphine sulfate or 
fentanyl (with additional doses timed with ablation treatments as appropriate) should be considered. 
Blood pressure, O2 saturation, and heart rate should be closely monitored both during the procedure and 
throughout the recovery phase from the conscious sedation administered. 
 
The goal of the denervation procedure in this protocol is to ablate renal nerves where they are in close 
proximity to the vessel lumen by delivering RF energy in a helical pattern in the distal main renal artery 
and branch vessels coming off the main renal artery (first order branches). 

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The following are required: 
 
• 
Placement of the catheter in each accessible renal artery branch vessel coming off the main 
renal artery to achieve ≤ 4 lesions in a helical pattern 
and 
• 
Placement of the catheter in the most distal, treatable portion of the main renal and/or renal 
accessory arteries to achieve ≤ 4 lesions in a helical pattern 
Note 1: Initial placement of the Symplicity Spyral catheter should not extend into the renal parenchyma 
as identified on fluoroscopic imaging. 
 
Note 2: Depending on anatomy, branch and main renal artery should be treated with the goal of applying 
4 ablations in each location. 
 
Note 3: Uncommon subject anatomy variations may be treated per investigators discretion in accordance 
with protocol guidelines and procedural training. 
 
Figure 7: Schematic representation of positioning of Symplicity Spyral catheter. 
 
Blue dots represent the required placement of the Symplicity Spyral catheter in eligible arteries for an 
example anatomy. More information and training will be provided as part of the procedural training. 
 
Upon completion of the denervation procedure either manual compression or commercialized closure 
devices can be used to achieve hemostasis at the puncture site. As per usual clinical practice, consider use 
of short acting anti-hypertensive medications for blood pressure control in the cath lab and prior to 
removing arterial access. Strict adherence to anticoagulation parameters prior to sheath withdrawal 
following either hospital protocol or standard of care practices are strongly recommended. 

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9.1.5.3. 
Post-procedure data collection requirements 
A copy of the renal angiogram cine procedure will be submitted to the angiographic core laboratory. 
Sedation type, procedure information, fluoroscopy time and contrast dye amount will be collected. 
 
Symplicity G3 generator data will be downloaded by and submitted to Medtronic. 
 
9.1.5.4. 
Post-procedure care 
All subjects will be hospitalized overnight following the renal angiogram and procedure and standard-of- 
care post-intervention monitoring procedures will be followed. 
 
Prior to discharge, the research staff will collect blood samples, assess for adverse events, and review 
study requirements with the subject to help ensure compliance with the follow-up schedule. An office 
blood pressure will also be obtained by study personnel. Various contact details (including telephone 
numbers and email address) should be obtained from the participant (not supplied to the sponsor) to 
ensure the ability to contact the subject at the required follow-up times (e.g., home, work, cell, and 
primary physician). 
 
Subjects shall be prescribed a minimum of 75 mg aspirin for one month post-procedure. If the subject has 
a documented allergy to aspirin, at least 75 mg clopidogrel per day for one month post-procedure may be 
prescribed. 
 
9.1.6. Follow -up Visits 
See Table 3 for details on follow-up visit window and modality requirements for follow-up visits. See 
Table 4 and section 9.1.9 for escape subject requirements. Subjects will return for follow-up visits at      
2 weeks, 1 month, 6 weeks, 8 weeks (non-escape only), 10 weeks, 3 months, 6 months, and 12 months 
post-procedure. Additionally, a 1 month and 4 month post-procedure in-office follow up is required for 
subjects with a systolic OBP >140 at the 3-month follow-up visit (see section 9.1.10). 
 
Follow-up procedures for subjects treated are listed below and must be performed through 12 months 
follow up for each subject unless otherwise specified. After completion of the study required follow ups, 
the subjects will return to receiving standard of care follow up. 
 
• 
Clinical assessment will be conducted at the 2 week, 1 and 3-months post-procedure follow-up 
visit to evaluate the subject’s current medical condition. At 4, 6, and 12-months follow up an 
abbreviated clinical assessment of weight only is required. 
• 
Office blood pressure measurements will be obtained in accordance with guidelines in 
Appendix 16.5 at all follow-up visits. 

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• 
Laboratory tests are required at 1, 3, 6, and 12-month follow-up visits: 
 
Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, potassium, blood 
urea nitrogen (BUN) or urea, bicarbonate, chloride, and glucose. Bicarbonate will 
not be measured for subjects enrolled in Europe. 
 
eGFR will be calculated from the serum-creatinine in the Chem-7 panel for eligibility 
criteria by using the 4 variable Modification of Diet in Renal Disease (MDRD) 
Formula. 
• 
Medication and adverse event reviews will be completed at each follow-up visit to assess any 
changes in medication usage or medical condition: 
 
Enrollment (consent) to 6-months follow up: all medications and all adverse events 
 
After 6-months follow up to 12-months follow up: all medications and all serious 
adverse events 
• 
Renal artery imaging will be performed at the 6-month follow-up visit to assess if a renal artery 
stenosis is suspected. A renal duplex ultrasound (DUS) will be obtained at 6-months follow up 
and submitted to the DUS Core Laboratory. If the DUS is determined to be nondiagnostic a 
repeat DUS, a MRA, CT or angiogram will be performed (repeat imaging is to be completed 
within 30 days after confirmation of non-diagnostic imaging). If evidence of a clinically 
significant stenosis is indicated by the DUS or MRA/CT Core Laboratory, an angiogram must be 
obtained and submitted to the angiographic core laboratory. 
 
If renal imaging is not obtained at the 6-month follow-up visit due to extenuating 
circumstances, renal imaging is required at the next scheduled study visit. 
• 
24-hour ABPM will be conducted at the 3, 6, and 12-month follow-up visits post-procedure 
according to the guidelines in Appendix 16.5. A repeat ABPM will be required in the event of 
technical issues, failure to follow ABPM guidelines or if the minimum required number of 
daytime and nighttime readings is not obtained. If ABPM is repeated office blood pressure and 
drug testing (for 3-month follow up only) must be repeated on day the ABPM is applied. 
 
Initiate medication re-Introduction for subjects with systolic OBP ≥140 mmHg at 
3-month follow-up visit. Starting at the 3-month follow up after clinical assessment 
and a valid ABPM are completed. 
• 
Mortality assessment will be completed by the investigational site when a subject cannot be 
reached after each of the protocol required follow-up visits. 
• 
Drug testing (urine/blood) to ensure medications are no longer present in the subject’s system. 
A urine sample will be collected, preferably using the subject’s first morning urine. A blood 
sample will be collected at the time of the visit. Drug testing samples collected for subjects that 
screen fail after obtaining the sample, must not be sent to the core lab for analysis. 

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Alternative methods of data collection may be necessary in the case of extenuating circumstances, such 
as a global pandemic, when subjects are prohibited from coming into the office for required assessments. 
For all assessments completed via alternative methods in these circumstances, sites are not required to 
enter a protocol deviation for missing, and/or alternative data collection. Data unable to be collected 
remotely or via an alternative method should be collected at the next possible in-person visit. In the event 
a subject is unable to return for an in-office follow-up visit, the alternative methods of obtaining follow- 
up assessments are listed below: 
 
In-home visit by trained and delegated site personnel or designee, for example, home health care 
personnel. The following assessments may not be completed with an in-home visit: 
 
• 
Renal artery imaging: 
 
Make every effort to schedule in-person renal artery imaging as soon as possible. 
 
When possible, the subjects may be referred to a local imaging center for 
assessment. Local imaging technicians would require study training and delegation 
prior to assessment. 
Virtual visit, inclusive of video with study subject, or a phone visit. 
 
The following assessments may not be completed with a virtual visit or a phone visit: 
 
• 
Clinical assessment: limited review to be completed per physician discretion. 
• 
Laboratory tests: 
 
When possible, the subject should be referred to a local laboratory to collect 
samples. Laboratory kits to be provided to subjects in advance of the visit by study 
site. 
• 
Renal artery imaging: 
 
Make every effort to schedule in-person renal artery imaging as soon as possible. 
 
When possible, the subjects could be referred to a local imaging center for 
assessment. Local imaging technicians would require study training and delegation 
prior to assessment. 
• 
Office blood pressure and ABPM units to be provided to the subjects in advance of the visit by 
the study site. Measurements collected by the subject may be collected and designated as 
subject-reported in the CRF. 
 
Witnessed pill intake prior to ABPM, if applicable. 
 
Documentation of pill intake will be assessed virtually or as confirmed verbally by 
subject. 

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9.1.7. Unscheduled Follow-up Visits 
If subject returns to the institution between the protocol-required screening or follow-up visits for one of 
the following reasons: evaluation of subject for safety reasons, repeat procedures (serum creatinine blood 
draw, repeat renal imaging, or ABPM), or re-consenting, the visit will be treated as an unscheduled visit. 
The reason for the unscheduled visit, as well as any assessment data will be recorded on the Unscheduled 
Follow-up CRF and AE data on the Unscheduled visit CRF (if applicable). If the subject returns for another 
reason, documentation is not required. 
 
9.1.8. Confirmatory Blood Draw s to Assess Renal Function 
Serum creatinine values will be assessed throughout the study. A second blood draw will be required to 
confirm a sustained change in renal function in the event of one of the following: 
 
• 
>50% increase in serum creatinine from baseline (Screening Visit 2) 
• 
eGFR <15 mL/min/1.73m2 using the 4 variable MDRD calculation 
The additional blood draw must be taken at least 21 days from the date of the event noted above and 
documented on an Unscheduled Follow-up CRF. In the event the second blood draw results in the same 
event (e.g., >50% increase in serum creatinine from baseline), an adverse event must be reported. If the 
event is a continuation of an already-identified sustained elevation that did not return to <50% of baseline 
value, another blood draw is not necessary. 
 
9.1.9. Anti-hypertensive medication escape criteria 
In the event a subject’s office SBP ≥180 mmHg, or there is a safety concern, from discharge up to and 
including the 3-month visit, the subject will be seen a second time within 72 hours for a repeat office BP. 
If the subject’s office SBP remains ≥180 mmHg, the subject will be put back on an antihypertensive 
medication regimen per the investigator’s discretion. All efforts should be made to obtain an ABPM and 
Chem-7 panel, and urine and blood for antihypertensive drug testing, prior to the subject being put back 
on medications. If the subject already started medications, the subject and investigator should consider if 
it is safe to take the subject off medications for at least two weeks prior to the 3M visit in order to obtain 
the requirements at the 3-month visit to ensure endpoint data is collected. The subject will be exited from 
the off medications portion of the study and will be followed according to Table 4. If the subject’s office 
SBP< 180 mmHg, the subject will continue to be followed per Table 3. At any time while the subject is not 
taking antihypertensive medications, either the subject or the investigator may restart antihypertensive 
medications if there is a safety concern and the subject will be followed according to Table 4. All blood 
pressures must be taken according to the guidelines in Appendix 16.5 with the exception of needing to 
be completed by 10:30 am. Visits for monitoring the subject’s BP for these purposes must be documented 
on the CRF. 

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9.1.10. 
Medication Re-Introduction for Subjects with 3 M Systolic OBP ≥ 
140 mm Hg 
Upon completion of a valid ABPM at the 3-month follow-up visit, subjects with an office SBP<140 mmHg 
do not need to be followed up for study purposes until the 6-month follow-up visit. Subjects with an office 
SBP ≥ 140 mmHg will begin an antihypertensive medication regimen of one or more of the following 
classes individually or in a combination pill with dosing at the discretion of the study investigator: 
 
• 
ACE/ARB 
• 
Calcium Channel Blocker 
• 
Thiazide-Type Diuretic 
 
Subjects will return at 4 months (±7 days) to perform a clinical assessment and obtain an Office Blood 
Pressure according to the guidelines in Appendix 16.5. 
 
• 
The investigator may utilize his or her discretion in modifying the antihypertensive 
regimen. 
• 
Any modification to the anti-hypertensive medication regimen must be documented on 
the CRFs. 
 
To provide the appropriate oversight for study subjects, the visit schedule between the required 4-month 
and 6-month visits may need to be adapted to account for a subject's clinical status, complexity of the 
medication regimen, and/or the subject’s blood pressure. If additional changes to the anti-hypertensive 
medication regimen are made between 3 and up to 6 months post-procedure, complete an unscheduled 
follow-up visit, and obtain an OPB according to the guidelines in Appendix 16.5. In addition, all medication 
changes are to be documented on the CRF. All medication used should be commercially available in the 
respective geographies and compliant with local labeling. 

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Table 3: Schedule of Treatments and Assessments 
 
Screening 
Procedure 
Post-procedure follow up 
Required Assessments 
SV1 
2Wk 
SV2 
Proced 
ure 
DC 
2Wk 
1M 
6Wk 
8Wk 
10Wk 
3M 
4M1 
6M 
12M 
Mode (O- in office, P-phone) 
O 
O 
O 
O 
O 
P2 
P2 
P2 
O 
O 
O 
O 
Window (M-month, Wk-week, d-days) 
-- 
±3 d 
-- 
±3 d 
±7 d 
±3 d 
±7 d 
±3 d 
±14 d 
±7 d 
±14 d 
±30 d 
Medical history 
X 
Clinical assessment 
X 
X 
X 
X 
X 
X8 
X8 
X8 
Renal denervation procedure 
X 
OBP per study guidelines 
X 
X 
X 
X 
X 
X 
X4 
X4 
X4 
X 
X 
X 
X 
24h ABPM per study guidelines 
X 
X 
X 
X 
Witnessed pill intake3 
X 
X 
Medications prescribed1 
X1 
Blood tests (Chem7)4 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancy test 
X 
Drug testing 
X 
X 
Renal artery imaging– angiogram 
X 
Renal artery imaging-DUS5 
X 
Mortality assessment6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication and event review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
1: 4M follow-up is only required if 3M systolic OBP≥140 mmHg, prescribe AH medications according to section 9.1.9 if SBP ≥ 140 mmHg 
2: If medically necessary, phone contact may be replaced with office visit. OBP (per Appendix 16.5) to be obtained for an office visit or following alternative methods of data collection as described in section 9.1.6. 
3: Witnessed pill intake (if subject is taking AH medications), complete after OBP measurements 
4: Bicarbonate will not be measured for subjects enrolled in Europe. 
5: DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CT or angiogram to be used if DUS is nondiagnostic. Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic or stenosis >60- 
70% is suspected. If renal imaging is not captured at the 6M follow-up visit due to extenuating circumstances, renal imaging is required at the next scheduled study visit. 
6: Mortality assessment will be completed by the investigational site when a subject cannot be reached after each of the protocol required follow-up visits 
7: SAE only review required at 12M visit 
8: Clinical assessment of weight only 8: Clinical assessment of weight only 
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Table 4: Schedule of testing through 12 months for subjects with office SBP ≥180 mmHg (confirmed via 2 sets of measurements) or 
escape via investigator discretion during off-medication period post-procedure 
 
Procedure 
Post-Procedure 
Required Assessments 
Procedure 
DC 
2Wk 
1M 
6Wk 
10Wk 
3M 
6M 
12M 
Mode (O- in office, P-phone) 
O 
O 
O 
O 
O 
O 
O 
Window (M-month, Wk-week, d-days) 
-- 
-- 
± 3 d 
±7 d 
± 3 d 
± 3 d 
± 14 d 
± 14 d 
± 30 d 
OBP per study guidelines 
X 
X 
X 
X 
X 
X 
X 
X 
Renal artery imaging1 
X1 
Mortality assessment2 
X 
X 
X 
X 
X 
X 
X 
Medication and event review 
X 
X 
X 
X 
X 
X 
X 
X3 
1: DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CT or angiogram to be used if DUS is nondiagnostic. Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic 
or stenosis >60-70% is suspected. If renal imaging is not captured at the 6M follow-up visit due to extenuating circumstances, renal imaging is required at the next scheduled study visit. 
2: Mortality assessment will be completed by the investigational site when a subject cannot be reached after each of the protocol required follow-up visits 
3: SAE only review required at 12M visit 
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9.2. 
Assessment of Safety 
Adverse event (AE) information will be collected by the site from subject enrollment (consent) through 6- 
months follow up. After the 6-month follow-up visit and until study termination only serious adverse 
events will be collected. AEs will be followed until the event has resolved (in the case of permanent 
impairment, the event will be followed until it stabilizes, and the overall clinical outcome has been 
ascertained), or subject participation in the study has ended, or study termination. 
 
The Investigator will report any adverse events that may occur to the sponsor, and will assess seriousness, 
relationship (to the device, procedure, and renal denervation therapy where applicable), subsequent 
intervention required, resolution status and whether the adverse event resulted in the subject’s 
discontinuation from the study. The Investigator will provide further information regarding adverse 
events as requested by the sponsor. 
 
9.3. 
Recording Data 
 
9.3.1. 
Database/  Case Report Forms 
Data collected on each subject will be recorded on a web-based CRF. This study will utilize an Oracle 
Clinical Remote Data Capture (RDC) system that is the property of Medtronic. Each enrolled subject is 
assigned a unique study ID number. Records of the subject/subject ID relationship will be maintained by 
the study site. Individual subject medical information obtained as a result of this study will be considered 
confidential. 
 
Authorized site personnel as indicated on the Delegation Task List (DTL) will record the required data on 
CRFs. Study personnel delegated for CRF completion and/or approval per the DTL will be trained on the 
use of the RDC system and thereafter be provided with a username and password to access the system. 
Passwords are individual and cannot be shared. 
 
The CRFs must be completed and updated to reflect the latest observations on the subjects participating 
in the study. The investigator (or approved sub-investigator) will electronically sign the appropriate pages 
of each CRF. The Oracle Clinical RDC system maintains an audit trail of entries, changes, and corrections 
in CRFs. If a person only authorized to complete CRFs makes changes to an already signed CRF, the 
investigator shall re-approve this CRF. 
 
The hospital files (electronic or paper) will constitute source data. For the purpose of adjudication of 
events by the CEC, relevant event-related source documents will be redacted and collected for events 
that need to be adjudicated by the CEC. 
 
The CRFs may not serve as source documents. Source documentation for data elements not routinely 
captured in medical records (e.g., renal angiogram variables, procedural details) may vary from center to 

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center. The site may use technical worksheets if identified as source documents. Worksheets need to be 
signed and dated by the principal investigator or a delegated investigator. 
 
The principal investigator is responsible for ensuring that all sections of each CRF are complete and correct 
and that those entries can be verified against source data. 
 
Medtronic will be responsible for the processing and quality control of the data. Data review, database 
cleaning and issuing and resolving data queries will be done according to Medtronic internal SOPs and the 
Data Management Plan for this study. The study database will employ validation programs (e.g., range 
and logic checks) on entered data to identify possible data entry errors and to facilitate data validation. 
 
9.3.2. 
Blood Pressure Monitors 
The following equipment will be provided to the sites and utilized for assessing the endpoints of the study: 
 
• 
Office blood pressure monitors 
• 
24-hour ambulatory blood pressure monitors 
Medtronic will provide automated blood pressure monitors to participating centers for recording office 
based systolic and diastolic blood pressure through the course of the study. Blood pressure monitors will 
be provided to the sites for use with subjects to record ambulatory systolic and diastolic blood pressure 
at baseline and through subsequent follow ups. Medtronic will be responsible for the timely calibration 
of the monitors and replacement of monitors, in case of malfunction or failure to record accurate and 
reliable blood pressure data. 
 
9.4. 
Deviation Handling 
A study deviation is defined as an event where the investigator or site personnel did not conduct the study 
according to the CIP, EC/IRB, applicable laws or regulations, or the investigator agreement. 
 
Regulations require that investigators maintain accurate, complete, and current records, including 
documentation of any deviations from the CIP including the date of and reason for the deviation. The 
deviations must be reported to the sponsor on the CRF. 
 
Investigators are not allowed to deviate from the protocol, except under emergency circumstances to 
protect the rights, safety, and well-being of human subjects. Investigators are required whenever possible 
to obtain prior approval from the Medtronic Clinical Research Department before initiating changes in or 
deviations from the CIP, except where necessary to protect the life or physical well-being of a subject in 
an emergency. Such approval will be documented in writing and maintained in the study files. Prior 
approval is not expected in situations where unforeseen circumstances are beyond the investigator’s 
control (e.g., subject did not attend scheduled follow-up visit, blood sample lost by laboratory), however, 
the event, is still considered a deviation. 

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Deviations shall be reported to Medtronic regardless of whether medically justifiable, pre-approved by 
Medtronic, or taken to protect the subject in an emergency. Deviations to protect the life or physical 
wellbeing of the subject in an emergency must be reported to Medtronic and the EC/IRB within five 
working days. 
 
Subject-specific deviations will be reported on the Deviation CRF. Deviations that are not subject specific 
(e.g., unauthorized use of an investigational device outside the study, unauthorized use of an 
investigational device by a physician who has not signed an investigator agreement) will be reported to 
Medtronic in writing. Investigators will also adhere to procedures for reporting study deviations to their 
EC/IRB in accordance with their EC/IRB requirements. 
 
The investigational site’s compliance with the CIP will be assessed on an ongoing basis. Corrective and 
preventive action plans will be developed and implemented to secure compliance. In cases of serious non- 
compliance, the sponsor may decide to stop subject enrollment and site participation at an investigational 
site based on its assessment of repeated occurrences of significant non-compliance. 
 
Examples of deviations include but are not limited to the following: 
 
• 
Failure to obtain informed consent prior to participation 
• 
Incorrect version of the Subject Informed Consent used 
• 
Failure to obtain EC/IRB approval before the start of the study 
• 
Treated subject did not meet inclusion/exclusion criteria 
• 
Follow-up visit not done 
• 
Adverse events not reported in the required time frame as required by regulation or as specified 
in CIP 
• 
Source data permanently lost 
• 
Enrollment of subjects during lapse of EC/IRB approval 
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, additional training, terminate the 
study, etc.). Repetitive or serious investigator compliance issues may result in the need to initiate a 
corrective action plan, and in some cases freeze enrollment or ultimately terminate the investigator’s 
participation in the clinical study. The sponsor shall consider terminating or suspending the participation 
of a particular investigational center or investigator in in the clinical investigation if monitoring or auditing 
identifies serious or repeated deviations on the part of an investigator. 
 
Medtronic will provide investigational site-specific reports to the investigators on a periodic basis 
summarizing information on deviations that occurred at the investigation site. 

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9.5. 
Reporting Requirements 
 
9.5.1. 
Investigator Reporting Responsibilities 
 
Report 
Submitted to 
Description 
Adverse events 
Sponsor, EC/IRB, and 
local Competent 
Authority, where 
applicable 
Refer to Section 11.2 for reporting requirements. 
Progress report 
Sponsor and EC/IRB 
Provide if required by local law or EC/IRB. 
(ISO 14155). 
Withdrawal of EC/IRB 
approval 
Sponsor 
Investigator will inform Medtronic as soon as 
possible in case EC/IRB approval is withdrawn. 
In the US, the investigator must report a 
withdrawal of the reviewing IRB within five 
working days of the IRB’s withdrawal. 
Final report 
EC/IRB (all sites), 
sponsor (US sites) 
A copy of the Final Clinical Study Report will be 
provided to the EC/IRB and submitted in 
accordance with the EC/IRB policies and 
procedures. 
In the US, the site’s final report must be 
submitted to the sponsor and IRB within three 
months after termination or completion of the 
investigation or the investigator’s part of the 
investigation. 
Deviations from Investigational Plan 
Planned deviation 
Sponsor, EC/IRB, 
regulatory authority, as 
applicable by local 
regulations 
Prior approval from Medtronic must always be 
obtained from Medtronic. If the deviation affects 
scientific soundness of the clinical study or the 
rights, safety, or welfare of the subject and is not 
an emergency, prior approval must be obtained 
from the EC/IRB and Competent Authority as 
applicable. 

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Report 
Submitted to 
Description 
Other deviations 
Sponsor, EC/IRB, 
regulatory authority, if 
applicable 
Deviations that are beyond the control of the 
investigator (such as subject who fails to return 
to follow-up visit) or deviations that do not affect 
the scientific soundness of the clinical study or 
the rights, safety, or welfare of the subject and 
are not an emergency, should be submitted as 
they are identified by the investigational site or 
Medtronic staff. 
For emergency deviations to protect the life or 
physical wellbeing of the subject in an 
emergency, these must be reported to Medtronic 
and the EC/IRB within five working days. 
If an investigator uses a device without obtaining 
subject consent, the investigator shall report such 
use within 5 working days after device use. 
 
 
9.5.2. Sponsor Reporting Responsibilities 
 
Report 
Submit to 
Description 
Withdrawal of EC/IRB 
or RA approval 
EC/IRB, Investigators, 
and regulatory 
authorities, where 
applicable 
In case of withdrawal of EC/IRB approval 
Medtronic will suspend the clinical study as 
described below. 
In the US, notification within 5 working days. 
Premature termination 
or suspension of study 
EC/IRB, Investigators, 
and regulatory 
authorities, where 
applicable 
Medtronic will provide prompt notification of 
termination or suspension and reason(s) to 
investigator and where required to EC/IRB and 
regulatory authorities. 
Progress report 
IRB/EC and 
RAs 
This will be submitted to the IRB/EC only if 
required by the IRB/EC. 
In the US, progress reports will be submitted per 
FDA requirements. 

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Report 
Submit to 
Description 
Final report 
Investigators, and 
regulatory authorities, 
where applicable 
Medtronic will provide all investigators with a 
copy of the final clinical study report of the 
clinical study. 
EC/IRBs and regulatory authorities will be 
informed when required. 
• The investigator shall have the opportunity 
to review and comment on the final report. 
• If a clinical investigator does not agree with 
the final report, his/her comments shall be 
communicated to the other investigator(s). 
The coordinating investigator shall sign the 
report. If no coordinating investigator is 
appointed, then the signature of the principal 
investigator in each study site should be 
obtained. 
Emergency deviations 
from CIP 
Regulatory authorities, 
where applicable 
If required, Medtronic will inform regulatory 
authorities as soon as possible about any 
emergency deviations that affect scientific 
soundness of the clinical study or the rights, 
safety, or welfare of the subject. 
Study deviation 
Investigators 
Ensure that all deviations from the CIP are 
reviewed with the appropriate clinical 
investigator(s), are reported on the CRFs and the 
final report of the clinical investigation. (ISO 
14155:2020) 
Study site specific study deviations will be 
submitted to investigators periodically. 

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9.6. 
Subject Withdrawal or Discontinuation 
 
9.6.1. Subject Exit from Study 
There are many scenarios in which a subject may exit the study. Table 5 details how the data will be 
handled for each scenario. 
 
It is the subject’s right to withdraw from the study at any time and for any reason without sanction, 
penalty, or loss of benefits to which the subject is otherwise entitled, and without jeopardizing their future 
medical care. The investigator may withdraw the subject at any time to protect the health, safety, or 
welfare of the subject. The subject’s vital status should be recorded at the last point of contact (if outside 
a study-required visit). Every effort should be made to collect the status of any ongoing adverse events, 
at a minimum. The subject will not be considered lost to follow up during the course of this study. 
 
All subjects will be encouraged to remain in the study through the last follow-up visit, including receipt of 
any results such as valid ABPM, labs, imaging, etc. Subjects who discontinue participation prematurely will 
be included in the analysis of results; but will not be replaced in the enrollment of total study subjects. If 
the subject discontinues participating in the study prior to completing the study requirements, the reason 
for withdrawal will be recorded in the subject’s study records. 
If withdrawal from the study is due to problems related to the investigational device safety or 
performance, the investigator shall ask for the subject’s permission to follow the subject’s status outside 
the clinical study. 
 
Table 5: Scenarios for Subject Exit from Study 
 
Scenario 
Follow up Required 
Subject enrolled (Patient Information and 
Informed Consent form signed), but the 
procedure is never attempted 
None 
Subject enrolled and exits the study early due to 
any of the following: 
- death 
- withdrawal 
Through point of death, withdrawal, or last visit 
completed; consent to continue to allow data 
collection from their medical records is required 
Subject enrolled, undergoes renal denervation 
and completes the study requirements 
Through a minimum of 12 months follow up post- 
procedure up to a maximum of 5 years follow up 
post-procedure. 

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9.6.2. Missed Follow -up Visits 
Every effort should be made to ensure subjects return to the investigational site for all protocol required 
follow-up visits. If the subject is unable to complete an in-office, in-home, virtual or phone visit, the 
Investigator (or designee) must document the reason the subject was unable to complete the visit and, if 
applicable, follow the requirements for deviation reporting as outlined in section 9.4. If a subject misses 
a follow-up visit, they will not be considered lost to follow up and all remaining follow-up visits will be 
scheduled per protocol. The Investigator should also make every effort to contact the subject within the 
visit window, to collect the subject’s vital status as well as information related to potential adverse events. 
 
At a minimum, four attempts must be made to contact the subject and documented in the subject’s study 
records before a visit can become a missed visit: 
 
• 
3 telephone attempts to the subject’s last known phone number, and if unsuccessful, 
• 
1 letter from the PI to the subject’s last known address sent by courier with tracking 
information. 

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10.1. 
Potential Risks 
The inexorable progression from asymptomatic hypertension to evidence of end organ disease is well 
known. Both embolic and thrombotic stroke as well as both systolic and diastolic heart failure, and 
progressive renal dysfunction are known to be companions of chronic hypertension. Beyond contributing 
to renal failure, hypertension plagues the treatment of subjects with end stage renal disease treated with 
dialysis and transplant. In aggregate, reduction of blood pressure is linearly related to reduction of 
mortality in population studies19,20, with large individual subject variability depending on the presence of 
additional cardiovascular risk factors, such as lipid abnormalities, diabetes, cigarette smoking, and 
antecedent heart disease. Despite the availability of numerous pharmaceuticals from many different 
pharmaceutical classes, subjects often fail to attain adequate blood pressure control. Additionally, 
pharmaceutical interventions that rely on numerous medications are plagued with drug interactions and 
side effects, which contribute to physician decisions to discontinue medications and subject decisions to 
not remain persistent or compliant with the prescribed drug strategies. The development of an effective 
alternative treatment of hypertension, which offers an adjunct to pharmaceutical care or an alternative 
to undesirable pharmaceutical complications, may prove to be of obvious value to subjects, physicians, 
and the health system. 
 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life of a product, 
from the business analysis phase through development, market release, and post-market surveillance. 
 
The primary risks of the renal denervation procedure are similar to the risks of all diagnostic procedures 
requiring catheterization of the arteries of the body. The following are potential risks of the 
catheterization procedure (including renal angiogram) in accordance with the IFU: 
 
• 
Death – a complication or deterioration of health ultimately leading to a subject’s death. 
• 
Cardiopulmonary arrest – cessation of blood circulation and/or respiration due to dysfunction 
of the heart and/or lungs. 
• 
Heart rhythm disturbances – disruption of normal heart rate or rhythm, including bradycardia 
treated with atropine. 
• 
Embolism – formation and dislodgement of a blood clot (thrombus) or dislodgement of 
cholesterol/plaque within the blood vessel, which travels downstream into small vessels, 
blocking blood flow and causing temporary or permanent damage to organs distal to 
blockage. Emboli are known to cause myocardial infarction, stroke or kidney damage, 
peripheral ischemia and may ultimately lead to incapacitation or death. 
• 
Complications at catheter insertion site in the groin: 
- 
Pain – discomfort at the catheter insertion site that can range from mild to severe. 
10. Risks and Benefits 

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- 
Hematoma/Bruising – a collection of blood in the tissue surrounding the catheter 
insertion site. 
- 
Pseudoaneurysm – a collection of blood in the tissue surrounding the catheter 
insertion site due to ongoing leaking of blood from a blood vessel. 
- 
AV fistula – an abnormal connection between an artery and a vein (i.e., caused by 
needle insertion through the femoral artery and vein). 
- 
Infection – localized redness, heat swelling and pain at the catheter insertion site. 
- 
Significant bleeding – blood loss from the catheter insertion site requiring surgery or 
transfusion of 2 or more units of packed red blood cells (PRBCs). 
• 
Retroperitoneal bleeding – bleeding into the retroperitoneal space. 
• 
Vascular complications requiring surgery – damage to an artery (e.g., femoral) or vein 
requiring surgical repair. 
• 
Perforation of a blood vessel – unintended puncture through the wall of a blood vessel, such 
as a renal artery, requiring repair. 
• 
Dissection of a blood vessel – a tear within the wall of a blood vessel, which allows blood to 
separate the wall layers. 
• 
Hypotension – low blood pressure. 
• 
Hypertension – high blood pressure. 
• 
Nausea – a sensation of unease and discomfort in the upper stomach with an urge to vomit. 
• 
Vomiting – forceful expulsion of stomach contents through the mouth and/or nose. 
• 
Complications associated with the contrast agents – adverse effects of contrast agents used 
during the procedure (e.g., allergic reaction or radiocontrast nephropathy). 
• 
Complications associated with medications commonly utilized during the procedure – known 
risks of medications commonly used during the procedure (e.g., narcotics, anxiolytics, other 
pain medications, anti-vasospasm agents). 
There are additional risks that could possibly be associated with the denervation procedure/therapy. 
These potential risks have not yet been quantified, but may include: 
 
• 
Pain – discomfort that can range from mild to severe that may occur peri- and/or post- 
procedure. 
• 
Damage to one or both kidneys, loss of kidney function, and/or need to remove a kidney – 
perforation of kidney or an occlusion of blood flow to the kidney (e.g., from stenosis or 
embolism) and/or reduction of glomerular filtration rate or need for nephrectomy. If severe 
enough, this could require dialysis. 
• 
Renal artery aneurysm – localized weakening and ballooning of the renal artery from the 
interventional procedure or the delivery of RF energy. 
• 
Renal artery stenosis - narrowing of the renal artery due to the interventional procedure or 
the delivery of RF energy. 

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• 
Arterial spasm or constriction – Acute or chronic narrowing of the renal artery lumen diameter 
at denervation locations due to arterial muscle contraction, local tissue contraction or local 
edema. 
• 
Thermal injury to the vasculature or other structure from energy application - damage to an 
artery, vein, or other structure due to the delivery of energy. 
• 
Hypertension – worsening high blood pressure. 
• 
Hypotension – low blood pressure. BP reduction may occur too far and/or too quickly and 
may cause end organ hypoperfusion. 
• 
Orthostatic hypotension – temporary reduction of blood pressure when going from lying to 
standing, coupled with symptoms (e.g., dizziness, light headedness). 
• 
Hematuria – blood in urine. 
• 
Hemorrhage – significant blood loss. 
• 
Proteinuria – elevated levels of protein in urine. 
• 
Electrolyte disturbances – an imbalance of the electrolytes (sodium, potassium). 
• 
Skin burn – damage to the skin caused by energy conduction via the ground pad used with 
the Symplicity renal denervation system 
 
The risks associated with not having a controlled blood pressure during the first four months include: 
 
• 
Angina (chest pain, pressure or squeezing) 
• 
Myocardial infarction (improper blood flow to the heart) 
• 
Pulmonary edema (fluid accumulation in the air spaces of the lungs) 
• 
Heart failure 
• 
Stroke (disturbance in the blood supply to the brain) 
• 
Atrial fibrillation (abnormal heart rhythm) 
• 
Death 
 
There are additional risks that could possibly be associated with the tests and procedures performed for 
the clinical study. These potential risks are described below. 
 
The risks associated with subjects being off their antihypertensive medications during the washout period 
through three months post-procedure include: 
 
• 
Death 
• 
Stroke 
• 
MI 
• 
Angina 
• 
Heart Failure 
• 
Atrial fibrillation 

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• 
Pulmonary Edema 
 
There are risks related to the blood tests required for the study, (e.g., excessive bleeding, fainting or light- 
headedness, hematoma (bruising), infection, or the requirement of multiple punctures to locate a vein to 
draw the sample). 
 
This study involves exposure to a small amount of radiation. As part of everyday living, people are exposed 
to naturally occurring background radiation and receive a dose of about 3 millisieverts (mSv) each year. 
The effective dose from the denervation procedure is less than 5.5 mSv. The dose from this procedure is 
comparable to that received from many diagnostic medical x-ray and nuclear medicine procedures. 
 
Subjects may undergo additional renal imaging via computerized tomographic angiography (CTA). The 
risks of undergoing a CT scan include ionizing radiation and contrast-induced neuropathy. 
 
There is a possibility of risks to an unborn child. These risks are unknown. Women who are pregnant, 
nursing or expect to become pregnant during the course of the study are excluded from participating. 
 
The study may involve unknown or unforeseen side effects or complications other than those mentioned 
above. If the above complications occur, they may lead to repeat or prolonged hospitalization, repeat 
procedures, emergency surgery, other emergency procedures, or, in rare cases, death. 
 
The risks must be continuously monitored, assessed, and documented by the investigator. 
 
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are 
specifically defined in the CIP plan and constantly monitored. 
 
10.2. 
Potential Benefits 
Although no assurances or guarantees can be made, there is a reasonable expectation that the renal 
denervation procedure may be beneficial to the subject. Treatment with the Medtronic Symplicity Spyral 
multi-electrode renal denervation catheter and the Symplicity G3 renal denervation RF generator may 
reduce the nerve activity to and from the kidneys and cause a reduction in blood pressure. Evidence in 
the literature suggests that reduction of efferent sympathetic nerve activity to the kidney can a) cause 
relief of renal vasoconstriction, resulting in improved kidney function; b) reduce sodium retention, which 
can improve the clinical condition of subjects with medical problems related to excess salt and water; and 
c) reduce the release of renin - a renal produced hormone which is often elevated in subjects with either 
severe hypertension or heart failure.21 Interference of afferent nerve activity from the kidneys can reduce 
central sympathetic activity, also causing reduction of blood pressure. 

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A reduction in blood pressure may result in the decrease or elimination of any symptoms associated with 
high blood pressure and/or reduction of blood pressure medications and the side effects related to 
medications. In addition, reduction in blood pressure may decrease the risk of other related adverse 
events associated with high blood pressure (risk of stroke, heart attack, renal failure, etc.). 
 
Hyperactive sympathetic nervous system activity is associated with increased risk of death in subjects with 
heart failure.22-26 With a reduction in renal sympathetic nervous system activity, the combination of 
reduced intra and extra renal neurohormonal activity may either retard the progression of ventricular 
hypertrophy or induce regression of hypertrophy - both of which could ameliorate symptoms associated 
with heart failure.27 
Reduction of central sympathetic activity may also reduce resistance to the action of insulin – potentially 
improving glycemic control.28,29 
 
10.3. 
Risk-Benefit Rationale 
Residual risks of the Symplicity renal denervation system have been characterized as acceptable per 
Medtronic standard operating procedures for risk management. No further risk mitigation is required at 
this time. Medtronic will continue to evaluate the risk/benefit profile, safety, and performance of the 
product as data becomes available. 
 
The following measures will also be taken to minimize risk to participants as part of this CIP: 
 
• 
Physicians and staff will receive appropriate training prior to using the study devices. Training 
will include instruction on equipment and lab setup, assessing renal anatomy, intra-procedural 
subject management and monitoring, Symplicity Spyral catheter delivery and RF ablation, and 
post-procedural care. 
• 
Instructions for Use are provided with each Symplicity Spyral catheter and a User’s Manual is 
provided with each Symplicity G3 generator to ensure consistent use of the device within pre- 
tested parameters. 
• 
The system’s design and software include several safety mechanisms to reduce risk to the 
subject (limitations on temperature, time, impedance, and power delivered to the subject). 
• 
Subjects will be closely monitored by appropriately trained personnel during the procedure and 
at regularly scheduled intervals for the duration of the study. 
• 
Physicians will employ usual and customary clinical technique (e.g., sterile technique during 
catheter use and aseptic wound care procedures). 
• 
A Data Safety Monitoring Board (DSMB) will be established to monitor the health, safety, and 
welfare of subjects and provide safety surveillance. The DSMB will review safety and efficacy 
data at pre-specified time points and provide recommendations regarding the continuation of 
the study to the sponsor. 

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The detrimental effects of uncontrolled hypertension are well established and an alternative treatment is 
worth investigation. Renal denervation using the Symplicity Spyral renal denervation system is one such 
alternative. Although there are several theoretical risks that could be associated with the device and 
procedure, the likelihood of those risks is believed to be low and will be carefully monitored in the study. 
The potential benefits, including blood pressure reduction and the associated effects of lowered blood 
pressure, justify the investigation of renal denervation in this study. 
 
The Symplicity renal denervation system is considered a significant risk (SR) 21 CFR 812. 

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11.1. 
Definitions/Classifications 
For each reported adverse event, the Investigator will assess the events in terms of relationship to the 
device, relationship to the procedure and relationship to the renal denervation therapy (if applicable) as 
defined below: 
 
• 
Device: A device related AE is defined as any AE for which a causal relationship between the 
event and the Symplicity Spyral catheter or Symplicity G3 generator can be established. 
• 
Procedure: A procedure related AE is defined as any AE occurring within seven days post- 
procedure associated with the renal angiogram and intervention techniques involved in 
preparing for the actual renal denervation treatment. 
• 
Therapy: A therapy related AE is a defined as any AE associated with a subject’s physiological 
response to the renal denervation procedure. 
For the purposes of the clinical report, Medtronic will classify each adverse event according to 
International Organization of Standardization (ISO) ISO 14155:2020. 
 
Where the definition indicates “device”, it refers to any device used in the study. This might be the device 
under investigation, or any market released component of the system. This does not apply to the OBP or 
ABPM devices used within the study. 
 
Adverse Event (AE): (ISO14155 3.2) 
 
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 
investigational medical device and whether anticipated or unanticipated. 
 
NOTE 1: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
Adverse Device Effect (ADE): (ISO14155 3.1) 
 
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
11. Adverse Events and Device Deficiencies 

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NOTE 2: This definition includes any event resulting from an error use or from intentional misuse 
of the investigational medical device. 
NOTE 3: this included ‘comparator’ if the comparator is a medical device. 
Device Deficiency (DD): (ISO14155 3.19) 
 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, 
safety, or performance. 
 
NOTE 1: DD include malfunctions, use errors and inadequacy in the information supplied by the 
manufacturer including labeling. 
NOTE2: This definition includes device deficiencies related to the investigational medical device or 
the comparator. Potential for SADE is defined as device deficiencies that did not lead to an adverse 
event but could have led to a SADE (ISO14155 7.4.3) 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate 
Malfunction: (21 CFR 803.3(m)) 
 
The failure of a device to meet its performance specifications or otherwise perform as intended. 
Performance specifications include all claims made in the labeling for the device. The intended 
performance of a device refers to the intended use for which the device is labeled or marketed. 
Product labels, Instructions for Use, and User Manuals for this study are provided separately. 
 
Product Complaint: 
 
Any written, electronic, or oral communication that alleges deficiencies related to the identity, 
quality, durability, reliability, safety, effectiveness, or performance of a medical device that has 
been placed on the market. 
 
- 
Abuse: abnormal use 
- 
Misuse: user error 
 
 
Serious Adverse Event (SAE): (ISO 14155 3.45) 
 
Adverse event that led to any of the following 
 
a) 
death, 

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b) 
serious deterioration in the health of the subject, users or other persons as defined 
by one or more of the following: 
 
1) 
a life-threatening illness or injury, or 
2) 
a permanent impairment of a body structure or a body function, including 
chronic diseases or 
3) 
in-patient or prolonged hospitalization, or 
4) 
medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, 
 
c) 
fetal distress, fetal death or a congenital abnormality or birth defect including 
physical or mental impairment. 
NOTE 1: 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. 
Serious Adverse Device Effect (SADE): (ISO 14155 3.44) 
 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
Serious Adverse Health Consequences: (21 CFR 814) 
 
Any significant adverse experience, including those which may be either life-threatening or 
involve permanent or long-term injuries, but excluding injuries that are non-life-threatening and 
that are temporary and reasonably reversible. 
 
Serious Health Threat: (ISO 14155 3.46) 
 
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a 
serious deterioration in the health in subjects, users, or other persons, and that requires prompt 
remedial action for other subjects, users, or other persons 
 
NOTE 1: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring 
at short intervals. 
As this study will be conducted in compliance to US Code of Federal Regulations (CFR) 21 CFR Part 812 the 
following definitions will apply: 
 
Unanticipated Adverse Device Effect (UADE): (21 CFR 812.3) 
 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death, was not previously identified in 

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nature, severity, or degree of incidence in the clinical investigation plan or application (or a 
supplementary plan or application), or any other unanticipated problem associated with a device 
that relates to the rights, safety, or welfare of subjects. 
 
11.2. 
Reporting of Adverse Events and Device Deficiencies 
Adverse event (AE) information will be collected by the site from subject enrollment (consent) through 
study termination or study exit (AEs up to 6-months follow up, SAEs up to 12-months follow up). AEs will 
be followed until the event has resolved (in the case of permanent impairment, the event will be followed 
until it stabilizes and the overall clinical outcome has been ascertained), subject exit or study termination. 
 
The Investigator will report any adverse events that occur to the sponsor, will indicate the date of the 
adverse event, and will assess seriousness, relationship (to the device, procedure, and renal denervation 
therapy where applicable), subsequent treatment or intervention required, resolution status and whether 
the adverse event resulted in the subject’s discontinuation from the study. The Investigator will provide 
further information regarding adverse events as requested by the sponsor. In the event of an unexpected 
death, an autopsy should be requested. 
 
Investigator reporting requirements of events and device deficiencies are outlined in Table 6. 
 
Table 6: Required Timeframes for Adverse Event and Device Deficiency reporting from 
Investigator to Medtronic 
 
Event Type 
Timeframe for Reporting 
Serious adverse event (SAE) 
Immediately (but no later than 10 calendar days) 
after the investigator first learns of the event or 
of new information in relation with an already 
reported event. 
Serious adverse device effect (SADE) 
Adverse device effect (ADE) or device 
related adverse event 
Unanticipated adverse device effect (UADE) 
All other adverse events (AE) 
Device deficiencies with SADE potential 
As soon as possible, but no later than 48 hours 
after the investigator first learns of the event. 
All other device deficiencies 

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Adverse Event Sponsor reporting requirements in EU/EEA 
 
In the EU/EEA region, MDR Art. 80(2) should be followed. Table 7 documents the events to be reported 
and the relevant timeframe. 
 
Table 7: Sponsor Adverse Events Reporting Requirements to National Competent Authority 
in EU/EEA 
 
Events to Report 
Reporting Requirements and Timeframe 
Preceding investigational procedure related SAE 
(occurred in the study under same CIP) – 
including updates. 
Immediately, but no later than 7 calendar days 
after awareness 
 
 
In addition, it is the responsibility of the investigator and the sponsor to abide by AE reporting 
requirements stipulated by local law and the study site’s EC/IRB. 
 
11.2.1. 
Reporting Process 
All adverse events, regardless of relatedness or outcome, must be recorded and reported through the 6- 
month follow up. After the 6-month visit has been completed, only serious adverse events (SAEs) are 
required to be recorded and reported. Adverse events will be documented on the appropriate CRF, 
reported by the investigational site to Medtronic, and to the EC/IRB (if required) within the EC/IRB 
required timeframe and local and national regulations, as applicable. Adverse events shall be reported on 
the adverse event CRF, one CRF for each adverse event term. The site should make all effort to provide 
the information required on the Adverse Event CRF and all adverse events should be reported within the 
event reporting timeframe requirements (refer to Section 1.1.1). For adverse events that require 
immediate reporting, initial reporting will be done on the CRF by completing as much information as is 
available. The AE CRF must be “saved as Complete” in the remote data capture (RDC) system to ensure it 
is reported to Medtronic as soon as possible. For any changes in status of a previously reported adverse 
event or DD (i.e. change in actions taken, change in outcome, change in relatedness), information needs 
to be updated on, or added to the original AE or DD form. 
 
All adverse events and device deficiencies will be reviewed by the Medtronic Core Clinical Solutions Safety 
Department. This review will include the determination whether the adverse event meets regulatory 
reporting requirements. The sponsor will ensure timely adverse event/device deficiency reporting to meet 
global regulatory requirements. In case the adverse event/device deficiency is related to a Medtronic 
market released device used during the study, the Medtronic employee who first becomes aware will 
report this device related adverse event/device deficiency to the Medtronic Product Experience 

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Management (PXM) within 48 hour timeframe.. The Medtronic Product Experience Management (PXM) 
will ensure prompt review and appropriate reporting. 
 
Table 8: Adverse Event Classification Responsibilities 
 
What is 
classified? 
Who 
classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, procedure, therapy 
Sponsor 
Device, procedure, therapy, outside standard of care CIP procedure 
Seriousness 
Investigator 
SAE, DD with SADE potential 
Sponsor 
SAE, UADE (for all system or procedure related AEs), DD with SADE 
potential 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other supporting data 
Sponsor 
MedDRA term assigned based on the data provided by investigator 
 
11.2.2. 
Non-reportable and Unavoidable Adverse Events 
The following events do not qualify as adverse events and do not need to be reported: 
 
• 
Documented pre-existing conditions without a change in the nature or severity of the 
condition 
• 
Pre-planned hospitalizations for device change out (e.g. CRT, ICD, IPG) 
• 
Appropriate cardiac device therapies received as a result of pre-existing arrhythmias 
• 
SBP below 100 mmHg without producing symptoms suggestive of hypotension 
• 
Unavoidable adverse events (Table 9) 

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The following table indicates the unavoidable adverse events that do not need to be reported. However, 
onset of any events listed in Table 9 after the specified timeframes should be reported as an AE. 
 
Table 9: Unavoidable Adverse Events 
 
Event Description 
Time Frame (hours) from the Renal 
Denervation Procedure 
Anesthesia related nausea/vomiting 
24 
Low grade fever (<100ᴼF or <37.8ᴼC) 
48 
Mild to moderate bruising/ecchymosis (at insertion site) 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Elevated blood pressure 
During the procedure 
 
11.2.3. 
Unanticipated Adverse Device Effect 
Medtronic will conduct an evaluation of the unanticipated adverse device effect (UADE) in accordance 
with 21 CFR 812.46(b) and shall report the results of such evaluation to US FDA and to all reviewing ethics 
committees and participating investigators within 10 working days after Medtronic first receives notice of 
the effect. Thereafter, Medtronic shall submit such additional reports concerning the effect as FDA 
requests. Events reported for this study from all geographies will be reviewed and assessed for UADE 
reporting to the FDA. Events deemed to be UADEs will be submitted per local reporting requirements 
 
11.2.4. 
Device Deficiencies 
All device deficiencies and malfunctions will be documented on the appropriate CRF, reported to 
Medtronic, and reported to the EC/IRB (if required) within the EC/IRB required timeframe and local and 
national regulations. Device deficiencies that did not lead to an adverse event should be reported on a 
device deficiency form, one for each device deficiency. Please refer to the device deficiency CRF for the 
information to be reported for each device deficiency that did not lead to an adverse event. The device 
deficiency CRF must be “saved as Complete” in the remote data capture (RDC) system to ensure it is 
reported to Medtronic as soon as possible. 
 
Device deficiency reporting requirements do not apply to the OBP or ABPM devices used within the study 
and will not be collected for these devices. 

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11.2.5. 
Product Complaint Reporting 
Product complaint reporting and vigilance reporting are applicable, and AEs related to any market- 
released device during the study must be reported. Refer to local regulations for reporting requirements. 
 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless whether they are related to intended use, misuse, or abuse 
of the product. Reporting must be done immediately and via the regular channels for market-released 
products. The reporting of product complaints by the sponsor must be done according to the local 
standard operating procedures. Medtronic will notify the RAs (e.g. CA) as applicable for the following 
incidents immediately upon learning of them and is not limited to AEs and DDs only: 
 
• 
Any malfunction or deterioration in the characteristics and/or performance of a device, as 
well as any inadequacy in the labeling or instructions for use which led or might have led to 
the death or serious deterioration in the state of health of a subject, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
• 
Any serious deterioration in the state of health, including: 
- 
Life-threatening illness or injury, 
- 
Permanent impairment of a body function or permanent damage to a body 
structure, 
- 
A condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure. 
 
11.2.6. 
Emergency Contact 
Investigators should contact their responsible Medtronic study representative if they have any questions 
regarding reportable AEs or device deficiencies. sponsor contact information (including name, title, 
address, and telephone number(s)) is subject to change and will be maintained in a document separate 
from the CIP and provided to sites. 
 
For reportable AEs or device deficiencies that require immediate reporting (see Table 6), initial reporting 
shall be done by completing the appropriate CRF. If the CRF is not available, the reportable AE or device 
deficiency form in the Investigator Site File must be completed, signed, and dated by the principal 
investigator or his/her authorized designee(s), and submitted to the RS MC2 Safety Portfolio APV CRDN 
rs.mc2safetyportfolioapvcrdn@medtronic.com email box or to the responsible Medtronic study 
representative. In due time, the AE or device deficiency needs to be entered in the CRF as well. 

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12.1. 
Clinical Event Committee 
The clinical event committee (CEC) is composed of multiple clinicians with pertinent expertise who are 
not participants in the study and who do not have any other real or potential conflicts of interest. The CEC 
is charged with the development of specific criteria used for the categorization of clinical events and 
clinical endpoints in the study. Criteria will be established for selected complications and clinical events. 
At the onset of the study, the CEC will establish explicit rules outlining the minimum amount of data 
required, and the algorithm followed in order to classify a clinical event. The CEC will meet regularly to 
review and adjudicate pre-defined clinical endpoint events. If needed, the adjudication committee will 
require collection of additional source documentation from the clinical centers. The procedures by which 
the CEC will operate will be documented in a separate charter. 
 
12.2. 
Data Safety Monitoring Board 
The primary responsibility of the data safety monitoring board (DSMB) is to monitor the health, safety, 
and welfare of subjects. The DSMB will be composed of physicians who have experience in clinical studies 
in hypertension and/or cardiovascular indications and one biostatistician with experience in analysis of 
clinical trials. The members of the DSMB will not be investigators in the study and will be independent of 
Medtronic. Medtronic personnel may attend the meetings to answer questions but will not have a vote 
in determining the committee’s recommendations. 
 
Prior to the first DSMB review, guidelines for the identification, and evaluation of significant safety 
findings and/or increased frequency of events that may impact the rights, safety, or welfare of subjects 
will be established. All materials, discussions, and proceedings of the DSMB are completely confidential. 
The proceedings of each DSMB meeting will be recorded in minutes. The DSMB Chairperson will be 
responsible for providing a written recommendation regarding study conduct (e.g. continue as planned, 
specify a modification, or termination) to Medtronic and the study principal investigators. Additional 
details on the DSMB process, meeting, and data review schedule, as well as reporting expectations will be 
provided in the DSMB Charter. 
 
12.3. 
Study Coordinating Investigators 
The study coordinating investigators’ (CI) role will be to provide overall supervision of the study, advise in 
study design, provide feedback on current practice and to assist in communications with clinical 
investigational sites in partnership with Medtronic. The study CIs will meet periodically by teleconference 
or in person to monitor the progress of the study, including subject enrollment, clinical site progress, and 
protocol compliance. The study coordinating investigators will also be responsible for reviewing the final 
results and determining the methods of presentation and publication together with Medtronic. 
12. Data Review Committees 

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13.1. 
General Methods 
Descriptive statistics of continuous outcomes will be presented and include sample size, mean, standard 
deviation, median, interquartile range, minimum and maximum. For categorical outcomes, the number 
and percentage of subjects in each category will be presented. Paired t-tests will be used to compare 
changes in continuous measures from baseline to follow up. All statistical analyses will be performed using 
SAS for Windows (version 9.2 or higher) or other widely accepted statistical or graphical software. Subject 
data listings and tabular or graphical presentations of results will be provided, as applicable. Additional 
details on the analysis will be provided separately in the statistical analysis plan (SAP) for this study. 
 
In accordance with the US FDA guidance document “FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Pandemic” [8], additional analyses will be performed to assess the effect of the 
COVID-19 pandemic on the study outcomes as described in the statistical analysis plan. 
 
13.2. 
Analysis Sets 
 
13.2.1. 
Intention-To-Treat Population 
All enrolled subjects are included in the intention-to-treat (ITT) population. Subjects who meet the anti- 
hypertensive medication escape criteria (OSBP≥180 mmHg or safety reasons) will be analyzed using last 
observation carried forward (LOCF) for their blood pressure measurements. More details on the algorithm 
can be found in the table specifications document. Safety outcomes, and office and ambulatory blood 
pressure outcomes out to three months will be presented for this population. 
 
13.2.2. 
Modified Intention-To-Treat Population 
All enrolled subjects except subjects who meet the anti-hypertensive medication escape criteria 
(OSBP≥180 mmHg or safety reasons) will be excluded from the modified ITT population. Office and 
ambulatory blood pressure outcomes out to three months will be presented for this population. 
 
13.2.3. 
Per Protocol Population 
All treated subjects, meeting the following criteria are included in the per protocol population analysis:: 
 
1. Subjects showing medication compliance in blood and/or urine (via drug testing data) at Screening 
Visit 2 (SV2) and three months post-procedure. 
 
2. Exclude subjects with protocol deviation code 101 (consent not obtained). 
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3. Exclude subjects who do not meet the following inclusion/exclusion criteria: 
 
• 
Inclusion: Individual has an office systolic blood pressure (SBP) ≥150 mmHg and <180 mmHg and 
an office DBP ≥ 90 mmHg measured at Screening Visit 2, according to the guidelines in Appendix 
16.5 of the CIP. 
 
• 
Inclusion: Individual has a 24-hour ABPM average SBP ≥140 and <170 mmHg measured at 
Screening Visit 2, according to guidelines in Appendix 16.5 of the study protocol. 
 
• 
Exclusion: Individual has undergone prior renal denervation. 
• 
Exclusion: Individual has renal artery anatomy that is ineligible for treatment. 
• 
Exclusion: Individual has one or more of the following conditions: stable or unstable angina 
within three months of enrollment, myocardial infarction within three months of enrollment; 
heart failure, cerebrovascular accident or transient ischemic attack, or atrial fibrillation at any 
time. 
 
4. Exclude subjects meeting the anti-hypertensive medication escape criteria (OSBP >180 mmHg or 
safety reasons). 
 
Office and ambulatory blood pressure outcomes out to three months will be presented for this 
population. 
 
13.3. 
Sample Size Justification 
This study does not have a statistically powered hypothesis to determine if renal denervation performed 
in the distal main renal arteries and first order branches is as effective as the procedural approach in the 
SPYRAL HTN-OFF MED clinical study. The sample size of 50 subjects was chosen to provide a reasonable 
estimate of the efficacy of this procedural approach. In the original first phase of the SPYRAL HTN-OFF 
MED, only 38 subjects were sufficient in demonstrating efficacy (ASBP drop of -5.5 mmHg, with 95% CI of 
-9.1 to -2.0 and significant p-value of 0.003). By enrolling 50 subjects in the current study, we allow for 
potential missing outcomes data. 
 
13.4. 
Efficacy Endpoints – Propensity Score Adjustment 
Because this is a single arm study, the efficacy endpoints at three months will be compared to the RDN 
treated subjects from the SPYRAL HTN-OFF MED clinical study using propensity score stratification 
(subclassification) adjustment. The following covariates will be considered for propensity score analysis: 
baseline BP, age, gender, BMI, and diabetes. 

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The treatment effect will be assessed within each propensity score stratum, and the strata-specific effects 
combined to yield an overall treatment effect (DYSTAL minus SPYRAL HTN-OFF MED RDN arm), together 
with a two-sided 95% confidence interval. 
 
The ITT population defined in 13.2.1 will be the primary analysis population, and secondary analyses will 
be performed on the modified ITT and per protocol populations in 13.2.2 and 13.2.3. 
 
Further details will be provided in the study SAP. 
 
13.5. 
Safety Endpoint Analysis 
All the safety endpoints will be adjudicated by the clinical events committee (CEC). The safety endpoints 
will be summarized using counts and percentages, and no comparison group will be used for the safety 
analysis. 
 
These analyses will be performed for the ITT population defined in 13.2.1. 
 
13.6. 
Analysis of Baseline Characteristics 
All clinically relevant baseline variables will be tabulated and reported. Categorical variables will be 
reported using counts and percentages, and continuous variables will be reported by giving the number 
of known values, the mean, standard deviation, median, interquartile range, minimum and maximum 
values. 
 
13.7. 
Missing Data 
Every effort will be undertaken to minimize missing data. Unless otherwise specified, no statistical 
techniques will be used to impute missing data for continuous or categorical outcomes. The number of 
subjects included in each analysis will be reported so that the reader can assess the potential impact of 
missing data. 

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14.1. 
Monitoring 
Monitoring oversight will be provided by Medtronic and detailed in a Medtronic internal monitoring plan 
separate from this CIP. 
 
Monitoring visits will be conducted during the course of the study in accordance with Medtronic SOPs and 
the monitoring plan. The site initiation visit (SIV) will be performed before the first subject is enrolled once 
it has been verified that the site is prepared for the study and the requirements for starting subject 
enrollment are met. Documentation of training of the site team will be collected during the SIV, as well as 
all required regulatory documentation such as curriculum vitae, delegated task listing, etc. 
 
In order to ensure a high degree of data quality, periodic monitoring visits will be performed at recruiting 
clinical centers. Site monitoring will be conducted to monitor compliance with the protocol and adherence 
to the data collection procedures, to assess the accuracy and completeness of submitted clinical data, and 
to verify that records and documents are being properly maintained for the duration of the study. 
Frequency and timing of monitoring visits shall be determined by the sponsor for each site based on 
enrollment rate and volume, study compliance and findings from previous visits. 
 
The monitor will perform source data verification by reviewing subject documents according to the 
monitoring plan. After the 3-month follow-up visit through study closure, subject-level data will be 
monitored for adverse events and blood pressure data only. All Patient Information and Informed Consent 
forms will be checked for subjects undergoing the procedure. The monitor will perform review of key 
variables for all treated subjects (including but not limited to, inclusion/exclusion criteria, endpoints, and 
safety) on the CRFs against subject’s source documents per the monitoring plan. In addition, all available 
source documentation will be reviewed for potential adverse events and device deficiencies. Any 
discrepancies will be noted and resolved. The principal investigator(s), his/her delegate(s) and the study 
coordinator(s) shall be accessible to Medtronic study personnel during these monitoring visits. The site 
staff should be also available outside of monitoring visits by email or phone when questions arise 
regarding subject information. In the case the principal investigator is not available during the monitoring 
visit, a phone call follow up with the monitor can be performed to discuss the observations of the 
monitoring visit. 
 
The monitor will confirm periodic testing, calibration and maintenance of equipment used for study 
assessments such as the automated office blood pressure and ambulatory blood pressure monitors 
according to local standard of practice. Furthermore, the calibration and maintenance of the Symplicity 
G3 generator that is to be conducted by Medtronic’s technical support staff. 
 
Monitoring activities will be documented in the monitoring visit follow-up letters to be sent to the 
principal investigator and include a summary of what the monitor reviewed and the observations 
14. Study Administration 

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regarding the completion of previous action items, significant findings, facts, deviations, conclusions, and 
recommended actions to be taken to secure compliance. 
 
The sponsor will provide updated contact lists to the investigational sites. 
 
14.2. 
Data Management 
All records and other information about subjects participating in this study will be treated as confidential. 
The investigator will mark clinical records to indicate that the subject is enrolled in this clinical 
investigation. 
 
Medtronic will collect data and monitor study records. Auditors, EC/IRB members, inspectors 
(governmental regulatory authorities) may also have access to the study records. Participating subjects 
will not be identified by name in any published reports about this study. 
 
14.2.1. 
Electronic Data Capture 
Medtronic will use the Oracle Clinical Remote Data Capture database system for data collection. All data 
will be stored in a secure, password-protected database. All users will be trained on the use of the 
database prior to obtaining access. Once access is granted, users will have a unique user ID and will create 
their own password. Data stored electronically shall be maintained in compliance with 21 CFR Part 11. 
The database for this study will be maintained according to corporate policy and record retention 
schedule. 
 
The investigator must ensure accuracy, completeness and timeliness of the data reported in the CRFs and 
in all other required reports. Data reported on the CRFs which are derived from source documents must 
be consistent with the source documents and discrepancies need to be justified in a documented 
rationale, signed, and dated by the principal investigator, and filed in the subject medical file. Only 
authorized persons can complete CRFs. CRFs shall be signed by investigators (physicians only) as specified 
on the delegated tasks list included in the investigator site file. 
 
The electronic data capture (EDC) system maintains an audit trail on entries, changes, or corrections in 
CRFs. Upon completion of a CRF the investigator shall sign the CRF in a timely manner, if a change to an 
already signed CRF occurs, the investigator shall re-sign this CRF. 
 
Sites will be instructed to upload or transmit renal imaging media, source documents, raw 24-hour ABPM 
data, and other data required to be collected during the course of the study. The site should make every 
effort to de-identify personal subject information prior to transmission. 

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14.2.2. 
Source data on Case Report Forms 
Data entered must be traceable to source documents. Source documentation is defined as the first time 
data appear, and may include original documents, data and records (e.g., hospital records, clinical and 
office charts, procedure reports, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico- 
technical departments involved in the clinical study). 
 
CRFs (or paper copies) may not serve as source documents. Source documentation for data elements not 
routinely captured in medical records (e.g., echocardiography variables) may vary from site to site; the 
site may use source document worksheets if identified as source documents and are signed and dated 
appropriately. 
 
14.2.3. 
Time w indow s for completion and submission of Case Report Forms 
CRFs are recommended to be entered into the RDC system within 10 working days of the completion of 
the protocol-specified follow-up visit or sooner as requested by the sponsor. 
 
14.2.4. 
Data review and processing 
Data management will be done according to Medtronic SOPs and the data management plan for this 
clinical study. These documents will be made available on request. All collected data will be reviewed for 
completeness, correctness, and consistency. In case of issues, queries will be sent to the investigator to 
complete, correct or comment on the data. 
 
14.3. 
Direct Access to Source Data/Documents 
 
14.3.1. 
Accessibility of investigational site staff and study materials 
The principal investigator(s), his/her delegate(s) and the study coordinator(s) shall be accessible to 
Medtronic field personnel and the clinical study manager. This accessibility is of particular importance for 
reviewing data in the CRF. Direct access to subject medical files for source data verification will need to 
be granted and prepared for monitoring visits, audits and regulatory inspections. 
 
14.3.2. 
Audits and investigation site inspections 
Medtronic may conduct audits at participating investigational sites. The purpose of an audit is to verify 
the adequate performance of the clinical study related activities, independently of the employees 
involved in the clinical study. Regulatory bodies may also perform inspections at participating 

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investigation sites. Any regulatory authority inspection announcements shall be forwarded immediately 
to the clinical study manager. 
 
The investigator and/or institution shall permit Medtronic and regulatory bodies direct access to source 
data and documents, taking into account any restrictions due to local law, to perform clinical study - 
related monitoring, audits, EC/IRB review, and regulatory inspections. 
 
14.4. 
Confidentiality 
Subject confidentiality will be maintained throughout the clinical study to the extent permitted by law. 
That is, every attempt will be made to remove subject identifiers from clinical study documents. All 
information and data sent to parties involved in study conduct concerning subjects or their participation 
in this study will be considered confidential. Study sites will assign a unique subject ID number (SID) to 
each subject. Records of the subject/SID relationship will be maintained by the study site. The SID number 
is to be recorded on all study documents to link them to the subject’s medical records at the site. A subject 
identification log will be maintained as part of the investigator site file. This log will serve as the link 
between the subject study ID and an individual subject. This log must remain at the study site at all times. 
 
Confidentiality of data will be observed by all parties involved at all times throughout the clinical 
investigation. All data shall be secured against unauthorized access. The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any data. 
 
Investigational sites will protect the personal information of subjects in accordance with national, local 
and EC/IRB requirements. Data relating to the study might be made available to third parties (for example 
in case of an audit performed by regulatory authorities), provided the data are treated as confidential and 
that the subject’s privacy is guaranteed. No identifiable subject information will be published. 
 
14.5. 
Liability 
 
14.5.1. 
Insurance 
Medtronic, Inc. (including all wholly owned subsidiaries, including Medtronic Bakken Research Center 
(BRC) maintains appropriate clinical study liability insurance coverage as required under applicable laws 
and regulations and will comply with applicable law and custom concerning specific insurance coverage. 
If required, a clinical study insurance statement/certificate will be provided to the EC/IRB. 
 
14.5.2. 
Subject compensation and indemnification 
Subjects may receive compensation for their participation in this study, according to local EC/IRB policies 
and procedures. Medtronic will provide subject indemnification according to local laws where this study 

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will be conducted and as outlined in the clinical trial agreement. Reimbursement of travel cost will be 
considered if allowed by local regulations. 
 
14.6. 
Clinical Investigation Plan Amendments 
All CIP amendments need to be approved by Medtronic, respective EC/IRB, and regulatory authorities. 
Medtronic is responsible for regulatory authority approval or notification of CIP updates or amendments 
if applicable according to local regulations. In Europe, the sponsor might be responsible for submission to 
the EC/IRB if allowed by local regulation. The investigator will only implement the amendment after 
approval of the EC/IRB, regulatory authority, and sponsor. Furthermore, investigators shall sign any 
approved amendment for agreement. 
 
The investigator may propose any appropriate modification(s) of the CIP or investigational device/product 
or investigational device/product use. Medtronic will review this proposal and decide whether the 
modification(s) will be implemented. 
 
14.7. 
Record Retention 
 
14.7.1. 
Investigator Records 
The investigator must retain the investigator site file, subject medical files and CRFs in accordance with 
local law and regulations for a minimum period of two years after study closure (or longer if local laws 
require) after study completion in the investigational site. 
 
No study document or image will be destroyed without prior written agreement between the sponsor and 
the investigator. The investigator should take measures to prevent accidental or early destruction of the 
clinical study related materials. The sponsor must be consulted if the investigator wishes to assign the files 
to someone else, move them to another location, or is unable to retain them for the specified period. 
 
The sponsor will retain the study records according to Medtronic corporate policy and record retention 
schedule. 
 
If Medtronic wishes to retain these records for a shorter or longer period than specified above, Medtronic 
will notify the investigational sites of the intent and consult with the institutions on the methods of 
discarding or moving records. In addition, Medtronic will inform the investigational sites of expiration of 
the retention period prior to when the retention period expires. Upon the completion or termination of 
the investigation, Medtronic will maintain study records under its responsibility and Medtronic policy. 

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At a minimum, the following records must be kept by the investigator: 
 
• 
Medtronic and EC/IRB approved CIP and any amendments 
• 
Investigator’s Brochure (if applicable) and/or Instructions for Use and any amendments 
• 
Medtronic and EC/IRB approved Patient Information and Informed Consent Form 
• 
EC/IRB notification, correspondence, and approval 
• 
EC/IRB voting list 
• 
Any reports to EC/IRB and regulatory authority 
• 
Source documentation 
• 
Subject Identification log 
• 
Normal values or ranges for lab tests 
• 
Lab certificate 
• 
Documentation for equipment maintenance and calibration 
• 
Regulatory authority approval or notification and relevant correspondence 
• 
Fully signed clinical investigation agreement and confidentiality agreement (if not included 
in the clinical investigation agreement) 
• 
Financial disclosures from investigators 
• 
Insurance certificates, if applicable 
• 
Completed delegated task list and curriculum vitae of investigation site personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Signed, dated, and fully executed Patient Information and Informed Consent form 
• 
Fully executed CRFs and corrections 
• 
Reports of adverse events and device deficiencies 
• 
Device and drug accountability records 
• 
List of investigational sites 
• 
Statistician analysis and clinical investigation report (final report) 
• 
Any other records that may be required by hospital regulations or local law 
 
14.7.2. 
Sponsor Records 
At a minimum, the sponsor will keep the following records: 
 
• 
All essential study documents and correspondence that pertains to the clinical study 
• 
All approved versions of the CIP and any amendments 
• 
All approved versions of the Investigator Brochure and/or Instructions for Use and any 
amendments 
• 
Sample of labeling attached to the investigational device 

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• 
Curriculum vitae of investigators and investigational site personnel (as required by local 
law) 
• 
Delegated task lists and training records of investigators and investigational site personnel 
• 
List of investigational sites 
• 
Names/contact information of monitors 
• 
EC/IRB approvals/notifications and regulatory approvals/notifications 
• 
EC/IRB voting list 
• 
Normal values or ranges for lab test 
• 
Documentation for equipment maintenance and calibration 
• 
Lab certificate 
• 
Any reports to EC/IRB and regulatory authority 
• 
Statistical 
analysis 
and 
clinical 
investigation 
report 
(final 
report) 
EC/IRB 
approvals/notifications and regulatory approvals/notifications 
• 
Signed clinical investigation agreements and signed agreements with third parties 
• 
Insurance certificates 
• 
Shipping records for investigational devices, drugs provided for purposes of the study, and 
clinical-investigation related documents and materials 
• 
Sample of approved Patient Information and Informed Consent forms 
• 
Site visit reports 
• 
Adverse event and device deficiency reports 
• 
Financial disclosure information 
• 
Fully executed CRFs and corrections 
 
14.7.3. 
Source Documents 
Data entered on the CRF must be traceable to source documents. Source documentation is defined as the 
first time data appear, and may include original documents, data and records (e.g., hospital records, 
clinical and office charts, procedure reports, laboratory notes, memoranda, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, subject files, and records kept at the pharmacy, at the laboratories and at medico- 
technical departments involved in the clinical study). Information in source documents (i.e., medical 
history/physical condition) dated prior to the Patient Information and Informed Consent form signature 
date may be used to verify subject eligibility criteria. 
 
Clinical records must be marked to indicate a subject has been enrolled into the clinical study. 
 
The CRFs (or paper copies) may not serve as source documents. Source documentation for data elements 
not routinely captured in medical records may vary from site to site; the site may use source document 
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The investigator must ensure the availability of source documents from which the information on the CRFs 
was derived. The type and location of source documents should be documented. Where printouts of 
electronic medical records are provided as source documents, or where copies of source documents are 
retained as source documents, they should be signed and dated by a member of the investigational site 
team making a copy with a statement indicating they are a true reproduction of the original source 
document. 
 
The source documents must be made available for monitoring or auditing by the sponsor’s representative 
or representatives of the competent authorities and other applicable regulatory agencies. 
 
Copies of pseudonymized source documents will be requested to support event adjudication by the 
clinical events committee. 
 
14.8. 
Publication and Use of Information 
Transparency of clinical study results will be maintained by the following means: 
 
• 
A final report, describing the results of all objectives and analysis, will be distributed to all 
investigators, EC/IRBs and CAs of participating countries when required by local law. 
• 
Registering and posting the study results on a publicly accessible database, ClinicalTrials.gov 
based on the posting rules stipulated. 
• 
Submitting for publication the primary study results after the study ends. 
• 
Disclosing conflicts of interest (e.g., financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences. 
• 
Making an individual study sites study data accessible to the corresponding investigator after the 
completion of the study, if requested. 
Medtronic may form a publications review committee. Member(s) of the publications review committee 
may include, but are not limited to, the study PIs, the Medtronic clinical study manager or publication 
manager, and other Medtronic personnel. 
 
Participating investigators and members of the study PI’s research teams may submit publication ideas 
through the publication committee and may author publications. The publications review committee is 
responsible for developing a publication plan overseeing the development of case reports, manuscripts, 
and abstracts, identifying and appointing the manuscript/abstract first author(s)/writer(s), and identifying 
Medtronic personnel responsible for assisting the first author. The publications review committee may 
refine the publication plan during the course of the study if needed. 
 
At the conclusion of the study, a multi-center manuscript may be prepared for publication in a reputable 
scientific journal. The publication of the principal results from any single study center experience within 

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the study is not allowed until the preparation and publication of the multi-center results. Any follow-up 
publications would require prior written approval by publications review committee. 
 
Authorship will be determined based on the International Committee of Medical Journal Editors (ICMJE) 
published guidelines and GPP2 (Good Publication Practice) guidelines and will include, at a minimum: 
 
a. Substantial contributions to conception and design, or acquisition of data, or analysis and 
interpretation of data 
b. Drafting the article or revising it critically for important intellectual content 
c. Final approval of the version to be published 
d. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
Final criteria for selecting first and subsequent authors will be determined and documented in the 
publication plan. 
 
14.9. 
Suspension or Early Termination 
Early termination of the study is discontinuance, by sponsor or by withdrawal of EC/IRB or local regulatory 
body approval, of an investigation before completion. This is possible for the whole study, for all centers 
in a country, or for a single center. 
 
Study suspension is a temporary postponement of study activities related to enrollment and distribution 
of the investigational product(s). This is possible for the whole study, for all centers in a country or a single 
center. In the case of study suspension or early termination, it is up to the sponsor’s discretion to assess 
whether or not to continue the clinical study at the respective investigational site(s). 
 
14.9.1. 
Study-w ide termination or suspension 
Possible reasons for considering study suspension or termination of the study for all centers include but 
are not limited to: 
 
• 
AEs and device deficiencies associated with the system or product under investigation 
which might endanger the safety or welfare of subjects 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic or regulatory body (medically/ethically justifiable) where the 
study is operating under regulatory body authority 

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14.9.2. 
Investigator/  study site termination or suspension 
Possible reasons for clinical investigator or center termination or suspension include but are not limited 
to: 
 
• 
Failure to obtain initial EC/IRB approval or annual renewal of the study 
• 
Consistent non-compliance to the CIP (e.g., failure to adhere to inclusion/exclusion 
criteria, failure to follow subjects per scheduled follow ups, etc.) 
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the clinical trial agreement (e.g., failure 
to submit data in a timely manner, failure to follow up on data queries and monitoring 
findings in a timely manner, etc.) 
• 
EC/IRB suspension of the center 
• 
Fraud or fraudulent misconduct (as defined by local law and regulations) 
• 
Investigator request (e.g., no longer able to support the study) 
14.9.3. 
Procedures for planned study closure, termination, or suspension 
14.9.3.1. 
Medtronic-initiated 
Medtronic will promptly inform the clinical investigators of the reasons for a study termination or 
suspension and inform the regulatory authority(ies) (where required per regulatory requirements). 
 
• 
In the case of study termination or suspension for reasons other than a temporary EC/IRB 
approval lapse, the investigator will promptly inform the EC/IRB. 
• 
In the case of study termination, the investigator must inform the subjects and may 
inform the personal physician of the subjects to ensure appropriate care and follow up is 
provided. 
• 
In the case of a study suspension, subject enrollment must stop until the suspension is 
lifted by Medtronic. Subjects already enrolled should continue to be followed out of 
consideration of their safety, rights, and welfare. 
 
14.9.3.2. 
Investigator-initiated 
The investigator will promptly inform: 
 
• 
Medtronic and provide a detailed written explanation of the termination or suspension. 
• 
The institution (where required per regulatory requirements). 
• 
The EC/IRB. 
• 
The subjects and may inform the personal physicians of the subjects to ensure 
appropriate care and follow up is provided. 

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In the case of a study suspension: 
 
• 
Subject enrollment must stop until the suspension is lifted. 
• 
Subjects already enrolled should continue to be followed out of consideration of their 
safety, rights, and welfare. 
 
14.9.3.3. 
Ethics Committee/  Institutional Review Board initiated 
The investigator will promptly inform: 
 
• 
Medtronic and provide a detailed written explanation of the termination or suspension 
within five business days. 
• 
The institution (where required per regulatory requirements). 
• 
The subjects and may inform the personal physicians of the subjects, with the rationale 
for the study termination or suspension. 
In the case of a study suspension: 
 
• 
Subject enrollment must stop until the EC/IRB suspension is lifted. 
• 
Subjects already enrolled should continue to be followed in accordance with EC/IRB policy 
or its determination that an overriding safety concern or ethical issue is involved. 
 
14.10. 
Role of Sponsor Representatives 
As the sponsor of this clinical study, Medtronic has the overall responsibility for the conduct of the study, 
including assurance that the study will be conducted according to international guidelines including latest 
version of ISO 14155 and local laws. In this study, Medtronic will have certain direct responsibilities and 
may delegate other responsibilities to consultants and/or contract research organizations. 
 
The principles of the Declaration of Helsinki have all been implemented in this study by means of the 
Patient Information and Informed Consent process, EC/IRB approval, study training, clinical trial 
registration, preclinical testing, risk benefit assessment, publication policy, etc. 
 
Medtronic’s general duties consist of submitting applications and information to appropriate regulatory 
authorities, obtaining EC/IRB approvals prior to allowing shipment of devices, selecting qualified 
investigators, ensuring proper clinical site monitoring, ensuring subject informed consent is obtained and 
ensuring that the EC/IRB and relevant regulatory authorities are promptly notified of significant new 
information about the investigation. 
 
Medtronic is responsible for providing quality data that satisfies regulations and informing investigators, 
EC/IRB, and relevant regulatory authorities of UADEs/SADEs and deviations from the investigational plan 
as appropriate. The Medtronic clinical study team will provide written progress reports and a final report. 

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Sponsor representatives may provide support at the study site as required for the study under 
supervision of the principal investigator, including: 
 
Provide study training relevant and pertinent to the involvement of personnel conducting 
study activities and investigator responsibilities 
 
Technical support at RDN procedure under the supervision of a study investigator, but no 
data entry, shall be performed by Medtronic personnel or their representatives at study 
sites 
 
Monitoring and auditing activities 
 
In addition, for this study, sponsor representatives may be authorized by the principal 
investigator to perform the following significant study related duties: 
 
Support study investigators in performing the study procedure 
 
Support data collection during the procedure and device testing 
Support data collection during the study follow-up visits. 
 
 
 
 
14.11. 
Site Selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
study as well as ensure data integrity and the rights, safety and well-being of the subjects involved in the 
clinical study. 
 
An investigational site may be selected for participation in the clinical study if compliant with the following 
requirements: 
 
• 
Investigator has previous experience with the Symplicity Spyral renal denervation system. 
• 
Investigator should have adequate staff that is accessible and has time to manage the study. 
• 
Investigator should have adequate staff to perform blood pressure measurements. 
• 
Investigator, and sub-investigators (if applicable) and all key site staff must be willing to 
provide his/her curriculum vitae. 
• 
Investigational site must be willing to comply with the CIP and data collection requirements, 
including timely reporting of adverse events and device deficiencies as required by the CIP. 
• 
Investigational site has demonstrated experience with conducting clinical (device) studies 
that comply with applicable regulatory standards. 

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• 
Investigational site is willing to participate in follow-up of subjects for a minimum of 12 
months (and up to a maximum of 5 years). 
• 
Investigational site has an internet connection with sufficient speed of data transfer. 
• 
Investigational site agrees to one RDN operator per site unless an exception is granted in 
writing by the sponsor. 
A list of participating investigational sites and IRBs, including contact information, and investigators (with 
titles), will be available as a separate document. 
 
14.12. 
Site Activation 
Prior to investigational site activation or subsequent involvement in clinical study activities, Medtronic 
will provide clinical study training relevant to the involvement of personnel conducting clinical study 
activities. Medtronic will train site personnel on, but not limited to, the CIP, relevant standards and 
regulations, informed consent, written clinical investigation agreements, data collection and reporting 
tools, investigator responsibilities, as well as device/product training. Study specific training will be 
documented prior to investigational site activation. 

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Training will occur prior to site activation at each site, and will include at a minimum the following topics 
(as applicable to the role at the site): 
 
• 
Technical overview of device(s) 
• 
Procedural training for proceduralist 
• 
CIP overview and study procedures 
• 
Investigational device disposition and accountability procedures 
• 
Procedures for returning unused/explanted devices 
• 
CRF completion and management, including electronic data entry 
• 
Investigator and sponsor responsibilities 
• 
Procedures for obtaining informed consent 
• 
EC/IRB requirements 
• 
Adverse event/device deficiency reporting procedures and timelines 
• 
Deviation reporting procedures 
• 
Monitoring requirements and expectations 
• 
Potential regulatory inspections and audits by the sponsor or sponsor representative 
• 
Site record maintenance and retention 
• 
Regulatory requirements for commercially approved devices in a clinical study, including 
timely adverse event and complaint reporting 
• 
Any additional regulatory requirements 
The sponsor will supply all required study materials for appropriate data collection before study start. 
Data collected on each subject will be recorded on a web-based electronic CRF. The passwords for the 
electronic CRF will only be distributed to investigational centers where the sponsor has written 
documentation of site readiness. 
 
Investigational sites will receive a formal letter of site activation, upon receipt of or completion of the 
following: 
 
• 
Curriculum vitae of the principal and sub-investigators and all key site staff 
• 
A signed trial agreement. 
• 
Financial disclosure from the investigators 
• 
Competent Authority approval (as applicable to the geography) 
• 
A copy of the EC/IRB approval letter, along with the voting roster 
• 
The EC/IRB approved subject information and informed consent form 
• 
Documented training (at least CIP, CRF, EDC, ICF process and product training ( as applicable 
to their role)) of the investigative team 
• 
Lab certificate and lab normal values/ranges 
• 
Delegated task list 
• 
Confirmation of calibration and maintenance of equipment and maintenance of facilities 

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• 
Confirmation of adequacy of equipment/facilities (e.g., a quiet room to perform the blood 
pressure measurements) 
Medtronic will control the supply of study materials and will only grant site activation when above 
activation criteria are met, and the site receives a formal activation letter from Medtronic. 
 
14.12.1. 
Curriculum Vitae 
Prior to study start, a current signed and dated curriculum vitae from the principal investigator, all sub- 
investigators and all key site staff participating in this clinical study as listed on the delegated task list shall 
be obtained, evidencing the required qualifications, including the year, and where obtained, and including 
their current position at the investigational site. The signature on the CV must be dated within three years 
prior to the date of activation of the investigational site. 
 
14.12.2. 
Clinical Trial Agreement 
Medtronic contracts with participating institutions/investigators through a clinical trial agreement that 
defines the scope and responsibilities and associated compensation related to carrying out the obligations 
under a clinical study sponsored by Medtronic. A clinical trial agreement shall be in place, signed by the 
participating investigational site and/or principal investigator of each investigational site, as per the local 
legal requirements, and returned to Medtronic prior to the commencement of any clinical study activities. 
The investigator is indicating approval of the CIP and subsequent amendments, by a fully executed 
agreement. Amendments to the CIP shall be agreed upon between Medtronic and investigator(s) and be 
recorded with a justification for the amendments. 

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1. Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic activation in the pathogenesis of hypertension and 
progression of organ damage. Hypertension 1999;34:724-8. 
2. Charkoudian N, Rabbitts JA. Sympathetic neural mechanisms in human cardiovascular health and disease. Mayo 
Clin Proc 2009;84:822-30. 
3. Joles JA, Koomans HA. Causes and consequences of increased sympathetic activity in renal disease. 
Hypertension 2004;43:699-706. 
4. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant 
hypertension: a multicentre safety and proof-of-principle cohort study. The Lancet 2009;373:1275-81. 
5. Coruzzi P, Musiari L, Mossini GL, Ceriati R, Mutti A. The renin-aldosterone system and renal function in kidney 
transplantation. Clinical nephrology 1994;41:225-9. 
6. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled 
hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham- 
controlled, proof-of-concept trial. The Lancet 2017;390:2160-70. 
7. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of 
antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept 
randomised trial. The Lancet 2018;391:2346-55. 
8. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur 
Heart J 2015;36:219-27. 
9. Petrov I, Tasheva I, Garvanski I, Stankov Z, Simova I. Comparison of standard renal denervation procedure versus 
novel distal and branch vessel procedure with brachial arterial access. Cardiovasc Revasc Med 2019;20:38-42. 
10. Pekarskiy SE, Baev AE, Mordovin VF, et al. Denervation of the distal renal arterial branches vs. conventional 
main renal artery treatment: a randomized controlled trial for treatment of resistant hypertension. J Hypertens 
2017;35:369-75. 
11. Fengler K, Ewen S, Hollriegel R, et al. Blood Pressure Response to Main Renal Artery and Combined Main Renal 
Artery Plus Branch Renal Denervation in Patients With Resistant Hypertension. J Am Heart Assoc 2017;6. 
12. Bohm M. MG, Schmieder R., Schlaich M., Mahfoud F. Safety and efficacy measurements in the global 
SYMPLICITY registry. EuroIntervention 2017 (Euro17A-OP0338 (Abstract)). 
13. Mahfoud F, Tunev S, Ewen S, et al. Impact of Lesion Placement on Efficacy and Safety of Catheter-Based 
Radiofrequency Renal Denervation. J Am Coll Cardiol 2015;66:1766-75. 
14. Kiuchi MG, Schlaich MP, Chen S, et al. Relevance of Targeting the Distal Renal Artery and Branches with 
Radiofrequency Renal Denervation Approaches-A Secondary Analysis from a Hypertensive CKD Patient Cohort. J 
Clin Med 2019;8. 
15. Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or 
without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised 
controlled trial. The Lancet 2015;385:1957-65. 
16. Doltra A, Hartmann A, Stawowy P, et al. Effects of Renal Denervation on Renal Artery Function in Humans: 
Preliminary Study. PLoS One 2016;11:e0150662. 
17. Id D, Bertog SC, Ziegler AK, et al. Predictors of blood pressure response: Obesity is associated with a less 
pronounced treatment response after renal denervation. Catheter Cardiovasc Interv 2016;87:E30-8. 
18. Volz S, Spaak J, Elf J, et al. Renal sympathetic denervation in Sweden: a report from the Swedish registry for 
renal denervation. J Hypertens 2018;36:151-8. 
19. Zweiker D, Lambert T, Steinwender C, et al. Effects of Renal Denervation Documented in the Austrian National 
Multicentre Renal Denervation Registry. PLoS One 2016;11:e0161250. 
20. Fengler K, Rommel KP, Blazek S, et al. A Three-Arm Randomized Trial of Different Renal Denervation Devices 
and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN). Circulation 2019;139:590-600. 
15. References 

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21. Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal denervation as a therapeutic 
approach for hypertension: novel implications for an old concept. Hypertension 2009; 54:1195-1201. 
22. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a 
guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. 
23. Brunner-La Rocca HP, Esler MD, Jennings GL, Kaye DM. Effect of cardiac sympathetic nervous activity on mode 
of death in congestive heart failure. Eur Heart J. 2001;22:1136-1143. 
24. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine, plasma renin activity, 
and congestive heart failure. Relations to survival and the effects of therapy in C-HeFT II. the V-HeFT VA 
Cooperative Studies Group. Circulation. 1993;87:VI40-48. 
25. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic 
nervous activity in the failing human heart. J Am Coll Cardiol. 1995;26:1257-1263. 
26. Petersson M, Friberg P, Eisenhofer G, Lambert G, Rundqvist B. Long-term outcome in relation to renal 
sympathetic activity in patients with chronic heart failure. Eur Heart J. 2005;26:906-913. 
27. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, Hoppe UC. Renal Sympathetic denervation 
reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. Journal 
of the American College of Cardiology. 2012;59:901-909. 
28. Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, 
Sobotka PA, Krum H, Esler M, Böhm M. Effect of renal sympathetic denervation on glucose metabolism in patients 
with resistant hypertension: a pilot study. Circulation. 2011;58:559-565. 
29. Witkowski A, Pejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, Michalowska I, Kabat M, Warchol E, 
Januszewicz M, Narkiewicz K, Somers VK, Sobotka PA, Januszewicz A. Effects of renal sympathetic denervation on 
blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. 
Hypertension. 2011;58:559-565. 

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16.1. 
Contact Information 
 
16.1.1. 
Coordinating Investigators 
The following investigators will serve as Coordinating Investigators on the study: 
 
Prof. Dr. David Lee 
Stanford University Medical Center 
300 Pasteur Drive 
Stanford, California 94305 
US 
 
Prof. Dr. Andrew Sharp 
Department of Cardiology 
University Hospital of Wales 
Heath Park Way 
Cardiff, Wales 
CF14 4CX 
UK 
 
16.1.2. 
Other contacts 
A list with addresses of third parties, including the identification of the head of any core laboratory and 
the scope and duties to be entrusted is provided below. The sponsor will maintain a current list and it will 
be provided separately if updates from the below table are made. 
 
Table 10: Other Contacts 
 
Service Provider 
Contact Information 
Services 
Scope and Duties Entrusted 
Medtronic, Inc. 
(global sponsor) 
3576 Unocal Place 
Santa Rosa, CA 95403 
USA 
Monitoring 
Medtronic is responsible for the 
source data verification and 
compliance with the study CIP 
and applicable regulations 
(Monitoring); review and 
cleaning of the data (Data 
Management) and statistical 
programming and data analysis. 
Data management 
Statistical 
programming and 
data analysis 
16. Appendices 

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Service Provider 
Contact Information 
Services 
Scope and Duties Entrusted 
Beth Israel Deaconess 
Medical Center, Inc. 
375 Longwood Avenue 
3rd Floor 
Boston, MA 02215 
USA 
Angiographic core 
laboratory 
The angiographic core 
laboratory is responsible for 
review and analysis of 
angiographic renal imaging to 
assess renal artery stenosis. 
Duane Pinto, MD 
Cardiovascular 
Research Foundation 
(CRF) 
1700 Broadway 
Floor 9 
New York, NY 10019USA 
Clinical events 
committee (CEC) 
The CEC is an independent 
group whose primary 
responsibilities are to 
adjudicate any events that are 
part of study safety endpoints. 
The CEC will be composed of 
physicians who have experience 
in clinical studies in 
hypertension and/or 
cardiovascular indications. 
Data safety 
monitoring board 
(DSMB) 
The DSMB is an independent 
group whose primary 
responsibility is to monitor the 
health, safety, and welfare of 
subjects. The DSMB will be 
composed of physicians who 
have experience in clinical 
studies in hypertension and/or 
cardiovascular indications and 
one biostatistician with 
experience in analysis of clinical 
trials. 
Klinische Toxikologie 
Universitätsklinikum 
des Saarlandes 
Klinische Toxikologie 
Universitätsklinikum des 
Saarlandes, Geb. 46 
D-66421 Homburg (Saar) 
Germany 
Drug testing core 
laboratory 
Drug testing core laboratory is 
responsible for processing and 
analyzing plasma and urine test 
samples to confirm the absence 
or presence of anti- 
hypertensive medications. 
Prof. Dr. Markus R. 
Meyer 
Medidata Solutions, 
700 W. Pete Rose Way 
Media (i.e., imaging Provide platform to allow for 
Inc. (formerly known 
Suite 436 
and file) upload 
the submission and 
as Intelemage) 
Cincinnati, OH 45203 
management of files and study 
USA 
data/imaging studies. 

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Service Provider 
Contact Information 
Services 
Scope and Duties Entrusted 
Morristown Medical 
Center 
Cardiovascular Core Lab 
Morristown Medical 
Center 
100 Madison Avenue 
Morristown, NJ 07960 
MRA/CTA core 
laboratory 
The MRA/CTA core laboratory is 
responsible for review and 
analysis of the MRA/CTA renal 
imaging to assess renal artery 
stenosis. 
Linda D. Gillam, MD, 
MPH, FACC, FAHA, FESC, 
FASE 
VasCore – The 
Vascular Ultrasound 
Core Laboratory 
The Vascular Ultrasound 
Core Laboratory 
1 Bowdoin Square 
Tenth Floor 
Boston, MA 02114 
USA 
Renal artery duplex 
ultrasound (DUS) 
core laboratory 
The DUS core laboratory is 
responsible for review and 
analysis of DUS renal imaging to 
assess renal artery stenosis. 
Michael R. Jaff, D.O., 
RPVI 
 
16.1.3. 
List of participating investigational sites and investigators 
A list of investigational sites, IRBs and investigators will be provided under a separate cover. 
 
16.2. 
Case Report Forms 
A copy of the CRFs will be provided under a separate cover. 
 
16.3. 
Sample Investigator Agreement 
A sample investigator agreement will be provided under a separate cover. 
 
16.4. 
Event Definitions 
All-cause mortality: Death irrespective of cause. 
 
Cardiovascular death: Any death due to immediate cardiac or vascular cause (e.g., sudden cardiac death, 
AMI, stroke, heart failure, fatal arrhythmia, or any procedure-related death). 
 
Hospitalization for hypertensive crisis: Severely elevated blood pressure (BP), usually higher than 
180/110 mm Hg, together with progressive or impending target organ damage, requiring in-patient 

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hospitalization and typically admission to the intensive care unit (ICU) (e.g., with parenteral [IV] 
antihypertensive medications), not related to confirmed nonadherence with medication or the protocol. 
Non-cardiovascular death: Any death not covered by the above definition for cardiovascular death, 
including death due to infection, sepsis, pulmonary causes, accident, suicide, or trauma. 
 
End-stage renal disease (ESRD): Two or more eGFR measurements <15 mL/min/m2 at least 21 days apart 
and requiring dialysis for one or more of the following: 
 
• 
Volume management refractory to diuretics 
• 
Hyperkalemia unmanageable by diet and diuretics 
• 
Acidosis bicarbonate <18 unmanageable with HCO3 supplements 
• 
Symptoms of uremia, nausea, vomiting 
Major adverse events (MAE), defined as a composite of the following events: 
 
• 
All-cause mortality 
• 
ESRD 
• 
Significant embolic event resulting in end-organ damage (e.g., kidney/bowel infarct, lower 
extremity ulceration or gangrene, or doubling of serum creatinine documented by at least 
two measurements at least 21 days apart) 
• 
Renal artery perforation requiring reintervention 
• 
Renal artery dissection requiring intervention 
• 
Vascular complications 
• 
Hospitalization for hypertensive crisis not related to confirmed non-adherence with 
medications 
• 
New renal artery stenosis > 70%, confirmed by angiography by the angiographic core lab 
Major bleeding according to TIMI definition: Intracranial hemorrhage; ≥5g/dl decrease in hemoglobin 
concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within seven days of the 
procedure) 
 
Myocardial infarction (MI): MI is defined as the concurrent documentation of two of the three elements 
listed below in the appropriate clinical circumstance: 
 
1. Chest pain or ischemic equivalent 
2. New pathologic q waves in at least 2 contiguous ECG leads 
3. Cardiac biomarker elevation by any of the definitions below: 
Appropriate cardiac enzyme data (respecting top-down hierarchy): 

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a) CK greater than or equal to 2* URL confirmed by: 
 
• 
CKMB > l*URL or 
• 
in the absence of CKMB: Troponin > l*URL or 
b) in the absence of CK: 
 
• 
CKMB > 3*URL 
• 
In the absence of CK and CKMB: Troponin > 3*URL 
• 
In the absence of CK, CKMB and Troponin, clinical decision based upon clinical 
scenario 
 
New renal artery stenosis: Greater than 70% renal artery stenosis confirmed by analysis of angiography 
by the core lab. If core lab analyses are unavailable, site reported analysis may be used. The date of the 
event will be the date of confirmatory angiography. 
Renal artery dissection: Creation of a false lumen between the layers of the artery requiring intervention. 
 
Renal artery perforation: Puncture creating a hole in the vessel wall requiring intervention. 
Renal artery reintervention: Interventional procedure performed on the renal artery following 
completion of the renal denervation procedure and removal of the guide catheter. 
 
Significant embolic event: Sudden obstruction of a blood vessel by debris (i.e., blood clot, plaques, fat, 
bacterial mass, cancer cells, or air bubbles) resulting in end-organ damage. Examples include: 
 
• 
Kidney/bowel Infarct: necrosis (cell death) of an area of tissue in all or part of the organ due 
to cessation of the blood supply due to stenosis or occlusion 
• 
Lower extremity ulceration: a non-healing lesion on a body surface (i.e., skin, mucous 
membrane) 
• 
Gangrene: necrosis of tissue usually resulting from deficient or absent blood supply 
• 
Doubling of serum creatinine confirmed by at least two measurements over 21 days apart 
• 
DOES NOT INCLUDE MI OR STROKE WHICH ARE ADJUDICATED SEPARATELY 
 
Stroke: Sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects, dysarthria, or other 
focal neurological deficits due to vascular defects in the brain such as hemorrhage, embolism, thrombosis, 
or rupturing aneurysm, that persists more than 24 hours. 
 
Vascular Complications: Complications that require surgical repair, interventional procedure (not 
including manual compression), thrombin injection, or blood transfusion (requiring more than 2 units of 
packed red blood cells within any 24-hour period during the first 7 days post-procedure); possible 
vascular complications are as follows: 

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• 
Clinically significant groin hematoma: swelling due to the accumulation of blood around an 
organ, tissue or space caused by the leakage of blood from a vessel 
• 
Arteriovenous fistula: formation of an abnormal connection between an artery and a vein 
• 
Pseudoaneurysm: a hematoma that forms as the result of a leaking hole in an artery. Note 
that the hematoma forms outside the arterial wall, so it is contained by the surrounding 
tissues. Also, it must continue to communicate with the artery to be considered a 
pseudoaneurysm 
• 
Excessive Bleeding: requires >2 units of packed red blood cells (PCRB) within any 24-hour 
period during the first 7 days post-randomization and documented bleeding 

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 At Screening Visit 1 (SV1), the appropriate arm for study measures must be selected as 
specified in section A below and used for all subsequent follow-up visits. 
 All study visits should begin before 10:30 am, with the following exceptions: 
- SV1, if the subject is consented at SV1 
- Unscheduled follow-up visits 
- medication reintroduction visits 
- the discharge visit. 
 
16.5. 
Blood Pressure Measurement Procedures 
 
16.5.1. 
Office Blood Pressure 
All office blood pressure (OBP) measurements must be taken with the automatic blood pressure monitor 
as specified by the sponsor. 
 
Subjects should not take antihypertensive medication the morning of the visit, but rather bring their 
medications to the visit. Pill taking should be observed after the OBP measurement (if applicable), or in 
the case of in-home, virtual or telephone visits, the subject should delay taking antihypertensive 
medication until the blood pressure measurement is completed. 
 
A. ARM SELECTION AT SCREENING VISIT 1 (SV1) ONLY 
1) If the subject is taking antihypertensive medications, the visit should begin before 10:30 am. If the 
subject normally takes their anti-hypertensive medication(s) in the afternoon, the visit may occur 
in the afternoon. 
2) With the subject prepped per “Preparation” section B below, measure BP in each arm. Ensure 
each measurement is recorded and identify on which arm the BP was measured. 
3) Use the arm with the higher systolic BP for screening measurements and all subsequent study- 
required measurements 
a. If there is a reason to use a particular arm, document the reason, and use that arm for all 
measurements. 
 
B. PREPARATION AT ALL VISITS 
1) Ensure the BP monitor and all necessary equipment are functioning correctly (per sponsor 
instructions). 
2) Confirm the subject did not drink coffee or alcohol, smoke, or exercise, within 30 minutes prior to 
taking BP measurements. 
3) Request that the subject use the bathroom prior to taking BP measurements (a full bladder can 
affect the reading). 

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4) The subject should be seated comfortably with the back supported, the upper arm bared with no 
clothing between the arm and BP cuff. The legs should not be crossed. 
5) Ensure that the BP cuff is appropriately sized (see Table 11 below) and that the upper arm is 
supported at the level of the heart (e.g., resting on a table at the level of the subject’s heart). The 
same cuff size should be used as selected at SV1 for the remainder of the study. 
 
Table 11: BP Cuff Size Chart 
 
Cuff Size* 
Fits Arm Circumference of (inches) 
Fits Arm Circumference of 
(centimeters) 
Small 
7 – 9 
17 – 22 
Medium-Large 
9 - 17 
22 - 42 
*If a subject is on the border of two cuff sizes, opt for the larger of the two sizes 
**Subjects requiring greater than a large cuff size at time of screening must be excluded from the study (screen 
failure). 
6) Perform a “test” BP measurement. Ensure test measurement is recorded. 
7) Have the subject sit comfortably and quietly for at least five minutes, but no more than 10 
minutes, with back supported and feet flat on the ground (i.e., not on an exam table, legs not 
crossed) prior to proceeding with the actual BP measurement. 
 
C. METHOD FOR TAKING BP AT ALL VISITS 
1) General Instructions 
a. With subject prepared per section B above and using arm selected at SV1, take at 
least three (3) seated BP measurements in order to obtain the BP average. 
b. Wait at least one (1) minute between each BP measurement. Ensure that the same 
time clock is used for tracking the time intervals to avoid deviations due to 
insufficient wait time between measurements. 
c. Document and label after each measurement. 
2) Three (3) consecutive, consistent seated blood pressure measurements must be used to 
obtain the blood pressure average. 
a. If the lowest and highest systolic BP (SBP) values of the first three consecutive BP 
measurements are >15 mmHg apart, take one additional reading and average the last 
three consecutive measurements (measurements 2-4). 

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b. If the measurements are still >15 mmHg apart, take one additional reading and 
average the last three consecutive measurements (measurements 3-5). 
c. If the measurements are still >15 mmHg apart, take one final measurement and 
average the last three consecutive measurements (measurements 4-6). 
3) At screening visits: If the lowest and highest SBP values for the readings are >20 mmHg apart 
after six measurements, the subject must be excluded from the study (screen failure). 
4) At all subsequent follow-up visits: If the lowest and highest SBP values for the readings are 
>20 mmHg apart after six measurements, take the average of the last three measurements 
(measurements 4 – 6) and record the value on the CRF. 
5) Record the last three consecutive, consistent readings on the CRF (do not pick the ‘best’ 
three). 
 
16.5.2. 
Orthostatic Hypotension Evaluation (SV2 ONLY) 
In addition to the seated OBP recordings above, measure supine and standing BP at SV2 only. 
1) Have the subject lie supine for at least five minutes prior to taking the supine BP 
measurement. 
2) Measure BP within 1-3 minutes upon standing for the standing measurement. Standing must 
follow the supine to measure orthostatic effect. 
3) Evaluate for any symptoms (e.g., dizziness) that may occur within three minutes after 
standing. 
 
16.5.3. 
Ambulatory Blood Pressure Monitoring 
1) All 24-hour ABPM measurements must be taken with the 24-hour ABPM device provided by 
the sponsor to ensure consistency. 
2) Cuff size identified at SV1 should be used for the duration of the study. 
3) If the subject is on antihypertensive medications, the visit should begin before 10:30am. If the 
subject normally takes antihypertensive medication in the afternoon, the subject visit may 
occur in the afternoon. 
4) Study personnel should observe the subject swallowing the antihypertensive medication(s), 
if applicable (or verbally confirmed in the case of a phone or virtual visit). 
5) Once medication consumption is completed and documented, the ABPM device should be 
applied to the subject and the recording started before the subject leaves the office (or 
completes the call in the case of a phone or virtual visit). 

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6) Place cuff on the subject’s non-dominant arm. 
7) Instruct the subject in proper cuff positioning in case they must remove it but stress the 
importance of leaving the BP cuff on. 
a. The ABPM has pre-set parameters and should not be adjusted. These parameters are 
set to record BP every 30 minutes. 
8) Instruct the subject: 
a. To engage in their usual level of physical activity, but to avoid strenuous exercise 
during the monitoring period, 
b. To hold the arm still by the side while the device is taking a reading 
9) Upon the return of the ABPM machine: 
a. Submit the 24-hour ABPM data to Medtronic 
b. A 24-hour ABPM will be considered adequate if the number of successful daytime 
readings captured is ≥21 and the number of successful nighttime readings captured 
is ≥12. 
c. At SV2, a single repeat ABPM will be allowed in case of the following: 
- The 24-hr systolic ABPM measured is between 135 - <140 mmHg or 170-175 
mmHg 
- A valid number of readings is not obtained 
- There is a technical issue with the BP monitor or failure to follow the ABPM 
instructions 
d. In all other instances at SV2, the ABPM will not be allowed to be repeated and the 
subject will be considered a screen failure. 
e. For all other time points with ABPM, make all efforts to obtain repeat ABPM from 
subject until the minimum number of readings is obtained. 

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Version 
Summary of Changes 
Author(s)/Title 
1.0 
• Not Applicable, New Document 
Marianne Wanten, 
Sr. Clinical Research 
Manager 
2.0 
• Implemented 6 months follow-up renal imaging 
• Added bicarbonate to Chem-7 panel 
• Added 2 week in-person follow-up visit 
• Added 6 and 10 week phone follow up 
Marianne Wanten, 
Sr. Clinical Research 
Manager 
3.0 
• Added alternate follow-up methods to allow more flexibility during 
extenuating circumstances, such as a global pandemic in section 9.1.6 
• Implemented ISO14155 updates 
• Added safety event definitions in section 16.4 
• Added Statement that study will be registered on CT.gov in section 7.1 
• Added Clarification regarding renal imaging not obtained at 6 month 
follow-up visit in section 9.1.6 
• Clarification added for taking anti-hypertensive medication in cases of 
in-home, virtual or telephone visit in section 16.5 
• Clarification to verbally confirm subject’s medication use in cases of 
telephone visits in section 16.5 
Marianne Wanten, 
Sr. Clinical Research 
Manager 
4.0 
• Remove sentence in section 9.1.6. “These alternative methods have no 
potential impact on patient safety, do not affect data integrity and do 
not introduce study bias Add changes.” 
Yuliya Korytchenko, 
Clinical Research 
Specialist 
5.0 
Update to CIP v5, to align with the ISO14155 2020 guidelines, EU MDR 
requirements and to incorporate CIP clarification letter updates. These 
changes have no potential impact on performance, effectiveness, safety or 
other study endpoints nor any affect to study documents. 
For clarification purposes: 
• Update Glossary, remove unused terms, add missing terms 
• Add EUDAMED number to Synopsis per ISO requirements 
• Update ‘Lead Principal Investigator’ to ‘Coordinating Investigator’ 
throughout for consistency 
• Clarified Role of the Sponsor 
• Reformat of Tables 1, 2, 3, 4 for clarity 
• Update study duration, number of sites, enrollment timelines 
Marina Ostanniy, Pr 
Clinical Research 
Specialist 
17. Version History 

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Version 
Summary of Changes 
Author(s)/Title 
• Update AE and DD reporting requirements 
• Remove MDD 93/42/ECC 
• Clarify follow-up visit requirements (9.1.6) 
• Add definitions for malfunction, product complaint, 
• Add AE classification responsibilities 
• Add product complaint reporting requirements 
• Update AE reporting requirements per EU MDR requirements 
• Update reference to EC/IRB for consistency throughout 
• Update co-investigator to sub-investigator 
• Update event definitions to match CEC Charter 
• Update Section 16.5 Blood Pressure Measurement Procedures for 
clarity 
• Added CIP template vC requirements 
• Administrative updates: 
• Update formatting throughout for consistency and clarity; update word 
‘patient’ to ‘subject throughout; 
• Correct grammar and punctuation throughout 
• Update formatting of Tables 1, 2, 3, 4 for clarity 
• Format sub-headings for consistency throughout 
• Remove generic phone number, updated contact for study information 
• Add Table of Tables and Table of Figures 
• Updates per MDT style guide throughout