Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy (SPYRAL HTN-ON MED)
Phase: NA
Conditions: Hypertension, Vascular Diseases, Cardiovascular Diseases
Sponsor: Medtronic Vascular

SPYRAL HTN-ON MED Clinical Investigation Plan 
Version 10.0 
Page 1 of 111 
Medtronic Confidential 
056-F275, v3.0 Clinical Investigation Plan Template
SPYRAL HTN-ON MED 
Clinical Investigation Plan 
Version 10.0 
10 September 2020
IDE #: G150036 
NCT#:  
NCT02439775

SPYRAL HTN-ON MED Clinical Investigation Plan 
Version 10.0 
Page 2 of 111 
Medtronic Confidential 
056-F275, v3.0 Clinical Investigation Plan Template
Global Sponsor 
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, California 95403 
United States 
Phone: +1 (800) 633-8766 
Note: this clinical study is funded by the sponsor 
Regional Sponsors 
Medtronic Australasia Pty. Ltd 
2 Alma Road, Macquarie Park, 
NSW 2113 
Australia 
Phone: (+61) 2 0 9857 9000 
Medtronic Bakken Research Center (BRC) B.V. 
Endepolsdomein 5, 
6229 GW Maastricht, 
The Netherlands 
Phone: +31-43-35-66-566 
Medtronic of Canada, Ltd.  
99 Hereford Street  
Brampton, Ontario, L6Y 0R3 
Canada  
Phone: +1-800-268-5346 
Medtronic Japan Co., Ltd 
1-2-70 Konan,
Minato-ku, Tokyo 108-0075 
Japan 
Phone: (+81) 3-6774-4611 
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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 3 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Approval sheet 
 
Author/Medical Writer/Clinical Study Manager (document owner): 
Pamela McKenna 
Sr. Prin. Clinical Research Specialist 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Clinical Leadership: 
Vanessa DeBruin  
Clinical Research Director  
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
 
Sandeep Brar 
Sr. Clinical Research Director 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
 
Vinny Parthasarathy 
APAC CL Lead  
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
 
Christina Zhong 
VP of Clinical Research  
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
 
Garrett Pilcher  
Sr. Clinical Research Director 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
 
Aarthi Kamath  
Sr. Clinical Research Specialist 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 4 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Statistics Management: 
Minglei Liu 
Senior Statistics Manager 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
QA: 
Jennifer Loushin 
Senior Clinical Quality Compliance Specialist 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Regulatory Affairs: 
Anna Dyer 
Regulatory Affairs Manager 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Safety: 
Carine Van Deursen  
Clinical Safety Specialist 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Monitoring: 
PJ Belmont  
Sr. Clinical Research Monitor 
(name) 
(functional role) 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 
 
Therapy Subject Matter Expert: 
Oscar Sanchez  
Sr. Clinical Research Manager 
(name) 
(functional role) 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 5 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Electronic sign-off 
Electronic sign-off 
(signature) 
(date) (dd MMM yyyy) 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 6 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Change History record 
CIP Change History 
Version 
Summary of Changes 
Author 
1.0 
Initial 
Vanessa DeBruin 
2.0 
Changes include the list below: 
1. 
Updated Time Course.  
2. 
Revisions of exclusion criteria. 
3. 
Updated/clarified safety and efficacy endpoints.  
4. 
Added baseline duplex ultrasound if obtained per standard of 
care. 
5. 
Updated anti-platelet/anti-coagulation language. 
6. 
Added Drug testing for Hypertensive Crises. 
7. 
Added/revised adverse event reporting language in Japan 
and Australia. 
8. 
Added contact information for the services providers. 
9. 
Updated Blood Pressure Measurement Procedures. 
10. Added list of Appendices. 
11. Minor formatting, typo, and clarifying language changes 
throughout protocol. 
Vanessa DeBruin 
3.0 
Changes include the list below: 
1. 
Updated approval signatories. 
2. 
Updated Time Course.  
3. 
Updated total number of subjects to be screened from 400 to 
700. 
4. 
Revisions of inclusion and exclusion criteria. 
5. 
Updated screening criteria. 
6. 
Clarified study ISO14155:2011 compliant except for AEs not 
reported for Control subjects after 12 months post-
randomization. 
7. 
Updated Section E.6 Study device/product traceability. 
8. 
Updated Section F Study Methods. 
9. 
Revised Figure 8 for consistency with protocol changes. 
10. Added CT/MRA Service Provider on Section L.1.1. 
11. Updated 
Section 
L.7 
Blood 
Pressure 
Measurement 
Procedures. 
12. Minor formatting, typo, and clarifying language changes 
throughout protocol. 
Vanessa DeBruin 
4.0 
Changes include the list below: 
1. Updated total number of subjects to be randomized from 100 
to 110.  
2. Removed “non-fasting” when referring to blood draws. 
3. Added “Updated address for Cardiovascular Research 
Foundation. 
4. Removed statement that a 6 French sheath should be used for 
renal angiogram. 
Vanessa DeBruin 
5.0 
Changes include the list below: 
1. 
Updated approval signatories. 
2. 
Updated study purpose throughout protocol to include 
hypothesis test. 
Kelsey Anderson 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 7 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
3. 
Added reference to inclusion of additional geographies, 
including Canada and applicable regulatory requirements. 
4. 
Updated/Clarified Safety and Efficacy Endpoints.  
5. 
Updated Time Course.  
6. 
Updated randomization ratio to 2:1. 
7. 
Updated total number of subjects to be screened from 750 to 
1600. 
8. 
Updated total number of participating study centers from 25 
to 55. 
9. 
Added 6-month crossover option for sham control subjects. 
10. Revisions of inclusion and exclusion criteria. 
11. Updated Follow-up Schedule. 
12. Updated interim analyses from 40, 60 and 80 subjects 
randomized to 175 and 220 randomized. 
13. Updated Procedures section. 
14. Addition of Lipid Panel (Total, High-Density Lipoprotein 
Cholesterol, Low-Density Lipoprotein Cholesterol, Total 
Cholesterol), Uric Acid And High-Sensitivity CRP (Hs-CRP) 
Laboratory Tests. 
15. Updated Clinical Experience section. 
16. Updated G3 generator manufacturer, Plexus Corp. address. 
17. Updated Sample Size section. 
18. Updated Training Requirements section. 
19. Added in 12M CTA/MRA Renal Imaging requirement for “a 
minimum of 50 and up to 340 patients” throughout the 
protocol. 
20. Added requirement to repeat office blood pressure and drug 
testing upon ABPM repeat. 
21. Updated Unavoidable Adverse Events Table. 
22. Updated Adverse Event Reporting Requirements Table. 
23. Clarified Investigator CRF signature requirements. 
24. Updated screening criteria. 
25. Revised Figures and Tables Throughout Protocol for 
Consistency with Protocol Changes. 
26. Updated Data Analysis and Reporting section. 
27. Minor formatting, typo, and clarifying language changes 
throughout protocol. 
6.0 
Changes include the list below: 
1.) Added 36 month follow-up visit for crossover subjects. 
2.) Updated > the range of 60-70% to >60% to indicate that 
anything above the range of 60-70% identified by DUS will 
require repeat imaging. 
Marianne Wanten 
7.0 
Changes include the list below: 
1. Update to indicate that SV1 can occur after 10.30 am if Informed 
Consent Form is signed at SV1, without a protocol deviation. 
2. Clarified that at least one antihypertensive medication needs to 
be at 50% of the maximum dose to qualify for the study. 
3. Added that subjects cannot be on other antihypertensive 
medications. 
4. Update to indicate no protocol deviation is required for not 
measuring hs-CRP when the site is unable to perform this blood 
test. 
Pamela McKenna 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 8 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
5. Added to exclusion criteria #9 that HbA1C will need to be re-
analyzed if the value in the medical  records is >3months old or 
if history of uncontrolled blood sugars raises concern. 
6. Exclusion criteria #13: updated to state “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”. 
7. Exclusion criteria # 16: updated to indicate that subjects need to 
be off NSAIDs for 1 month prior to SV2, not enrollment.  
8. Updated exclusion criteria # 18 to exclude Transient Ischemic 
attacks, or cerebrovascular accident altogether and not just if 
occurred within 3 months of screening. Added that patients who 
received catheter or surgical treatment for Atrial Fibrillation and 
are in sinus rhythm are not excluded. 
9. Updated statistics section, including sample size section and 
interim analyses. 
10. Updated Table 3 to include EQ-5D needed at 24/36M.  
11. Updated reasons when ABPM can be repeated to include if 
ABPM guidelines were not followed. 
12. Clarification added around cuff size for OBP and ABPM 
13. Update to clarify that patients who sign consent at SV1 are 
permitted to take their medication in the morning without 
protocol deviation. 
14. Updates to reflect OBP device without printer 
15. Minor formatting, typo and clarifying language changes 
throughout the protocol. 
8.0 
Changes include the list below: 
1. Updated Section F5 to include alternate Follow-up methods to 
allow more flexibility during extenuating circumstances, such as 
a global pandemic. 
2. Sample size updated 
3. Addition of clarification around when first and second interim 
analyses will take place. 
4. Planned completion of randomization changed to January 
2021 and planned study close-out changed to July 2024. 
5. Update to escape criteria that subject must meet the escape 
criteria and have medication changes in response. 
6. Update to analysis sets noting requirement of medication 
changes. 
7. 12-month imaging requirements clarified for UK and German 
subjects 
8. Updated table 10. 
9. Incorporated latest ISO1455 updates. 
10. Formatting and administrative updates. 
Pamela McKenna 
9.0 
1. Administrative update to remove the following sentence from the 
section F.5 ‘Follow-up Procedures’. ‘These alternative methods 
have no potential impact on patient safety, do not affect data 
integrity and do not introduce study bias.’  This sentence was 
added in version 8.0 of the CIP which was not implemented prior 
to version 9.0. 
Pamela McKenna 
10.0 
1. Updated sample size for first interim analysis. 
2. Updated operating characteristics for primary efficacy endpoint. 
Pamela McKenna 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 9 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Table of Contents 
 
A 
SYNOPSIS ...................................................................................................... 13 
B 
GENERAL INFORMATION ............................................................................. 22 
B.1 
Introduction ....................................................................................................................... 22 
B.1.1 Clinical Experience Using the Single Electrode RF Renal Denervation System ... 22 
B.1.2 Clinical Experience Using the Multi Electrode RF renal denervation system 
(Spyral) ................................................................................................................... 25 
B.2 
Device information ............................................................................................................ 31 
B.2.1 The Symplicity™ renal denervation system ........................................................... 31 
B.2.2 Symplicity Spyral™ Catheter.................................................................................. 31 
B.2.3 Symplicity G3™ Generator..................................................................................... 32 
B.2.4 Labeling .................................................................................................................. 34 
B.2.5 Intended clinical performance ................................................................................ 34 
B.3 
Comparator information .................................................................................................... 35 
C 
STUDY PLAN .................................................................................................. 36 
C.1 
Study Objective................................................................................................................. 36 
C.2 
Clinical endpoints.............................................................................................................. 36 
C.2.1 Primary Endpoints: ................................................................................................. 36 
C.2.2 Secondary Endpoints ............................................................................................. 37 
C.3 
Study Population............................................................................................................... 39 
C.4 
Study Design .................................................................................................................... 39 
C.5 
Randomization and blinding ............................................................................................. 39 
C.6 
Sample Size ...................................................................................................................... 40 
C.7 
Number of investigation sites and study duration ............................................................. 42 
D 
SUBJECT SELECTION ................................................................................... 42 
D.1 
Inclusion criteria ................................................................................................................ 42 
D.2 
Exclusion criteria............................................................................................................... 42 
E 
STUDY PREPARATION PROCEDURES ....................................................... 44 
E.1 
Investigator/Investigation site selection ............................................................................ 44 
E.1.1 Investigator selection criteria .................................................................................. 44 
E.1.2 Investigational site selection criteria ....................................................................... 45 
E.1.3 Clinical Trial Agreement ......................................................................................... 45 
E.1.4 Curriculum Vitae ..................................................................................................... 45 
E.2 
Ethics ................................................................................................................................ 46 
E.2.1 EC/IRB approval ..................................................................................................... 46 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 10 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
E.2.2 Patient Information and Informed consent process ............................................... 46 
E.2.3 Revisions in Patient Information and Informed Consent Form .............................. 47 
E.2.4 Regulatory submission ........................................................................................... 47 
E.3 
Regulatory compliance ..................................................................................................... 48 
E.4 
Training requirements ....................................................................................................... 48 
E.5 
Clinical study materials and clinical study-specific equipment ......................................... 49 
E.6 
Study device/product handling and traceability ................................................................ 49 
E.6.1 Supply of investigational devices/products ............................................................ 50 
E.6.2 Storage and handling of investigational devices/products ..................................... 50 
E.6.3 Device explant and return procedures/products .................................................... 50 
E.6.4 Device/product disposition requirements ............................................................... 51 
F 
STUDY METHODS .......................................................................................... 51 
F.1 
Point of enrollment ............................................................................................................ 51 
F.2 
Screening Visit 1 ............................................................................................................... 53 
F.3 
Screening Visit 2 ............................................................................................................... 53 
F.4 
Procedure ......................................................................................................................... 55 
F.5 
Follow-Up Procedures ...................................................................................................... 57 
F.6 
Crossover Procedures ...................................................................................................... 60 
F.7 
Confirmatory Blood Draws to Assess Renal Function...................................................... 63 
F.8 
Antihypertensive medication escape criteria .................................................................... 63 
F.9 
Drug testing for Emergency Room Visit or Hospitalization for Elevated Blood Pressure 64 
F.10 Data collection requirements ............................................................................................ 64 
F.11 Role of the sponsor’s representatives .............................................................................. 67 
F.12 Source documents ............................................................................................................ 67 
F.13 Adverse events and device deficiencies .......................................................................... 67 
F.13.1 Definition/classification ........................................................................................... 67 
F.13.2 Recording, reporting, and review of Adverse Events ............................................. 69 
F.13.3 Recording, reporting, and review of Device Deficiencies ....................................... 70 
F.13.4 Adverse Event Reporting Requirements ................................................................ 71 
F.13.5 Data Safety Monitoring Board and Clinical Events Committees ............................ 73 
F.13.6 Emergency contact details in case of serious AEs ................................................ 73 
F.14 Subject accountability ....................................................................................................... 73 
F.14.1 Missed Follow-up Visits .......................................................................................... 73 
F.14.2 Unscheduled Follow-up Visits ................................................................................ 74 
F.14.3 Subject Withdrawal or Lost to Follow-up ................................................................ 74 
F.14.4 Subject Exit from Trial ............................................................................................ 74 
F.15 Study deviations and CIP changes................................................................................... 75 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 11 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
F.15.1 Request for Approval of Study Deviations ............................................................. 75 
F.15.2 Reporting requirements for study deviations.......................................................... 75 
F.15.3 Amendments to the Clinical Investigation Plan ...................................................... 76 
G 
QUALITY CONTROL PROCEDURES ............................................................ 77 
G.1 
Procedures for database management ............................................................................ 77 
G.1.1 Data collection ........................................................................................................ 77 
G.1.2 Source data to be directly recorded on the Case Report Forms............................ 77 
G.1.3 Time windows for completion and submission of Case Report Forms .................. 77 
G.1.4 Data review and processing ................................................................................... 77 
G.2 
Monitoring procedures ...................................................................................................... 77 
G.2.1 Accessibility of investigational site staff and study materials ................................. 78 
G.2.2 Audits and investigation site inspections ................................................................ 78 
G.3 
Study suspension or early termination ............................................................................. 78 
G.3.1 Early Study Suspension or Termination ................................................................. 79 
G.3.2 Early investigation site suspension or termination ................................................. 79 
G.3.3 Subject follow-up in case of termination ................................................................. 79 
G.3.4 Criteria for unblinding ............................................................................................. 80 
G.4 
Study close out ................................................................................................................. 80 
H 
DATA ANALYSIS AND REPORTING ............................................................. 80 
H.1 
Analysis of clinical data .................................................................................................... 81 
H.2 
Primary Safety Objective .................................................................................................. 82 
H.3 
Secondary Safety Objectives ........................................................................................... 83 
H.3.1 Renal Artery Stenosis Evaluation at 12 Months ..................................................... 83 
H.4 
Primary Efficacy Objective ................................................................................................ 83 
H.4.1 Primary Efficacy Endpoint Operating Characteristics ............................................ 84 
H.5 
Secondary Efficacy Objectives ......................................................................................... 85 
H.6 
Additional Objectives ........................................................................................................ 85 
H.7 
Safety Evaluation .............................................................................................................. 86 
H.8 
Subgroup Analyses .......................................................................................................... 86 
H.9 
Publication Policy.............................................................................................................. 87 
I 
STUDY MANAGEMENT .................................................................................. 87 
I.1 
Study staff ......................................................................................................................... 87 
I.2 
Advisory committees ........................................................................................................ 88 
I.2.1 Executive Steering Committee ............................................................................... 88 
I.2.2 Data Safety Monitoring Board (DSMB) .................................................................. 88 
I.2.3 Clinical Events Committee (CEC) .......................................................................... 88 
I.2.4 Publications Review Committee ............................................................................. 89 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 12 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
I.3 
Records and reports ......................................................................................................... 89 
I.3.1 Investigator records ................................................................................................ 89 
I.3.2 Investigator reporting responsibilities ..................................................................... 90 
I.3.3 Sponsor records ..................................................................................................... 91 
I.3.4 Sponsor reporting responsibilities .......................................................................... 91 
I.3.5 Record retention ..................................................................................................... 92 
I.4 
Miscellaneous ................................................................................................................... 92 
I.4.1 Insurance ................................................................................................................ 92 
I.4.2 Subject compensation and indemnification ............................................................ 92 
I.4.3 Subject confidentiality ............................................................................................. 93 
J 
RISKS AND BENEFITS .................................................................................. 93 
J.1 
Anticipated Clinical Benefits ............................................................................................. 93 
J.2 
Risks ................................................................................................................................. 94 
J.3 
Minimization of Risk .......................................................................................................... 96 
J.4 
Risk-to-Benefit Rationale .................................................................................................. 97 
K 
REFERENCES ................................................................................................ 97 
L 
APPENDICES ............................................................................................... 100 
L.1 
Names and addresses .................................................................................................... 100 
L.1.1 List of contact persons ......................................................................................... 100 
L.1.2 List of participating investigation sites and investigators ..................................... 102 
L.2 
Case Report Forms ........................................................................................................ 102 
L.3 
Sample Investigator Agreement ..................................................................................... 102 
L.4 
Abbreviations .................................................................................................................. 103 
L.5 
Definitions ....................................................................................................................... 106 
L.6 
Center for Medicare and Medicaid Services (CMS) IDE Study Criteria ......................... 106 
L.7 
Blood Pressure Measurement Procedures .................................................................... 108 
L.8 
Sample Patient Information and Informed Consent Form .............................................. 111 
L.9 
Subject Blinding Assessment ......................................................................................... 111 
L.10 EQ-5D (Quality of Life) Survey ....................................................................................... 111 
L.11 ABPM Guidelines............................................................................................................ 111 
L.12 Serious or Unanticipated Adverse Event Report (Rush form) – Japan only .................. 111 
L.13 Angiographic Core Laboratory Guidelines ..................................................................... 111 
L.14 Renal Duplex Ultrasound (DUS) Core Laboratory Guidelines ....................................... 111 
L.15 Magnetic Resonance Angiographic (MRA) / Computerized Tomography (CT) Core 
Laboratory Guidelines .................................................................................................... 111 
L.16 Blood Core Laboratory Guidelines ................................................................................. 111 
L.17 Drug Testing Core Laboratory Guidelines ...................................................................... 111 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 13 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
A SYNOPSIS 
Title 
Global Clinical Study of Renal Denervation with the Symplicity Spyral™ multi-electrode renal 
denervation system in Patients with Uncontrolled Hypertension on Standard Medical Therapy. 
Purpose 
The purpose of this study is to test the hypothesis that renal denervation decreases blood pressure and 
is safe when studied in the presence of up to three standard antihypertensive medications. 
Design 
Multi-center, international, prospective, blinded, 2:1 (treatment to control) randomized, interventional, 
sham-controlled study. 
Medical device/product 
The Symplicity SpyralTM multi-electrode renal denervation catheter (Symplicity SpyralTM catheter) and 
the Symplicity G3TM renal denervation RF generator (Symplicity G3TM generator) will be used in this 
clinical study. These components of the SymplicityTM renal denervation system are investigational in 
the United States, Canada and Japan (referred to as MDT-2115). Both the Symplicity SpyralTM catheter 
and Symplicity G3TM generator are commercially available in Australia and countries where CE-mark 
applies. Additional geographies may be added to the clinical study and the approval status will be 
documented under a separate cover.  
Objective 
The objective of this study is to test the hypothesis that renal denervation is safe and reduces systolic 
blood pressure (SBP) in patients with uncontrolled hypertension on one, two, or three standard 
antihypertensive medications compared to a sham-controlled population. In this study, “uncontrolled 
hypertension” is defined as an office systolic blood pressure (SBP) ≥ 150 mmHg and <180 mmHg, an 
office Diastolic Blood Pressure (DBP) ≥90 mmHg and a 24-hour Ambulatory Blood Pressure Monitoring 
(ABPM) average SBP ≥140 mmHg to <170 mmHg, all of which are measured at Screening Visit 2 (per 
Appendix L7). Data obtained will be used to confirm the effect of renal denervation on elevated blood 
pressure in patients on 1, 2 or 3 antihypertensive medications. Data collected during the SPYRAL HTN-
ON MED trial may be used to gain market approval or additional indications for the Symplicity SpyralTM 
multi-electrode renal denervation catheter (Symplicity SpyralTM catheter) and the Symplicity G3TM renal 
denervation RF generator from regulatory entities, including, but not limited to: the Pharmaceuticals and 
Medical Device Agency (PMDA), Health Canada, and the U.S. Food and Drug Administration (FDA).  
 
Endpoints 
Primary Endpoints  
There are two primary endpoints in this study (one efficacy and one safety). The study will be considered 
successful if both the primary safety and efficacy endpoint hypotheses are met.  
Powered Primary Efficacy Endpoint: 
• 
Baseline adjusted change (using Analysis of Covariance) in systolic blood pressure (SBP) 
from baseline (Screening Visit 2) to 6 months post-procedure as measured by 24-hour 
Ambulatory Blood Pressure Monitoring (ABPM). 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 14 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Powered Primary Safety Endpoint: 
• 
Incidence of Major Adverse Events (MAE), defined as a composite of the following events, 
through one-month post-randomization (6 months for new renal artery stenosis): 
• 
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 and/or the protocol.  
• 
New renal artery stenosis > 70%, confirmed by angiography and as determined 
by the angiographic core laboratory 
Secondary Endpoints 
Secondary Efficacy Endpoints  
• 
Change in systolic blood pressure (SBP) from baseline (Screening Visit 2) as measured by 
24-hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24 and 36 months post-
procedure 
• 
Change in office systolic blood pressure from baseline (Screening Visit 2) at 1, 3, 6, 12, 24 
and 36 months post-procedure  
• 
Change in diastolic blood pressure from baseline (Screening Visit 2) as measured by 24-
hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24 and 36 months post-
procedure 
• 
Change in office diastolic blood pressure from baseline (Screening Visit 2) at 1, 3, 6, 12, 
24 and 36 months post-procedure 
• 
Incidence of achieving target office systolic blood pressure (SBP<140 mmHg) at 1, 3, 6, 
12, 24 and 36 months post-procedure 
Secondary Safety Endpoints 
• 
Acute/procedural safety at 1-month post-procedure 
• 
Significant embolic event resulting in end-organ damage 
• 
Renal artery perforation requiring intervention 
• 
Renal artery dissection requiring intervention 
• 
Vascular complications  
• 
End-Stage Renal Disease 
• 
≥ 40% decline in eGFR  
• 
Increase in serum creatinine >50% from Screening Visit 2 
• 
New Myocardial Infarction 
• 
New Stroke 
• 
Renal artery re-intervention 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 15 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl 
decrease in hemoglobin concentration, a ≥15% absolute decrease in 
hematocrit, or death due to bleeding within 7 days of the procedure) 
• 
New renal artery stenosis >70%, confirmed by angiography and as determined 
by the angiographic core laboratory 
• 
Hospitalization for hypertensive crisis not related to confirmed non-adherence 
with medication and/or protocol 
 
• 
Chronic Safety Secondary Endpoints at 3, 6, 12, 24 and 36 months post-procedure 
• 
Composite Safety Endpoint, defined as a composite 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 and/or the protocol.  
 
New renal artery stenosis > 70%, confirmed by angiography 
and as determined by the angiographic core laboratory 
• 
≥ 40% decline in eGFR  
• 
Increase in serum creatinine >50% from Screening Visit 2 
• 
New Myocardial Infarct 
• 
New Stroke 
• 
Renal artery re-intervention 
• 
Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl 
decrease in hemoglobin concentration, a ≥15% absolute decrease in 
hematocrit, or death due to bleeding within 7 days of the procedure) 
• 
Hospitalization for hypertensive crisis not related to confirmed non-adherence 
with medication and/or protocol  
• 
Summary of Health-related Quality of Life (HRQoL) analysis based on reporting measures 
using accepted QoL instruments (EQ5D) 
 
Additional analyses 
 
The following additional analyses will be conducted:  
• 
Antihypertensive medication usage throughout the study, including escape patients and 
subjects with medication changes within 6-month follow-up.  
• 
Additional procedural characteristics e.g. treatment duration, frequency of distal renal 
artery treatment, ablations per vessel, location of ablations, number of ablations per 
patient and other characteristics will be analyzed to assess their impact on blood 
pressure. 
• 
Medication adherence using results from drug testing. In addition, we will perform 
analyses to evaluate the effect of medications adherence on BP. 
• 
Long term imaging of renal arteries 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 16 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Subject population 
Patients with uncontrolled hypertension on one, two, or three antihypertensive medications (of which at 
least one is at least 50% of maximum manufacturer’s recommended dosage of a thiazide-type diuretic, 
a dihydropyridine calcium channel blocker, an ACE-inhibitor/angiotensin receptor blocker (ACE-I/ARB), 
or a beta blocker) will be enrolled in accordance with the Inclusion and Exclusion criteria specified in 
the protocol. Subjects cannot be on other antihypertensive medications. Note: In Japan, patients may 
be prescribed less than 50% of maximum manufacturer’s recommended dosage of a thiazide-type 
diuretic per standard of care. Approximately 1600 subjects will be screened in order to randomize 
approximately 340 subjects (including up to 80 subjects used as an informative prior see Section C.6), 
at up to 55 study centers in the United States, Japan, Australia, Canada and countries where CE-mark 
applies. Additional geographies may be added to the clinical study at a later date and the approval 
status will be documented under a separate cover. Enrollment in the prospective cohort is expected to 
take approximately 20 months.  
Subjects are expected to participate in the study from the time of signing consent until completion of 
three to six years of follow-up after randomization as described in Table 1 and Table 2. If a subject is 
randomized to the renal-denervation arm their participation will be 3 years. If a subject is randomized 
to the control (sham) arm, they may be offered renal denervation therapy (crossover) after their 6-month 
follow-up visit and will, if they undergo crossover denervation therapy, continue to be followed for 36-
months after the renal-denervation procedure, according to Table 2.  There will be some subjects that 
receive the crossover visit after their 6-month visit, for those subjects the participation time will be 
increased to a maximum of 6 years, specifically for any subject that is offered the crossover procedure 
at the 36-month follow visit as they will need to be followed for 36-months following the crossover.  
Screening Criteria 
Eligible patients will be screened for participation into the study if they are aged 20-80 years, have a 
diagnosis of hypertension, are taking one, two, or three antihypertensive medications of which at least 
one is at least 50% of maximum manufacturer’s recommended dosage of a thiazide-type diuretic, a 
dihydropyridine calcium channel blocker, an ACE-I/ARB or a beta blocker (When prescribed with other 
qualifying medications, 12.5 mg hydrochlorothiazide is acceptable as the minimum dosage) for at least 
six weeks prior to screening visit 1 and who have a blood pressure within the range required for 
randomization (ABPM SBP ≥ 140 mmHg and < 170 mmHg, office SBP ≥ 150 mmHg and < 180 mmHg 
and office DBP ≥ 90 mmHg measured according to guidelines in Appendix L.7). Note: In Japan, patients 
may be prescribed less than 50% of maximum manufacturer’s recommended dosage of a thiazide-type 
diuretic per standard of care. If a patient is initially screened per inclusion criterion 2 on a certain number 
of medications (e.g., two) and screen fails with an OBP > 140 mmHg but < 150 mmHg, the subject may 
subsequently be re-screened at least 6 weeks after the medication change for the study as long as the 
patient is on fewer medications (but still meeting minimum medication requirements) than when initially 
screened.  
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 (according to guidelines in Appendix L.7) 
at Screening Visit 1 and Screening Visit 2 when receiving a medication regimen of one, two, 
or three antihypertensive medication classes of which at least one is at least 50% of the 
maximum manufacturer’s dosage. The antihypertensive medication classes must include a 
thiazide-type diuretic, a dihydropyridine calcium channel blocker, an ACE-I/ARB, or a beta 
blocker and the subject must be on a stable dose of each medication for at least six weeks 
prior to Screening Visit 1 and up to Screening Visit 2. When prescribed with other qualifying 
medications, 12.5 mg hydrochlorothiazide is acceptable as the minimum dosage. Note: In 
Japan, patients may be prescribed less than 50% of maximum manufacturer’s recommended 
dosage of a thiazide-type diuretic per standard of care. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 17 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
3. Individual has a valid 24-hour ABPM average of SBP ≥ 140 and < 170 mmHg measured at 
Screening Visit 2 according to guidelines in Appendix L.7 after witnessed antihypertensive 
drug ingestion prior to applying the ABPM device. (ABPM is considered valid if the number 
of successful daytime readings captured is ≥21 and the number of successful nighttime 
readings captured is ≥ 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. 
Exclusion Criteria 
1. Individual has undergone prior renal denervation. 
2. Individual has renal artery anatomy that is ineligible for treatment including:  
a. Main renal artery for each kidney is less than 3mm or greater than 8mm 
b. Lacks a main renal arterial vessel that does not allow 4 simultaneous quadrantic 
(4SQ) radio frequency ablations in the main renal artery or equivalent (defined as 
4SQ ablations in all branch vessels between 3mm and 8mm) 
3. Presence of FMD (fibromuscular dysplasia) (defined as visible beading of the artery on 
angiography) 
4. Has >50% stenosis in any treatable vessel. 
5. Has a renal artery stent placed <3 months prior to the denervation procedure. 
6. Presence of an aneurysm defined as any localized increase in the diameter of the vessel 
7. Treatment area within 5mm of a segment in the renal artery which contains any of the 
following: 
a. Atheroma, 
b. Calcification, or 
c. Renal artery stent 
8. 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)). (Note: an eGFR calculation specific to Japanese 
patients will be used for subjects enrolled in Japan).  
9. 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 SV2), or history of uncontrolled blood 
sugars raises concern it is required to analyze glycosylated hemoglobin as part of SV2 labs.) 
10. Individual is taking SGLT2 inhibitors or GLP-1 agonists that have been prescribed <90 days 
prior to Screening Visit 1 or who does not plan to remain on these drugs for the duration of 
the trial. 
11. Individual has had ≥ 1 episode(s) of orthostatic hypotension not related to medication 
changes within the past year or has a reduction of SBP of ≥ 20 mmHg or DBP of ≥10 mmHg 
within 3 minutes of standing coupled with symptoms during the screening process (at SV2). 
12. Individual requires chronic oxygen support or mechanical ventilation other than nocturnal 
respiratory support for sleep apnea (e.g. CPAP, BiPAP). 
13. 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. 
14. Individual has documented primary pulmonary hypertension. 
15. Individual has untreated secondary cause of hypertension (either known or suspected) or is 
taking drugs that increase sympathetic tone that could contribute to hypertension. 
16. 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 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 18 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Screening Visit 2. (Patients are permitted to take aspirin or clopidogrel for cardiovascular risk 
reduction). 
17. Individual with HIV on anti-retroviral drug therapy without documentation that hypertension 
preceded initiation of anti-retroviral drug treatment. 
18. 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.  
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. 
Treatment 
Subjects taking one, two, or three eligible antihypertensive medications for at least six weeks and with 
an office SBP ≥ 150 mmHg and < 180 mmHg and an office DBP ≥ 90 mmHg can be enrolled and 
proceed to Screening Visit 1 (SV1). Subjects meeting the eligibility criteria can continue to Screening 
Visit 2 (SV2) 2-4 weeks after SV1. Subjects who continue to meet eligibility criteria after completion of 
SV2 and who have received randomization approval by the sponsor will be randomized and the 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 19 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
procedure will occur within a maximum of two weeks (14 calendar days) following the completion of 
SV2. Subjects must not meet any anatomic exclusion criteria in aortography or renal angiography to 
continue in the study.  
 
Following the renal denervation or control procedure, subjects will complete follow-up at 1, 3, 6, and 
12 months. Subjects and blinded study personnel will be unblinded to their randomization assignment 
upon completion of the 6-month follow-up. All subjects will be followed annually through 36 months 
post-procedure (Table 1). Control (sham) subjects may be offered renal denervation therapy 
(crossover) after the completion of their 6-month follow up visit and ensuring they meet key inclusion 
criteria and no key exclusion criteria.  If a subject undergoes the crossover denervation therapy, they 
will be followed for 36 months after the renal-denervation procedure, according to Table 2 and Section 
F.6.  For subjects who undergo crossover at a later time, they will be followed for 36 months from 
when the crossover occurred.  
Interim Analyses 
Interim analyses will take place after a minimum of 110 and 149 subjects (excluding the first 
consecutively randomized 80 subjects in the SPYRAL HTN-ON MED Study) have 6-month efficacy 
endpoint data available. This will require randomizing approximately 130 and 175 subjects to account 
for attrition. A decision to stop or continue the study will be made after each interim analysis has been 
reviewed.   
 
Time Course 
Start of enrollment (consent): July 2015 
Planned completion of randomization: January 2021 
Planned study close-out:  July 2024

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 20 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Clinical Procedures 
Table 1: Schedule of Testing for All Subjects (See Table 2 for Crossover Subjects’ Testing) 
1 month (30 days): 16-44 days, 3 months (90 days): 76-104 days, 6 months (180 days): 166-194 days, 12 months 
(360 days): 330-390 days, 24 months (720 days): 690-750 days, 36 months (1080 days): 1050-1110 days. 
Post-Procedure 
(M=months ± 14 days for 1M, 3M and 6M visits, ± 30 days for 12M-36M visits) 
Required Assessments 
SV1 
SV2 
Procedure 
Prior to 
Discharge 
1M 
3M 
6M 
12M 
24M 
36M 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Clinical assessment 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Renal Denervation or Sham Procedure 
 
 
X 
 
 
 
 
 
 
 
Office Blood Pressure according to guidelines in Appendix L.7 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
24-Hour ABPM according to guidelines in Appendix L.7 
 
X 
 
 
 
X 
X 
X 
X 
X 
Witnessed pill taking  
 
X 
 
 
 
X 
X 
X 
X 
X 
Blood tests (uric acid, lipid panel and high sensitivity CRP6) 
 
X 
 
 
 
 
 
 
 
 
Blood Tests (Chem-7)3 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
Drug testing 
 
X 
 
 
 
X 
X 
X 
X 
X 
Renal Artery Imaging – Angiogram 
 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging  
 
X4 
 
 
 
 
X1 
X5 
(X)5 
(X)5 
Blinding Assessment for Subjects and Assessors 
 
 
 
X 
 
X 
X 
 
 
 
EQ-5D  
 
X 
 
 
 
X 
X 
X 
X 
X 
Mortality Assessment2 
 
 
 
 
X 
X 
X 
X 
X 
X 
Medication Review and Event Review 
All adverse events (AE) and all medication review 
After 12 months, previously reported AEs will need to be reviewed and updated as needed 
Serious AEs and all 
medication review 
1 DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CTA 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.  The 6M DUS will not be required for subjects crossing over at 6M if crossover is completed within 30 days of 6M visit.   
2 Conduct if follow-up missed. 
3 Bicarbonate will not be measured for subjects enrolled in Japan and Europe. 
4 Submit baseline duplex ultrasound, CT, or MRA if obtained per standard of care prior to procedure within one year from the date of screening visit 1.5 CTA/MRA  required as first line imaging modality 
at 12M (and 24M and 36M as applicable). For treatment and crossover subjects only: Repeat DUS, MRA, or CTA to be used if prior imaging modality is nondiagnostic. If repeat DUS/CTA/MRA is nondiagnostic or evidence 
of a clinically significant stenosis (>60-70%) is indicated, an angiogram must be obtained and submitted to the Angiographic Core Laboratory.  Subjects who have already completed their 12-month without renal imaging 
will be required to undergo renal imaging at their next scheduled follow-up unless they have a renal angiogram due to crossover. For the participating sites in Germany and the UK, only renal MRA imaging at the 12-month 
follow-up visit (or 24 or 36M follow-up as applicable) will be performed. For these countries, if the initial MRA is non-diagnostic, a repeat MRA should be performed. If the initial MRA or repeat renal MRAs are non-diagnostic 
and an additional repeat MRA is not expected to yield the required information for a diagnostic study, a DUS can be completed.6 High-sensitivity CRP is not required to be measured for subjects enrolled at sites where high-
sensitivity CRP test cannot be locally performed.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 21 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Table 2: Schedule of Testing for Crossover Subjects  
1 month (30 days): 16-44 days, 3 months (90 days): 76-104 days, 6 months (180 days): 166-194 days, 12 
months (360 days): 330-390 days, 24 months (720 days): 690-750 days, 36 months (1080 days): 1050-1110 
days 
Post-Procedure 
 (M=months ± 14 days for 1M, 3M and 6M visit, ± 30 days for 12M-36M visits) 
Required Assessments 
Baseline5 
Renal 
Denervation 
Prior to 
Discharge 
1M 
3M 
6M 
12M 
24M 
36M 
Clinical assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood Tests (Chem-7)3 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Tests (uric acid, lipid panel, and high-
sensitivity CRP6) 
 
X (prior to 
procedure)5 
 
 
 
 
 
 
 
Office Blood Pressure according to guidelines in 
Appendix L.7 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
 
X (prior to 
procedure)5 
 
 
 
 
 
 
 
Witnessed pill taking 
X 
 
 
 
X 
X 
X 
X 
X 
24-Hour ABPM according to guidelines in 
Appendix L.7 
X 
 
 
 
X 
X 
X 
X 
X 
EQ-5D  
X 
 
 
 
X 
X 
X 
X 
X 
Renal Denervation 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging - Angiogram 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging  
 
 
 
 
 
X1 
X4 
(X)4 
(X)4 
Drug Testing 
X 
 
 
 
X 
X 
X 
X 
X 
Mortality Assessment2 
 
 
 
X 
X 
X 
X 
X 
X 
Medication Review, Event Review 
All adverse events (AE) and all medication review 
After 12 months, previously reported AEs will need to be reviewed and updated as needed  
Serious AEs and all medication 
review 
 
1 DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CTA or angiogram to be used if DUS is non-diagnostic.  Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic or stenosis 
>60-70% is suspected. 
2 Conduct if follow-up visit missed. 
3 Bicarbonate will not be measured for subjects enrolled in Japan and Europe. 
4 CTA/MRA  required as first line imaging modality at 12M (and 24M and 36M as applicable). Repeat DUS, MRA, or CTA to be used if prior imaging modality is nondiagnostic. If repeat DUS/CTA/MRA is nondiagnostic 
or evidence of a clinically significant stenosis (>60-70%) is indicated, an angiogram must be obtained and submitted to the Angiographic Core Laboratory.  Subjects who have already completed their 12-month without 
renal imaging will be required to undergo renal imaging at their next scheduled follow-up. For the participating sites in Germany and the UK, only renal MRA imaging at the 12-month follow-up visit (or 24 or 36M follow-
up as applicable) will be performed. For these countries, if the initial MRA is non-diagnostic, a repeat MRA should be performed. If the initial MRA or repeat renal MRAs are non-diagnostic and an additional repeat MRA 
is not expected to yield the required information for a diagnostic study, a DUS can be completed. 
5 If not already collected at previous follow up visits (within 30 days of crossover procedure).6 High-sensitivity CRP is not required to be measured for subjects enrolled at sites where high-sensitivity CRP test cannot be 
locally performed.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 22 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
B GENERAL INFORMATION 
B.1 Introduction 
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 disease1,2,3. 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 elevation4. It is important to 
note that the kidneys maintain appropriate electrolyte and volume homeostasis, despite being 
denervated, as demonstrated by the human kidney transplant experience5. Prior to pharmacological 
treatment, hypertension was sometimes treated in man with complex invasive procedures, such as 
surgical nephrectomy and even radical surgical sympathectomy.   
Medtronic has developed a radiofrequency catheter with four 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, allowing for a single treatment 
in each renal artery and thus reduces the total procedure time compared to the single electrode 
SymplicityTM renal denervation system. 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 G3TM 
generator. With reduced procedure time, the patient is potentially exposed to less radiation and 
radiopaque contrast injections. 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 SpyralTM catheter and 
Symplicity G3TM 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.  
B.1.1 
Clinical Experience Using the Single Electrode RF Renal Denervation System 
SYMPLICITY HTN-1 and SYMPLICITY HTN-2  
Initial human studies of patients with resistant hypertension have demonstrated that the Symplicity renal 
denervation (RDN) system can safely denervate the kidney and that renal denervation has resulted in 
significant and sustained reductions of blood pressure out to three years6,7. SYMPLICITY HTN-1 utilized 
the Symplicity renal denervation system (which included the single electrode catheter design) for 
treating patients with resistant hypertension. A total of 153 resistant hypertension patients with baseline 
office systolic blood pressure (SBP) ≥160 mmHg on 3 antihypertensive medications were treated. At 
the primary endpoint, 6 months post-denervation, the investigators reported a -22/-10 mmHg change in 
office SBP. Blood pressure reductions at 12, 24, and 36 months were -27/-14 mmHg, -29/-14 mmHg, 
and -32/-14 mmHg, respectively. There were no unanticipated adverse device effects or serious device-
related or procedure-related complications. Through the 36- month follow-up, there were no late serious 
adverse events and no clinically significant changes in mean eGFR were reported8.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 23 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The SYMPLICITY HTN-2 randomized, controlled study was conducted on a similar patient population 
as SYMPLICITY HTN-1 and the efficacy of RDN with the Symplicity catheter was compared with 
conventional medical therapy. Mean baseline blood pressure for the treatment group was 178/97 mmHg 
± 18/16 mmHg; mean baseline blood pressure for the control group was 178/98 mmHg ± 16/17 mmHg. 
Ambulatory blood pressure recordings were available for 20 patients in the renal denervation group, 
showing a mean decrease of -11/-7 mmHg (SD 15/11; p=0.006 for systolic blood pressure change, 
p=0.014 for diastolic blood pressure change) from baseline to 6 months, whereas averages did not 
change for 25 patients in the control group (-3/-1 mmHg [19/12]; p=0.51 for systolic, p=0.75 for diastolic). 
At the 6-month primary endpoint, the investigators reported a -32/-12 mmHg change in office BP in the 
RDN group compared to a +1/0 change in the control group (p<0.0001)9. At 24 months, subjects in both 
RDN and crossover groups had significant and sustained blood pressure reductions. 
Thirty-six months results showed sustained lowering of office blood pressure at 3 years in subjects with 
severe, treatment-resistant hypertension without serious safety concerns. Blood pressure reduction at 
36 months was -33/-14 mmHg in the RDN group. In the Pooled RDN and crossover group, BP reduction 
at 30 months was -34/-13 mm Hg (n=69). Blood pressure reductions were achieved in absence of 
increases in blood pressure medications.  
The safety profile for this study has been consistent with the SYMPLICITY HTN-1 study. In the 
SYMPLICITY HTN-2 population, there was one renal artery dissection from the injection of contrast into 
the renal artery wall during dye angiography; the lesion was stented without further consequences.  One 
patient endured prolonged hospitalization in the crossover group due to hypotension following the RDN 
procedure. IV fluids were administered along with a decrease in antihypertensive medications and the 
patient was discharged without further incident.  Other than these events with follow up to 36 months, 
no other device, procedure or therapy related serious adverse events related to the delivery of 
radiofrequency energy to the renal artery with the Symplicity FlexTM catheter were reported. Importantly, 
the results of the SYMPLICITY HTN-2 study reaffirm the results of the SYMPLICITY HTN-1 study and 
showed a significant reduction in blood pressure compared to optimal medical management in the 
control, without having a safety signal.     
 
SYMPLICITY HTN-3  
The SYMPLICITY HTN-3 Clinical Study was a multi-center, prospective, single-blind, randomized and 
controlled study that randomized 545 subjects in a 2:1 ratio to renal denervation plus best medical 
therapy vs. best medical therapy in the United States. The 6-month SYMPLICITY HTN-3 clinical study 
results were presented at the 63rd Scientific Sessions of the American College of Cardiology (ACC) 
March, 2014 and published concurrently in the New England Journal of Medicine10. In office SBP, 
change (from baseline to 6 months follow-up) between the renal denervation arm and the control arm 
as the primary efficacy endpoint was a statistically non-significant difference of 2.39 mmHg [95% CI: -
2.12 to 6.89, p=0.26], with a SBP reduction of 14.1 mm Hg in the renal denervation arm vs. 11.7mmHg 
reduction in the control arm. The secondary endpoint was the comparison of SBP change (from baseline 
to 6 months follow-up) in mean 24-hour ambulatory blood pressure (ABP) between the renal 
denervation arm and the control arm using an automated ambulatory blood pressure monitor (ABPM). 
The result was a statistically non-significant difference of 1.96 mmHg, [95% CI, -1.06 to 4.97, p=0.98], 
with a SBP reduction of 6.8 mm Hg in the renal denervation arm vs. 4.8 mmHg reduction in the control 
arm. The major explanation for the difference in efficacy findings between HTN-1, HTN-2 and HTN-3 
studies was the inclusion of sham to the control arm.  
The SYMPLICITY HTN-3 study met the primary safety endpoint, with a major adverse events rate of 
1.4% (upper 95% confidence bound 2.9%) in the renal denervation arm, which was significantly 
(p<0.001) less than the pre-specified objective performance criterion of 9.8%. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 24 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Twelve-month11 data indicated there was no difference in major adverse events between the 
denervation and control groups. Subjects in the denervation group, control group that did not cross 
over, and control group subjects that crossed over at 6 months showed similar reductions in office and 
ambulatory blood pressure 12 months post-randomization.  
Subjects randomized into SYMPLICITY HTN-3 were planned to be followed for up to 5 years post-
procedure. However, it was decided to prematurely terminate the study after completion of 3-year follow 
up visits for active subjects. Subjects had been allowed to crossover from sham to treatment after the 
completion of the 6-months follow-up visit. In the overview below, the office blood pressure results from 
all treated subjects with the data available at the time of study closure is shown in Figure 1.
 
Figure 1: Change in Office Blood Pressure Through 36 and 48 Months Post-RDN 
 
GLOBAL SYMPLICITY REGISTRY  
The Global SYMPLICITY Registry is a prospective, multi-center, single-arm, non-interventional and 
open label registry that will collect descriptive data from a minimum of 3000 patients that receive renal 
denervation using the commercially available components of the Symplicity renal denervation system. 
Enrollment is ongoing in the Global SYMPLICITY Registry. As of 15 May 2018, 2583 patients had been 
enrolled. The purpose of the registry is to document the long-term safety and effectiveness of renal 
denervation in a real-world patient population with hypertension. Of the 2583 subjects enrolled at the 
time of presentation at EuroPCR 2018, 2232 patients were treated with the Symplicity FlexTM catheter 
(Medtronic’s first generation RDN catheter and 351 with the Symplicity SpyralTM catheter.  1035 subjects 
that were treated with the Symplicity FlexTM have 36-month follow-up data available, office blood 
pressure decreased on average by -16.47/-6.13 mmHg (p<0.001) from baseline to 36 months. In 
addition, 439 of those subjects had matched baseline and 6 months ABPM available at 36 months, 
although ABPM is not required in the GSR. In these subjects, the ambulatory systolic blood pressure 
reduction was -8.4 mmHg at 36 months.  
In the 58 Spyral subjects with 36-month follow-up data available, office blood pressure decreased on 
average by -15.98 /7.14 mmHg (p<0.001) from baseline to 36 months. In addition, 26 subjects had 
ABPM data available at 36 months, although ABPM is not required in the GSR.  In these subjects, the 
ABPM reduction was 17.62/6.19 mmHg (p<0.05) at 36 months.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 25 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The renal denervation procedure was associated with minimal complications and no unanticipated 
adverse device effects. Similar to SYMPLICITY HTN-1, HTN-2 and HTN-3, renal denervation did not 
elicit a significant change in measured renal function from baseline to 6 months.12 
B.1.2 
Clinical Experience Using the Multi Electrode RF renal denervation system 
(Spyral) 
 
Multi-electrode RF Renal Denervation System Feasibility Study (SPYRAL FIM) 
The SYMPLICITY Spyral FIM was a prospective, single-arm, non-randomized feasibility study to 
evaluate acute procedural and long-term safety and effectiveness of the multi-electrode renal 
denervation system. Fifty (50) subjects at four centers were treated in Australia and New Zealand. 
Follow-up data through six months was presented at EuroPCR 201414. The mean baseline office blood 
pressure was 181/95 ± 17/12 mmHg and patients were taking an average of 4.6 ± 1.3 antihypertensive 
medications. Mean baseline ambulatory systolic and diastolic BP were 154.4 ± 17.4 mm Hg and 80.9 ± 
11.7 mm Hg during 24-hour ABPM, respectively. There was a reduction in 24-hour ABPM at 6 months 
with a change in systolic blood pressure of -5.7 mmHg and a change in diastolic of -4.5 mmHg.  At 12 
months, the difference in systolic ABPM from baseline was -7.5 mmHg and the difference in diastolic 
was -6.0 mmHg.  The mean systolic ambulatory blood pressure change from baseline was decreased 
by 7.6 mmHg at the 36 months visit.  
At six months post treatment, there was a -20/-7 mmHg change in office blood pressure (Figure 2) and 
subjects were on an average of 4.8 ± 1.1 antihypertensive medications. Sixty-six percent of patients 
had an office SBP reduction of at least 10 mmHg at 6 months. Follow-up data through 12 months were 
published in EuroIntervention in May 2015.40 The mean change of office systolic blood pressure at 36 
months from baseline was 20.8 ± 28.6 mmHg. Twenty-eight out of 41 (68.3%) of the subjects achieved 
a reduction in systolic BP of ≥ 10 mmHg while 53.7% (22/41) had a systolic BP reduction of ≥ 20 mm 
Hg. 
 
Figure 2: Change in Office Blood Pressure from Baseline through 6 Months 
 
There were no unanticipated adverse device effects. Three subjects developed a pseudoaneurysm at 
the femoral access site and two of these subjects also reported a hematoma. All five access-site related 
events were treated without any subsequent complication. Follow-up renal artery imaging (duplex 
ultrasound) was performed at six months post treatment, with no reports of renal artery stenosis. One 
subject had a myocardial infarction (MI) one month after renal denervation treatment. The subject 
underwent a percutaneous coronary intervention (PCI) and was stented. The MI event was reviewed 
and determined to be unrelated to the device, therapy, or procedure by the Clinical Events Committee. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 26 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The change in Serum Creatinine at 36 months was 0.1 ± 0.2 (p=0.014 for change from baseline). The 
change in eGFR at 36 months was -6.7 ± 16.6 (p=0.013 for change from baseline). There were 2 
cardiovascular deaths (4.3%), 3 subjects with MI (6.5%), 3 subjects with serum creatinine elevation > 
50% (6.5%), 3 subjects with vascular complications (6.5%), and 2 subjects with stroke (4.3%). These 
are all at levels that are expected within a patient population of severe drug resistant hypertension. 
The Symplicity SpyralTM catheter and Symplicity G3TM generator had a sustained safety profile at 36 
months with 2 deaths described above, no new hypertensive crisis and no end stage renal disease at 
the time of the 36 months data analysis.  The 2 deaths were adjudicated by the CEC as not related to 
the device, therapy, or procedure. One subject died from a subarachnoid hemorrhage while the other 
subject died from an intracranial hemorrhage.  
SPYRAL COHORT OF THE GLOBAL SYMPLICITY REGISTRY (GSR)  
An addendum to the GSR allowed use of the Symplicity Spyral™ catheter and Symplicity G3™ 
generator following CE-mark approval in Europe. In addition to the general registry, a sub-study of 
patients treated with the Spyral catheter is being enrolled. This registry sub-study will be 100% 
monitored for increased data quality. The recommended follow-up for these patients is 3, 6, and 12 
months and then annually for a minimum of 3 years and up to 5 years. Data from 351 subjects in the 
Spyral sub-study was presented at EuroPCR 2018 with data out to two years for 175 subjects. Subjects 
presented with a mean ambulatory systolic blood pressure of 158 ± 18 Hg and a mean baseline office 
systolic blood pressure of 170 ± 18 mmHg. Ambulatory SBP showed sustained reductions to two years 
with a mean decrease of 13 mmHg. Sustained reductions in office SBP were also reported to two years 
with a mean reduction of 11 mmHg. These data demonstrate that renal denervation in this real-world 
population resulted in significant reductions in both ambulatory and office blood pressure that were 
sustained out to 2 years post-procedure with a very low rate of safety events.  
Safety results from the Spyral sub-study of the GSR to 24 months continue to support the safety profile 
of the Symplicity Spyral™ catheter. 
SPYRAL HTN-OFF MED 80-PATIENT COHORT 
SPYRAL HTN-OFF MED is a multicenter, international, single-blind, randomized, sham-controlled trial. 
Eligible patients are drug-naive or discontinue their antihypertensive medications. Patients with an office 
systolic blood pressure (SBP) of 150 mmHg or greater and less than 180 mmHg, office diastolic blood 
pressure (DBP) of 90 mmHg or greater, and a mean 24-h ambulatory SBP of 140 mmHg or greater and 
less than 170 mmHg at second screening, have renal angiography and are randomly assigned to renal 
denervation or sham control. Patients, caregivers, and those assessing blood pressure are blinded to 
randomization assignments.  
While study enrollment is ongoing, data from the initial 80 patients with 3 months follow-up from the 
SPYRAL HTN-OFF MED study was presented at ESC Congress in August 2017. Concurrently, an 
article presenting the data was published in The Lancet13.   
The primary endpoint, change in 24-hour blood pressure at 3 months, was compared between 
randomization 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 at 3 months.  
Between June 25, 2015, and January 30, 2017, 353 patients were screened. 80 patients were 
randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months 
at 21 centers in the USA, Europe, Japan, and Australia.  
There were no major adverse events in either group. No major procedural or clinical safety events were 
observed in either the renal denervation or sham control groups throughout the 3 months. Specifically, 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 27 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
there were no deaths or occurrences of myocardial infarction, stroke, major bleeding, serum creatinine 
elevation greater than 50%, significant embolic events, vascular complications, renal artery re-
intervention, new or worsening renal failure, or hypertensive emergency or crisis.  
Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the 
renal denervation group (Figure 3). No significant changes were seen in the sham-control group. 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.  
 
Figure 3: Changes at 3 Months iIn Office and Ambulatory SBP and DBP For Renal 
Denervation and Sham Control Groups 
 
SPYRAL Pivotal - SPYRAL HTN-OFF MED First Interim Analysis 
The SPYRAL PIVOTAL - SPYRAL HTN-OFF MED study is a multi-center, international, prospective, 
single blinded, randomized, interventional, sham-controlled study. In order to test the hypothesis that 
renal denervation decreases blood pressure and is safe when studied in the absence of 
antihypertensive medications, study subjects will be 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 will also be blinded to study subjects’ 
randomization assignment through the primary endpoint to prevent potential bias of results. Subjects 
will be 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 intetim analysis in February 2020. Data from 
the initial 80 patients with 3 months follow up from the SPYRAL HTN-OFF MED study  was combined 
with data from the initial 251 patients with 3 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 3 months, was compared between groups. 
Drug surveillance was done to ensure patient compliance with absence of antihypertensive 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 28 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
medication. The primary analysis was done in the intention-to-treat population. Safety events were 
assessed to 3 months.  
 
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 1 month. There was one major safety event in each 
treatment group up to 3 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 3 
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 3-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 analysed using 
the prespecified ANCOVA-adjusted frequentist analysis of the overall population show similar 
changes in blood pressure to Bayesian results (Figure 4).  
 
Figure 4: Changes in 24-h and office systolic and diastolic blood pressure from 
baseline to 3 months 
 
SPYRAL HTN-ON MED 80-PATIENT COHORT 
SPYRAL HTN-ON MED is a multicenter, international, single-blind, randomized, sham-controlled trial. 
Eligible patients are on a stable dose of one to three antihypertensive medications for at least 6 weeks. 
Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 29 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 
140 mm Hg or greater and less than 170 mm Hg at second screening, have renal angiography and are 
randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing 
blood pressure are blinded to randomization assignments.  
While study enrollment is ongoing, data from the initial 80 patients with 6 months follow up from the 
SPYRAL HTN-ON MED study was presented at ESC Congress in May 2018.  Concurrently, an article 
presenting the data was published in The Lancet42. A summary of the SPYRAL HTN-ON MED data is 
provided below.  
The primary endpoint, change in 24-h blood pressure at 6 months, was compared between 
randomization groups. Drug surveillance was done to ensure patient compliance with absence of their 
prescribed antihypertensive medication. The primary analysis was done in the intention-to-treat 
population. Safety events were assessed at 6 months.  
Between June 22, 2015, and June 14, 2017, 467 patients were screened. 80 patients were randomly 
assigned to renal denervation (n=38) or sham control (n=42) and followed up for 6 months at 25 centers 
in the USA, Europe, Japan, and Australia.  
There were no major adverse events in either group. No major procedural or clinical safety events were 
observed in either the renal denervation or sham control groups throughout the 6 months. Specifically, 
there were no deaths or occurrences of myocardial infarction, stroke, major bleeding, serum creatinine 
elevation greater than 50%, significant embolic events, vascular complications, renal artery re-
intervention, new or worsening renal failure, or hypertensive emergency or crisis.  
Office and 24-hour ambulatory blood pressure decreased significantly from baseline to 6 months in the 
renal denervation group (Figure 5). No significant changes were seen in the sham-control group. The 
mean difference between the groups favored renal denervation for 6-months change in both office and 
24-h blood pressure from baseline: 24-h SBP –7·4 mm Hg (95% CI –12.5 to –2.3; p=0·0051), 24-h DBP 
–4·1 mm Hg (–7·8 to –0.4; p=0·0292), office SBP –6.8 mm Hg (–12.5 to –1.1; p=0·0205), and office 
DBP –3.5 mm Hg (–7.0 to –0; p=0·0478). Baseline-adjusted analyses showed similar findings.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 30 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Figure 5: Changes at 6 Months in Office and Ambulatory SBP and DBP for Renal 
Denervation and Sham Control Groups 
 
These initial results from SPYRAL HTN-ON MED in combination with SPYRAL HTN-OFF MED 
demonstrated biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. 
The data indicates that renal denervation is safe with no major adverse events at 3 and 6 months. The 
SPYRAL HTN-ON MED data will be utilized as the informative prior dataset for the continuation of the 
current SPYRAL HTN-ON MED study. 
 
Clinical Summary and Future Studies 
Extensive data has been collected on the predicate of the Symplicity SpyralTM catheter, the single-
electrode Symplicity catheter. This includes data from the SYMPLICITY HTN-1 trial (36 months), the 
SYMPLICITY HTN-2 trial (36 months), as well as the data from the SYMPLICITY HTN-3 Trial (36 
months) and the Global SYMPLICITY Registry.  
The combined experience from these trials in over 4200 subjects enrolled to date indicates that use of 
the Symplicity renal denervation system to denervate the kidneys is safe. In contrast to findings from 
earlier trials, patients treated with RDN in SYMPLICITY HTN-3 did not have a significant reduction in 
office and ambulatory BP at 6 months compared to the control group, and the primary efficacy endpoint 
was not met. Possible confounding factors such as inadequate denervation during the procedure, the 
target patient population studied, and uncontrolled medication adherence are believed to have impacted 
the SYMPLICITY HTN-3 results.  
The SPYRAL FIM, GSR Spyral sub-study, SPYRAL HTN-OFF MED Feasibility and SPYRAL HTN-ON 
MED Feasibility studies include over 420 patients and demonstrate safety and efficacy of the Spyral 
renal denervation system in resistant hypertensive, real-world, and off-medication populations. 
Specifically, results from the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED trials provide 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 31 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
biological and real-world proof of principle for the efficacy of catheter-based renal denervation to reduce 
blood pressure in patients with hypertension not treated with antihypertensive medications and those 
on up to three antihypertensive medications, respectively. The SPYRAL HTN-OFF MED study 
demonstrated a clinically-significant reduction in office and 24-h ambulatory SBP and DBP at 3 months 
in patients with mild to moderate hypertension following renal denervation in the absence of 
antihypertensive medications.  This reduction was not observed in the sham control group. The 
SPYRAL HTN-ON MED study demonstrated a clinically significant reduction in office and 24-h 
ambulatory SBP and DBP at 6 months in patients with mild to moderate hypertension following renal 
denervation in the presence up to three antihypertensive medications.  This reduction was not observed 
in the sham control group. There were no major safety events in either randomization group for either 
study. The aims of this study, SPYRAL HTN ON-MED, is to demonstrate that renal denervation, using 
Medtronic’s next generation Symplicity SpyralTM catheter, decreases blood pressure and is safe when 
studied in the presence of up to three standard antihypertensive medications.   
B.2 Device information 
B.2.1 
The Symplicity™ renal denervation system 
The Symplicity multi-electrode renal denervation system (Symplicity SpyralTM catheter and Symplicity 
G3TM 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 SpyralTM catheter and Symplicity G3TM generator 
received CE Mark in October 2013 and has been commercially available in selected geographies 
outside the United States, Canada, and Japan.  
The Symplicity SpyralTM catheter is manufactured at Medtronic Ireland. The Symplicity G3TM generator 
is manufactured by Plexus Corp. (Pinnacle Hill, Kelso, TD5 8XX, UK) for Medtronic Inc. 
 
B.2.2 
Symplicity Spyral™ Catheter 
The Symplicity SpyralTM catheter is an iteration of the single-electrode Symplicity catheter and when 
used with the Symplicity G3TM generator will allow for rapid treatment of renal arteries by simultaneously 
delivering radiofrequency energy to four gold 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 6). 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 7). 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 SpyralTM 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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 32 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Figure 6: 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 G3TM generator. 
 
 
 
Figure 7: Overview of Symplicity Spyral™ Catheter 
 
Unlike the single-electrode Symplicity catheter, which had to be rotated to treat different segments of 
the vessel, 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.  
 
B.2.3 
Symplicity G3™ Generator 
The Symplicity G3TM generator (Figure 8) is an iteration of the existing Symplicity generator and is 
intended to provide a safe and effective means of delivering RF energy to the Symplicity SpyralTM 
catheter for controlled ablation of tissue. The Symplicity G3TM generator has been designed with the 
following features: 
• 
Automated safety algorithms similar in all aspects of safety and energy delivery and 
stoppage to previous Symplicity RF generator 
• 
Non-adjustable treatment parameters 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 33 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
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 SpyralTM catheter, to communicate with an RFID 
antenna located inside the Symplicity G3TM generator to ensure the catheter cannot be re-
used 
o 
Note: In Japan, the RFID module will be turned off 
• 
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 8: Symplicity G3™ Generator 
The Symplicity SpyralTM catheter leverages the safety aspects of the original algorithm while 
incorporating new features to allow for a shorter treatment time. 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. As with the previous generator the 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. Similar to the previous generation Symplicity 
generator, temperature and impedance values are monitored at each electrode and used to provide 
input to an algorithm controlling power delivery for individual electrodes (Figure 9). 
 
Figure 9: RF on Screen 
 
The following ancillary components may be used with the Symplicity G3TM generator.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 34 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Symplicity G3TM 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 G3TM 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 
B.2.4 
Labeling 
The Symplicity SpyralTM catheter and Symplicity G3TM generator will include, but not limited to, the 
following labeling information in geographies where the product is not commercially available: 
1. That the device is intended for investigational use in geographies where the product is not 
approved  
2. Identification number 
3. Model number  
4. Lot/Serial number 
5. Storage condition 
6. Expiration date 
7. Name and address of the sponsor 
In geographies where the product is not commercially approved, labeling will be provided according to 
geography requirements. 
An Instructions for Use document is included with each Symplicity SpyralTM catheter and a User’s 
Manual is included with each Symplicity G3TM generator.  
B.2.5 
Intended clinical performance 
In the past, surgical nephrectomy, and even radical surgical sympathectomy, were both used to treat 
severe hypertension. Importantly, a denervated kidney maintains appropriate electrolyte and volume 
homeostasis as demonstrated in the human transplant experience. The Symplicity SpyralTM catheter 
offers a significantly less-invasive approach to treating hypertension - a straightforward, catheter-based 
procedure with four electrodes spatially distributed along a spiral simultaneously delivering 
radiofrequency energy to shorten procedure time.   
 
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 10) without adversely affecting the wall of the artery or surrounding organs. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 35 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Figure 10: Illustration of renal artery anatomy 
 
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, 
and hypothesis that this will result 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. 
Recent preclinical studies and histological analyses 15-17 observed that renal nerves may have a 
positional bias, suggesting the distal nerves are closer to the arterial lumen (Figure 11). 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.  
 
Figure 11: Illustration of peri-arterial renal nerve location 
 
Initial clinical evidence18,19 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. Utilization of the 
branch and main renal artery treatment approach will be evaluated in the SPYRAL HTN-ON MED 
clinical study to confirm the safety and efficacy of this approach. 
B.3 Comparator information 
A review of hypertension studies of antihypertensive medications was undertaken in concert with a 
thorough review of the SYMPLICITY HTN-3 data. Based on this, Medtronic will study patients on up to  
three antihypertensive medications from three commonly used antihypertensive drug classes (i.e., the 
Nerves 
Lumen 
 
 
Endothelium 
 
 
 
Media 
 
 
Adventitia 
 
 
 
Fat 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 36 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
standard medical therapy comparator).The approach used in SYMPLICITY HTN-3 where patients were 
required to be treated with ≥ 3 medications at maximum tolerated doses believed to have introduced 
variation and bias due to medication adherence issues and to significant medication changes 
throughout the course of the study as many patients had difficulties sustaining this type of drug regimen. 
For these reasons, where patients will be taking medications, the intent will be to keep them on their 
prescribed stable medication regimen throughout the SPYRAL HTN-ON MED study.  
In this ON-MED study, a population with less severe hypertension, on fewer medications, and on 
medication not at maximum dose will be studied compared to the study population in SYMPLICITY 
HTN-3. This is consistent with the well-established pharmaceutical approach to drug approval where 
experience has showed it is possible to conduct a well-controlled study. Inclusion of a sham procedure 
will help  “blind” the subject to their randomization group and ensure no other unmeasured factors are 
contributing to a change in blood pressure. Additionally, maintaining standard medication therapy will 
minimize changes in patient medications and potentially minimize the Hawthorne effect that is believed 
to have affected the efficacy outcomes in SYMPLICITY HTN-3.  
C STUDY PLAN 
C.1 Study Objective 
The objective of this study is to test the hypothesis that renal denervation decreases blood pressure 
and is safe when studied in the presence of one, two, or three antihypertensive medications. In this 
study, “uncontrolled hypertension” means an office systolic blood pressure (SBP) ≥ 150 mmHg and 
<180 mmHg, an office DBP ≥90 mmHg and a 24-hour Ambulatory Blood Pressure Monitoring (ABPM) 
average SBP ≥140 mmHg to <170 mmHg, all of which are measured at Screening Visit 2 (per Appendix 
L7).  
Data obtained in this study will help determine whether commonly used antihypertensive medications 
synergize, antagonize, or have no impact on the effect of renal denervation on blood pressure.   
The data collected in the SPYRAL HTN-ON MED study may be used to gain market approval or 
additional indications for the Symplicity SpyralTM multi-electrode renal denervation catheter and the 
Symplicity G3TM renal denervation RF generator, from regulatory entities, including, but not limited to: 
the Pharmaceuticals Medical Device Agency (PMDA), Health Canada, and the U.S. Food and Drug 
Administration (FDA). 
C.2 Clinical endpoints 
C.2.1 
Primary Endpoints: 
There are two primary endpoints in this study (one efficacy and one safety). The study will be considered 
successful if both the primary safety and efficacy endpoint hypotheses are met. 
Powered Primary Efficacy Endpoint: 
• 
Baseline adjusted change (using Analysis of Covariance) in systolic blood pressure (SBP) 
from baseline (Screening Visit 2) to 6 months post-procedure as measured by 24-hour 
Ambulatory Blood Pressure Monitoring (ABPM). 
Powered Primary Safety Endpoint: 
• 
Incidence of Major Adverse Events (MAE), defined as a composite of the following events, 
through one-month post-randomization (6 months for new renal artery stenosis): 
• 
All-cause mortality 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 37 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
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 and/or the protocol.  
• 
New renal artery stenosis > 70%, confirmed by angiography and as determined 
by the angiographic core laboratory 
C.2.2 
Secondary Endpoints 
Secondary Efficacy Endpoints  
• 
Change in systolic blood pressure (SBP) from baseline (Screening Visit 2) as measured by 
24-hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24 and 36 months post-
procedure 
• 
Change in office systolic blood pressure from baseline (Screening Visit 2) at 1, 3, 6, 12, 24 
and 36 months post-procedure  
• 
Change in diastolic blood pressure from baseline (Screening Visit 2) as measured by 24-
hour Ambulatory Blood Pressure Monitoring (ABPM) at 3, 6, 12, 24 and 36 months post-
procedure 
• 
Change in office diastolic blood pressure from baseline (Screening Visit 2) at 1, 3, 6, 12, 
24 and 36 months post-procedure 
• 
Incidence of achieving target office systolic blood pressure (SBP<140 mmHg) at 1, 3, 6, 
12, 24 and 36 months post-procedure. 
Secondary Safety Endpoints 
• 
Acute/procedural safety at 1-month post-procedure 
• 
Significant embolic event resulting in end-organ damage 
• 
Renal artery perforation requiring intervention 
• 
Renal artery dissection requiring intervention 
• 
Vascular complications  
• 
End-Stage Renal Disease 
• 
≥ 40% decline in eGFR  
• 
Increase in serum creatinine >50% from Screening Visit 2 
• 
New Myocardial Infarct  
• 
New Stroke 
• 
Renal artery re-intervention 
• 
Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl 
decrease in hemoglobin concentration, a ≥15% absolute decrease in 
hematocrit, or death due to bleeding within 7 days of the procedure) 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 38 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
New renal artery stenosis >70%, confirmed by angiography and as determined 
by the angiographic core laboratory 
• 
Hospitalization for hypertensive crisis not related to confirmed non-adherence 
with medication and/or protocol 
 
• 
Chronic Safety Secondary Endpoints at 3, 6, 12, 24 and 36 months post-procedure 
• 
Composite Safety Endpoint, defined as a composite 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 and/or the protocol.  
 
New renal artery stenosis > 70%, confirmed by angiography 
and as determined by the angiographic core laboratory 
• 
≥ 40% decline in eGFR  
• 
Increase in serum creatinine >50% from Screening Visit 2 
• 
New Myocardial Infarct 
• 
New Stroke 
• 
Renal artery re-intervention 
• 
Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl 
decrease in hemoglobin concentration, a ≥15% absolute decrease in 
hematocrit, or death due to bleeding within 7 days of the procedure) 
• 
Hospitalization for hypertensive crisis not related to confirmed non-adherence 
with medication and/or protocol  
• 
Summary of Health-related Quality of Life (HRQoL) analysis based on reporting measures 
using accepted QoL instruments (EQ5D) 
 
 
Additional analyses 
 
The following additional analyses will be conducted:  
• 
Antihypertensive medication usage throughout the study, including escape patients and 
subjects with medication changes within 6-month follow-up.  
• 
Additional procedural characteristics e.g. treatment duration, frequency of distal renal 
artery treatment, ablations per vessel, location of ablations, number of ablations per 
patient and other characteristics will be analyzed to assess their impact on blood 
pressure. 
• 
Medication adherence will be assessed using results from drug testing. In addition, we 
will perform analyses to evaluate the effect of medications adherence on BP. 
• 
Analyses looking at long term imaging will be performed. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 39 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
C.3 Study Population 
This study will randomize subjects who meet the criteria as detailed in the Subject Selection portion 
(Section D) of this Clinical Investigation Plan. Potentially eligible subjects will be consented and entered 
into a screening period to establish treatment eligibility. Approximately 340 subjects (including the first 
consecutively randomized 80 subjects in the SPYRAL HTN-ON MED Study) will be allowed to be 
randomized.  
Eligible subjects will be randomized using a 2:1 (treatment to control) ratio to: 
• Denervation group: Subjects are treated with the renal denervation procedure after 
randomization. 
• Control group: Subjects undergo a sham renal denervation procedure. 
C.4 Study Design 
The SPYRAL HTN-ON MED study is a multi-center, international, prospective, blinded, randomized, 
interventional, sham-controlled study.  The purpose of this study is to test the hypothesis that renal 
denervation decreases blood pressure and is safe when studied in the presence of one, two, or three 
anti-hypertensive medication classes.  Subjects must be on at least one of these antihypertensive 
medications on at least 50% of the maximum manufacturer’s dosage of antihypertensive medication.  
Antihypertensive medication classes must include a thiazide-type diuretic, a dihydropyridine calcium 
channel blocker, an ACE-I/ARB, or a beta blocker, (when prescribed with other qualifying medications, 
12.5 mg hydrochlorothiazide is acceptable as the minimum dosage). Subjects cannot be on other 
antihypertensive medications. Study subjects will be randomized to the Denervation or Control group 
in a 2:1 (treatment to control) ratio. In addition to subjects being blinded to their randomization 
assignment, site personnel involved in the measurement of office blood pressure will also be blinded to 
study subjects’ randomization assignment through 6 months post procedure to prevent potential bias of 
results. See section C.5 for blinding techniques.  
The Symplicity SpyralTM catheter and Symplicity G3TM generator provide a spiral pattern of denervation, 
ensuring circumferential nerve ablation that is expected to minimize procedure variability. One 
Symplicity G3TM generator is used with a Symplicity SpyralTM catheter in subjects randomized to the 
Denervation group, or if applicable, in Control group subjects eligible for crossover. 
It is anticipated that several subjects will no longer meet study eligibility after renal imaging, and 
measurement of OBP, ABPM, and renal function. Approximately 1600 subjects will be enrolled to 
randomize approximately 340 subjects (including the first 80 consecutively randomized in the SPYRAL 
HTN-ON MED study) in the study. 
C.5 Randomization and blinding 
Randomization will be stratified by study center at a 2:1 (treatment to control) ratio to:  
 
• 
Denervation group: Subjects remain blinded and are treated with the renal denervation 
procedure.  
• 
Control group: Subjects remain blinded and remain on the catheterization lab table for at 
least 20 minutes prior to introducer sheath removal.  
Investigational sites will access randomization allocation via a password-protected system that can only 
be accessed by those approved by the study sponsor. 
All study staff and necessary hospital personnel will be instructed that subjects are not to be informed 
of their randomization assignments and appropriate measures should be taken to minimize the risk of 
premature unblinding. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 40 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The Investigator performing the catheterization lab procedures and his/her designated study staff will 
be blinded to a subject’s randomization group up until the angiography is completed and 
inclusion/exclusion confirmed following the angiography. However, investigators performing study 
follow-up visits and the subject’s referring/managing physicians will not be proactively informed of a 
subject’s treatment assignment to minimize potential bias in the subject’s care decisions. To minimize 
potential bias in the measurement of Office BP and ABPM, each investigational site will specify several 
designated “blinded” members of their study staff that will not be informed of the subject’s group 
assignments and will be responsible for performing the office blood pressure measurements, 
conducting ABPM preparation and printing results upon a patient completing the ABPM. Prior to 
unblinding, the effectiveness of blinding will be assessed by asking blinded study staff which group they 
believe the subject was randomized to. 
Subjects will be blinded during the renal angiogram by a combination of conscious sedation, sensory 
isolation (e.g., blindfold and music), and lack of familiarity with the procedural details and duration (i.e., 
subjects will not know the difference between the renal angiography procedure alone and the renal 
angiography and denervation procedure). Subjects will continue to be blinded by only interacting with 
blinded site personnel through the 6-month follow-up visit post-procedure. Blinding effectiveness will be 
assessed by asking the subject which group they believe they were randomized to. All subjects will be 
unblinded after the completion of their required 6-Month follow-up testing. 
If the subject’s medical condition requires knowledge of the randomization group in order to provide 
adequate care, prior to unblinding, the site personnel should contact the study sponsor with the 
justification for proposed unblinding.   
C.6 Sample Size 
This study will be conducted as an adaptive Bayesian trial with an informative prior.  A Bayesian power 
prior approach38,39 in conjunction with a discount function will be used to incorporate the prior data.  The 
discount function reduces the strength of the prior data if disagreements are observed with the 
prospective (subjects 81+) data. 
The prior data consists of the first consecutively randomized 80 subjects in the SPYRAL HTN-ON MED 
Study which were randomized in a 1:1 ratio to RDN to sham control.  The results from these 80 subjects 
have already been analyzed and published. 
The prospective data consists of the following two cohorts: 
1. Subjects 81 to 106 which have already been enrolled and were randomized in a 1:1 ratio to 
RDN vs sham control, and whose data has not been unblinded and analyzed by Medtronic. 
 
2. All remaining subjects in the SPYRAL HTN-ON MED Study from 107 onwards which will be 
randomized in a 2:1 ratio to RDN vs sham control. 
The weight of the prior data will be adjusted using a discount function, which scales from 0 to 1, 
according to the similarity of the prior and prospective data.  The discount function adjusts the amount 
of weight the prior receives.  This prevents the use of an informative prior where exchangeability issues 
are present (e.g., the prior and prospective data are quite different). This discount function approach 
was proposed by the Medical Device Innovative Consortium (MDIC) working group and is a 
collaborative effort between FDA and industry through the MDIC.36,37 If the analyses show a high level 
of agreement for prospective data compared to the prior, the prior will be weighted at or near 100%.  If 
the prospective data perform worse than or much better than the prior, then the prior will receive very 
little or zero weight.  The Bayesian adaptive design is set up to enroll patients until a sufficient sample 
size is achieved to have high probability of meeting the endpoint. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 41 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The sample size will vary from 110 to 221 evaluable subjects (not including the first consecutively 
randomized 80 subjects) due to the adaptive nature of the trial. This will require randomizing 
approximately 130 to 260 subjects to account for an expected 15% attrition at 6 months. The interim 
analyses will take place when a minimum of N=110 and N=149 subjects have 6-month follow-up data, 
with a maximum study size of 221 subjects if the study does not stop at either interim look. 
The SPYRAL HTN-ON MED study will thus, randomize approximately up to 340 subjects. Interim 
analyses will be conducted and reviewed by the DSMB, along with an independent organization that 
will be performing the Bayesian analyses. At each interim analysis, enrollment may be stopped for futility 
or efficacy. 
1. The first interim analysis takes place when a minimum of 110 subjects have evaluable 6-
month efficacy data, requiring approximately 130 randomized subjects to account for 15% 
attrition. If the attrition rate is higher than 15%, then additional subjects will be randomized in 
order to reach a minimum of 110 evaluable. The Bayesian efficacy analysis will be performed 
and P[suc] will be calculated, where P[suc] represents the efficacy endpoint hypotheses, 
𝑃𝑃൫𝜇𝜇< 0ห𝑦𝑦, 𝑦𝑦0, 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘)൯, and is defined in detail in section H4. 
a. If P[suc] > 0.975 then the study has met the efficacy hypothesis and enrollment will be 
stopped. Any additional subjects that have been enrolled before the decision is made 
to stop for efficacy will be pooled with the existing subjects and analyzed as a 
secondary cohort. 
b. The probability of futility is calculated based on the maximum study size of 221 
evaluable subjects which requires us to impute the outcomes for subjects who have 
not yet been enrolled. If the posterior probability of futility from this calculation is < 0.05 
for the primary efficacy endpoint, then the study will have met the futility boundary and 
enrollment will be stopped. Further details can be found in the SAP. Any additional 
subjects that have been enrolled before the decision is made to stop for futility will be 
pooled with the existing subjects and analyzed as a secondary cohort. 
c. If P[suc] is ≥0.05 and ≤0.975 then subject enrollment will continue to the second interim 
analysis. 
2. If the study doesn’t stop for efficacy or futility at the first interim analysis then enrollment will 
continue until the second interim analysis when the first 149 subjects have evaluable 6-month 
efficacy data, requiring 175 randomized subjects to account for attrition. If the attrition rate is 
higher than 15%, then additional subjects will be randomized in order to reach a minimum of 
149 evaluable.  The Bayesian efficacy analysis will be performed and P[suc] will be calculated. 
a. If P[suc] > 0.975 then the study has met the efficacy hypotheses and enrollment will 
be stopped. Any additional subjects that have been enrolled before the decision is 
made to stop for efficacy will be pooled with the existing subjects and analyzed as a 
secondary cohort. 
b. The probability of futility is calculated based on the maximum study size of 221 
evaluable subjects which requires us to impute the outcomes for subjects who have 
not yet been enrolled. If the posterior probability of futility from this calculation is < 0.05 
for the primary efficacy endpoint, then the study will have met the futility boundary and 
enrollment will be stopped. Further details can be found in the SAP. Any additional 
subjects that have been enrolled before the decision is made to stop for futility will be 
pooled with the existing subjects and analyzed as a secondary cohort. 
c. If P[suc] is ≥0.05 and ≤0.975 then we continue enrolling subjects to the final analysis. 
3. If the study doesn’t stop for efficacy or futility at the second interim analysis then enrollment will 
continue until the maximum study size of 221 subjects with 6-month follow-up data (requiring 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 42 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
approximately 260 randomized subjects to account for attrition). The Bayesian efficacy analysis 
will be performed and P[suc] will be calculated. 
a. If P[suc] > 0.975 for the primary efficacy endpoint, then the primary efficacy hypothesis 
is met. 
C.7 Number of investigation sites and study duration 
This study is expected to be conducted in up to 55 study centers located around the world. A multi-site, 
multi-national design helps to ensure a representative sample of the global population as well as 
maintaining a reasonable enrollment duration. Participating geographies include countries such as the 
United States, Japan, Australia, Canada and countries where CE-mark applies. A list of participating 
investigational sites including Investigators’ names who are responsible for conducting the trial, their 
title, address, and telephone number(s) are provided separately and will be maintained within the study 
files at each site. Additional geographies may be added to the clinical study at a later date and the 
approval status will be documented under a separate cover. Enrollment in the prospective cohort is 
expected to take approximately 20 months. To minimize bias, individual investigational sites may 
randomize up to 20% of the total study subjects. Subjects will participate in the study from the time of 
signing consent until study exit or the time of completion of 3 years of follow-up post-procedure.  Control 
(sham) subjects will be followed-up for three years post-denervation procedure, if they (and their study 
doctor) agree to have the renal denervation procedure (crossover) after their 6-month follow-up. 
If a site does not enroll any subjects within three months of activation, they may forfeit their participation 
in the clinical study to another site to ensure timely enrollment.  
D SUBJECT SELECTION 
D.1 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 (according to guidelines in Appendix L.7) 
at Screening Visit 1 and Screening Visit 2 when receiving a medication regimen of one, two, 
or three antihypertensive medication classes of which at least one is at least 50% of the 
maximum manufacturer’s dosage. The antihypertensive medication classes must include a 
thiazide-type diuretic, a dihydropyridine calcium channel blocker, an ACE-I/ARB, or a beta 
blocker and the subject must be on a stable dose of each medication for at least six weeks 
prior to Screening Visit 1 and up to Screening Visit 2. When prescribed with other qualifying 
medications, 12.5 mg hydrochlorothiazide is acceptable as the minimum dosage. Note: In 
Japan, patients may be prescribed less than 50% of maximum manufacturer’s recommended 
dosage of a thiazide-type diuretic per standard of care. 
3. Individual has a valid 24-hour ABPM average of SBP ≥140 and < 170 mm Hg measured at 
Screening Visit 2, according to guidelines in Appendix L.7 after witnessed antihypertensive 
drug ingestion prior to applying the ABPM device. (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. 
 
D.2 Exclusion criteria 
1. Individual has undergone prior renal denervation. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 43 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
2. Individual has renal artery anatomy that is ineligible for treatment including:  
a. Main renal artery for each kidney is less than 3mm or greater than 8mm 
b. Lacks a main renal arterial vessel that does not allow 4 simultaneous quadrantic 
(4SQ) radio frequency ablations in the main renal artery or equivalent (defined as 
4SQ ablations in all branch vessels between 3mm and 8mm). 
3. Presence of FMD (fibromuscular dysplasia) (defined as visible beading of the artery on 
angiography). 
4. Has >50% stenosis in any treatable vessel. 
5. Has a renal artery stent placed <3 months prior to the denervation procedure. 
6. Presence of an aneurysm defined as any localized increase in the diameter of the vessel. 
7. Treatment within 5mm of a segment in the renal artery which contains any of the following: 
a. Atheroma, 
b. Calcification, or 
c. Renal artery stent 
8. 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)). (Note: an eGFR calculation specific to Japanese 
patients will be used for subjects enrolled in Japan). 
9. 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 SV2), or history of uncontrolled blood 
sugars raises concern, it is required to analyze glycosylated hemoglobin as part of SV2 labs.) 
10. Individual  is taking SGLT2 inhibitors or GLP-1 agonists that have been prescribed <90 days 
prior to Screening Visit 1 or who does not plan to remain on these drugs for the duration of 
the trial. 
11. Individual has had ≥1 episode(s) of orthostatic hypotension not related to medication 
changes within the past year or reduction of SBP of ≥20 mmHg or DBP of ≥10 mmHg within 
3 minutes of standing coupled with symptoms during the screening process (at SV2).  
12. Individual requires chronic oxygen support or mechanical ventilation other than nocturnal 
respiratory support for sleep apnea (e.g. CPAP, BiPAP). 
13. 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.  
14. Individual has documented primary pulmonary hypertension. 
15. Individual has untreated secondary cause of hypertension (either known or suspected) or is 
taking drugs that increase sympathetic tone that could contribute to hypertension.  
16. 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 (patients are permitted to take aspirin or clopidogrel for cardiovascular risk 
reduction). 
17. Individual with HIV on anti-retroviral drug therapy without documentation that hypertension 
preceded initiation of anti-retroviral drug treatment.  
18. 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.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 44 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
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. 
E STUDY PREPARATION PROCEDURES 
E.1 Investigator/Investigation site selection 
E.1.1 
Investigator selection criteria 
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 investigator may be included in the clinical study if compliant with the following requirements: 
appropriately qualified practitioners legally entitled to practice and experienced in the diagnosis and 
treatment of patients requiring renal denervation. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 45 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
E.1.2 
Investigational site selection criteria 
An investigational site may be selected for participation in the clinical study if compliant with the following 
requirements:  
• 
Investigator should have adequate staff that is accessible and has time to manage the 
study. 
• 
Investigator should have adequate staff to perform blinded blood pressure 
measurements. 
• 
Investigator, co-investigators (if applicable), and all key site staff must be willing to 
provide his/her curriculum vitae (CV). 
• 
Investigational site must be willing to comply with the Clinical Investigation Plan and data 
collection requirements, including timely reporting Adverse Events and Device 
Deficiencies (Section F.13).  
• 
Investigational site has demonstrated experience with conducting clinical (device) 
studies that comply with applicable regulatory standards. 
• 
Investigational site is willing to participate in follow-up of patients for three 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. 
E.1.3 
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 
clinical investigation plan and subsequent amendments, by a fully executed agreement. Amendments 
to this clinical investigation plan shall be agreed upon between Medtronic and investigator(s) and be 
recorded with a justification for the amendments.  
E.1.4 
Curriculum Vitae  
A current signed and dated curriculum vitae from the principal investigator, all co-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 3 years prior to the 
date of activation of the investigational site.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 46 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
E.2 Ethics 
E.2.1 
EC/IRB approval 
Here and throughout the document, “EC/IRB” is the term that will be used collectively to refer to an 
Institutional Review Board (IRB), Ethics Committee (EC), Medical Ethics Committee (MEC), Head of 
Medical Institution (HOMI), Human Research Ethics Committee (HREC), or 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 Clinical Investigation Plan, the Patient Information and Informed Consent form, 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 
enough information to identify 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 enrolment. If any 
action is taken by an EC/IRB with respect to the clinical study, that information must be forwarded to 
Medtronic by the respective investigator. 
Medtronic may revise the Clinical Investigational Plan (CIP), Investigator’s Brochure (IB) (if applicable), 
Instructions for Use (IFU), Case Report Forms (CRF), 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 and will also request that sites submit to their EC/IRB for 
review per national and local requirements.  
In Japan, all protocol amendments will be reviewed by the sponsor and principal investigator. Upon 
agreement of the protocol changes, the Amended Protocol Signature Document must be signed or 
sealed and dated by the sponsor and investigator and submitted to the director of the investigational 
site according to the procedures of the investigational site. As necessary, the sponsor and investigator 
must comply with added requirements of IRB. 
E.2.2 
 Patient Information and Informed consent process 
The investigator or authorized designee must obtain written informed consent before any clinical study 
related activity takes place.   
The patient will receive the EC/IRB approved Patient Information (if required by geography) and 
Informed Consent Form. During the consent discussion the investigator or his/her authorized designee 
must fully inform the patient of all aspects of the clinical study that are relevant to the patient’s decision 
to participate in the clinical study. If a patient is illiterate, an impartial witness must be present during 
the entire informed consent discussion. All items addressed in the Patient Information and the Informed 
Consent Form must be read aloud and explained. The language used shall be as non-technical as 
possible and must be understandable to the patient and the impartial witness, where applicable.  
The patient must have ample time and opportunity to read and understand the Patient Information and 
the Informed Consent Form, to inquire about details of the clinical study, and to decide whether or not 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 47 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
to participate in the clinical study. All questions about the clinical study should be answered to the 
satisfaction of the patient. 
Neither the investigator, nor the investigational site staff shall coerce or unduly improper influence or 
induce a patient to participate or to continue to participate in the clinical study. The informed consent 
process shall not waive or appear to waive the patient’s rights. 
When the patient decides to participate in the clinical study, the Patient Information and Informed 
Consent Form must be signed and personally dated by the patient and investigator or authorized 
designee. If applicable, the witness shall also sign and personally date the consent form to attest that 
the information in the Patient Information and Informed Consent Form was accurately explained and 
clearly understood by the patient, and that informed consent was freely given. 
After all persons have signed and dated the Patient Information and Informed Consent Form, the 
investigator must provide the patient with a copy of the signed and dated Patient Information and 
Informed Consent Form.  
A patient contact card will be made available to the patient with emergency contact numbers. 
In Japan, the patient and investigator may provide their seal (with printed name) in lieu of a signature.  
The patient will be informed about the rights to “withdraw from the study at any time”, “withdraw without 
any disadvantage and without having to provide reason”. 
E.2.3 
Revisions in Patient Information and Informed Consent Form 
Medtronic will inform the investigators whenever information becomes available that may be relevant to 
the subject’s confirmed participation in the clinical study. The investigator or his/her authorized designee 
should inform the subject in a timely manner.  
Medtronic will revise the written Patient Information and Informed Consent Form whenever new 
information becomes available that may be relevant to the subject’s confirmed participation in the 
clinical study. The revised information will be sent to the investigator for approval by the EC/IRB and 
local regulatory authority, if applicable. After approval by the EC/IRB, a copy of this information must 
be provided to the participating subjects, and the informed consent process as described above needs 
to be repeated per EC/IRB requirements.  
E.2.4 
Regulatory submission 
In countries where submission to the regulatory authority is required per local law, no patients will be 
enrolled in the clinical study until the particular regulatory authority has approved the current Clinical 
Investigation Plan 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. 
Other documents that are referred to in this Clinical Investigation Plan are listed below and will be made 
available upon request: 
• 
Investigator’s Brochure (if applicable) 
• 
Case Report Forms 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 48 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
E.3 
Regulatory compliance 
This clinical study will be conducted in compliance with the Declaration of Helsinki 2013, the latest 
version of international standard ISO 1415520 ('Clinical Investigation of medical devices for human 
subjects' – Good Clinical Practice), laws and regulations of the countries in which the clinical study is 
conducted, including data protection laws, the Clinical Investigation Agreement and the Clinical 
Investigation Plan. The study is compliant with the latest version of ISO1415520, with the exception of 
adverse event collection after 12 months follow-up. 
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. 
21 CFR Part 54 (Financial Disclosure by Clinical Investigators) and Part 11 (Electronic Records; 
Electronic Signatures) apply to all geographies.  
All principles of the Declaration of Helsinki have been implemented in this clinical study by means of 
the informed consent process, EC/IRB approval, study training, preclinical testing, risk benefit 
assessment, publication policy, etc.  This clinical study will also be registered on clinicaltrials.gov and 
study results posted based on the posting rules stipulated.The sponsor will avoid improper influence 
on, or inducement of the subject, monitor, and investigator(s) or other parties participating in, or 
contributing to, the clinical study by implementing the informed consent process, Clinical Investigation 
Agreements, EC/IRB approval. 
In Japan, the planning and conduct of this clinical study are subject to Japanese laws. It will begin only 
when all the requirements of the appropriate regulatory authority have been fulfilled. The study will also 
be conducted in accordance with the ethical principles of the Japan GCP Ordinance and the 
Pharmaceutical and Medical Device Act. 
In Canada, the study will be conducted under an Investigational Testing Authorization in compliance 
with Medical Device Regulations, SOR/98-282. 
E.4 
Training requirements 
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 Clinical Investigation Plan, 
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. 
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 the proceduralist 
• 
CIP overview and study procedures 
• 
Investigational device disposition and accountability procedures 
• 
Procedures for returning unused/explanted devices 
• 
Case report form (CRF) completion and management, including electronic data entry 
• 
Investigator and sponsor responsibilities 
• 
Procedures for obtaining informed consent 
• 
Investigational Review Board (IRB)/ Ethics Committee (EC) requirements  
• 
Adverse event/device deficiency reporting procedures and timelines 
• 
Deviation reporting procedures 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 49 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
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 
E.5 
Clinical study materials and clinical study-specific equipment 
The sponsor will supply all required study materials for appropriate data collection before study start. 
Data collected on each patient will be recorded on a web-based electronic Case Report Form (eCRF). 
The passwords for the electronic CRF and for randomization will only be distributed to investigational 
centers where the sponsor has written documentation of site readiness.   
Medtronic will control the supply of devices and study materials. Investigational devices will not be sent 
to the site until receipt of or completion of the following: 
• 
Curriculum vitae of the principal investigator, and (if applicable) co-investigators and all 
key site staff  
• 
A signed Clinical Trial Agreement 
• 
Financial disclosure from the investigators 
• 
Competent authority/FDA approval (as applicable to the geography) 
• 
A copy of the IRB/EC approval letter, along with the voting roster 
• 
The IRB/EC approved Patient Information and Informed Consent Form 
• 
Documented training of the Principal Investigator, at a minimum. 
• 
Delegated Task List 
• 
Laboratory certificate and normal values/ranges 
• 
Confirmation of adequacy of equipment/facilities (e.g. a quiet room to perform the blood 
pressure measurements) 
E.6 
Study device/product handling and traceability 
The Symplicity SpyralTM catheter and Symplicity G3TM generator must be stored as labeled at all sites. 
In countries where the product is investigational (US, Canada, and Japan) and in countries where 
product is provided by Medtronic for purposes of the study and commercially available, product must 
be placed in a secure/locked location that meets the labeling requirements for device storage. 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) 
• 
Subject Identification Number (SID) of subject receiving or using the device (if applicable) 
• 
Disposition (implanted, disposed of, or returned to Medtronic) 
 
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 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 50 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
At the end of the study enrollment and crossover period (if applicable), all remaining investigational 
devices must be returned to Medtronic.  
The Symplicity SpyralTM catheter and Symplicity G3TM generator are commercially available in Europe 
and Australia and will be used within approved labelling for this study.  
E.6.1 
Supply of investigational devices/products 
Medtronic will only allow shipment of investigational devices/products to the investigational site or 
investigator, after the Clinical Study Manager or designee has declared the investigational site ready to 
start the clinical study. 
Shipment of the device/product should be requested through a representative of Medtronic. Medtronic 
registers the number of used investigational devices and will only ship additional investigational devices 
to the investigational site in case a substantial number of the previously shipped devices have been 
used and the CRFs have been received. 
E.6.2 
Storage and handling of investigational devices/products 
Investigational devices/products or products provided by Medtronic 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. In addition, all information for the use, storage, and 
handling of the investigational device/product, as indicated in the Instructions for Use and User Manual, 
must be taken into account. 
E.6.3 
Device explant and return procedures/products 
Non-functioning investigational devices must be returned to Medtronic as soon as possible for 
investigation.  
In case a Symplicity G3TM generator or Symplicity SpyralTM catheter needs to be returned, it will be 
returned to the address below, following local procedures:  
For Symplicity G3TM generators: 
Medtronic CardioVascular 
7611 Northland Drive 
Brooklyn Park, MN 55428 
Tel: +1 800-433-4311 
 
For Symplicity SpyralTM catheters: 
Medtronic PXM RGI Lab Building 4 
Parkmore Business Park West 
Ballybrit 
Galway 
H91 A2Y5 
Ireland 
 
Symplicity G3TM generator (Japan only): 
Plexus Manufacturing Sdn Bhd (Hillside) 
Bayan Lepas Free Industrial Zone 
Phase II, 11900 Bayan Lepas 
Pulau Pinang, Malaysia 
At the end of the clinical study, all remaining investigational devices/products must be returned to 
Medtronic in the applicable region.   

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 51 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
E.6.4 
Device/product disposition requirements 
Investigational devices/products will be traced during the clinical study by assigning specific numbers 
to each device/product. The investigator is responsible for maintenance of a device tracking log in the 
investigator site file. On this log, the receipt, use, return and disposal of the investigational 
devices/products shall be documented. At the end of the clinical study the principal investigator must 
sign and date the original device tracking log.  
F STUDY METHODS 
F.1 
Point of enrollment 
Patients will be pre-screened for potential enrollment in the clinical study based on prior medical history 
and records of office SBP. A pre-screening log will be maintained to determine the number of patients 
that do not meet study eligibility criteria and who will not be approached for participation in the study. 
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 the Screening Visit 1 (SV1). 
Investigational sites will maintain a subject identification log. However, this document will not be 
submitted to the sponsor. 
A schedule outlining protocol required visits and assessments for subjects enrolled in the study is 
displayed in Table 3 and Table 4. A flowchart depicting the study design overview is provided in Figure 
12. If subjects typically take their antihypertensive medications in the morning, it is recommended that 
study visits occur in the morning. If subjects typically take their antihypertensive medications in the 
afternoon, it is recommended that study visits occur in the afternoon. The following procedures will be 
followed for all subjects enrolled in this study until study exit. 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 52 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Figure 12: Study Design Overview 
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 53 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
F.2 
Screening Visit 1 
After confirmation that the investigator or authorized designee and subject have personally signed and 
dated Patient Information and Informed Consent Form, the following assessments will be performed at 
Screening Visit 1: 
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 Appendix 
L.7. The average baseline office blood pressure value will be used for comparison with 
follow-up visit office blood pressure values. Subjects with an office SBP ≥ 150 and <180 
mmHg and an office DBP ≥ 90 mmHg are eligible to continue to Screening Visit 2. 
Subjects with office SBP <150 mmHg or ≥ 180 mmHg, or 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 Screening Visit 2 will be exited from the study, as described 
in the Subject Exit from Trial section of this Clinical Investigation Plan. 
If the antihypertensive medication regimen is changed between Screening Visit 1 and 2 but still includes 
the required medications and doses, the new medication regimen must be established for a minimum 
of 6 weeks prior to Screening Visit 2. 
Notification to the subject’s family physician (i.e., the primary physician caring for the patient) of the 
subject’s participation in the study will be made by mail 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 from the time of randomization until after the 6-
month follow-up visit as this would impact the major endpoint for the study. 
 
F.3 
Screening Visit 2 
Screening Visit 2 must occur within 2-4 weeks from the completion of SV1, if the subjects medication 
regimen did not change. The following assessments will be performed at Screening Visit 2: 
a) EQ-5D: The EuroQol (EQ-5D) instrument will be administered to measure baseline 
health outcomes. 
b) 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.  
c) Office Blood Pressure measurements will be obtained in accordance with Appendix 
L.7. 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 
SBP ≥ 150 and <180 mmHg and an office DBP ≥ 90 mmHg are eligible to continue the 
screening process.   
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 54 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
d) Laboratory Tests: 
• 
Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, potassium, 
blood urea nitrogen (BUN), bicarbonate, chloride and glucose. Bicarbonate will 
not be measured for subjects enrolled in Japan and Europe. 
• 
Lipid Panel and hs-CRP (blood): total cholesterol, HDL, LDL, and triglycerides, 
as well as high sensitive-C reactive protein test are intended to evaluate a 
subject’s cardiovascular risk profile. High-sensitivity CRP is not required to be 
measured for subjects enrolled at sites where high-sensitivity CRP test cannot 
be locally performed. 
• 
Uric Acid (blood): This test is intended to potentially identify a marker for the 
renal denervation therapy responders. 
• 
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 or the local Japanese criteria for subjects enrolled in Japan 
The equation for estimated Glomerular Filtration Rate (eGFR) calculation 
method for Japanese subjects is as follows41:   
eGFR (mL/min/1.73 m2) = 194 x (sCr)－1.094× (Age)－0.287  x (0.739 if female). 
Note: If eGFR ≥42 and <45 mL/min/1.73m² then patient can be retested after 
hydration with a single, repeat test within 48 hours.  
• 
hCG pregnancy test in blood/urine for female subjects who are not post-
menopausal. 
• 
Drug testing (urine/blood) to ensure prescribed medications are 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. 
e) Witnessed pill taking prior to ABPM will be undertaken for all ABPM measurements. 
Subjects will be instructed to not take their antihypertensive medications on the day of 
the office visit and to bring their medications with them. Visits will begin prior to 10:30am 
for all patients who take their antihypertensive medications in the morning. Afternoon 
visits will be allowed for subjects that take their antihypertensive medications in the 
afternoon. Study personnel should document pill identity and observe the subject 
swallowing the antihypertensive medication(s). Once this is completed and documented, 
the ABPM device should be applied to the subject and the recording started before 
leaving the office. 
f) 
24-hour Ambulatory Blood Pressure Monitoring will be applied at the conclusion of 
Screening Visit 2, and after witnessed pill intake, to confirm subject’s baseline blood 
pressure. ABPM will be conducted according to the guidelines in Appendix L.7. This 
value will be utilized as the baseline value for calculating change in 24-hour ABPM at 
various time points post-randomization. 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 randomization (procedure or control) visit. A single repeat measurement is only 
allowed in case of the following:  
1. If the 24-hr systolic ABPM measured is between 135 and <140mmHg 
or 170-175 mmHg.  
2. If a valid number of readings is not obtained. 
3. If there is a technical issue with the blood pressure monitor or failure 
to follow ABPM instructions. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 55 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
If ABPM is repeated, office blood pressure, drug testing, and witnessed pill intake must 
be repeated on the day the ABPM is applied. 
g) Medication & Adverse Event Reviews will be completed to document baseline 
medication use and adverse events that occur after enrollment. 
h) Baseline Renal Imaging: If a baseline Duplex Ultrasound, CT, or MRA has been 
collected per standard of care prior to procedure within one year from the date of 
Screening Visit 1, image will be upload via Medidata Intelemage or send via courier. 
Subjects determined to not be eligible for randomization will be exited from the study, as described in 
the Subject Exit from Study section of this document. 
It is expected that subjects who are eligible to continue to randomization will be scheduled for the 
procedure 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 after 2 weeks following Screening Visit 2. Randomization 
confirmation and the control or denervation procedure will occur once all eligibility criteria have been 
met as evaluated at Screening Visit 2 and the renal angiogram.  
F.4 
Procedure 
1. Reconfirm Key Inclusion/Exclusion Criteria: To re-confirm that subjects still meet previously 
assessed eligibility criteria.  
 
2. Renal Angiography and Blinding  
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 (e.g., heparin or heparin analog in case of 
a documented heparin allergy should be initiated to maintain an ACT ≥ 250 seconds during the 
procedure for control and treatment groups).  While the protocol mandates that subjects only be 
treated with up to 3 antihypertensive agents from different classes (only thiazide-type diuretic, ACE-
I/ARB, dihydropyridine calcium channel blocker or  beta blockers are allowed) from randomization 
to 6 months following randomization, either 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. However, all 
medications used during the procedure should be commercially available in the respective 
geographies and compliant with local labeling.   
An aortogram and selective renal angiography will be performed with subjects blinded to treatment 
allocation according to methods outlined in section C.5 to confirm eligible renal artery anatomy. 
Ensure subject received a minimum aspirin dose of 250 mg intravenous (per local drug dose 
labelling) 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 patient 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 (per local drug dose labelling); 
under these circumstances, a loading dose of at least 150 mg clopidogrel may be administered 
prior to the procedure per physician discretion. In Japan, Canada, and Australia, use of antiplatelet 
agents should follow the hospital’s protocol for renal angiography.  
 
3. Randomization and Procedure 
Once subject’s renal anatomy has been confirmed to meet eligibility criteria, the subjects will be 
randomized and proceed as follows based on randomization assignment:  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 56 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
   
3.1. Control Group  
Subjects will be blinded during the renal angiogram by a combination of conscious sedation, 
sensory isolation (e.g., blindfold and music), and lack of familiarity with the procedural 
details and duration (i.e., subjects will not know the difference between the renal 
angiography procedure alone and the renal angiography and denervation procedure). If 
randomized to the control group, the subject will remain blinded and on the catheterization 
lab table for at least 20 minutes prior to the inducer sheath removal. Details of blinding 
procedure are described in Section C.5. 
3.2. Denervation Procedure  
If randomized to treatment, the renal artery denervation procedure will be performed 
according to the supplied Symplicity SpyralTM catheter Instructions for Use, Symplicity G3TM 
generator User Manual and associated training provided by Medtronic.  
Consider pre-treatment with both anxiolytic medications and analgesic medications, such 
as morphine sulfate or fentanyl (with additional doses timed with ablation treatments as 
appropriate). Blood pressure, oxygen saturation, and heart rate should be closely 
monitored both during the procedure and throughout the recovery phase from the 
conscious sedation administered. Investigators should attempt to apply treatment to any 
renal artery that meets the anatomy eligibility criteria. The Symplicity SpyralTM catheter will 
be inserted into the renal artery and the ablation treatments at multiple positions along the 
renal artery will be performed.  
Medtronic recommends performing ablations in all accessible renal arterial branch vessels 
between 3 mm and 8 mm in diameter including accessory, branch and main renal arteries 
that are outside the kidney parenchyma.   
Note: Initial placement of the Symplicity SpyralTM catheter should be just proximal to the 
renal parenchyma as identified on fluoroscopic imaging. Perform as many ablations within 
a segment as anatomy permits starting distally and working proximally without overlapping 
treatment zones.  Avoid ablations in a bifurcation and within 5mm of areas with calcification 
atheroma or stented lesions.  If the vessel segment cannot accommodate all 4 electrodes, 
then it is suggested to either 1) position a smaller number of electrodes and deselect 
electrodes or 2) advance all electrodes within the renal artery vessel segment and deselect 
the distal electrodes.    
Upon completion of the denervation procedure for the denervation group subjects, or renal 
angiogram for control subjects, 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 antihypertensive medications for blood pressure 
control in the cath lab 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. 
4. Post-procedure data collection requirements 
After the subject has completed their procedure, 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 G3TM generator data will be downloaded by Medtronic, loaded into the Case Report Form 
and submitted to Medtronic Research and Development Department. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 57 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
4.1. Post-procedure care 
All randomized subjects will be hospitalized overnight following the renal angiogram and standard-of-
care post-intervention monitoring procedures will be followed, while ensuring blinding is maintained.  
Prior to discharge, the subject and BP assessor will complete a blinding assessment form and 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 blinded study personnel. Due to medication already being administered during the 
hospital stay, witness pill intake will not be applicable for this visit. 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 him/her at the required follow-up times (e.g., home, work, cell, 
and primary physician). 
Patients shall be prescribed a minimum of 75 mg aspirin daily for 1-month post procedure. All 
medication used should be commercially available in the respective geographies and compliant with 
local labeling. If the subject has a documented allergy to aspirin, at least 75 mg clopidogrel per day for 
1 month post-procedure may be prescribed. Use of antiplatelet agents in Japan, Canada, and Australia 
should follow the hospital’s protocol for renal angiography. 
F.5 
Follow-Up Procedures 
Subjects will return for in-officefollow-up visits 1, 3, and 6 months (± 14 days) post-procedure to 
complete follow up visits. Subjects will additionally return at 12, 24, and 36 months (± 30 days) post-
procedure to complete follow up visits. In case of a crossover, subjects will return for in-office visits at 
1, 3, 6, 12, 24 and 36 months post-crossover procedure. 
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, i.e. home health care 
personnel. The following assessments may not be completed with an in-home visit: 
o 
Renal Artery Imaging: 
 
Make every effort to schedule in-person renal artery imaging as soon as 
possible. 
 
When possible, subjects may be referred to a local imaging center for 
assessment. Local imaging technicians would require study training and 
delegation prior to assessment. 
 
In the event an in-home visit is not possible, the alternate methods for obtaining follow-up assessments 
are listed below: 
• 
Virtual Visit, i.e. inclusive of video with study subject. The following assessments may not be 
completed with a virtual visit: 
o 
Clinical Assessment, limited review to be completed per physician discretion. 
o 
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 
o 
Renal Artery Imaging: 
 
Make every effort to scheduled in-person renal artery imaging as soon as 
possible. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 58 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
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. 
o 
Office blood pressure and ABPM measurements may be collected and designated as 
subject-reported in the case report form.  
 
Office blood pressure and ABPM units to be provided to the subjects in 
advance of the visit by study site. 
o 
Witnessed pill intake prior to ABPM. 
 
Documentation of pill intake will be assessed virtually. 
• 
Phone Visit, i.e. no video with the subject. The following assessments may not be completed 
with a phone visit: 
o 
Clinical Assessment, limited review to be completed per physician discretion. 
o 
Laboratory Tests: 
 
When possible, the subject should be referred to a local laboratory to collect 
samples. Kits to be provided to subjects in advance of the visit by study site. 
o 
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. 
o 
Office Blood Pressure and ABPM measurements may be collected and designated as 
subject-reported in the case report form. 
 
Office blood pressure and ABPM units to be provided to the subjects in 
advance of the visit by study site. 
o 
Witnessed pill intake prior to ABPM. 
 
Documentation of pill intake will be assessed over the phone as confirmed 
verbally by subject. 
In case the Symplicity SpyralTM catheter and Symplicity G3TM generator receive commercial approval in 
the United States, Canada, and/or Japan during the course of this clinical study, the follow-up 
assessments will continue to be conducted as planned unless otherwise instructed. 
Follow-up procedures for all subjects randomized are listed below and must be performed by blinded 
site personnel through 6 months follow-up for each subject.  
a) EQ-5D: The Euro-Qol 5D (EQ-5D) will be administered at the 3, 6, 12, 24 and 36-month 
post-randomization visits to measure health outcomes. 
b) Clinical Assessment will be conducted at all post-randomization follow-up visits to 
evaluate the subject’s current 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.  
c) Office Blood Pressure measurements will be obtained in accordance with Appendix L.7 
at all follow-up visits. 
d) Laboratory Tests:   
• Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, 
potassium, blood urea nitrogen (BUN), bicarbonate, chloride and glucose. 
Bicarbonate will not be measured for subjects enrolled in Japan and 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 or the local Japanese criteria for subjects enrolled in Japan. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 59 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• Drug testing (urine/blood) to ensure prescribed medications are present in 
the subject’s system (at 3 ,6, 12, 24 and 36-month follow-up). 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. 
e) Medication & Adverse Event Reviews will be completed at each follow-up visit to 
assess any changes in medication usage or medical condition: 
• 
Enrollment (consent) to 12-months post procedure: all medications and all 
adverse events 
• 
Twelve (12) to 36 months post procedure: all medications and serious 
adverse events only. Previously reported adverse events will be followed up 
through resolution until the end of the study. 
f) 
Renal Artery Imaging will be performed at the 6-month post-procedure visit to assess if 
renal artery stenosis is suspected. A renal duplex ultrasound (DUS) will be obtained at 
6-months and submitted to the DUS Core Laboratory. If the DUS is determined to be 
nondiagnostic, a repeat DUS, MRA, CTA or angiogram will be performed (repeat imaging 
is recommended 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/CTA Core Laboratories, an angiogram must be obtained and submitted to the 
Angiographic Core Laboratory.  
• 
A renal DUS at 6-month follow-up is not required for subjects 
randomized to the control group who are crossing over, if they 
are having the renal denervation procedure done within 30 days 
of their 6-month follow-up visit. If they are not having the renal 
denervation procedure done within 30 days of their 6-month 
follow-up visit, a renalDUS is required. 
• 
The 12-month renal CTA or MRA will be required from the 
treatment and crossover groups only. 12-month imaging is not 
required for control subjects who do not crossover.  If the CTA 
or MRA is determined to be nondiagnostic, a repeat DUS, MRA, 
CTA or angiogram will be performed.  If repeat DUS, CTA, or 
MRA is nondiagnostic or evidence of a clinically significant 
stenosis (>60-70%) is indicated, an angiogram must be 
obtained and submitted to the Angiographic Core Laboratory.  
Subjects who have already completed their 12-month visit follow 
up visit at the time of protocol approval will be required to 
undergo renal imaging at their next scheduled follow-up unless 
they have a renal angiogram due to crossover. For the 
participating sites in Germany and the UK, only renal MRA 
imaging at the 12-month follow-up visit (or 24 or 36M follow-up 
as applicable) will be performed. For these countries, if the initial 
MRA is non-diagnostic, a repeat MRA should be performed. If 
the initial MRA or repeat renal MRAs are non-diagnostic and an 
additional repeat MRA is not expected to yield the required 
information for a diagnostic study, a DUS can be completed.  
 
g) Witnessed pill taking prior to ABPM will be undertaken for all ABPM measurements. 
Subjects will be instructed to not take their antihypertensive medications on the day of 
the office visit and to bring their medications with them. Visits will start prior to 10:30am 
for all patients who take their antihypertensive medications in the morning. Afternoon 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 60 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
visits will be allowed for subjects that take their antihypertensive medications in the 
afternoon. Study personnel should document pill identity and observe the subject 
swallowing the antihypertensive medication(s). Once this is completed and documented, 
the ABPM device should be applied to the subject and the recording started before 
leaving the office. 
h) 24-hour Ambulatory Blood Pressure Monitoring will be applied at the conclusion of 
the 3-month through 36-month follow-up visits post-procedure according to the 
guidelines in Appendix L.7. A repeat ABPM will be allowed in the event of technical 
issues, if ABPM guidelines were not followed or if the minimum required number of 
daytime and nighttime readings is not obtained.  If ABPM is repeated, office blood 
pressure, drug testing and witnessed pill intake must be repeated on day the ABPM is 
applied. 
i) 
Blinding Assessment will be administered to all study subjects and study staff 
assessing office BP at the 3- and 6-month follow-up visits to assess validity of the study 
blinding. 
j) 
Mortality Assessment will be completed by the investigational site when a subject 
cannot be reached after each of the protocol required follow-up visits. 
F.6 
Crossover Procedures 
Control subjects may crossover to receive renal denervation therapy after completing their 6 month 
follow-up visit. For the subjects who have already completed their 6-month visit at the time crossover 
procedures are available per protocol version 7.0, the decision to crossover must take place at their 
next in-person visit (6, 12, 24 and 36-month follow-up or Unscheduled visit). All subjects will have 30 
days from that visit to undergo the crossover procedure. Subjects that are more than 30 days from 6, 
12, 24 or 36-month or Unscheduled visit, must complete a crossover baseline visit prior to having the 
crossover renal denervation procedure. To crossover, the required baseline data must be collected, 
and the subject cannot meet any of the anatomical or eGFR exclusion criteria.  Crossover subjects will 
undergo follow up visits at 1, 3, 6, 12, 24 and 36 months post-procedure. Subjects who do not meet 
required eligibility for crossover on the day of the procedure will undergo follow- up visits according to 
their original follow-up schedule. Crossover procedures will be offered once and will not be available at 
a later time if it was declined by the control subject during the allowed 30-day window.  
 
Baseline Crossover Data:  
Control subjects who are coming in for their scheduled 6, 12, 24,36-month or Unscheduled follow-up 
visits do not need to come in for a crossover baseline visit if all required crossover baseline procedures 
occurred during the respective follow-up visit, as listed below. An in-office visit is required for the 
baseline crossover visit assessments. Note, if the lipid panel, hs-CRP and uric acid were collected at 
SV2, these tests will not be required to be repeated.  If the lipid panel, hs-CRP and uric acid was not 
collected at SV2, they will need to be collected within 30 days prior to the crossover procedure.  For 
subjects accepting crossover at their 6-month visit, the 6-month DUS is not needed if the subject has 
the crossover procedure within 30 days of the visit. 
a) EQ-5D: The Euro-Qol 5D (EQ-5D) will be administered. 
b) Clinical Assessment will be conducted. 
c) Office Blood Pressure measurements will be obtained in accordance with Appendix 
L.7. 
d) Laboratory Tests:  
• 
Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, potassium, 
blood urea nitrogen (BUN), bicarbonate, chloride and glucose. Bicarbonate will 
not be measured for subjects enrolled in Japan and Europe. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 61 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Lipid Panel and hs-CRP (blood) (if not already collected at SV2): total 
cholesterol, HDL, LDL, and triglycerides, as well as high sensitive-C reactive 
protein tests are indented to evaluate a subject’s cardiovascular risk profile. 
High-sensitivity CRP is not required to be measured for subjects enrolled at sites 
where high-sensitivity CRP test cannot be locally performed. 
• 
Uric Acid (blood) (if not already collected at SV2): This test is intended to 
potentially identify a marker for the renal denervation therapy responder.  
• 
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 or the local Japanese criteria for subjects enrolled in Japan. 
• 
hCG (prior to procedure): pregnancy test in blood/urine for female subjects 
who are not post-menopausal 
Drug testing (urine/blood) to ensure prescribed medications are 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 
e) Medication & Adverse Event Reviews will be completed to assess any changes in 
medication usage or medical condition. 
f) 
Witnessed pill taking prior to ABPM will be undertaken for all ABPM measurements. 
Subjects will be instructed to not take their antihypertensive medications on the day of 
the office visit and to bring their medications with them. Visits will start prior to 10:30am 
for all patients who take their antihypertensive medications in the morning. Afternoon 
visits will be allowed for subjects that take their antihypertensive medications in the 
afternoon. Study personnel should document pill identity and observe the subject 
swallowing the antihypertensive medication(s). Once this is completed and documented, 
the ABPM device should be applied to the subject and the recording started before 
leaving the office. 
g) 24-hour Ambulatory Blood Pressure Monitoring will be conducted to evaluate the 
subject’s ambulatory blood pressure according to the guidelines in Appendix L.7. 
Witnessed intake of antihypertensive medications should be documented as per section 
F.5.h. 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, drug testing, and witnessed 
pill intake must be repeated on day the ABPM is applied.  
 
Crossover Follow-Up Data:  
Crossover subjects will undergo follow-up visits at 1, 3, and 6-months (± 14 days) post-procedure and 
annually at 12, 24 and 36-months (± 30 days) post-procedure. Follow-up procedures post-crossover 
procedure are listed below. Subjects who do not meet required eligibility criteria for crossover on the 
day of the procedure will undergo follow-up visits according to their original follow-up schedule.  
  
a) EQ-5D: The Euro-Qol 5D (EQ-5D) will be administered at the 3, 6, 12, 24 and 36-month 
post-procedure visits to measure health quality of life outcomes.  
b) Clinical Assessment will be conducted at all post-procedure follow-up visits to evaluate 
the subject’s current medical condition. 
c) Office Blood Pressure measurements will be obtained in accordance with Appendix L.7 
at all post-procedure follow-up visits. 
d) Laboratory Tests:  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 62 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Basic metabolic panel Chem-7 (blood): serum-creatinine, sodium, potassium, 
blood urea nitrogen (BUN), bicarbonate, chloride and glucose. Bicarbonate will 
not be measured for subjects enrolled in Japan and 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 or the local Japanese criteria for subjects enrolled in Japan. 
• 
Drug testing (urine/blood) to ensure prescribed medications are present in the 
subject’s system (at 3 ,6, 12, 24 and 36 months follow-up post crossover). 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. 
e) Medication & Adverse Event Reviews will be completed at each follow-up visit to 
assess any changes in medication usage or medical condition: 
• 
Procedure to 12-months post-procedure: all medications and all adverse 
events. 
• 
After the 12-month visit through 36 months post-procedure: all medications 
and serious adverse events only. Previously reported adverse events will be 
followed up through resolution until the end of the study. 
f) 
Renal Artery Imaging will be performed at the 6-month post-crossover procedure visit 
to assess if renal artery stenosis is suspected. A renal duplex ultrasound (DUS) will be 
obtained at 6-months and submitted to the DUS Core Laboratory. If the DUS is 
determined to be nondiagnostic, a repeat DUS, MRA, CTA or angiogram will be 
performed (repeat imaging is recommended 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/CTA Core Laboratories, an angiogram must be obtained 
and submitted to the Angiographic Core Laboratory.  
• 
The 12-month post-crossover renal CTA or MRA will be required. If the CTA or 
MRA is determined to be nondiagnostic, a repeat DUS, MRA, CTA or angiogram 
will be performed. If repeat DUS/CTA/MRA is nondiagnostic or evidence of a 
clinically significant stenosis (>60-70%) is indicated, an angiogram must be 
obtained and submitted to the Angiographic Core Laboratory.  Subjects who 
have already completed their 12-month visit follow up at the time of protocol 
approval will be required to undergo renal imaging at their next scheduled follow-
up unless they have a renal angiogram due to crossover.  
• For the participating sites in Germany and the UK, only renal MRA 
imaging at the 12-month follow-up visit (or 24 or 36M follow-up as 
applicable) will be performed. For these countries, if the initial MRA is 
non-diagnostic, a repeat MRA should be performed. If the initial MRA or 
repeat renal MRAs are non-diagnostic and an additional repeat MRA is 
not expected to yield the required information for a diagnostic study, a 
DUS can be completed.  
g) Witnessed pill taking prior to ABPM will be undertaken for all ABPM measurements. 
Subjects will be instructed to not take their antihypertensive medications on the day of 
the office visit and to bring their medications with them. Visits will start prior to 10:30am 
for all patients who take their antihypertensive medications in the morning. Afternoon 
visits will be allowed for subjects that take their antihypertensive medications in the 
afternoon. Study personnel should document pill identity and observe the subject 
swallowing the antihypertensive medication(s). Once this is completed and documented, 
the ABPM device should be applied to the subject and the recording started before 
leaving the office. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 63 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
h) 24-hour Ambulatory Blood Pressure Monitoring will be conducted at the 3, 6, 12, 24 
and 36-month post-procedure follow-up visits to evaluate the subject’s ambulatory blood 
pressure according to the guidelines in Appendix L.7. Witnessed intake of 
antihypertensive medications should be documented as per section F.5.h. 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, drug testing, and witnessed pill intake must be 
repeated on day the ABPM is applied.  
i) 
Mortality Assessment will be completed by the investigational site when a subject 
cannot be reached after each of the protocol required follow-up visits. 
For control subjects that the investigator considers to be at goal blood pressure prior to the crossover 
procedure and who undergo renal denervation, it is recommended that at the one month visit following 
the cross-over renal denervation procedure the site attempt to reduce either the antihypertensive 
medication dose and/or the number of prescribed antihypertensive drugs to determine whether the 
subject’s blood pressure will remain at goal following this change. If the subject remains below goal one 
month later after this change, the recommendation is to continue to reduce dose or number of 
prescribed antihypertensive medications on a monthly basis during follow-up to determine the minimum 
antihypertensive prescriptions and dose needed to maintain the blood pressure goal.  Visits that are not 
already scheduled (2, 4 and 5-month visits) will be documented under an Unscheduled Visit CRF. 
 
F.7 
Confirmatory Blood Draws 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. 
F.8 
Antihypertensive medication escape criteria  
Antihypertensive medication changes will not be allowed up to the 6-month follow-up visit, unless the 
following occurs: 
• 
In the event a subject’s office SBP > 180 mmHg from randomization up to the 6-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 antihypertensive medication regimen may be changed per the 
study investigator’s discretion. 
• 
In the event a subject’s office SBP < 115 mm Hg and is associated with symptoms of 
hypotension, the antihypertensive medication regimen may be changed and other therapy 
administered per the investigator’s discretion. 
Office blood pressures conducted according to Appendix L.7 must be conducted prior to the medication 
change. If the subject or another physician changes medications without first consulting the investigator, 
the investigator must evaluate the reason for the medication change and document any adverse events, 
symptoms, or blood pressure measurements leading to the change and determine if it is an appropriate 
prescription. If the medication change was made without proper justification, the investigator should 
consider putting the patient back on baseline medications/doses. All efforts should be made to obtain 
an ABPM and Chem-7 panel prior to changing the subject’s antihypertensive medication regimen. A 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 64 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
subject must meet the escape criteria and have medication changes in response to be considered an 
escape subject. 
F.9 
Drug testing for Emergency Room Visit or Hospitalization for Elevated 
Blood Pressure 
In the event a study subject is hospitalized or presents to the emergency room for elevated BP, the 
subject should be instructed to have site personnel notified and site personnel should attempt to obtain 
a urine and blood sample for drug testing to confirm if subject was complying with medication 
requirements as per the protocol. This can be obtained up to 24 hours after the subject has been 
discharged. 
F.10 Data collection requirements 
All study data will be entered into electronic Case Report Forms (eCRFs) in a database provided by the 
Sponsor. All eCRFs will be completed using de-identified data.  
eCRF completion may be delegated by the Principal Investigator (documented on the Delegated Task 
List) to other trained study personnel. A personal user ID and access code will be provided by the 
sponsor when all required documentation has been received. The Principal Investigator remains 
responsible for the accuracy and integrity of all data entered in eCRFs.  
Additional details regarding procedures used for data review, database cleaning, issuing and resolving 
data queries, and identification of steps for creation, modification, maintenance, archiving retrieval or 
transmission of source data via any computerized systems will be provided in the study specific Data 
Management Plan (DMP). 
The following equipment will be provided to the sites: 
• 
Office Blood Pressure Monitors 
• 
24-hour Ambulatory Blood Pressure Monitors (ABPM) 
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.  
Medtronic will be responsible for annual maintenance of the Symplicity G3TM generator and calibration 
of the Office Blood Pressure and ABPMs according to the manufacturer’s requirements. Documentation 
of the routine maintenance will be provided to the study site upon completion.

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 65 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Table 3: Schedule of Testing for All Subjects 
(See Table 4 for Crossover Subjects’ Testing) 
 
1 month (30 days): 16-44 days, 3 months (90 days): 76-104 days, 6 months (180 days): 166-194 days, 12 months (360 days): 
330-390 days, 24 months (720 days): 690-750 days, 36 months (1080 days): 1050-1110 days. 
Post-Procedure 
(M=months ± 14 days for 1M, 3M and 6M visits, months ± 30 days for 12M-36M 
visits) 
Required Assessments 
SV1 
SV2 
Procedure 
Prior to 
Discharge 
1M 
3M 
6M 
12M 
24M 
36M 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Clinical assessment 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Renal Denervation or Sham Procedure 
 
 
X 
 
 
 
 
 
 
 
Office Blood Pressure according to guidelines in Appendix L.7 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
24-Hour ABPM according to guidelines in Appendix L.7 
 
X 
 
 
 
X 
X 
X 
X 
X 
Witnessed pill taking  
 
X 
 
 
 
X 
X 
X 
X 
X 
Blood tests (uric acid, lipid panel and high sensitivity CRP6) 
 
X 
 
 
 
 
 
 
 
 
Blood Tests (Chem-7)3 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
 
X 
 
 
 
 
 
 
 
 
Drug testing 
 
X 
 
 
 
X 
X 
X 
X 
X 
Renal Artery Imaging - Angiogram 
 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging – Duplex Ultrasound 
 
X4 
 
 
 
 
X1 
X5 
(X)5 
(X)5 
Blinding Assessment for Subjects and Assessors 
 
 
 
X 
 
X 
X 
 
 
 
EQ-5D 
 
X 
 
 
 
X 
X 
X 
X 
X 
Mortality Assessment2 
 
 
 
 
X 
X 
X 
X 
X 
X 
Medication Review and Event Review 
All adverse events (AE) and all medication review 
After 12 months, previously reported AEs will need to be reviewed and updated as needed 
Serious AEs and all 
medication review 
1 DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CTA 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.  The 6M DUS will not be required for subjects crossing over at 6M if crossover is completed within 30 days of 6M visit.   
2 Conduct if follow-up missed. 
3 Bicarbonate will not be measured for subjects enrolled in Japan and Europe. 
4 Submit baseline duplex ultrasound, CTA, or MRA if obtained per standard of care prior to procedure within one year from the date of screening visit 1. 
5 CTA/MRA  required as first line imaging modality at 12M (and 24M and 36M as applicable). For treatment and crossover subjects only: Repeat DUS, MRA, or CTA to be used if prior imaging modality is nondiagnostic. 
If repeat DUS/CTA/MRA is nondiagnostic or evidence of a clinically significant stenosis (>60-70%) is indicated, an angiogram must be obtained and submitted to the Angiographic Core Laboratory.  Subjects who have 
already completed their 12-month without renal imaging will be required to undergo renal imaging at their next scheduled follow-up unless they have a renal angiogram due to crossover. For the participating sites in 
Germany and the UK, only renal MRA imaging at the 12-month follow-up visit (or 24 or 36M follow-up as applicable) will be performed. For these countries, if the initial MRA is non-diagnostic, a repeat MRA should be 
performed. If the initial MRA or repeat renal MRAs are non-diagnostic and an additional repeat MRA is not expected to yield the required information for a diagnostic study, a DUS can be completed. 
6 High-sensitivity CRP is not required to be measured for subjects enrolled at sites where high-sensitivity CRP test cannot be locally performed.  
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 66 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Table 4: Schedule of Testing for Crossover Subjects 
1 month (30 days): 16-44 days, 3 months (90 days): 76-104 days, 6 months (180 days): 166-194 days, 12 
months (360 days): 330-390 days, 24 months (720 days): 690-750 days,36 months (1080 days): 1050-1110 
days 
Post-Procedure 
 (M=months ± 14 days for 1M, 3M and 6M visit, months ± 30 days for 12M-36M visits) 
Required Assessments 
Baseline5 
Renal 
Denervation 
Prior to 
Discharge 
1M 
3M 
6M 
12M 
24M 
36M 
Clinical assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood Tests (Chem-7)3 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Tests (uric acid, lipid panel, and high-
sensitivity CRP)6 
 
X (prior to 
procedure)5 
 
 
 
 
 
 
 
Office Blood Pressure according to guidelines in 
Appendix L.7 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
 
X (prior to 
procedure)5 
 
 
 
 
 
 
 
Witnessed pill taking 
X 
 
 
 
X 
X 
X 
X 
X 
24-Hour ABPM according to guidelines in 
Appendix L.7 
X 
 
 
 
X 
X 
X 
X 
X 
EQ-5D  
X 
 
 
 
X 
X 
X 
X 
X 
Renal Denervation 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging - Angiogram 
 
X 
 
 
 
 
 
 
 
Renal Artery Imaging  
 
 
 
 
 
X1 
X4 
(X)4 
(X)4 
Drug Testing 
X 
 
 
 
X 
X 
X 
X 
X 
Mortality Assessment2 
 
 
 
X 
X 
X 
X 
X 
X 
Medication Review, Event Review 
All adverse events (AE) and all medication review 
After 12 months, previously reported AE’s will need to be reviewed and updated as needed  
Serious AE and all medication 
review 
1 DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CTA or angiogram to be used if DUS is non-diagnostic.  Renal angiography must be used if repeat DUS/CTA/MRA is nondiagnostic or stenosis 
>60-70% is suspected. 
2 Conduct if follow-up visit missed 
3Bicarbonate will not be measured for subjects enrolled in Japan and Europe 
4 CTA/MRA  required as first line imaging modality at 12M (and 24M and 36M as applicable). Repeat DUS, MRA, or CTA to be used if prior imaging modality is nondiagnostic. If repeat DUS/CTA/MRA is nondiagnostic 
or evidence of a clinically significant stenosis (>60-70%) is indicated, an angiogram must be obtained and submitted to the Angiographic Core Laboratory.  Subjects who have already completed their 12-month without 
renal imaging will be required to undergo renal imaging at their next scheduled follow-up. For the participating sites in Germany and the UK, only renal MRA imaging at the 12-month follow-up visit (or 24 or 36M follow-
up as applicable) will be performed. For these countries, if the initial MRA is non-diagnostic, a repeat MRA should be performed. If the initial MRA or repeat renal MRAs are non-diagnostic and an additional repeat MRA 
is not expected to yield the required information for a diagnostic study, a DUS can be completed. 
5 If not already collected at previous follow up visits (within 30 days of crossover procedure). 
6 High-sensitivity CRP is not required to be measured for subjects enrolled at sites where high-sensitivity CRP test cannot be locally performed. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 67 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
F.11 Role of the sponsor’s representatives 
Sponsor’s representatives will provide support as required for the clinical study, including but not limited 
to technical support during the procedure and/or technical support during follow-up in order to ensure 
that all study requirements are met and the procedure is performed according to the Instructions for 
Use. The sponsor’s representatives providing technical support may be listed on the sponsor technical 
support list.   
F.12 Source documents 
Data entered in the eCRF 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 patient eligibility criteria. 
Clinical records must be marked to indicate a subject has been enrolled into the clinical study. 
The eCRFs (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 worksheets if identified as source documents.  
The Investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived. Where printouts of electronic medical records, are provided as source documents, 
or where copies of source documents are retained as source documents, they must be signed and 
dated by a member of the investigational site team 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 source documents will be requested to support event adjudication by the Clinical Events 
Committee. In Japan, availability of source documentation may be limited due to hospital policies. If a 
specific source document is not available, necessary information may be transcribed onto the relevant 
CRF page. 
F.13 Adverse events and device deficiencies 
F.13.1 Definition/classification  
For each reported adverse event, the Investigator will assess the events in terms of relationship to the 
device, relationship to the procedure, 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 G3TM generator can be 
established. 
• 
Procedure: A procedure related AE is defined as any AE occurring within 7 days post-
procedure (or post-denervation in the case of a control group subject being denervated at 
cross over) 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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 68 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
For the purposes of the clinical report, Medtronic will classify each Adverse Event according to the latest 
version of International Organization of Standardization (ISO) ISO 14155. 
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. 
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. 
NOTE 2: This definition includes any event resulting from an error use or from intentional misuse of 
the investigational medical device 
Note 3:  This includes a “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. 
Serious Adverse Event (SAE): (ISO 14155 3.37) 
Adverse event that led to any of the following: 
a) 
death, 
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 functionincluding 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) 
foetal distress, foetal death or a congenital abnormality or birth defect including physical 
or mental impairment.   
NOTE: 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 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious Adverse 
Event  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 69 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Unanticipated Serious Adverse Device Effect (USADE): (ISO 14155 3.42) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the current version of the risk analysis report 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
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: 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) CRF 21 Part 
11 the following definitions will apply: 
Unanticipated Adverse Device Effect (UADE): (CFR 21-812.3) 
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 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.   
Serious Adverse Health Consequences: (CFR 21-814) 
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.  
F.13.2 Recording, reporting, and review of Adverse Events 
Adverse Event (AE) information will be collected by the site from subject enrollment (consent) through 
study termination or study exit per Table 6 reporting requirements. AEs will be followed until the event 
has resolved or study completion, whichever comes first.  (In the case of permanent impairment, the 
event will be followed until it stabilizes, and the overall clinical outcome has been ascertained).  
The Investigator will report any adverse events that may occur to the Sponsor, and will indicate the date 
of the 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 
or not 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. 
A list of AEs that may be associated with the use of the investigational device and/or the interventional 
procedure is provided in the Risks section (Section J). 
Events that do not qualify as AEs: 
• 
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 mm Hg without producing symptoms suggestive of hypotension 
• 
Unavoidable AEs (see Table 5) 
 
Table 5: Unavoidable Adverse Events 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 70 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
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 
 
In Japan, all adverse event information (including unavoidable AEs) will be collected by the site. 
Onset of any events listed in Table 5 after the specified timeframes and/or events lasting longer than 
the specified timeframe (if onset is at the time of procedure) should be reported as an AE. 
All Adverse Events, regardless of relatedness or outcome, must be reported until 12 months.  After 12 
months, only Serious Adverse Events (SAEs) are to be reported. Adverse events will be documented 
on the appropriate case report form, 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 eCRF, one eCRF for each Adverse Event term. 
See the Adverse Event eCRF for the information to be reported for each Adverse Event and Table 6 for 
the event reporting timeframe requirements. For Adverse Events that require immediate reporting (see 
Table 6), initial reporting will be done on the eCRF by completing as much information as is available. 
The AE eCRF must be “saved as Complete” in the Remote Data Capture (RDC) system to ensure it is 
reported to Medtronic as soon as possible. 
All Adverse Events and device deficiencies will be reviewed by the Medtronic Safety Department. This 
review will include the determination whether the Adverse Event meets regulatory reporting 
requirements (see Table 6). The Sponsor will ensure timely Adverse Event/ 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 promptly 
report this device related Adverse Event/Device Deficiency to the Medtronic Product Experience 
Management (PXM) Galway, Ireland. The Medtronic Product Experience Management (PXM) Galway, 
Ireland will ensure prompt review, and appropriate reporting. 
UADE Evaluation and Reporting: 
Medtronic will conduct an evaluation of the UADE in accordance with CFR 812.46(b) and shall report 
the results of such evaluation to 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.   
F.13.3 Recording, reporting, and review of Device Deficiencies 
Device deficiencies are defined as inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance (ISO 14155 3.15). Device deficiencies include malfunctions, 
use errors, and inadequacyin the information supplied by the manufacturer including labeling. 
Malfunction is defined as 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 [Ref. 21 CFR 803.3(m)]. Product labels, Instructions for Use, and User Manuals for this study 
are provided separately. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 71 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
All device deficiencies and malfunctions will be documented on the appropriate case report form, 
reported to Medtronic, and reported to the ethics committee (if required) within the ethics committee 
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 the Device Deficiency eCRF for the information to be reported for each Device Deficiency that did 
not lead to an Adverse Event. 
Device deficiencies that did not lead to an Adverse Event but could have led to an SADE (ISO 14155 
6.4.2) 
 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting (see Table 6). Initial reporting may be done by will be done on the eCRF 
by completing as much information as is available. The Device Deficiency eCRF must be “saved as 
Complete” in the Remote Data Capture (RDC) system to ensure it is reported to Medtronic as soon as 
possible.  
F.13.4 Adverse Event Reporting Requirements 
Investigator and Sponsor reporting requirements of events and device deficiencies are outlined in Table 
6.  
Table 6: Adverse Event reporting requirements 
Serious Adverse Device Effects (SADE), including Unanticipated Serious Adverse Device Effect 
(USADE) and Unanticipated Adverse Device Effects (UADE): 
Investigator submit to: 
Sponsor submit to: 
Medtronic: Submit as soon as possible, as per local reporting 
requirements, but not later than within 10 working days after the 
investigator first learns of the event. 
In Canada: USADEs/SADEs on the patient, the user or any other 
person must be reported to the Sponsor within 72 hours after it 
comes to the attention of the qualified investigator.  Incidents that 
could lead to USADEs/SADEs, were it to reoccur, must also be 
reported within 72 hours.  
 
In Japan: Submit as soon as possible but no later than 3 business 
days after the designated study site personnel first learns of the 
event and to the IRB within the IRB required timeframe. 
In Europe: Submit immediately (but no later than 10 working 
days) after investigator learns about new event or of new 
information related to an already reported event. 
 
Regulatory 
authorities 
(other 
than 
Canada and Australia): Submit as soon as 
possible, but not later than within 10 
working days after the Sponsor first 
receives notice of the event, as per local 
reporting requirement.  
In Canada: Medtronic will adhere to the 
Medical Devices Regulations, SOR/98-282.  
Mandatory Problem Reporting Sections 59-
61. 
In Australia: Medtronic will adhere to the 
adverse event reporting requirements for 
Post Market Release (PMR) studies as per 
the requirements of the Therapeutic Goods 
(Medical devices) Regulations 2002. 
EC/IRB: Reporting timeframe as per local EC/IRB requirement. 
 
EC/IRB: Reporting timeframe as per local 
EC/IRB requirement. 
Serious Adverse Events (SAE) 
Investigator submit to: 
Sponsor submit to: 
Medtronic: Submit as soon as possible as per local reporting 
requirement, but not later than within 10 working days after the 
investigator first learns of the event. 
In Canada: As required by Clinical Investigational Plan. (Section 
F.13.4)  
Regulatory 
authorities: 
Reporting 
timeframe as per local requirement. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 72 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Table 6: Adverse Event reporting requirements 
In Japan: SAE must be reported by the investigator or delegated 
study staff to Medtronic within 24 hours after the investigator first 
learns of the event by completion of an AE eCRF page. If the 
eCRF database is not available or the site is unable to complete 
the eCRF due to technical reasons, the Sponsor should be 
notified of the event using a faxed SAE Rush Form. If the SAE is 
reported using a SAE Rush Form, an AE page of the eCRF should 
be completed within 3 business days after the designated 
investigational site personnel first learns of the event if possible. 
In Europe: Submit immediately (but no later than 10 working 
days) after investigator learns about new event or of new 
information related to an already reported event. 
  
In Japan: All SAEs classified by Medtronic 
Japan Safety as reportable events will 
follow the applicable Pharmaceuticals and 
Medical Devices Agency (PMDA) reporting 
requirements (Ordinance for Enforcement 
of the Pharmaceutical and Medical Device 
Act, Article 274, paragraph 2). 
In Australia: Medtronic will adhere to the 
adverse event reporting requirements for 
Post Market Release (PMR) studies as per 
the requirements of the Therapeutic Goods 
(Medical devices) Regulations 2002. 
EC/IRB: Reporting timeframe as per local EC/IRB requirement. 
In Japan: Upon reporting the SAE within 24 hours to Medtronic, 
the event must be reported to the site director (if required) by the 
investigator within the IRB required timeframe. 
 
EC/IRB: Reporting timeframe as per local 
EC/IRB requirement. 
Adverse Device Effects (ADE) 
Investigator submit to: 
Sponsor submit to: 
Medtronic: Submit as soon as possible as per local reporting 
requirement, but not later than within 10 working days after the 
investigator first learns of the event.  
In Canada: As required by the Clinical Investigation Plan (Section 
F.13) 
In Australia: As required by Clinical Investigation Plan (Section 
F.13) 
In Europe: Submit immediately (but no later than 10 working 
days) after investigator learns about new event or of new 
information related to an already reported event. 
Regulatory 
authorities 
(other 
than 
Australia): Reporting timeframe as per 
local requirement 
In Australia: Medtronic will adhere to the 
adverse event reporting requirements for 
Post Market Release (PMR) studies as per 
the requirements of the Therapeutic Goods 
(Medical devices) Regulations 2002. 
EC/IRB: Reporting timeframe as per local EC/IRB requirement. 
 
EC/IRB: Reporting timeframe as per local 
EC/IRB requirement. 
All other AEs 
Investigator submit to: 
Sponsor submit to: 
Medtronic: Submit as soon as possible as per local reporting 
requirement after the investigator first learns of the event.  
In Australia: As required by Clinical Investigation Plan  
In Europe: Submit in a timely manner after investigator learns 
about new event or of new information related to an already 
reported event. 
In Canada: As required by the Clinical Investigation Plan 
Regulatory 
authorities 
(other 
than 
Australia): Reporting timeframe as per 
local requirement 
In Australia: Medtronic will adhere to the 
adverse event reporting requirements for 
Post Market Release (PMR) studies as per 
the requirements of the Therapeutic Goods 
(Medical devices) Regulations 2002. 
EC/IRB: Submit to EC/IRB per local reporting requirement. 
EC/IRB: Reporting timeframe as per local 
EC/IRB requirement. 
 
Regulatory Authority: As per local reporting requirement 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 73 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Table 6: Adverse Event reporting requirements 
Device Deficiency with SADE potential 
Investigator submit to: 
Sponsor submit to: 
Medtronic: Submit as soon as possible as per local reporting 
requirement, but not later than 48 hours after the investigator first 
learns of the event. 
In Europe: Submit in a timely manner (but no later than 48 hours) 
after investigator learns about new event or of new information 
related to an already reported event. 
In Canada: Device Deficiencies that have resulted in any of the 
consequences characteristic of a SADE on the patient, the user, 
or any person, or could do so where it could reoccur, must be 
reported to the Sponsor within 72 hours after it comes to the 
attention of the qualified investigator.  
Regulatory 
authorities: 
Reporting 
timeframe as per local requirement 
In Australia: Medtronic will adhere to the 
adverse event reporting requirements for 
PMR studies as per the requirements of the 
Therapeutic 
Goods 
(Medical 
devices) 
Regulations 2002. 
 
In Canada: Medtronic will adhere to the 
Medtronic Device Regulations, SOR/98-
282, Mandatory Problem Reporting Section 
59-61. 
EC/IRB: Reporting timeframe as per local EC/IRB requirement. 
EC/IRB: Reporting timeframe as per local 
EC/IRB requirement. 
All other Device Deficiencies 
Investigator submit to: 
 
Medtronic 
Submit as soon as possible as per local reporting requirement, but not later 
than 48 hours after the investigator first learns of the event. 
In Europe: Submit in a timely manner (but no later than 48 hours) after 
investigator learns about new event or of new information related to an 
already reported event. 
Regulatory Authority 
As per local reporting requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
 
F.13.5 Data Safety Monitoring Board and Clinical Events Committees  
A Data Safety Monitoring Board (DSMB) will be established to monitor the health, safety and welfare of 
patients. Additionally, a Clinical Events Committee (CEC) will be established to adjudicate any safety 
endpoint events. See Section I.2 Advisory Committees.  
F.13.6 Emergency contact details in case of serious AEs 
In the case a Serious Adverse Event or Serious Adverse Device Effect occurs and requires immediate 
consultation, the investigators can contact the sponsor (or designee) as outlined in the Investigator Site 
File. 
F.14 Subject accountability 
F.14.1 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 F.14. 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 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 74 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
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. 
F.14.2 Unscheduled Follow-up Visits 
If a subject returns to the institution between the protocol-required screening or follow-up visits for one 
of the following reasons: an escape medication change, evaluating subjects during medication changes, 
repeat procedures (serum creatinine blood draw, ABPM, renal imaging), re-consenting, or drug testing 
for elevated blood pressure resulting in a hospitalization or emergency room visit, the visit will be treated 
as an unscheduled visit.  (This visit does not have to be before 10:30 a.m.) The reason for the 
unscheduled visit, as well as any assessment data will be recorded on the Unscheduled Follow-up 
eCRF and AE data on the AE eCRF (if applicable). If the subject returns for another reason, this will not 
need to be documented.  
F.14.3 Subject Withdrawal or Lost to Follow-up 
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. Subjects who 
discontinue participation prematurely will be included in the analysis of results and 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 should ask for the subject’s permission to follow his/her status outside 
the clinical study. 
F.14.4 Subject Exit from Trial 
There are several scenarios in which a subject may exit the study. Table 7 details how the data will be 
handled for each scenario.  
Table 7: 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 (not randomized) 
None 
Subject enrolled, randomized 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 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 75 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Subject 
enrolled, 
randomized 
and 
completes 
the 
study 
requirements 
Through 3-year follow-up 
Subject enrolled, randomized, completed crossover procedure and 
completes the study requirements 
Through 3-year follow-up 
F.15 Study deviations and CIP changes 
A study deviation is an event where the investigator or investigational site personnel did not conduct 
the clinical study according to the Clinical Investigation Plan or Clinical Trial Agreement. The 
investigator is not allowed to deviate from the above-mentioned documents except with prior approval 
and under emergency circumstances. All deviations shall be documented and explained, regardless 
the reason for the deviation. 
Medtronic will assess the significance of all deviations and evaluate the need to amend the Clinical 
Investigation Plan or to early terminate the investigation, in accordance with Medtronic SOPs. 
F.15.1 Request for Approval of Study Deviations 
The investigator shall obtain documented approval from Medtronic, before implementation, for any 
change in or deviation from the Clinical Investigation Plan. In case of study deviations that can affect 
the subject’s rights, safety and well-being or the scientific integrity of the clinical study, approval from 
the EC/IRB and regulatory authority (if applicable) must also be obtained before implementation. The 
investigator shall contact the Clinical Study Manager for review of the proposed change/deviation. 
Prior approval is not always possible in situations where unforeseen circumstances are beyond the 
investigator’s control. However, also in these cases, the event is considered a deviation, and shall be 
reported.  
In any emergency, the investigator shall exercise his/her judgment to safeguard the subject’s interest. 
Such deviations from the Clinical Investigation Plan do not require the prior approval of Medtronic. The 
investigator shall report the deviation as soon as possible to Medtronic and the reviewing EC/IRB, if 
applicable. Medtronic will inform the regulatory authorities, if required. 
F.15.2 Reporting requirements for study deviations 
For reporting purposes Medtronic classifies deviations as major or minor protocol (Clinical Investigation 
Plan) deviations. Major protocol (Clinical Investigation Plan) deviations are deviations with respect to 
inclusion/exclusion criteria, and no patient informed consent prior to study procedures. 
Deviations will be recorded at the site and reported to Medtronic on the eCRF. The deviation document 
shall be signed and dated by the investigator or his authorized designee. At a minimum the following 
information will be recorded: 
• 
identification of the investigator and site 
• 
description of deviation 
• 
date of occurrence 
• 
reason for the deviation 
• 
patient identifier, if associated with the event 
Deviations will be entered into a database to allow a comprehensive review on a regular basis for 
identifying trends that warrant additional preventive or corrective actions to mitigate further occurrence. 
Clinical study management at Medtronic shall conduct this review. 
Study deviations must be reported to Medtronic, regardless of whether medically justifiable, pre-
approved by the study leader (see contact details section), or taken to protect the subject in an 
emergency. In the case the deviation involves a failure to obtain a subject’s informed consent or is made 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 76 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
to protect the life or physical well-being of a subject in an emergency, the deviation must be reported to 
the EC/IRB and the study leader as soon as possible after the occurrence of the event. Reporting of all 
other study deviations should comply with EC/IRB policies and/or local laws. The investigator shall 
adhere to EC/IRB requirements and procedures for reporting study deviations. 
The clinical study team shall provide regular site-specific reports to the investigator(s) summarizing 
information on deviations that occurred at the investigational site. The frequency of these reports will 
depend on the stage in the study and number and details of protocol deviations. 
All deviations from the CIP will be included in the final report. 
 
Specific examples of study deviations are, but not limited to: 
• 
failure to obtain the Patient Information and Informed Consent Form prior to 
participation 
• 
incorrect version of the Patient Information and Informed Consent Form used 
• 
no EC/IRB approval before the start of the study 
• 
randomized patient did not meet inclusion/exclusion criteria 
• 
randomization processes not followed 
• 
CIP required testing and/or measurements not done or incorrectly done 
• 
subject did not attend follow up visit or follow up visit outside window 
• 
Adverse Events not reported by investigators in the required time frame as specified in 
the CIP 
• 
source data permanently lost 
• 
enrollment of patients 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 any particular investigational center or investigator 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 investigational site.  
F.15.3 Amendments to the Clinical Investigation Plan 
The investigator will propose any appropriate modification(s) of the Clinical Investigation Plan or 
investigational device/product or investigational device/product use. Medtronic will review this proposal 
and decide whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the Clinical Investigation Plan, including a 
justification for this amendment, to the appropriate regulatory authorities and to the investigators to 
obtain approval from their EC/IRB. The investigator will only implement the amendment after approval 
of the EC/IRB, regulatory authority, and sponsor. Administrative amendments to the Clinical 
Investigation Plan will be submitted to the EC/IRB for notification. Furthermore, investigators shall sign 
any approved amendment for agreement.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 77 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
G QUALITY CONTROL PROCEDURES 
G.1 Procedures for database management 
G.1.1 Data collection 
The investigator must ensure accuracy, completeness and timeliness of the data reported in the eCRFs 
and in all other required reports. Data reported on the eCRFs 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 patient medical file. 
Only authorized persons can complete eCRFs. eCRFs shall be signed off 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 eCRFs. Upon completion of an eCRF the investigator shall sign the CRF in a timely manner. If a 
change is made to an already signed eCRF, the investigator shall re-sign this eCRF. 
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.  
G.1.2 Source data to be directly recorded on the 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). 
The eCRFs (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. 
 
G.1.3 Time windows for completion and submission of Case Report Forms 
eCRFs are recommended to be entered into the RDC system within 10 days of the completion of the 
protocol-specified follow-up visit, or sooner if requested by the sponsor.  
G.1.4 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 the data. 
G.2 Monitoring procedures 
Monitoring visits will be conducted at the start, during, and at the closure of the clinical study in 
accordance with Medtronic SOPs and the monitoring plan. Frequency and timing of monitoring visits 
will be determined by the Sponsor for each site based on enrollment rate and volume, study compliance, 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 78 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
and findings from previous visits. A site initiation visit will be performed to prepare the site and it may 
include training and collection of the required documentation such as Curricula Vitae..  
Monitors will verify whether signed and dated patient information, if applicable, and informed consent 
forms have been obtained from each subject at the point of enrollment, before any study procedure has 
been performed. 
Specific monitoring requirements are detailed in the monitoring plan. In order to ensure a high degree 
of data quality, all enrolling clinical centres will be monitored frequently. The aim is to monitor the source 
data of minimally 90% of data collected in the study. In addition, the aim, is to verify all available 
informed consent forms of  enrolled patients at the center during the monitoring visits. The principal 
investigator should be available during monitoring visits. The sponsor will provide updated contact lists 
to the investigational sites. 
For the duration of the study, Medtronic or designee will conduct site monitoring visits to assess, A)  
compliance with the protocol, clinical trial agreement, and applicable regulations, B) adherence to the 
data collection procedures, C) accuracy and completeness of submitted clinical data, and D) proper 
maintenance of records . 
Monitoring activities will be documented, including a summary of items the monitor reviewed and 
observations regarding the completion of previous action items, significant findings, facts, deviations, 
conclusions, and recommended actions to be taken to secure compliance. 
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 
G3TM generator will be performed by Medtronic’s technical support staff on an annual basis. 
In Japan, monitors will follow the Japan GCP Ordinance to ensure compliance with the study protocol 
and Good Clinical Practice for Medical Devices. 
G.2.1 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 Case Report Form (CRF). Direct access to patient medical files for source data 
verification will need to be granted and prepared prior to any monitoring visits, if applicable.  
G.2.2 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. Independent of the employees involved 
in the clinical study. Regulatory bodies may also perform inspections at participating 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. 
G.3 Study suspension or early termination 
Termination of the Study is discontinuation, by sponsor or by withdrawal of IRB/EC or local regulatory 
body approval, of an investigation before completion. This is possible for the entire study, all centers in 
a country, or a single center.  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 79 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Study suspension is a temporary postponement of study activities related to enrollment and distribution 
of the investigational product(s). This is possible for the entire study, all centers in a country or a single 
center. In case of study suspension or early termination, it is up to the investigator’s discretion to assess 
whether or not to continue the clinical study at the respective investigational site.  
G.3.1 Early Study Suspension or Termination 
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 
G.3.2 Early investigation site suspension or termination 
Possible reasons for clinical investigator or center termination or suspension include but are not limited 
to: 
• 
Failure to obtain initial IRB/EC 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.) 
• 
IRB/EC 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) 
G.3.3 Subject follow-up in case of termination 
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). 
G.3.3.1 Medtronic-initiated 
• 
In the case of study termination or suspension for reasons other than a temporary IRB/EC 
approval lapse, the investigator will promptly inform the IRB/EC.  
• 
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. 
G.3.3.2 Investigator-initiated 
• 
The investigator will promptly inform: 
o 
Medtronic and provide a detailed written explanation of the termination or suspension. 
o 
The institution (where required per regulatory requirements). 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 80 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
o 
The IRB/EC. 
o 
The subjects and may inform the personal physicians of the subjects to ensure 
appropriate care and follow-up is provided. 
• 
In the case of a study suspension: 
o 
Subject enrollment must stop until the suspension is lifted. 
o 
Subjects already enrolled should continue to be followed up on, out of consideration of 
their safety, rights, and welfare. 
G.3.3.3 IRB/EC initiated 
• 
The investigator will promptly inform: 
o 
Medtronic and provide a detailed written explanation of the termination or suspension 
within 5 business days. 
o 
The institution (if required per regulatory requirements). 
o 
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: 
o 
Subject enrollment must stop until the IRB/EC suspension is lifted. 
o 
Subjects already enrolled should continue to be followed in accordance with IRB/EC 
policy or its determination that an overriding safety concern or ethical issue is involved. 
G.3.4 Criteria for unblinding 
Reasons for unblinding are: 
• 
All randomized patients will be unblinded during the 6-month follow-up visit. A crossover 
procedure will be offered to the randomized Control patients that continue to meet eligibility 
criteria after this visit. 
• 
All randomized patients will immediately be unblinded in case of study termination. 
• 
When a site is terminated, all randomized patients of the site will immediately be unblinded. 
Unblinding must be documented including the signature of site study personnel, date and reason for 
unblinding and must be reported to the clinical study manager. The unblinding will be documented on 
a separate file that can be found in the ISF. 
G.4 Study close out 
Upon study completion or termination, site closeout visits will be conducted, as outlined in the 
monitoring plan. After the study has been completed or terminated, medical care will be provided to the 
subjects upon the discretion of the treating physician.  
In Japan, upon completion of the clinical study (when enrollment of all prospective subjects has been 
completed, all follow-up visits have been completed and data queries resolved, and all eCRFs have 
been approved), the investigator will notify the institution director of the site closeout. Medtronic Japan 
will submit a clinical trial notification to the regulatory authority at the time of study close-out. 
H DATA ANALYSIS AND REPORTING 
Any deviations from this section and/or the Statistical Analysis Plan will be described and justified in the 
Final Clinical Study Report, as appropriate or justified in the CIP, if applicable. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 81 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
H.1 Analysis of clinical data 
General Analysis Overview 
Descriptive statistics of continuous outcomes will be presented by treatment arm and include sample 
size, mean, median, standard deviation, minimum and maximum. For categorical outcomes, the number 
and percentage of subjects in each category will be presented by treatment arm.  
RDN vs. control arms will be compared out to 6-months post randomization prior to the crossover 
procedure. Statistical comparisons between RDN and control arms will be made using t-tests for 
continuous outcomes and chi-square or Fisher’s exact test (depending on overall event rates) for 
categorical outcomes. Paired t-tests will be used to compare changes from baseline to follow-up 
within each treatment arm. All statistical analyses will be performed using SAS for Windows (version 
9.2 or higher) or other widely accepted statistical or graphical software. Patient data listings and 
tabular and graphical presentations of results will be provided. Unless otherwise specified, a two-
sided 0.05 level of significance will be used to declare treatment arms significantly different. Additional 
details on the analysis will be provided separately in the Statistical Analysis Plan (SAP) for this study. 
RDN vs. Crossover vs. Non-Crossover groups will be compared out to 36 months post-procedure. 
Analysis Sets 
a. Intent-to-Treat (ITT): All randomized subjects, analyzed according to their randomized 
treatment. Subjects who meet the antihypertensive medication escape criteria (Office 
SBP>180 or <115 associated with symptoms of hypotension or safety concern requiring 
medication changes) will be analyzed using Last Observation Carried Forward (LOCF) 
for their blood pressure measurements. 
b. Modified Intent-to-Treat (modified ITT): All randomized subjects, analyzed according to 
their randomized treatment. Subjects who meet the antihypertensive medication escape 
criteria (Office SBP>180 or <115 associated with symptoms of hypotension or safety 
concern requiring medication changes) will be excluded from this population. 
c. Per-Protocol (PP): All randomized subjects, meeting the following criteria: 
1. Subjects showing medication compliance in blood and/or urine (via drug testing 
data) at SV2, 3-months, and 6-months 
 
2. Exclude subjects with protocol deviation code 101 (consent not obtained) 
3. Exclude subjects who do not meet the following Inclusion 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 L7.  
 
• 
Inclusion: Individual has a 24-hour ABPM average SBP ≥140 and < 170 
mmHg measured at Screening Visit 2, according to guidelines in 
Appendix L7. 
 
4.  Exclude subjects who meet the following Exclusion criteria 
• 
Exclusion: Individual has undergone prior renal denervation 
• 
Exclusion: Individual has renal artery anatomy that is ineligible for 
treatment 
5. Exclude subjects meeting the antihypertensive medication escape criteria 
(Office SBP>180 OR <115 associated with symptoms of hypotension or safety 
concern requiring medication changes).  
6. Exclude subjects who did not receive the treatment they were randomized to. 
d. As Treated Population: All randomized subjects, analyzed according to the actual 
treatment received. Subjects randomized to RDN who do not get treated will be 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 82 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
analyzed in the control arm. Subjects who meet the anti-hypertensive medication 
escape criteria will be analyzed using Last Observation Carried Forward (LOCF) for 
their blood pressure measurements. 
H.2 Primary Safety Objective 
Medtronic is using a performance goal approach to analyze the primary safety endpoint as 
defined in section C.2.1. The safety performance goal for the Major Adverse Event (MAE) rate 
was developed based on review of and comparison to event rates of other renal interventions. 
The reported events differed among the studies; however, for a subset of these studies, we 
could estimate rates for a composite of events similar to our protocol’s MAE composite. The 
major adverse event rate from these studies was 7.1% which will be used as the performance 
goal for the primary safety endpoint. Additional details on the performance goal calculation can 
be found in the SAP.  
The primary safety null and alternative hypotheses are: 
H0: π ≥ 7.1% vs.  
Ha: π < 7.1% 
where π is the MAE rate for patients undergoing renal denervation. Under the assumption that 
the true rate is 3.5%, and using a one-sided 0.05 level of significance, an evaluable sample size 
of 253 renal denervation patients yields 80% power to reject the null hypothesis in favor of the 
alternative. The exact binomial test was used for the sample size calculation for the primary 
safety endpoint hypothesis.   
 
In other words, the primary safety endpoint hypotheses is designed to show whether the true 
MAE rate is lower than 7.1%. Compared to the literature reported event rates for renal 
intervention, it is believed that these thresholds are appropriate for demonstrating safety of the 
device given the expected performance rates of similar renal intervention trials, particularly when 
balanced with the expected blood pressure reductions.  
 
Medtronic proposes multiple sources of study patients as shown in Table 8 below to ensure 253 
patients treated with the Symplicity Spyral catheter (including branch treatment) are available for 
analysis. The first consecutively enrolled 253 subjects with evaluable safety data from the 
sources in Table 8 will be used to perform the primary safety endpoint analysis.  
 
With a sample size of 253 and a one-sided significance level of 0.05, a maximum of 11 subjects 
with MAE will enable us to meet the safety primary endpoint, resulting in an event rate of 4.3% 
with a one-sided 95% upper confidence bound of 7.09% using the exact binomial method.  The 
primary safety endpoint analysis will only be performed once using the first 253 subjects as 
detailed in this section. We will continue to report safety outcomes for all study subjects under 
secondary safety objectives 
Table 8: Study Sources of Patients for Primary Safety Endpoint Data 
Study 
SPYRAL HTN-OFF MED (First 80 Subjects) 
Randomized 1:1 to RDN:Control 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 83 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
SPYRAL PIVOTAL – SPYRAL HTN-OFF 
MED 
Randomized 1:1 to RDN:Control 
SPYRAL HTN-ON MED (First 106 Subjects) 
Randomized 1:1 to RDN:Control 
SPYRAL HTN ON MED Extension 
Randomized 2:1 to RDN:Control 
SPYRAL HTN-OFF MED Crossovers 
(from first 80 subjects and Pivotal) 
SPYRAL HTN-ON MED Crossovers 
 
H.3 Secondary Safety Objectives 
The secondary safety endpoints defined in section C.2.2. will be analyzed as follows: 
All the safety endpoints will be adjudicated by the Clinical Events Committee (CEC). The following 
algorithm will be used to evaluate the safety event rates: The denominator will include all subjects 
who either had a CEC adjudicated event prior to the time of interest (180 days for 6 months 
events, for example), or had last contact date that is beyond the lower window of the follow up 
(166 days for 6-month events, for example).  The numerator will include all subjects who had 
CEC adjudicated events up to the time of interest (180 days for 6 months events, for example).  
RDN vs. control arms will be compared out to 6-months post randomization prior to the crossover 
procedure. Fisher’s exact test will be used to perform statistical comparisons between the 
randomized groups. 
RDN vs. Crossover vs. Non-Crossover groups will be compared out to 36 months post-procedure 
for the RDN, Non-Crossover groups and Crossover groups using chi-square tests for categorical 
data and ANOVA for continuous data. 
The secondary safety analyses will be performed using the ITT population defined in H1. 
H.3.1 
Renal Artery Stenosis Evaluation at 12 Months 
With the expected rate of 3.1% for stenosis at 12 months41, a sample size of 50 subjects will 
provide a 95% confidence interval of approximately (0.5%, 13.7%) using the exact method 
(calculated using an event rate of 2/50=4%).  
Descriptive statistics of this endpoint at 12 months will be provided using counts, percentages 
and the 95% confidence interval.  
H.4 Primary Efficacy Objective 
The primary efficacy endpoint of the study is the baseline adjusted (analysis of 
covariance/ANCOVA) change in SBP from baseline (screening visit 2) to 6-months post-
procedure as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). 
In the context of an ANCOVA linear regression model, 𝜇𝜇= 𝜇𝜇𝑡𝑡−𝜇𝜇𝑐𝑐  represents the baseline-
adjusted treatment effect of BP change comparing test and control groups where 𝜇𝜇𝑡𝑡 and 𝜇𝜇𝑐𝑐 are 
the baseline adjusted BP changes in the denervation and control arms respectively. Let 𝑦𝑦=
{𝑦𝑦𝑡𝑡, 𝑦𝑦𝑐𝑐} and 𝑦𝑦0 = {𝑦𝑦0𝑡𝑡, 𝑦𝑦0𝑐𝑐} represent the current data and historical data respectively, where 𝑡𝑡= 
test group and 𝑐𝑐= control group. Let the hypotheses for the study be the following:  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 84 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
𝐻𝐻0: 𝜇𝜇 = 0 
𝐻𝐻𝑎𝑎: 𝜇𝜇 < 0 
We reject 𝐻𝐻0 if the probability of 𝐻𝐻𝑎𝑎 is greater than  97.5%, i.e. 
𝑃𝑃(𝜇𝜇< 0|𝑦𝑦, 𝑦𝑦0, 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) ) > 0.975 
where the notation 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘)   is used to denote that the estimate of 𝛼𝛼0
ෞ depends on the 
current data, the prior data, the Weibull shape and scale parameters. In conjunction with a pre-
specified decision rule controlling the prior data weight, the estimate of 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘)  represents 
a measure of similarity between current and prior data. Alternatively, in the absence of 
𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) i.e., 𝑃𝑃(𝜇𝜇< 0|𝑦𝑦, 𝑦𝑦0), full weight would be given to the prior data. 
The power prior discount function approach is used to estimate 𝜇𝜇, and determine 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) , 
the strength of the historical data used to estimate 𝜇𝜇. 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘)   ranges from 0 to 1, where 1 
means that 100% of the historical data is used and 0 means that no historical data is used. Before 
beginning the study, an initial value is chosen for 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) , call this value 𝛼𝛼𝑚𝑚𝑚𝑚𝑚𝑚. This 𝛼𝛼𝑚𝑚𝑚𝑚𝑚𝑚 
value is the maximum strength the historical data can receive. We intend to use the same 
enrollment criteria for the prior and prospective studies, and therefore believe that a value of 
𝛼𝛼𝑚𝑚𝑚𝑚𝑚𝑚= 1 is appropriate.  
At interim looks and at the final analysis, we analyze the data using the power prior discount 
function method, this method will discount 𝛼𝛼𝑚𝑚𝑚𝑚𝑚𝑚 to an appropriate value 𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) where 
𝛼𝛼0
ෞ(𝑦𝑦, 𝑦𝑦0, 𝜆𝜆, 𝑘𝑘) ≤𝛼𝛼𝑚𝑚𝑚𝑚𝑚𝑚. This discounting is based on the discount function which is discussed in 
more detail in the SAP. Under the adaptive procedure, if the current data diverges from the 
historical data at an interim look, the discount function will discount the strength of the historical 
data, thus requiring continued enrollment to maintain power to achieve the endpoint. 
Alternatively, if the historical and current data agree, there will be a smaller penalty from the 
discount function, thus fewer prospective patients would be needed to maintain power, and 
enrollment may stop early.   
The ITT population defined in section H1 will be used as the primary analysis population for this 
endpoint. Secondary effectiveness analyses will also be performed using the modified ITT  per-
protocol and as- treated populations. 
H.4.1 
Primary Efficacy Endpoint Operating Characteristics 
Simulations were performed to assess operating characteristics for the primary efficacy endpoint 
and are presented in the two tables below. Eight thousand trial simulations were used to estimate 
the power and 15000 simulations to estimate the type I error. The overall power for the primary 
efficacy endpoint from Table 10 is 96%, with a one-sided type I error rate of 0.038. 
Table 9: Simulation Parameters for Primary Efficacy Endpoint 
Prior Baseline Adjusted Treatment Arm Mean/SE 
-8.85 / 1.75 mmHg 
Prior Treatment Arm N 
36 
Prior Baseline Adjusted Control Arm Mean/SE 
-1.80 / 1.75 mmHg 
Prior Control Arm N 
36 
Maximum Prior Patients 
36 + 36 = 72 
Prospective Study Expected Treatment Difference 
5.0 mmHg 
Prospective Study Treatment Arm Mean/SD 
-6.8 / 12 mmHg 
Prospective Study Control Arm Mean/SD 
-1.8 / 12 mmHg 
Weibull Discount Function Parameters 
Shape: 𝑘𝑘= 3, Scale: 𝜆𝜆= 0.25 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 85 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
Table 10: Study Operating Characteristics for Primary Efficacy Endpoint 
Trial Success Rate (Power) 
96% 
Type I Error 
0.038 
First Interim Look N 
N=110 evaluable (130 
randomized) 
Power at First Interim Look 
83% 
Second Interim Look N 
N=149 evaluable (175 
randomized) 
Power at Second Interim Look 
91% 
Maximum Study Size 
N=221 evaluable (260 
randomized) 
% of Simulations that Stop for Futility  
1.71% 
H.5 Secondary Efficacy Objectives 
The secondary efficacy endpoints defined in section C.2.2. will be analyzed as follows: 
RDN vs. control arms will be compared out to 6-months post randomization, prior to the crossover 
procedure. Statistical comparisons will be performed using t-tests for continuous endpoints and 
Fisher’s exact test for categorical endpoints. In addition, two-sided 95% confidence intervals of 
the difference between RDN and control arms will be presented.  
RDN vs. Crossover vs. Non-Crossover groups will be compared out to 36 months post-procedure 
for the RDN, Non-Crossover groups and Crossover groups using chi-square tests for categorical 
data and ANOVA for continuous data. 
Changes in blood pressure measurements from baseline to follow-up within each treatment group 
will be assessed using paired t-tests. Two-sided 95% confidence intervals of the mean change 
from baseline will be presented for each treatment group.  
Analysis of Covariance (ANCOVA) models, adjusting the treatment effect for the baseline BP 
measurements will also be applied to all continuous secondary endpoints. 
The secondary efficacy analyses will be presented for all the study populations defined in 
section H1. 
H.6 Additional Objectives 
The following additional analyses will be conducted: 
• 
Quality of Life (QOL) EQ-5D measures. 
• 
Antihypertensive medication usage throughout the study, including escape patients and 
subjects with medication changes within 6-month follow-up.  
• 
Additional procedural characteristics e.g. treatment duration, frequency of distal renal artery 
treatment, ablations per vessel, location of ablations, number of ablations per patient and other 
characteristics will be analyzed to assess their impact on blood pressure. 
• 
Medication adherence will be assessed using results from drug testing. In addition, we will 
perform analyses to evaluate the effect of medications adherence on BP. 
• 
Analyses looking at long term imaging will be performed. 
• 
COVID-19 - In accordance with FDA guidance document “FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Pandemic” [8], we will perform additional analyses 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 86 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
to assess the effect of the COVID-19 pandemic on the study outcomes as described in the 
statistical analysis plan. 
RDN vs. control arms will be compared out to 6-months post randomization, prior to the crossover 
procedure. Statistical comparisons will be performed using t-tests for continuous endpoints and 
Fisher’s exact test for categorical endpoints. In addition, two-sided 95% confidence intervals of 
the difference between RDN and control arms will be presented. 
RDN vs. Crossover vs. Non-Crossover groups will be compared out to 36 months post-procedure 
for the RDN, Non-Crossover groups and Crossover groups using chi-square tests for categorical 
data and ANOVA for continuous data.  
Changes in blood pressure measurements from baseline to follow-up within each group will be 
assessed using paired t-tests. Two-sided 95% confidence intervals of the mean change from 
baseline will also be presented for each group. 
These additional analyses will be presented for the ITT study population defined in section H1. 
H.7 
Safety Evaluation  
Adverse Event (AE) information will be collected by the site from subject enrollment (consent) 
through study termination. 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. 
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 or not 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.  
 
H.8 
Subgroup Analyses 
Analysis will be carried out for the following subgroups to assess consistency of results: 
• 
Female vs. male gender 
• 
Age at baseline <65 vs. ≥ 65 years 
• 
BMI by tertiles (kg/m2) 
• 
Type 2 diabetics vs. non-diabetics 
• 
Current smokers vs. former smokers vs non-smokers 
• 
Baseline eGFR <60 vs. ≥60 mL/min/1.73 m2 
• 
Obstructive sleep apnea yes vs. no 
• 
US vs. OUS subjects 
• 
US African American vs. US non-African American subjects 
• 
OUS European vs. Japanese vs. Australian subjects 
• 
Baseline ambulatory SBP by tertiles and medians (mmHg) 
• 
Baseline office SBP by tertiles and medians (mmHg) 
• 
Baseline ambulatory heart rate by tertiles and medians (bpm) 
• 
Baseline office heart rate by tertiles and medians (bpm) 
• 
24-Hour Pulse Pressure <60 vs. ≥60 mmHg (mmHg) 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 87 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Orthostatic hypertension at baseline yes vs. no 
• 
Orthostatic tachycardia at baseline yes vs. no 
• 
Baseline plasma renin activity <0.65 vs. ≥0.65 (ng/mL/h) 
• 
Baseline aldosterone-renin ratio by tertiles 
• 
Baseline aldosterone by tertiles (ng/dL) 
• 
Number of ablations performed by tertiles (RDN arm only) 
• 
Total number of ablations performed in branch vessels by tertiles (RDN arm only) 
• 
Total number of ablations performed in main renal artery vessels by tertiles (RDN arm 
only) 
• 
Total number of 45 second ablations performed by tertiles (RDN arm only) 
• 
Medication adherent vs. non-adherent subjects at screening visit 2 and 6 months (from 
urine and serum tests) 
H.9 Publication Policy 
Medtronic may form a Publications Review Committee. Member(s) of the Publications Review 
Committee may include, but are not limited to, the Steering Committee, the Medtronic Clinical Study 
Manager or Publication Manager, and other Medtronic personnel.   
Participating investigators and members of the Steering Committee 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 
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 guidelines21 and GPP2 guidelines22 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. 
I 
STUDY MANAGEMENT 
I.1 
Study staff 
A list of sponsor staff (including sponsor’s medical expert(s)), suppliers, and core laboratories for this 
trial along with their contact information (i.e., name, title, address, and telephone number(s)) will be 
provided separately and will be maintained within the study files at each site. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 88 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
I.2 
Advisory committees 
I.2.1 
Executive Steering Committee 
The Executive Steering Committee is comprised of the Study Coordinating Investigators and selected 
members of Medtronic. Additional individuals may be consulted as appropriate. The main 
responsibilities of the Executive Steering Committee are to provide oversight and general guidance for 
the global study design and execution, to define the primary publication plan, and to prioritize publication 
requests and approvals. 
The Executive Steering Committee will meet periodically by teleconference and in-person to discuss 
patient enrollment and clinical site progress, as well as generally assist sites with the successful conduct 
of the study. The Executive Steering Committee will be responsible for reviewing the final results, 
determining the methods of presentation and publication, and selection of secondary projects and 
publications. 
I.2.2 
Data Safety Monitoring Board (DSMB) 
The primary responsibility of the Data Safety Monitoring Board (DSMB) is to monitor the health, safety 
and welfare of patients. 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 patients 
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. 
I.2.3 
Clinical Events Committee (CEC) 
The primary responsibilities of the Clinical Events Committee (CEC) 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. The members of the CEC will not be 
investigators in the study or members of the DSMB and will be independent of Medtronic.  
During the first CEC meeting guidelines for the AE adjudication process will be established. Additional 
details on the definitions utilized for adjudication, the adjudication process as well as reporting of 
outcomes will be provided in the CEC Charter. The proceedings of each CEC meeting will be recorded 
in minutes.  
Medtronic personnel may attend the meetings to answer questions but will not have a vote in 
determining the committee’s recommendations. The Medtronic Safety Department will identify safety 
events meeting criteria for review by the CEC. They will provide this information based upon the 
established rules of the CEC. The CEC will meet regularly to review and adjudicate all events for which 
the required minimum data are available. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 89 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
I.2.4 
Publications Review Committee 
Member(s) of the Publications Review Committee may include, but are not limited to, the Executive 
Steering Committee, the Medtronic Clinical Study Manager or Publication Manager, and other 
Medtronic personnel. As this committee represents the Medtronic Global Renal Denervation Program 
and may not be study-specific, there is no specific timeframe for this committee to disband. See Section 
H.9 Publication Policy for details on the activities of this committee. 
I.3 
Records and reports 
I.3.1 
Investigator records 
At a minimum, the following records must be kept by the investigator:  
• 
Medtronic and EC/IRB Clinical Investigation Plan 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 or letter of regulatory compliance 
• 
Any reports to EC/IRB and regulatory authority 
• 
Source documentation 
• 
Subject Identification log 
• 
Subject Enrollment log 
• 
Normal values or ranges for lab tests 
• 
Laboratory certificates 
• 
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 
• 
Completed Delegated Task List and Curriculum Vitae of all investigation site personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Subject screening log and/or subject identification log  
• 
Signed, dated and fully executed Patient Information and Informed Consent Form 
• 
Fully executed eCRFs and corrections 
• 
Reports of Adverse Events and Device Deficiencies 
• 
Device accountability records 
• 
Randomization list and randomization forms 
• 
List of investigational sites 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 90 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
Statistician analysis and clinical investigation report (final report) 
• 
Any other records that may be required by hospital regulations or local law 
I.3.2 
Investigator reporting responsibilities 
Report 
Submitted to 
Description 
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 5 working 
days of the investigator’s part of the investigation. 
Final Clinical Study 
Report 
EC/IRB (all sites), 
Sponsor (US sites) 
A copy of the Final Clinical Study Report will be 
provided to the EC/IRB. The report will be 
submitted to the local EC/IRB in accordance with 
the EC/IRB policies and procedures. 
In the US, the final report must be submitted to 
the Sponsor within 3 months after termination or 
completion of the investigation or the 
investigator’s part of the investigation. 
• 
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.    
Deviations from Clinical Investigational Plan 
Emergency Use 
Sponsor, EC/IRB, 
regulatory authority, 
as applicable by local 
regulations 
Investigator will report deviation as soon as 
possible to the sponsor and EC/IRB. 
Planned deviation 
Sponsor, EC/IRB, 
regulatory authority, 
as applicable by local 
regulations 
Prior approval 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 regulatory authority. 
Other Deviations 
Sponsor 
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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 91 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
I.3.3 
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 
• 
Curriculum Vitae of investigators and investigational site personnel 
• 
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 or letter of regulatory compliance 
• 
Normal values or ranges for laboratory test 
• 
Documentation for equipment maintenance and calibration 
• 
Laboratory certificates 
• 
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 and clinical-investigation related documents 
and materials 
• 
Sample of approved Patient Informed Consent Forms 
• 
Site visit reports  
• 
Adverse event and Device Deficiency reports 
• 
Financial disclosure information 
• 
Fully executed CRFs and corrections 
• 
Randomization list and randomization forms 
I.3.4 
Sponsor reporting responsibilities 
Report 
Submit to 
Description 
Withdrawal of EC/IRB 
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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 92 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Report 
Submit to 
Description 
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. 
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. 
Emergency 
Deviations from 
Clinical 
Investigational Plan 
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. 
I.3.5 
Record retention  
The investigator must retain the Investigator Site File, patient medical files and CRFs in accordance 
with local law and regulations for a minimum period of 2 year (or longer if local laws require) after study 
closure in his/her region. The investigator should take measures to prevent accidental or early 
destruction of the clinical study related materials. 
In Japan, investigational sites must retain all study-related documents until the later date of the time 
points below: 
• 
Day of marketing approval of the investigational device (day 3 years from the date of the 
decision to discontinue development when notification that development will be 
discontinued pursuant to the provisions of the J-GCP Ordinance has been received) 
• 
3 years from the date of termination or closure of the clinical study 
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 in accordance with J-
GCP and Medtronic policy. 
I.4 
Miscellaneous 
I.4.1 
Insurance 
Medtronic, Inc. (including all wholly owned subsidiaries) maintains appropriate clinical trial 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 Trial Insurance 
statement/certificate will be provided to the EC/IRB. 
I.4.2 
Subject compensation and indemnification 
Subjects will not receive any compensation for their participation in this study. Medtronic will provide 
subject indemnification according to local laws where this study will be conducted and as outlined in the 
Clinical Trial Agreement. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 93 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
I.4.3 
Subject confidentiality 
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 SID and an individual patient. 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.  
In the United States, “Protected Health Information” (PHI) will be maintained in compliance with the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). To maintain confidentiality, the 
subject’s name or any other PHI should not be recorded on any study document other than the informed 
consent form, as required by EN ISO5840: 2009. This scenario will be covered in the Patient 
Information-Informed Consent Form. In the event a subject’s name/PHI is included for any reason, it 
will be blinded as applicable. In the event of inability to blind the identification (e.g., digital media), it will 
be handled in a confidential manner by the authorized personnel.  
In geographies outside the United States, investigational sites will protect the personal information of 
subjects in accordance with national, local and 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 is treated as confidential and that the subject’s privacy is guaranteed. No identifiable 
subject information will be published. 
J 
RISKS AND BENEFITS 
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 patients 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 studies 
23,24, with large individual patient 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, patients 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 patient 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 patients, physicians and the health system.  
J.1 
Anticipated Clinical 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 
SpyralTM multi-electrode renal denervation catheter and the Symplicity G3TM renal denervation RF 
generator may reduce the nerve activity to and from the kidneys, and cause a reduction in blood 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 94 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
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 patients 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 patients with either severe hypertension or heart failure25. Interference of afferent nerve 
activity from the kidneys can reduce central sympathetic activity, also causing reduction of blood 
pressure.  
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 patients 
with heart failure.26-30     
 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. 31 
Reduction of central sympathetic activity may also reduce resistance to the action of insulin – potentially 
improving glycemic control.32,33  
There are no guaranteed benefits from participation in the study. 
J.2 
Risks 
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): 
• 
Death – a complication or deterioration of health ultimately leading to a patient’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:  
o 
Pain – discomfort at the catheter insertion site that can range from mild to severe. 
o 
Hematoma/Bruising – a collection of blood in the tissue surrounding the catheter 
insertion site. 
o 
Pseudoaneurysm – a collection of blood in the tissue surrounding the catheter 
insertion site due to ongoing leaking of blood from a blood vessel. 
o 
AV fistula – an abnormal connection between an artery and a vein (i.e., caused by 
needle insertion through the femoral artery and vein). 
o 
Infection – localized redness, heat swelling and pain at the catheter insertion site, 
o 
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. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 95 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
• 
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 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.  
• 
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 6 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 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 96 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
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. 
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 magnetic resonance imaging (MRA) or 
computerized tomographic angiography (CTA). The risks of undergoing an MRA include: medication 
patches can cause a skin burn, claustrophobia from being enclosed within the MRA magnet, and allergic 
reaction to the contrast material (if used). The presence of implanted metal devices may be a 
contraindication to undergoing MRA due to heating, movement, or disruption of programming of 
electronic devices. Nephrogenic systemic fibrosis (NSF) may occur when Gadolinium is administered 
to subjects with reduced eGFR. 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 
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. 
J.3 
Minimization of Risk 
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 clinical 
investigation plan: 
1. 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 patient management and monitoring, Symplicity SpyralTM catheter delivery 
and RF ablation, and post-procedural care. 
2. Instructions for Use are provided with each Symplicity SpyralTM catheter and a User’s 
Manual is provided with each Symplicity G3TM generator to ensure consistent use of the 
device within pre-tested parameters. 
3. The system’s design and software include several safety mechanisms to reduce risk to the 
patient (limitations on temperature, time, impedance, and power delivered to the subject). 
4. Subjects will be closely monitored by appropriately trained personnel during the procedure 
and at regularly scheduled intervals for the duration of the study. 
5. Physicians will employ usual and customary clinical technique (e.g., sterile technique 
during catheter use and aseptic wound care procedures).  

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 97 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
6. A Data Safety Monitoring Board (DSMB) will be established to monitor the health, safety 
and welfare of patients 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. 
J.4 
Risk-to-Benefit Rationale 
The detrimental effects of uncontrolled hypertension are well established, and an alternative treatment 
is worth investigation. Renal denervation using the Symplicity SpyralTM 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. 
K REFERENCES 
1. 
Charkoudian N, Rabbitts JA. Sympathetic neural mechanisms in human cardiovascular 
health and disease. Mayo Clin Proc. 2009;84:822-830 
2. 
Joles JA. Koomans HA. Causes and consequences of increased sympathetic activity in 
renal disease. Hypertension. 2004;43:699-706 
3. 
Mancia G, Grassi G, Giannattasio, Seravalle G. Sympathetic activation in the pathogenesis 
of hypertension and progression of organ damage. Hypertension. 1999;34:724-728 
4. 
Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton 
A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic 
denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort 
study. Lancet. 2009;373:1275-1281 
5. 
Coruzzi P, Musiari L, Mossini GL, Ceriati R, Mutti A. The renin-aldosterone system and renal 
function in kidney transplantation. Clin Nephrol. 1994;41:225-229 
6. 
Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant 
hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 
2011;57:911-917 
7. 
Symplicity HTN-2 Investigators , Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder 
RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant 
hypertension (the Symplicity HTN-2 study): A randomised controlled study. Lancet. 
2010;376:1903-1909 
8. 
Krum H, Schlaich MP, Böhm M, Sobotka PA, Mahfoud F, Rocha-Singh K, Katholi R, Esler 
MD. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 
3-year report of the Symplicity HTN-1 study. Lancet. 2014;383:622–629. 
9. 
Esler MD, Böhm M, Sievert H, Rump CL, Schmieder RE, Krum H, Mahfoud F, Schlaich MP. 
Catheter-based renal denervation for treatment of patients with treatment-resistant 
hypertension: 36 month results from the Symplicity HTN-2 randomized controlled study. Eur 
Heart J. 2014;35:1752–1759. 
10. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, 
Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; 
SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant 
hypertension. N Engl J Med. 2014;370:1393-1401. 
11. Bakris GL, Townsend RR, Flack JM, et al. SYMPLICITY HTN-3 Outcomes: Results at 
Twelve Months. J Am Coll Cardiol 2015 in press. 
12. Böhm M, Mahfoud F, Ukena C et al. The First Report of the Global SYMPLICITY Registry 
on the effect of Renal Artery Denervation in Patients with Uncontrolled Hypertension. 
Hypertension 2015 in press.  
13. Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, Ewen S, Tsioufis 
K, Tousoulis D, Sharp AS, Watkinson AF. 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 Aug 
28. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 98 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
14. Walton, T. Renal artery denervation with a new simultaneous multielectrode catheter for 
treatment of resistant hypertension: 6-month safety results from the SYMPLICITY Spyral 
First-in-Man Study. Abstract presented at: EuroPCR conference; 2014; Paris, France 2014 
15. Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler DR, Kolodgie FD, Virmani R, 
Joner M. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll 
Cardiol. 2014;19;64:635-643 
16. Tzafriri AR, Mahfoud F, Keating JH, Markham PM, Spognardi A, Wong G, Fuimaono K, 
Böhm M, Edelman ER. Innervation patterns may limit response to endovascular renal 
denervation. J Am Coll Cardiol. 2014;64:1079-1087 
17. Mahfoud F, Edelman ER, Böhm M. Catheter-based renal denervation is no simple matter. 
lessons to be learned from our anatomy? J Am Coll Cardiol. 2014;64:644-646 
18. Pekarskiy S, Baev A, Mordovin V, Ripp T, Semke G, Sitkova E, Krylov A, Popov S.  Low 
efficacy of renal denervation as a result of anatomically inadequate operative technique 
Moderated poster presented at: European Society of Cardiology (ESC) Conference; 2014; 
Barcelona, Spain 2014. 
19. Plehn A. First experience with a new renal denervation device and technology: the Spyral 
device. Confluence 8, 2014 
20. White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, Kupfer S. Effects of the 
angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on 
ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. 
Hypertension. 2011;57:413–420 
21. “Recommendations.” ICMJE | Recommendations, www.icmje.org/recommendations/ 
22.  “GPP2.” The International Society for Medical Publication Professionals, 
www.ismpp.org/gpp2. 
23. Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA, Roccella EJ, Stout R, Vallbona 
C, Winston MC, Karimbakas J; National High Blood Pressure Education Program 
Coordinating Committee. Primary prevention of hypertension: clinical and public health 
advisory from The National High Blood Pressure Education Program. JAMA 2002; 
288:1882-1888 
24. Law MR, Morris JK, Wald NJ. Use of Blood Pressure Lowering Drugs in the Prevention of 
Cardiovascular Disease: Meta-analysis of 147 Randomised Studies in the Context of 
Expectations from Prospective Epidemiological Studies. BMJ. 2009;338:b1665 
25. 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 
26. 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 
27. 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 
28. 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 V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation. 
1993;87:VI40-48 
29. 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 
30. 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 
31. Brandt Mathias C, Mahfoud F, Reda S, Schirmer Stephan H, Erdmann E, Bohm M, Hoppe 
Uta C. 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 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 99 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
32. 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;123:1940-1946 
33. Witkowski A, Prejbisz A, Florczak E, Kadziela J, Śliwinski P, Bieleń P, Michałowska I, Kabat 
M, Warchoł 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. 
34. Medtronic Internal data. 
35. Calhoun, et al. “Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific 
Statement From the American Heart Association Professional Education Committee of the 
Council for High Blood Pressure Research.” Circulation. 2008; 117;e510-e526. 
36. http://mdic.org/computer-modeling/virtual-patients/ 
37. T. Haddad, A. Himes, L. Thompson, T. Irony, R. Nair, " Incorporation of stochastic 
engineering models as prior information in Bayesian medical device trials", Journal of 
Biopharmaceutical Statistics, (2017) DOI: 10.1080/10543406.2017.1300907 
38. J. G. Ibrahim and M.-H. Chen, "Power prior distributions for regression models," Statistical 
Science, (2000), 15(1) 46-60. 
39. A. Gelman, J. Carlin, H. Stern and D. Rubin, Bayesian Data Analysis, Boca Raton: Chapman 
& Hall / CRC, 2004. 
40. Whitbourn R, Harding SA, Walton A. Symplicity multi-electrode radiofrequency renal 
denervation system feasibility study. EuroIntervention 2015; 11:104-109.  
41. Sanders, Margreet F., et al. "Renal artery and parenchymal changes after renal denervation: 
assessment by magnetic resonance angiography." European radiology 27.9 (2017): 3934-
3941. 
42. Kandzari DE, Böhm M, Mahfoud F, Townsend RR, Weber MA, Pocokc S, Tsioufis K, 
Tousoulis D, Choi JW, East C, Brar S, Cohen S, Fahy M, Pilcher G, Kauomi K. Effect of 
renal denervation on blood pressure in the presecent of antihypertenisve drugs: 6-month 
efficacy and safety results from the SPYRAL HTN-ON MED proof of concept reandomised 
trial. The Lancet. 2015 May 23: http://dx.doi.org/10.1016/ S0140-6736(18)30951-6 
43. Japanese Society of Hypertension Guidelines (JSH 2014), Hypertension Research (2014) 
37, 266–278. 
44. Franklin, S.S., Jacobs, M.J., Wong, N.D., L’Italien, G. J., Lapuerta, P.  Predominance of 
Isolated Systolic Hypertension Among Middle-Aged and Elderly US Hypertensives: Analysis 
Based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 
2001;37:869-874. 
45. Rapsomaniki, E., Timmis, A., George, J., Pujades-Rodriguez, M., Shah, A.D., Danaxas, S., 
White, I.R., Caulfield, M. J., Deanfield, J. E., Smeeth, L., Williams, B., Hingorani, A., 
Hemingway, H.  Blood pressure and incidence of twelve cardiovascular diseases: lifetime 
risks, healthy life-years lost, and age-specific associations in 1.25 million people.  Lancet. 
2014;383:1899-911. 
46. Townsend RR, Leonard CE, López de Nava K, et al. Utilization of antihypertensive drug 
classes among Medicare beneficiaries with hypertension, 2007–2009. Cardiovascular 
Issues. Data Points #8 (prepared by the University of Pennsylvania DEcIDE Center under 
contract no. HHSA29020050041I). Rockville, MD: Agency for Healthcare Research and 
Quality. 2011. AHRQ Publication No. 11-EHCO73-EF. 
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 100 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
L 
APPENDICES 
L.1 
Names and addresses 
L.1.1 
List of contact persons 
Coordinating investigators 
The following investigators will serve as Coordinating Investigators on the study: 
 
Professor Dr. Michael Böhm 
Universitätsklinikum des Saarlandes 
Kirrberger Strasse 1 
66421 Homburg 
Germany 
 
David Kandzari, MD 
Piedmont Hospital 
275 Collier Rd. NW, Suite 300 
Atlanta, Georgia 30309-1711 
United States 
 
Kazuomi Kario, MD 
Jichi Medical University Hospital 
3311-1 Yakushiji 
Shimotsuke, Tochigi, 329-0498 
Japan 
  
Raymond Townsend, MD 
University of Pennsylvania Medical Center 
210 White Building 
3400 Spruce Street 
Philadelphia, Pennsylvania 19104-5127 
United States 
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. 
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 
Clinical Investigation Plan 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 
Beth Israel 
Deaconess Medical 
Center, Inc.  
 
375 Longwood Avenue 
3rd Floor  
Boston, MA 02215  
USA  
 
Duane Pinto, MD 
Angiographic Core 
Laboratory 
The Angiographic Core 
Laboratory is responsible for 
review and analysis of 
angiographic renal imaging to 
assess renal artery stenosis. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 101 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Service Provider 
Contact Information 
Services 
Scope and Duties Entrusted 
ACM Global 
Laboratory  
160 Elmgrove Park  
Rochester, NY 14624 
USA   
Blood Core 
Laboratory  
Blood Core Lab is responsible 
for processing and analyzing test 
samples for renin and 
aldosterone. 
ICON Clinical 
Research 
2800 Kelly Road 
Suite 200 
Warrington, PA 18976 
USA  
Central 
Registration and 
Randomization 
Center 
The Central Registration and 
Randomization Center will be 
responsible for developing and 
maintaining the randomization 
system for the study.  
Cardiovascular 
Research 
Foundation (CRF) 
1700 Broadway 
Floor 9 
New York, NY 10019 
USA  
 
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 
patients. 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 
 
Prof. Dr. Markus R. Meyer 
Drug Adherence 
Core Laboratory 
Drug Adherence Core 
Laboratory is responsible for 
processing and analyzing plasma 
and urine test samples to confirm 
the absence or presence of 
antihypertensive medications.  
Medidata Solutions 
Inc. (formerly 
known as 
Intelemage) 
700 W. Pete Rose Way 
Suite 436 
Cincinnati, OH 45203 
USA 
Media (i.e., 
imaging and file) 
upload 
Provide platform to allow for the 
submission and management of 
files and study data/imaging 
studies. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 102 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Service Provider 
Contact Information 
Services 
Scope and Duties Entrusted 
Morristown Medical 
Center 
Cardiovascular Core Lab 
Morristown Medical 
Center 
100 Madison Avenue 
Morristown, NJ  07960 
 
Linda D. Gillam, MD, 
MPH, FACC, FAHA, 
FESC, FASE 
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.  
VasCore – The 
Vascular Ultrasound 
Core Laboratory  
 
The Vascular Ultrasound 
Core Laboratory 
1 Bowdoin Square 
Tenth Floor 
Boston, MA 02114 
USA 
 
Michael R. Jaff, D.O., 
RPVI  
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. 
Cytel 
460 Totten Pond Rd, Suite 
640, Waltham, MA 02451 
USA 
Statistical 
Programming and 
Data Analysis 
Independent statistical data 
analysis and validation 
 
L.1.2 
List of participating investigation sites and investigators 
A list of investigational sites and investigators will be provided separately. 
L.2 
Case Report Forms 
A copy of the Case Report Forms will be provided under a separate cover. 
L.3 
Sample Investigator Agreement 
A sample investigator Agreement will be provided under a separate cover 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 103 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
L.4 
Abbreviations 
4SQ 
4 simultaneous quadrantic 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACC 
American College of Cardiology 
ACE 
Angiotensin-converting-enzyme 
ACE-I 
Angiotensin-converting-enzyme inhibitors 
ACT 
Activated clotting time 
ADE 
Adverse Device Effect 
AE 
Adverse event 
AV 
Aortic Valve 
AF 
Atrial fibrillation 
ARB 
Angiotensin receptor blockers  
BP 
Blood pressure 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
CEC 
Clinical Events Committee 
CIN 
Contrast induced nephropathy  
CIP 
Clinical Investigation Plan 
CMS 
Center for Medicare and Medicaid Services 
CPAP 
Continuous positive airway pressure 
CRF 
Case Report Form 
CRO 
Clinical Research Organization  
CTA 
Computerized Tomographic Angiography 
CV 
Curriculum Vitae 
DBP 
Diastolic blood pressure 
DD 
Device Deficiency 
DSMB 
Data Safety Monitoring Board 
DUS 
Duplex Ultrasound 
DVI-D 
Digital Visual Interface 
EC 
Ethics Committee  
eGFR      estimated Glomerular Filtration Rate 
ESC 
European Society of Cardiology  
ESRD 
End-stage renal disease 
e-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FIM 
First in man 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 104 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
FMD 
Fibromuscular Dysplasia 
FU 
Follow up 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
hCG 
Human Chorionic Gonadotropin 
HDL 
High-density lipoprotein  
HIV 
Human immunodeficiency virus  
HOMI 
Head of Medical Institution 
HRED 
Human Research Ethics Committee 
hs-CRP High-sensitivity c-reactive protein 
HTN 
Hypertension 
IB  
Investigator Brochure 
ICD 
Implantable Cardioverter Defibrillator 
ICH-GCP International Conference on Harmonization – Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IFU 
Instructions for use 
IPG 
Implantable pulse generator 
IRB  
Institutional Review Board  
ISO 
International Organization for Standardization  
ITT 
Intent-to-treat 
J-GCP 
Japan Good Clinical Practices   
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MAE 
Major Adverse Event 
MDIC 
Medical Device Innovative Consortium 
MDRD 
Modification of Diet in Renal Disease 
MDT 
Medtronic 
MEC 
Medical Ethics Committee 
MI 
Myocardial infarction  
MRA 
Magnetic Resonance Angiography 
mSv 
millisieverts 
NSAIDs Non-steroidal anti-inflammatory drugs 
NSF 
Nephrogenic systemic fibrosis 
OBP 
Office Blood Pressure 
PCI 
Percutaneous Coronary Intervention 
PHI 
Protected Health Information   
PMDA 
Pharmaceuticals and Medical Devices Agency 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 105 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
PMR 
Post Market Release 
PP 
Per-Protocol 
PRBCs 
Packed red blood cells 
PXM 
Product Experience Management 
QA 
Quality Assurance 
QOL 
Quality of Life 
RCT 
Randomized Control Trial 
RDC 
Remote data capture 
RDN 
Renal Denervation 
REB 
Research Ethics Board 
RF 
Radiofrequency 
RX 
Rapid Exchange 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SBP 
Systolic Blood Pressure 
SID 
Subject Identification Number 
SNS 
Sympathetic nervous system 
SOP 
Standard operating procedure 
SV1 
Screening Visit 1 
SV2  
Screening Visit 2 
TGA 
Therapeutic Goods Administration 
TIA  
Transient Ischemic Attack 
TIMI 
Thrombolysis in Myocardial Infarction  
UADE 
Unanticipated adverse device effect 
USADE Unanticipated serious adverse device effect  
 
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 106 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
L.5 
Definitions 
Event definitions: 
• 
Major Adverse Events (MAE), defined as a composite of the following events, compared 
between groups: 
o All-cause mortality 
o End-stage Renal Disease (ESRD) – defined as two or more eGFR 
measurements <15 mL/min/1.73m2 at least 21 days apart and 
requiring dialysis for one of 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 
o 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) 
o Renal artery perforation requiring intervention  
o Renal artery dissection requiring intervention 
o Vascular complications (e.g., clinically significant groin hematoma, 
arteriovenous fistula, pseudoaneurysm, excessive bleeding) requiring 
surgical repair, interventional procedure, thrombin injection, or blood 
transfusion (requiring more than 2 units of packed red blood cells 
within any 24-hour period during the first 7 days post renal denervation 
procedure) 
o Hospitalization for hypertensive crisis not related to confirmed non-
adherence with medications. 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 hospitalization and typically admission to the Intensive Care 
Unit (ICU) (e.g., with parenteral [IV] antihypertensive medications), not 
related to confirmed non-adherence with medication 
o New renal artery stenosis >70%, confirmed by angiography by the 
angiographic core lab 
• 
Major bleeding according to TIMI definition (i.e. intracranial hemorrhage; ≥5g/dl 
decrease in hemoglobin concentration; a ≥15% absolute decrease in hematocrit, or 
death due to bleeding within 7 days of the procedure.) 
Estimated Glomerular Filtration Rate (eGFR) calculation method for Japanese:  eGFR (mL/min/1.73 
m2) = 194 x (sCr)－1.094 x (Age)－0.287  x (0.739 if Female) 
L.6 
Center for Medicare and Medicaid Services (CMS) IDE Study Criteria 
Generalizability to Medicare Beneficiaries 
The results of this study are expected to be generalizable to the Medicare population based on the 
incidences of uncontrolled hypertension and combined hypertension in patients ≥65 years old, as well 
as estimates of the number of elderly patients taking at least one class of antihypertensive 
medication. 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 107 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
The incidence of uncontrolled hypertension is strongly correlated with older age; in a cross-sectional 
analysis of data from the Framingham Heart Study, only 48% of treated participants had their blood 
pressure controlled to <140/90 mmHg.  Among elderly participants >75 years of age, fewer than 40% 
had achieved a goal blood pressure.   Framingham data also showed that older age was the strongest 
predictor of blood pressure being uncontrolled.35 
In an analysis of NHANES III data, approximately 13% of the untreated & inadequately treated (i.e., 
uncontrolled) hypertensive elderly population age 65 years or older were found to have combined 
systolic and diastolic hypertension (SBP ≥ 140mmHg, DBP ≥ 90mmHg).44  While the combined 
hypertensive population comprises a smaller percentage of elderly patients relative to isolated systolic 
hypertension, combined hypertension is associated with as many years of life lost to cardiovascular 
disease in elderly patients as with isolated systolic hypertension.45  Thus, the study of effective 
treatment of combined hypertension in elderly patients is expected to have relevance and benefit to 
the improvement of cardiovascular health of Medicare beneficiaries. 
 
 
Figure 13: Rapsomaniki, et al., 2014 
 
In a study of Medicare data between 2007 and 2009, Townsend et al reported that 87% to 88% of 
Medicare beneficiaries with hypertension used at least one prescription for an antihypertensive drug; 
as patient age increased, this percentage of Medicare beneficiaries increased (upwards to >89% for 
patients 85 years and over), along with the mean number of antihypertensive drug classes used by all 
hypertensive beneficiaries (from 1.8±1.3 to 2.0±1.2).46 Previous data from Symplicity HTN-3 showed 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 108 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
that, on average, patients in both the renal denervation and sham procedure arms were on 
approximately 5 antihypertensive medications at baseline measurement. Approximately 28% of 
patients enrolled were 65 years or older.34The results of this study are thus expected to be 
generalizable to the populations of Medicare beneficiaries with uncontrolled, combined hypertension 
and are prescribed at least one antihypertensive class of medication. 
L.7 
Blood Pressure Measurement Procedures  
 
1. OFFICE BLOOD PRESSURE 
 
ALL OFFICE BLOOD PRESSURE (OBP) MEASUREMENTS MUST BE TAKEN WITH THE AUTOMATIC BP 
MONITOR & PRINTER (IF APPLICABLE) AS SPECIFIED BY THE SPONSOR. 
 AT SCREENING VISIT 1, the appropriate arm for study measures must be selected as specified 
in section A below and then used for all subsequent follow-up visits. 
 FOR EACH STUDY VISIT, the study visit should begin before 10:30 am. This does not apply to 
Screening Visit 1 (if subject is consented at SV1) and Unscheduled follow-up visits.  
 PATIENT SHOULD NOT TAKE THEIR ANTIHYPERTENSIVE MEDICATION IN THE MORNING OF THE 
VISIT, BUT RATHER BRING THE MEDICATION WITH THEM TO THE VISIT TO HAVE OBSERVED PILL 
TAKING AFTER OFFICE BLOOD PRESSURE MEASUREMENT (OR HOLD OFF TAKING THEIR 
ANTIHYPERTENSIVE MEDICATION UNTIL THE OFFICE BLOOD PRESSURE MEASUREMENT IS 
COMPLETED IN THE CASE OF IN-HOME, VIRTUAL OR TELEPHONE VISITS). THE REQUIREMENT FOR 
NOT TAKING THE MEDICATION IN THE MORNING OF THE VISIT DOES NOT APPLY TO UNSCHEDULED 
VISITS, THE DISCHARGE VISIT OR SCREENING VISIT 1 IF THE SUBJECT SIGNED THE INFORMED 
CONSENT FORM AT SV1. 
 
A. ARM SELECTION AT SCREENING VISIT 1 ONLY 
(1) The subject visit should begin before 10:30 am unless the subject normally takes their 
antihypertensive medication in the afternoon in which the subject’s visit can occur in the 
afternoon. 
(2) With subject prepped per “Preparation” section below, measure BP in each arm. Ensure each 
measurement is captured/recorded and identifies on which arm the BP was measured. 
(3) Use the arm with the higher systolic BP for screening measurements and all subsequent 
measurements 
• 
If there is a reason to use a particular arm, document the reason and use that arm for 
all measures going forward. 
• 
In the event systolic BP is the same on both arms, the subject should choose the arm 
for all measures going forward. 
 
 
B. PREPARATION AT ALL VISITS 
(1) Ensure the BP monitor and all necessary equipment are functioning appropriately (per sponsor 
instructions). 
(2) Confirm the subject did not drink coffee or alcohol, smoke, or exercise within 30 minutes prior 
to the measurements. 
(3) Request the subject to use the bathroom prior to measurements (a full bladder can affect the 
reading). 
(4) The subject should be seated comfortably with the back supported and the upper arm bared 
with no clothing between arm and BP cuff. The legs should not be crossed. 
(5) Ensure that the BP cuff is appropriately sized (see Table 11) and that the upper arm is 
supported at the level of the heart (e.g. resting on a table at the level of his/her heart). The 
same cuff size should be used as selected at Screening Visit 1 for the remainder of the study.  
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 109 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
Table 11: BP Cuff Size Chart 
Cuff Size* 
Fits Arm Circumference of 
(inches) 
Fits Arm Circumference of 
(centimeters) 
Small 
7 – 9  
17 – 22 
Medium 
9 – 13 
22 – 32 
Medium-Large 
9 – 17  
22 – 42  
Large 
13 – 17  
32 – 42 
Extra-Large** 
17-20 
42 – 50 
* If a subject is on the border of two cuff sizes, opt for the larger of the two sizes 
** Subjects requiring greater than an extra-large cuff size at time of screening must be excluded from 
the study 
 
(6) Perform a “test” BP measure. Ensure test measurement is captured/recorded. 
(7) Have the subject sit comfortably and quietly for at least 5 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) 
C. METHOD FOR TAKING BP AT ALL VISITS 
(1) General Instructions  
a. With subject prepared per “Preparation” section above and using arm selected at 
Screening, take at least three (3) seated BP measurements in order to obtain the BP 
average. 
b. Wait at least 1 minute between each measurement. Ensure that the blood pressure 
monitor time clock is used for tracking the time intervals to avoid deviations due 
to insufficient wait time between measurements. 
c. Print (if available) and label after each measurement.  
(2) Three (3) consecutive, consistent seated BP measurements must be used to obtain the BP 
average. 
a. If the lowest and highest systolic BP (SBP) values of the first 3 consecutive measurements 
are >15 mm Hg apart, take one additional reading and average the last 3 consecutive 
measurements (measurements 2-4). If the measurements are still >15 mm Hg apart, take 
one additional reading and average the last 3 consecutive measurements (measurements 
3-5). If the measurements are still >15 mm Hg apart, take one final measurement and 
average the last 3 consecutive measurements (measurements 4-6). 
(3) At Screening Visit: If the lowest and highest SBP values for the readings are more than 20 
mm Hg apart after 6 measurements, the subject must be excluded from the study. 
(4) At all Subsequent Follow Up Visits: If the lowest and highest SBP values for the readings 
are more than 20 mm Hg apart after 6 measurements, take the average of the last three 
measurements (measurements 4 – 6) and record the value on the CRF. 
(5) Record the last 3 consecutive, consistent readings on the CRF (i.e. cannot pick the ‘best’ 3). 
NOTE: To better ensure long-term preservation of the OBP source data, a photocopy labeled as 
certified of all automatic BP Monitor printouts (if applicable) should be made and attached to the 
originals. If unable to print, document BP & HR values, dates and exact times of readings, and label 
appropriately. 
 
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 110 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
ORTHOSTATIC HYPOTENSION EVALUATION (AT SCREENING VISIT 2 ONLY) 
In addition to the seated OBP recordings above, measure supine and standing BPs.  
(1) Have the subject lie supine for at least 5 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. 
o 
Evaluate for any symptoms (e.g., dizziness) that may occur in the subject within the 
first 3 minutes after standing. 
 
2. AMBULATORY BLOOD PRESSURE MONITORING 
ALL 24-HOUR AMBULATORY BLOOD PRESSURE MONITORING (ABPM) MEASUREMENTS MUST BE 
TAKEN WITH THE 24-HOUR ABPM DEVICE PROVIDED BY THE SPONSOR TO ENSURE CONSISTENCY. 
 ALL PATIENTS MUST BE OBSERVED SWALLOWING THEIR ANTIHYPERTENSIVE MEDICATION PRIOR 
TO APPLYING THE ABPM DEVICE (OR VERBALLY CONFIRMED IN THE CASE OF A PHONE VISIT). 
 CUFF SIZE IDENTIFIED AT SCREENING VISIT 2 SHOULD BE USED FOR THE DURATION OF THE 
STUDY. 
  
(1) The subject office visit should begin before 10:30 am unless the subject normally takes their 
antihypertensive medication in the afternoon in which the subject’s visit can occur in the afternoon. 
(2) Study personnel should document pill identity and observe the subject swallowing the 
antihypertensive medication(s) (or verbally confirmed in the case of a phone visit). Once this is 
completed and documented, the ABPM device should be applied to the subject and the recording 
started before leaving the office. 
(3) Place cuff on the subject’s non-dominant arm.  
(4) Instruct the subject in proper cuff positioning in case they must remove it but stress the importance 
of leaving the BP cuff on. 
(5) The ABPM has pre-set parameters and should not be adjusted. These parameters are set to 
record blood pressure every 30 minutes.   
(6) Instruct subjects that they should engage in their usual physical level but should avoid 
strenuous exercise during the monitoring period 
(7) Instruct the subject to hold the arm still by the side while the device is taking a reading 
(8) Upon the return of the ABPM machine: 
o 
Submit the 24-Hour ABPM data to Medtronic 
o 
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.   At SV2, a single repeat ABPM will be allowed in case of the following: 
 
If the 24-hr systolic ABPM measured is between 135 and <140 mmHg or 170-
175 mmHg 
 
If a valid number of readings is not obtained 
 
If there is a technical issue with the blood pressure monitor or failure to follow 
ABPM guidelines. 
In all other instances at SV2, the ABPM will not be allowed to be repeated and the 
subject will be considered a screen failure.  
For all other time points with ABPM, make all efforts to obtain repeat ABPM from subject until the 
minimum number of readings is obtained.  
 
 
 
 

SPYRAL HTN-ON MED Clinical Investigation Plan  
 
 
 
Version 10.0 
Page 111 of 111 
 
Medtronic Confidential 
 
 
056-F275, v3.0 Clinical Investigation Plan Template 
L.8 
Sample Patient Information and Informed Consent Form 
Geography-specific informed consents will be provided separately. 
L.9 
Subject Blinding Assessment 
Assessment will be provided separately. 
L.10 EQ-5D (Quality of Life) Survey 
Geography-specific EQ-5D will be provided separately. 
L.11 ABPM Guidelines 
Guidelines will be provided separately. 
L.12 Serious or Unanticipated Adverse Event Report (Rush form) – Japan only  
Rush form only applies to Japan and will be provided separately. 
L.13 Angiographic Core Laboratory Guidelines 
Core Laboratory guidelines will be provided separately. 
L.14 Renal Duplex Ultrasound (DUS) Core Laboratory Guidelines  
Core Laboratory guidelines will be provided separately. 
L.15 Magnetic Resonance Angiographic (MRA) / Computerized Tomography 
(CT) Core Laboratory Guidelines  
Core Laboratory guidelines will be provided separately. 
L.16 Blood Core Laboratory Guidelines  
Blood Core Laboratory guidelines will be provided separately. 
L.17 Drug Testing Core Laboratory Guidelines 
Core Laboratory guidelines will be provided separately.