REmodeling the Left Ventricle With Atrial Modulated Pacing
Phase: NA
Conditions: Heart Failure
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

Signed By
Meaning of Signature
Date/Time (UTC)
APPROVALS
CONFIDENTIAL
  
DOCUMENT/RECORD 
 
 
This document/record is electronically controlled; printed copies are considered uncontrolled. 
System of Record: Regulatory Affairs Domain 
 
Document Name
Version
Title
Document Approver
Document Approver
Document Approver
05/03/2018 16:25:36
1.0
Document Approver
05/02/2018 13:57:27
Lande, Jeff
REVAMP Study Clean Version 3. 27APR2018 docx.pdf
Document Approver
Wallace, Kristie
05/03/2018 16:07:20
Chesness, Dana
05/01/2018 16:56:19
Berg, Melinda, RN
Jackson, Troy
Document Approver
Document Author
05/01/2018 17:51:00
Hannon, Cole
05/03/2018 15:40:01
Randall, Taryn
Heim, Jennifer
05/01/2018 16:59:14
05/01/2018 17:25:07
Document Approver
05/03/2018 17:21:02
Pieper, Karen
Document Approver
REVAMP Study Clean Version 3. 27APR2018 docx.pdf

 
056-F275, Version 2.0 
Global Form 
Clinical Investigation Plan Template  
 
Version 3.0 
REVAMP Clinical Investigation Plan 
 
27 APR 2018 
Medtronic Confidential 
 
 
 
Clinical Investigation Plan 
Clinical Investigation Plan/Study Title REVAMP Study (REmodeling the Left Ventricle 
with Atrial Modulated Pacing) 
Sponsor/Local Sponsor Medtronic, Inc. 
Cardiac Rhythm and Heart Failure Clinical 
Research 
8200 Coral Sea Street NE 
Mounds View, MN 55112 U.S.A.  
1-800-328-2518 
 
Document Version 3.0   27 APR 2018 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 

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Sponsor Contact 
Medtronic, Inc. is sponsoring the REVAMP Clinical Research Study. Regional contact information is 
provided below. This information may be subject to change during the course of the clinical study. 
Periodic updates to study contact information will be sent to sites as needed. 
Table 1: Study Sponsor Contact Information 
Study Contacts 
Clinical Study Leader  
 
Andrea DeRoche, Principal Clinical Research Specialist 
Direct Phone: (+1-508) 532-1965 
andrea.j.deroche@medtronic.com 
Study Monitors and Contacts 
Monitoring Leader 
 
Taryn Randall, Clinical Monitoring Manager 
Direct Phone: (+1-763) 250-0785  
Direct Fax: (+1-651) 367-0759 
taryn.randall@medtronic.com 
Sponsor’s Medical Expert 
Robert Kowal, VP Medical Affairs, CRHF 
 
8200 Coral Sea Street N.E., MVC42 
Mounds View, MN 55112 
United States 
Phone: (+1-763) 526-5705 
robert.kowal@medtronic.com 
 
 

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CROs/Core Laboratories 
This information may be subject to change during the course of the clinical study. Periodic updates to 
study contact information will be sent to sites as needed. 
Table 2: CRO and Core Laboratory Information 
Contact Information 
Role 
Cognizant Technology Solutions 
500 Frank W. Burr Blvd. 
Teaneck, NJ 07666 
United States 
Direct Phone: (201) 801-0233 
Direct Fax: (201) 801-0243 
Review of electronic case report forms and 
management of discrepancies 
Echocardiography Core Laboratory 
 
The Ohio State University 
1960 Kenny Road, Columbus, Ohio 43210 
Review of study echocardiograms 
Blood Core Laboratory 
 
ACM Global Central Laboratory 
160 Elmgrove Park | Rochester, NY 14624 
 
Review of blood samples 
 
 

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1.   Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document  
Nancy Bennett, Prin. Field Clinical 
Site Specialist 
Jeff Lande, Prin. Statistician  
Teri Whitman, Sr. Prinicipal 
Scientist 
Matt Zmijewski, Distinguished 
Field Clinical Engineer 
 
2.0 
• 
Refer to Appendix G Table 17 for detailed 
changes 
Andrea DeRoche, Prin. Clinical 
Research Specialist 
Teri Whitman, Sr. Prinicipal 
Scientist 
 
3.0 
• 
Refer to Appendix G Table 18 for detailed 
changes 
Melinda Berg, Prin Field Clinical 
Engineer 
Jeff Lande, Prin Statistician 
Kristie Wallace, Sr Statistician 
Troy Jackson, Sr Prin Scientist 
 
2.   Investigator Statement 
Investigators will be provided with a separate investigator agreement to document their obligation and 
commitment with respect to study conduct. 
 
 

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Table of Contents  
Table of Contents 
Sponsor Contact ................................................................................................................... 2 
CROs/Core Laboratories ..................................................................................................... 3 
1.   Version History ............................................................................................................... 4 
2.   Investigator Statement ......................................................................................................... 4 
Table of Contents ................................................................................................................. 5 
3.   Glossary .......................................................................................................................... 9 
4.   Synopsis ........................................................................................................................ 12 
5.   Introduction .................................................................................................................. 17 
5.1.   Background ......................................................................................................................... 17 
5.2.   Purpose ............................................................................................................................... 19 
6.    Objectives and Endpoints ............................................................................................ 20 
6.1   Objectives .................................................................................................................................. 20 
6.1.1.  Primary Objectives ....................................................................................................................................... 20 
6.1.2.  Ancillary/Exploratory Objectives .............................................................................................................. 20 
6.2.   Endpoints ................................................................................................................................. 20 
6.2.1.   Primary Endpoint ........................................................................................................................................ 20 
7.   Study Design ...................................................................................................................... 21 
7.1.   Duration ................................................................................................................................... 22 
7.2.   Rationale .................................................................................................................................. 22 
7.3.  Study Oversight ......................................................................................................................... 23 
8.   Product Description ........................................................................................................... 24 
8.1.   General ..................................................................................................................................... 24 
8.2.   Intended Population ................................................................................................................ 24 
8.3.   Study Components ................................................................................................................... 24 
8.4.   Product Use.............................................................................................................................. 24 
8.5.   Product Receipt and Tracking ................................................................................................. 25 
9.   Selection of Subjects .......................................................................................................... 25 
9.1.   Study Population ...................................................................................................................... 25 
9.2.   Subject Enrollment .................................................................................................................. 26 
9.3.   Inclusion Criteria ..................................................................................................................... 26 
9.4.   Exclusion Criteria .................................................................................................................... 26 
9.5.   Minimization of Bias ............................................................................................................... 27 
10.   Study Procedures .............................................................................................................. 27 
10.1.   Study Personnel Requirements ............................................................................................... 28 
10.2.   Role of the Sponsor Representative ........................................................................................ 28 
10.3.   Site Activation ......................................................................................................................... 28 
10.4.   Equipment Requirements ...................................................................................................... 29 
10.5.   Schedule of Events ................................................................................................................. 29 
10.6.   Prior and Concomitant Medications ...................................................................................... 32 

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10.7.   Subject Consent ...................................................................................................................... 32 
10.8.   Enrollment .............................................................................................................................. 34 
10.9.   Baseline Visit .......................................................................................................................... 34 
10.9.1.   Programming Recommendations at Baseline ....................................................................................... 35 
10.10.   Scheduled Follow-Up Phone Calls ....................................................................................... 36 
10.11.   Randomization (4 Week Follow-Up) .................................................................................... 36 
10.11.1.   Blinding ..................................................................................................................................................... 37 
10.11.2.   Programming Recommendations at 4 Week Follow-Up .................................................................. 37 
10.12.   8 Week Follow-Up ................................................................................................................. 38 
10.12.1.   Programming Recommendations ......................................................................................................... 39 
10.13.   Unscheduled Follow-Up Visits ............................................................................................. 40 
10.14.   12 Week Visit (Study Exit) .................................................................................................... 40 
10.15.   Study Exit ............................................................................................................................... 41 
10.15.1.   Lost to Follow-Up ................................................................................................................................... 41 
10.15.2.   Subject Does Not Meet Eligibility Criteria.......................................................................................... 41 
10.15.3.   Subject chooses to exit (i.e. revokes informed consent) ................................................................... 41 
10.15.4.   Investigator Withdraws Subject ............................................................................................................ 42 
10.16.   Device Interrogation / Save-to-Media .................................................................................. 42 
10.17.   System Modification ............................................................................................................. 42 
10.18.   Deviation Handling .............................................................................................................. 42 
10.19.   Assessment of Safety ............................................................................................................. 43 
10.20.   Assessment of Efficacy ......................................................................................................... 43 
10.21.   Recording Data ..................................................................................................................... 44 
11.   Risks and Benefits ............................................................................................................ 44 
11.1.   Potential Risks ........................................................................................................................ 44 
11.2.   Risk Minimization .................................................................................................................. 46 
11.3.   Potential Benefits .................................................................................................................... 46 
11.4.   Risk-Benefit Rationale ............................................................................................................ 46 
12.   Adverse Event Assessments ............................................................................................. 46 
12.1.   Adverse Events ....................................................................................................................... 47 
12.2.   Device Deficiencies ................................................................................................................ 47 
12.3.   Processing Updates and Resolution....................................................................................... 47 
12.4.   Definitions/Classifications .................................................................................................... 48 
12.5.   Reporting of Adverse Events .................................................................................................. 49 
12.5.1.   Adverse Event and Device Deficiency Classification .......................................................................... 49 
12.5.2.   Adverse Event and Device Deficiency Reporting Requirements ...................................................... 50 
12.6.   Subject Death .......................................................................................................................... 51 
12.6.1.   Death Data Collection .............................................................................................................................. 51 
12.6.2.   Death Classification and Reporting ........................................................................................................ 51 
12.7.   Product Complaint Reporting ................................................................................................ 52 
13.   Data Review Committees ................................................................................................. 52 
13.1.   Echocardiography Core Laboratory ....................................................................................... 52 
13.2.   Blood Core Laboratory ........................................................................................................... 52 
14.   Statistical Design and Methods ....................................................................................... 53 
14.1.   Endpoint Definitions .............................................................................................................. 56 
14.1.1.   Ancillary Safety and Tolerability Endpoint ........................................................................................... 56 
14.1.2.   Ancillary Safety Endpoint – NT-proBNP, troponin, LVEF .............................................................. 56 
14.1.3.   Ancillary Safety Endpoint – Adverse Events ........................................................................................ 57 
14.1.4.   Ancillary Efficacy Endpoint - Quality of Life....................................................................................... 58 
14.1.5.   Ancillary Efficacy Endpoint - Mobility and Activity ........................................................................... 59 
14.1.6.   Ancillary Efficacy Endpoint – Echo Measurements ........................................................................... 61 

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14.1.7.   Ancillary Efficacy Endpoint – Collagen Degradation Biomarker Measurements .......................... 62 
14.1.8.   Ancillary Efficacy Endpoint – Sustained effects of elevated night pacing ....................................... 63 
15.   Ethics ................................................................................................................................ 63 
15.1.   Statement(s) of Compliance ................................................................................................... 63 
16.   Study Administration........................................................................................................ 64 
16.1.   Monitoring .............................................................................................................................. 64 
16.2.   Data Management .................................................................................................................. 64 
16.3.   Direct Access to Source Data/Documents ............................................................................ 65 
16.4.   Confidentiality ........................................................................................................................ 65 
16.5.   CIP Amendments ................................................................................................................... 65 
16.6.   Warranty/Insurance Information ........................................................................................... 65 
16.6.1.   Warranty ...................................................................................................................................................... 65 
16.7.   Record Retention .................................................................................................................... 65 
16.7.1.   Investigator Records ................................................................................................................................. 65 
16.7.2.   Investigator Reports .................................................................................................................................. 66 
16.7.3.   Sponsor Records ........................................................................................................................................ 67 
16.7.4.   Sponsor Reports ........................................................................................................................................ 67 
16.8.   Publication and Use of Information ....................................................................................... 68 
16.8.1.   Publication Committee ............................................................................................................................. 68 
16.8.2.   Management of Primary, Secondary, and Ancillary Publications ...................................................... 69 
16.8.3.   Criteria for Determining Authorship ..................................................................................................... 69 
16.8.4.   Transparency .............................................................................................................................................. 69 
16.9.   Suspension or Early Termination ........................................................................................... 70 
16.9.1.   Planned Study Closure .............................................................................................................................. 70 
16.9.2.   Early Termination or Suspension ........................................................................................................... 70 
16.9.3.   Procedures for Termination or Suspension .......................................................................................... 71 
17.   Appendices ....................................................................................................................... 72 
18.   References ........................................................................................................................ 89 
 
 
 

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Table 1: Study Sponsor Contact Information ................................................................................................ 2 
Table 2: CRO and Core Laboratory Information ........................................................................................... 3 
Table 3: Steering Committee Members ...................................................................................................... 23 
Table 4: Study Procedures ...................................................................................................................... 30 
Table 5: Visit windows .......................................................................................................................... 32 
Table 6: Programming Recommendations at Baseline ................................................................................... 36 
Table 7: Programming Recommendations at 4 Week Follow-Up ..................................................................... 38 
Table 8: Programming Recommendations at 8 Week Follow-Up ..................................................................... 39 
Table 9: Risks Related to Elevated Pacing .................................................................................................. 44 
Table 10: Adverse Event and Device Deficiency Definitions .......................................................................... 48 
Table 11: Adverse Event Classification Responsibilities ................................................................................. 50 
Table 12: Reporting Requirements ........................................................................................................... 50 
Table 13: Subject Death Classification Responsibilities .................................................................................. 52 
Table 14: Investigator Reports for the United States ..................................................................................... 66 
Table 15: Sponsor Reports for the United States ......................................................................................... 68 
Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) ..................... 72 
Table 17: Change History CIP V1.0 to CIP V2.0 ......................................................................................... 81 
Table 18: Change History CIP V2.0 to CIP V3.0 ......................................................................................... 86 
 
Table of Figures 
Figure 1: In Office Study Visits ............................................................................................................... 22 
Figure 2: Sleep Function On During the Day .............................................................................................. 25 
Figure 3: 95% Confidence Interval Widths for Various Proportions of 4 Week Safety and Tolerability Endpoint ........ 54 
 
 
 

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3.   Glossary 
Term/Abbreviation 
Definition 
ACE 
Angiotensin Converting Enzyme 
ADE 
Adverse Device Effect 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ARB 
Angiotensin Receptor Blocker 
Bpm 
Beats per minute 
BNP 
B-type Natriuretic Peptide 
CIP 
Clinical Investigation Plan 
CH 
Concentric Hypertrophy 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
Data protection authorization 
A/an Authorization to Use and Disclose Personal 
Health Information/Research Authorization/other 
privacy language  
DD 
Device Deficiency 
Echo 
Echocardiography 
eCRF 
Electronic Case Report Form 
ERI 
Elective Replacement Indicator 
Ethics Committee 
MEC/IRB/HREB/Ethics Board 
FAL 
Foreseeable Adverse Event List 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 

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Term/Abbreviation 
Definition 
GCP 
Good Clinical Practice 
Hall Walk 
6 Minute Walk Test 
HF 
Heart Failure 
HFpEF 
Heart Failure With Preserved Ejection Fraction 
HFrEF 
Heart Failure With Reduced Ejection Fraction 
IC Form 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
LBBB 
Left Bundle Branch Block 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
LVH 
Left Ventricular Hypertrophy 
MN 
Minnesota 
MNLWHF 
Minnesota Living With Heart Failure 
MMPs 
Matrix Metalloproteinases 
MRA 
Mineralocorticoid Receptors Antagonist 
MRI 
Magnetic Resonance Imaging 
NSR 
Non-Significant Risk 
NT-proBNP 
N-terminal pro b-type Natriuretic Peptide 
NYHA 
New York Heart Association 
OC 
Oracle Clinical (electronic database) 
QOL 
Quality of Life 
RA 
Right Atrial 

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Term/Abbreviation 
Definition 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SVT 
Supraventricular Tachycardia 
TIC 
Tachycardia induced dilated cardiomyopathy 
TIMPs 
Tissue inibitors of metalloproteinases 
TriV 
Tri-ventricular  
UR 
Upper Rate 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
WO 
Work Order 
 
 

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4.   Synopsis 
Title 
REVAMP Clinical Study (REmodeling the Left Ventricle with Atrial 
Modulated Pacing) 
Clinical Study Type 
Feasibility 
Product Name 
Medtronic dual chamber pacemakers with a Sleep function including: 
Kappa 700, Kappa 900, Adapta, Versa, Sensia, EnPulse, Advisa, Advisa 
MRI, and additional Medtronic dual chamber pacemakers with the 
Sleep Function as they become market released 
Sponsor/Local Sponsor 
Medtronic, Inc. 
Cardiac Rhythm and Heart Failure Clinical Research 
8200 Coral Sea Street NE 
Mounds View, MN 55112 U.S.A. 
1-800-328-2518 
Indication under 
investigation  
New therapy tested in heart failure with preserved ejection fraction 
(HFpEF) patients with approved indications for pacing 
Investigation Purpose 
The REVAMP Clinical Study is a feasibility study in heart failure with 
preserved ejection fraction (HFpEF) patients who have normal to small 
left ventricular volumes and evidence of hypertrophy.   The pacemaker 
Sleep function will be used in order to deliver a 5 hour block of 
sustained pacing at 100 bpm during the night for 4-8 weeks.  The 
purpose is to investigate whether this elevated pacing therapy is 
tolerated and whether there is a signal of efficacy. 
Product Status 
The study will be conducted using market-released Medtronic dual 
chamber pacemaker devices with a Sleep function and a Medtronic 
programmer.  The protocol will specify the programming of the Sleep 
Rate and Pacing Parameters in order to deliver elevated atrial pacing 
rates during the time when the patient is sleeping. 
Primary Objective(s) 
The primary objective of this study is to assess the feasibility of using 
elevated night pacing as a therapy for heart failure with preserved 
ejection fraction. 
Ancillary/Exploratory 
Objective(s) 
Collect and characterize adverse events, quality of life, 6 Minute Walk 
Test, echo measurements and blood biomarker data at Baseline and 
follow-up visits 
Study Design 
The REVAMP Clinical Study will be a multi-center, prospective, 
randomized, single-blinded, clinical feasibility study.  
Randomization 
Subjects will be randomized at the 4 week follow-up visit to a 2:1 ratio 
to elevated night pacing ON or elevated night pacing OFF.  

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Sample Size 
It is expected that up to 50 subjects may be enrolled to ensure 30 
subjects undergo elevated night pacing at approximately 10 sites in 
the United States only. 
Inclusion/Exclusion 
Criteria 
Inclusion criteria: 
• 
Subject has had a market released dual chamber Medtronic 
Pacemaker with a Sleep function for at least 3 months 
• 
Subject is stable on current medications  
• 
Subject has dyspnea with exertion or diagnosed as NYHA Class II 
or III heart failure. 
• 
Subject has had a prior Echo in past 6 months with: EF ≥ 50% 
and Diastolic volume <80 ml/m2  
• 
Subject has evidence of hypertrophy (indexed to body surface 
area: men 115 g/m2, women 95 g/m2  or indexed to height: men 
49.2 g/m2.7 , women 46.7 g/m2.7 ) or Relative Wall thickness 
>0.42, or Wall Thickness>1.2cm (posterior wall) 
• 
Subject is willing to sign and date the study Informed Consent 
Form 
• 
Subject is 18 years of age or older, or of legal age to give 
informed consent per local law 
• 
Subject is expected to remain available for follow-up visits 
Exclusion criteria: 
• 
Subject has permanent AF or AF noted on baseline interrogation 
rhythm strip 
• 
Subject has uncontrolled BP; (systolic pressure needs to be 
>100mmHg and <160mmHg on medications) 
• 
Subject has severe stenosis of the aortic or mitral valve, defined as 
a valve area ≤ 1.0 cm2 or subject has severe regurgitation of the 
aortic or mitral valve. 
• 
Subject has symptomatic COPD requiring oxygen 
• 
Subject’s Pacemaker has less than 6 months of Pacemaker battery 
life 
• 
Subject had an aortic valve replacement (surgical or TAVR) 
procedure less than 9 months prior to enrollment 
• 
Subject’s programmed upper rate limit is less than 100 bpm 
because of concerns of elevated pacing 
• 
Subject is unable or unwilling to perform the 6 Minute Walk Test 
at all scheduled study visits 
• 
Subject is currently enrolled or planning to enroll in a potentially 
confounding trial during the course of the study (co-enrollment in 
concurrent studies is only allowed when documented pre-approval 
is obtained from the Medtronic study manager) 
• 
Subject is pregnant  
• 
Subject meets any exclusion criteria required by local law 

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• 
Subject’s life expectancy is less than 12 weeks 
• 
Subject with a medical condition that precludes the patient from 
participation in the opinion of the investigator 
• 
Subject has known coronary disease with Class II angina 
Study Procedures and 
Assessments 
In Office Visits: Study procedures, assessments and in-clinic data 
collection will be at Enrollment/Baseline, 4 weeks, 8 weeks and 12 
week visits.  
Telephone Call Follow Up Visits: Subjects will be called at regular 
intervals after their Baseline visit: 24 hours, 5 days, 2 weeks, 6 weeks, 
and 10 weeks to inquire about symptoms. Subjects will also be asked 
their heart rate which the subject can read using a finger pulse 
oximeter monitor that will be given to them at Baseline to use. 
Enrollment Baseline: 
• 
Informed Consent 
• 
Verification of Inclusion/Exclusion criteria 
• 
Subject Demographics 
• 
Medical History 
• 
Medications 
• 
Physical Assessment (including height, weight, heart rate 
and blood pressure) 
• 
NYHA classification 
• 
MN Living with Heart Failure Questionnaire 
• 
EQ-5D-5L Questionnaire 
• 
6 Minute Walk Test  
• 
Blood Draw 
• 
Echo  
• 
Device Interrogation (initial) 
• 
Save to media (initial) 
• 
Program the sleep function to ON and program the pacing 
parameters 
• 
Subject observation of at least 30 minutes to ensure the 
subject can tolerate 100 bpm pacing post programming 
• 
Device Interrogation (final) - this needs to be completed 
at the end of the visit after programming has been 
completed 
• 
Save-to-Media (final) 
24 Hour Telephone Call Follow Up Visit: 
• 
Symptom Assessment 
• 
Heart Rate 
5 Day  Telephone Call Follow Up Visit:  
• 
Symptom Assessment 
• 
Heart Rate 
2 Week Telephone Call Follow Up Visit:  

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• 
Symptom Assessment 
• 
Heart Rate 
 4 Week In-Clinic Follow Up Visit (Randomization): 
• 
Medications 
• 
Physical Assessment (including weight, heart rate and 
blood pressure) 
• 
NYHA classification 
• 
MN Living with Heart Failure Questionnaire 
• 
6 Minute Walk Test  
• 
Blood Draw 
• 
Echo 
• 
Device Interrogation (initial) 
• 
Save-to-Media  (initial) 
• 
Program the sleep function to OFF if randomization 
assignment is OFF (and program the pacing parameters) 
• 
Device Interrogation (final) - this needs to be completed 
at the end of the visit after programming has been 
completed 
• 
Save-to-Media (final) 
• 
Adverse Events (report new/assess ongoing AEs), Study 
Deviations, System Modifications, Device Deficiencies, 
Crossovers (as they occur) 
6 Week Telephone Call Follow Up Visit:  
• 
Symptom Assessment 
• 
Heart Rate 
 8 Week In-Clinic Follow Up Visit:  
• 
Medications 
• 
Physical Assessment (including weight, heart rate and 
blood pressure) 
• 
NYHA classification 
• 
MN Living with Heart Failure Questionnaire 
• 
EQ-5D-5L Questionnaire 
• 
6 Minute Walk Test  
• 
Blood Draw 
• 
Echo 
• 
Device Interrogation (initial) 
• 
Save-to-Media (initial) 
• 
Program the sleep function to OFF if subject still has sleep 
function ON (and program the pacing parameters) 
• 
Device Interrogation (final) - this needs to be completed 
at the end of the visit after programming has been 
completed 
• 
Save-to-Media (final) 

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• 
Adverse Events (report new/assess ongoing AEs), Study 
Deviations, System Modifications, Device Deficiencies, 
Crossovers (as they occur) 
10 Week Telephone Call Follow Up Visit:  
• 
Symptom Assessment 
• 
Heart Rate 
 12 Week In-Clinic Follow Up Visit (Exit):  
• 
Medications 
• 
Physical Assessment (including weight, heart rate and 
blood pressure) 
• 
NYHA classification 
• 
MN Living with Heart Failure Questionnaire 
• 
6 Minute Walk Test  
• 
Blood Draw 
• 
Echo 
• 
Device Interrogation (initial) 
• 
Save-to-Media  (initial) 
• 
Device Interrogation (final) - this needs to be completed 
at the end of the visit after programming has been 
completed 
• 
Save-to-Media  (final) 
• 
Adverse Events (report new/assess ongoing AEs), Study 
Deviations, System Modifications, Device Deficiencies, 
Crossovers 
Early study exit (prior to 12 week visit):  
• 
Date of visit 
• 
Reason for exit 
• 
Adverse Events (report new/assess ongoing AEs), Study 
Deviations, System Modifications, Device Deficiencies, 
Crossovers  
• 
Complete a Scheduled/Unscheduled Follow Up eCRF, if 
applicable 
Unscheduled Follow Up: 
The following are recommended at the discretion of the 
investigator if deemed necessary: 
• 
Physical Assessment (including weight, heart rate and 
blood pressure)  
• 
Medications 
• 
Echo 
• 
Blood draw 
• 
Device Interrogation (initial) 
• 
Save-to-Media (initial) 
• 
Program the Sleep Function to protocol 

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• 
Device Interrogation (final) - this needs to be completed at the 
end of the visit after programming has been completedSave to 
Media (final) 
 
The following are required: 
• 
Adverse Events (report new/assess ongoing AEs), Study 
Deviations, System Modifications, Device Deficiencies, Crossovers  
Safety Assessments 
Levels of Troponin and NT-proBNP will be monitored at all in office 
visits to assess for ischemia and elevated wall stress that may indicate 
worsening heart failure.  All Adverse Events (AEs) that are potentially 
relevant will be collected which include system-related, programming-
related,  cardiovascular and serious adverse event information 
throughout the study duration, starting at the time of signing the 
Informed Consent Form. All new and/or worsening AE information, 
including all deaths will be collected throughout the clinical study 
duration. NT-pro BNP and Troponin will be collected at Baseline and at 
each subsequent in-office visit and changes will be assessed to ensure 
that the therapy is not leading to undue cardiac stress or ischemia.  
Documented pre-existing conditions are not considered an AE unless 
the nature or severity of the condition has worsened.  
Endpoints 
A number of measures of therapy safety, tolerability and efficacy will 
be explored as ancillary endpoints.   
 Statistics 
As a feasibility study, this study is not powered to meet any specific 
endpoints.   
5.   Introduction  
5.1.   Background  
An estimated 8.5 million people in the United States will have heart failure (HF) by 2030 [1], and 
approximately 50% of these HF patients will  have a preserved ejection fraction (HFpEF) [2].  In contrast 
to HF with reduced EF (HFrEF), no effective drug or device therapies have been identified that improve 
the prognosis of the disease. 
A large proportion of HFpEF patients have hypertension and have a concentric hypertrophic (CH) etiology 
described as an increased heart mass with increased relative wall thickness [3].  Cardiomyocytes in 
HFpEF are thicker than HFrEF, and collagen content is increased compared to controls [4].  Patients with 
concentric hypertrophy or evidence of increased wall thickness are characterized by an increase in end 
diastolic pressures and isovolumic relaxation time [5] compared to normal controls.  HFpEF patients have 
relatively normal volumes and EF, but they have a reduced ability to adequately fill a stiffened left 
ventricle (LV).   The impact of this diastolic dysfunction is more notable during exercise; HFpEF left 
ventricles are reliant on high left atrial pressures to fill the LV  [4].   A search for a therapy that improves 
the compliance of the ventricle and improves early diastolic filling in these patients has not been 
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We are proposing a pacing therapy that titrates a bolus of atrial pacing at 100 bpm delivered during 
sleeping hours with the hypothesis that raising heart rates can promote a beneficial LV dilation, which will 
reduce chamber stiffness and improve diastolic filling in HFpEF patients that have thickened ventricular 
walls and normal to small LV volumes.  One challenge is finding a therapeutic heart rate dose that does 
not cause undesirable symptoms in ambulatory HF patients and a dose that achieves a desirable level of 
dilation to improve filling.  Studies in animal models show that the dilatory effects of rapid pacing 
diminishes once the elevated pacing rates are discontinued [6-8] ; the study of dose response to elevated 
atrial pacing rate also includes monitoring the reaction of the heart to withdrawal of the pacing therapy.  
Clinical studies of SupraVentricular Tachycardia (SVT) rates and durations that cause LV dilation are 
limited.  An extreme example of elevated heart rates promoting significant dilation and LV dysfunction 
comes from the clinical observation of SVT induced cardiomyopathy.  Medi et al [9] reported 10% 
incidence of tachycardia induced dilated cardiomyopathy (TIC) in N=345 patients undergoing ablation for 
atrial tachycardia.   EF improved from 35 ± 11% to 59 ± 3% in the 2 months post-ablation.  At the time 
of ablation treatment, the patients with LV dilation were characterized by slower ventricular response 
rates (117 ± 21 bpm vs 132 ± 33 bpm, p=0.05) and these patients reported that the duration of their 
symptoms started one or more years before seeking treatment.   Conventional wisdom is that patients 
with more rapid ventricular responses are symptomatic and seek treatment more quickly before dilation 
and cardiomyopathy can occur from the rapid SVT.  
Animal studies that have been used to study TIC have reported LV dilation and increased pulmonary 
capillary wedge pressures within 1 to 3 weeks when hearts are paced at extremely fast rates such as 
240bpm [6].  However, the extent of dilation and symptoms can be titrated by choice of pacing rate and 
the duration of pacing. A study in a porcine model of concentric hypertrophy showed that 100% atrial 
pacing at 170bpm increased LV end-diastolic volumes by 246% in 4 weeks of pacing compared to an 
increase of 25% at a more modest rate of 125 bpm at 2 weeks of pacing (about 30bpm higher than 
normal sinus rhythm).  The atrial pacing rate of  125bpm did not cause measurable changes in 
biomarkers including B-type natriuretic peptide [7].   
Since this therapy is delivered in an ambulatory patient, the choice of pacing rate and duration to achieve 
a therapeutic dilation of the LV must not induce intolerable symptoms.  A rate of 100bpm may be suitable 
for most HFpEF patients to respond favorably to stimulus rate, without symptoms.  The nominal pacing 
rate setting for “Activities of Daily Living” (ADL) in Medtronic pacemakers is 95bpm and the upper pacing 
rate (UR) is 130 bpm, so a sustained pacing rate of 100bpm is well within normal pacing range [10].  The 
acute hemodynamic response to elevated pacing rates in supine patients with CH has been characterized 
to have a blunted inotropic response to pacing rates above 100bpm compared to normal subjects [5]. 
Stroke volumes have been shown to decrease from baseline as atrial pacing increases the rate above 
120bpm in supine patients [5, 11, 12].  The force-frequency effect was reported to be positive at rates 20 
and 40bpm above intrinsic rates in patients with left ventricular hypertrophy (LVH) [11].  However, 
Inagaki et al [13] showed that the force frequency relationship can be biphasic in some patients with 
severe LVH, with a decrease in LV max +dp/dt observed in some patients as pacing rates increased 
above a range of 100-130bpm. At a structural level, HFpEF is typically associated with concentric 
remodeling with an increased left ventricular (LV) mass-to-volume ratio or overt LV hypertrophy and 
fibrosis. A high prevalence of this structural phenotype in HFpEF was recently confirmed in the Treatment 
of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial [22]. Despite 
the inclusion of patients with LV chamber dilation in this trial, about a quarter of patients had below-
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Pacing at an elevated rate for 100% of the day may accelerate changes in cardiac structure, but could be 
symptomatic if elevated rates sustained for long periods of time.  Elevating heart rate for 5 hours during 
sleep at night may reduce the sensation to elevated rates and minimize symptoms for the patients.  
However, a heart rate dose of 5 hours will increase the overall duration required to promote dilation in 
the LV chamber. A measurable change in LV volumes was measured at 2 weeks of 100% pacing at 
125bpm in animals [7], so a reasonable therapy duration of 100bpm for 5 hours per day would  be 4 to 8 
weeks of pacing before changes in LV volume would be measured.   Measurement of biomarkers 
including matrix metalloproteinases (MMPs) and tissue inibitors of metalloproteinases (TIMPs) may be 
useful in understanding the time course of changes that lead changes in geometry.   The matrix 
metalloproteinases (MMPs) are part of an enzymatic system that contribute to the remodeling of the 
extracellular matrix during rapid pacing-induced cardiomyopathy  [14].  MMP-1, MMP-2, and MMP-3 were 
shown to increase in abundance at 7 days following initiation of rapid pacing, and were temporally 
related to a measured decrease in the collagen content as well as a lengthening of cardiomyocytes.   
TIMPs are also involved in inhibiting MMPs enzymatic activity and elevated TIMP-1 with reduction in 
MMPs were reported in HFpEF patients with LV hypertrophy [15].  
This proposed elevated atrial rate pacing therapy is aimed at improving exercise capacity in HFpEF 
patients.  In order to safeguard patients, we propose measuring blood biomarkers including troponin and 
NT-proBNP in order to monitor indications that the therapy is not causing ischemia or worsening heart 
failure.   Natriuretic peptide release occurs in response to myocardial stretch.  BNP and NT-proBNP are 
moderately elevated in HFpEF patients and may drop to normal levels in symptom-free periods [16].  The 
European Society of Cardiology guidelines propose a cut-off of >35 pg/ml for BNP and >125 pg/ml for 
NT-proBNP to identify chronic, stable HFpEF patients [17].  Thresholds for acute HF have been reported 
as 100pg/ml for BNP and 300 pg/ml for NT-proBNP, which give sensitivity of 0.95 and 0.99 respectively, 
and negative predictive value of 0.94 and 0.98, respectively [18].    In a study of patients hospitalized for 
acute decompensated heart failure, a positive Troponin test for myocardial infarction was defined using a 
threshold of 1.0 µg/L or higher for cardiac Troponin I or 0.1 µg/L for cardiac Troponin T [19].  In an 
ambulatory chronic HFpEF population in 157 patients, the median value for Troponin I was 14 pg/mL 
(0.014 µg/L) [20].  A Troponin T threshold of 0.02 ng/mL (0.02 µg/L) was used in ambulatory HFpEF 
patients to detect myocardial injury; patients that had elevated Troponin T had an 78% rate of death or 
hospitalization at 18 months compared to 13% [21].  
Metrics that will be used to evaluate whether there is a measurable therapeutic effect of the elevated 
atrial pacing rate therapy include serial measurements of quality of life, 6 Minute Walk Test, device-
measured activity, echo measurements of volumes and diastolic function, and chronic changes in resting 
heart rate. 
5.2.   Purpose 
Medtronic, Inc. is sponsoring the REVAMP study, a multi-center, prospective, randomized, single-blinded, 
clinical feasibility study. The REVAMP clinical study will include market-released pacemaker devices that 
incorporate the Sleep function. The purpose of the REVAMP Clinical Study is to assess whether elevating 
the atrial pacing rate for temporary periods of time is feasible.  Data will be collected to characterize 
whether temporary atrial pacing rate elevation can lead to beneficial left ventricular (LV) chamber 
dilation, improvements in exercise capacity, and quality of life in a specific etiology of Heart Failure with 
Preserved Ejection Fraction (HFpEF) patients who have normal to small LV chambers and evidence of 
thickened walls. 

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6.    Objectives and Endpoints 
6.1   Objectives 
 6.1.1.  Primary Objectives 
The primary objective of this study is to assess the feasibility of using elevated night pacing as a therapy 
for HFpEF patients. 
6.1.2.  Ancillary/Exploratory Objectives 
Adverse events, Minnesota Living With Heart Failure (MNLWHF) Questionnaire responses, EQ-5D-5L 
Questionnaire responses, 6 Minute Walk Test distances, resting heart rate, atrial fibrillation incidence, 
device-measured activity levels, echo measurements and blood samples will be collected at Baseline and 
follow-up visits as detailed in Section 10.   Study Procedures.  Adverse events will be collected as 
described in Section 12.1.   Adverse Events and will be characterized to assess the overall safety and 
tolerability of the therapy, as described in Section 12.5.1.   Adverse Event and Device Deficiency 
Classification.  Changes in NT-proBNP and troponin concentrations from Baseline will also be used to 
assess patient safety.  Early study patient withdrawals over the course of the study will be used to further 
assess therapy tolerability.  Changes in quality of life, as assessed by the MN Living With Heart Failure 
and EQ-5D-5L, changes in 6 Minute Walk Test distance and change in activity levels will be compared 
from baseline to the various follow up time points to assess for therapy efficacy.  Echo measurements 
and, optionally, peripheral blood concentrations of extracellular matrix biomarkers will be characterized 
and changes will be correlated with changes in the safety and efficacy assessments.  End diastolic volume 
and mitral deceleration time could increase if the therapy works as hypothesized.  If the quality of life, 
changes in 6 Minute Walk Test distance and/or activity levels improve, it will be of interest to see if the 
end diastolic volume and mitral deceleration time correlate with improvements.  If the therapy works as 
hypothesized, other echo measurements, including left ventricular ejection fraction (LVEF), might also 
change over time, although the direction and magnitiude of these effects are difficult to predict.  
Characterizing these effects will be an important goal of the feasibility study. 
6.2.   Endpoints 
As part of the exploratory/ancillary safety, tolerability and efficacy effects described in Section 14.1.   
Endpoint Definitions, it will be of interest to characterize changes in collected measurements from 
Baseline to 4 weeks, compare changes in collected measurements at 4 weeks to 8 weeks in the subjects 
randomized to the elevated night pacing ON arm to subjects randomized to the elevated night pacing 
OFF arm and compare changes in collected measurements at 12 weeks to Baseline, 4 and 8 weeks to see 
whether any therapeutic improvements are sustained after the therapy is discontinued. 
6.2.1.   Primary Endpoint 
As a feasibility study, this study is not powered to meet any specific endpoints.   

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7.   Study Design  
The REVAMP Clinical Study will be a multi-center, prospective, randomized, single-blinded, clinical 
feasibility study. Subjects will be randomized in a 2:1 ratio to elevated night pacing ON or elevated night 
pacing OFF. 
It is expected that up to 50 subjects may be enrolled to ensure approximately 30 subjects undergo 
elevated night pacing at approximately 10 sites in the United States to ensure enrollment completion 
within the pre-specified timeframe. 
The REVAMP study will be conducted as a Non-Significant Risk (NSR) IDE study. The REVAMP Research 
System does not include an investigational device; the ability to program a lower rate of 100 bpm is 
available in market-released pacemakers, and the Sleep function (which allows a different rate to be 
programmed for part of a 24 hour clock) is an approved feature in market-released pacemakers that will 
be used in the clinical study. The study will be conducted in compliance with 21 CFR Parts 11, 50, 56, 
812.2(b)(1). This study does not require an IDE submission to FDA.  
The Sleep Function will be programmed so that the pacemaker can deliver an elevated pacing rate of 100 
bpm during the night for 5 hours and lower the rate during the daytime hours. This is within the FDA-
approved programmable parameters of the Sleep Function feature. The associated minimal risk will be 
minimized as described in Section 11.2.   Risk Minimization. 
The study will  collect the following information: demographics, medical history, medications, standard 
physical, NYHA class, blood samples to measure NT-proBNP, Troponin and other biomarkers, echo 
measurements, MN Living with Heart Failure Questionnaire, EQ-5D-5L Questionnaire, 6 Minute Walk Test, 
implanted device information, device interrogations, save-to-media, adverse events (including death), 
system modifications, and exit information.  The MN Living with Heart Failure Questionnaire was chosen 
to measure the quality of life for subjects with heart failure, which includes a question on how well the 
subject is sleeping at night. 
See Section 10.   Study Procedures. for further detail on study procedures and data collection as well as 
time-points for data collection.  
 
 

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Figure 1: In Office Study Visits 
7.1.   Duration 
The study duration is expected to be approximately 24 months. This represents 21 months for subject 
enrollment and 3 months for subject follow-up after the last subject is randomized. Subjects are 
anticipated to be in the study for approximately 12 weeks completing in office visits at 
Enrollment/Baseline, 4 weeks, 8 weeks, and 12 weeks.  Subject’s device programming will be returned to 
standard pacemaker device settings per physician discretion at either 4 or 8 weeks after initiation of 
elevated night pacing, and subjects will be exited after completing the 12 week visit.  
7.2.   Rationale  
It is expected that up to 50 subjects may be enrolled to ensure approximately 30 subjects will have 
elevated night pacing programmed ON for the first 4 weeks in order to evaluate whether the therapy is 
symptomatic. Limitations to the programming of the Sleep Function requires subjects to have a lower 
Randomization 2:1 
at 4 weeks  (n=30) 
Enrollment 
Night Pacing ON 
(n~20) 
Night Pacing Off 
(n~10) 
At 8 weeks  
Night Pacing Off  
Exit @ 12 
weeks 
Baseline 
Begin Elevated Night Pacing 
On 
Exit if intolerable  
At 8 weeks  
Night Pacing Off  
Exit @ 12 
weeks 

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rate of 100bpm programmed between the time they leave the Baseline visit and 5am the next morning 
when “Bed Time” will set the Sleep Rate at the pre-study lower rate of 60-70bpm.  At the 4 week visit, 
there will be a safety assessment. Measurements of NT-proBNP will be used to assess whether dilation of 
the heart is signalling worsening heart failure.  A Troponin assay will be used to ensure the elevated night 
pacing therapy isn’t leading to ischemia.  Subjects will be randomized at 4 weeks to elevated night pacing 
ON or OFF in order to gather data on the dose-response of the elevated night pacing therapy. Some 
patients may have sensation of an elevated heart rate from this programming, making blinded 
randomization difficult to achieve. All subjects will be followed for at least 4 weeks following termination 
of the elevated night pacing therapy in order to evaluate whether changes in quality of life, 6 minute 
walk tests and echo measurements persist after the therapy is discontinued. Previous work in animal 
studies have shown that cessation of elevated pacing rates can reverse the dilation of the LV chamber; 
this study will monitor the time course of that reversal by serial echo measurements, 6 minute walk tests 
and activity counts, and quality of life assessments. 
7.3.   Study Oversight 
The study will utilize a Steering Committee (SC). The SC is responsible for the scientific content of the 
study and provides input for the execution. Members of the SC may be study site investigators. The 
purpose of the SC is to provide unbiased opinions and expertise to the clinical study design and process. 
The SC will support the execution of the REVAMP clinical study and provide guidance, feedback and 
direction to the clinical study. The SC is comprised of the members as indicated below. 
Table 3: Steering Committee Members 
Committee Member  
Contact information 
Eugene S. Chung, MD 
 
CEO and President 
The Christ Hospital Cardiovascular Associates 
2123 Auburn Ave, Ste 424 
Cincinnati, OH 45219 
(513) 585-1777  
Eugene.Chung@thechristhospital.com 
Markus Meyer, MD 
 
Associate Professor of Medicine, Cardiovascular Medicine 
Department of Medicine 
Medicine-Cardiology, McClure Wing, 111 Colchester Avenue 
Burlington, VT 05401 
(802) 847-3734 
markus.meyer@uvm.edu 
Michael Zile, MD 
Professor of Medicine 
Medical University of South Carolina 
Department of Medicine 
Division of Cardiology 
25 Courtenay Drive, ART 7063 
MSC 592 
Charleston, SC 29425 
(843) 876-4761 
zilem@musc.edu 
 
The Echocardiography Core Laboratory (Echo Core Lab) will review and analyze all echo data collected 
for the study. 
Further details for the Echo Core Lab are provided in CROs/Core Laboratories. 

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The Blood Core Laboratory (Lab) will review and analyze all blood data collected for the study. 
Further details for the Blood Core Lab are provided in CROs/Core Laboratories. 
8.   Product Description 
8.1.   General 
All Medtronic implantable pacemakers and associated programmer and monitoring equipment must be 
market-released.  The Medtronic pacemakers must offer the Sleep Function feature.  The pacing 
parameter Lower Rate will be programmed to 100bpm, and the Sleep Function will be used to lower the 
Sleep Rate to the pre-study lower rate (50-70 bpm) during 19 hours of the day. The Sleep Function will 
be programmed to deliver the Sleep Rate between 5a.m.  and 11:30pm, using a Bed Time of 5a.m. and a 
Wake Time of 11:30pm.  Subjects will receive 5 hours of elevated night pacing at 100bpm and 1 hour of 
a transition rate between 100bpm and the Sleep Rate. See Figure 2. 
8.2.   Intended Population 
All subjects in this investigation have received a Medtronic dual chamber pacemaker for approved 
indications. HFpEF subjects who have a small to normal LV volume and evidence of LV hypertrophy 
and/or increased LV wall thickness will be selected for this study. 
8.3.   Study Components 
• 
All Medtronic dual chamber pacemakers that have the Sleep Function 
• 
Medtronic market-released programmers  
• 
Compatible market-released leads 
• 
Finger Pulse Oximeter Monitor (will be provided to the site) 
• 
Echocardiography machine capable of recording and exporting echo data in digital format 
• 
Access to dry ice to ship blood samples 
• 
Computer with high speed internet access using a web browser compatible with the electronic 
data management system for electronic database entry 
8.4.   Product Use 
The Sleep function in all Medtronic market-released devices was designed to temporarily substitute the 
programmed Lower Rate with a slower pacing rate (Sleep Rate) during the time of day that the patient 
normally sleeps.  This feature can be programmed to lower the rate to the Sleep Rate at “Bed time” and 
to increase the rate back to the Lower Rate at “Wake time”.  The design intent of this feature was that 
the slower Sleep Rate can be programmed to occur during any window in the 24 hour clock; the 
difference between Bed Time and Wake Time must be a minimum of 2 hours.  The REVAMP study 
proposes to use the lower Sleep Rate for 18 hours during the day, in order to elevate the Lower Rate to 
100bpm and pace the atrium at an elevated rate at night.  For the REVAMP study, we specify the Lower 
Rate programmed at 100bpm, with the Sleep Rate programmed to the pre-study value of the Lower Rate 
(e.g. 60bpm). 
 
 

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Figure 2: Sleep Function On During the Day 
 
The Sleep Function will be programmed to deliver the Sleep Rate between 5a.m. and 11:30pm, using a 
Bed Time of 5a.m. and a Wake Time of 11:30pm.    
The Sleep Function was designed to operate in conjunction with Rate Responsive pacing; however, the 
Rate Profile Optimization feature that automatically optimizes was not developed with 5 hours of 100bpm 
imposed on patients.  Therefore, Rate Profile Optimization will be turned OFF while the Sleep Function is 
programmed ON.   
The Sleep Function is suspended following any parameter programming operations.  If the Sleep Function 
is suspended, the pacing rate will immediately return to the programmed Lower Rate (100bpm per this 
protocol) until the next Bed Time is reached.  At the initial programming visit of this protocol, subjects 
will be evaluated for whether they are symptomatic at a Lower Rate of 100bpm.  Subjects will leave the 
Baseline visit experiencing a Lower pacing rate of 100 bpm until 5am the next morning, when Bed Time 
for the Sleep Function is reached.  After the elevated pacing has been turned ON, any telemetry 
activation, such as programming, magnet application or CareLink transmission will suspend the Sleep 
Function and the pacemaker will immediately return to the Lower Rate of 100 bpm until 5am. 
If a pacemaker reaches Estimated Replacement Indicator (ERI), the device will automatically turn OFF 
the Sleep Function and reprogram the pacemaker to VVI 65 mode. 
8.5.   Product Receipt and Tracking 
All product is market released and therefore does not need to be tracked.   
9.   Selection of Subjects 
9.1.   Study Population 
This study will enroll patients who have a Medtronic dual chamber pacemaker system with the Sleep 
function per local guidelines and who meet all of the specific study inclusion criteria and none of the 
exclusion criteria.  

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9.2.   Subject Enrollment 
In order for subjects to be considered for enrollment, they must meet all of the inclusion criteria and 
none of the exclusion criteria. Notification of site activation from Medtronic, and approval from the IRB of 
the REVAMP Clinical Investigation Plan (CIP), Informed Consent Form (IC Form), Authorization to Use 
and Disclose Personal Health Information/Research Authorization/other privacy language (data protection 
authorization) as required by law, and any other applicable documents must be obtained prior to 
enrolling subjects in the study.    
9.3.   Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to participate in the study: 
INC 1: Subject has had a market released dual chamber Medtronic Pacemaker with a Sleep 
function for at least 3 months 
INC 2: Subject is stable on current medications 
INC 3: Subject has dyspnea with exertion or diagnosed as NYHA Class II or III heart failure. 
INC 4: Subject has had a prior Echo in past 6 months with: EF ≥ 50% and Diastolic volume <80 
ml/m2  
INC 5: Subject has evidence of hypertrophy (indexed to body surface area: men 115 g/m2, 
women 95 g/m2  or indexed to height: men 49.2 g/m2.7 , women 46.7 g/m2.7 ) or Relative Wall 
thickness >0.42, or Wall Thickness>1.2cm (posterior wall) 
INC 6: Subject is willing to sign and date the study Informed Consent Form (IC Form) and 
Authorization to Use and Disclose Personal Health Information/Research Authorization/other 
privacy language (data protection authorization) as required by law  
INC 7: Subject is 18 years of age or older, or of legal age to give informed consent per local law 
INC 8: Subject is expected to remain available for follow-up visits 
9.4.   Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria to be eligible to participate in the study: 
EXC 1: Subject has permanent AF or  AF noted on baseline interrogation rhythm strip 
EXC 2: Subject has uncontrolled BP; (systolic pressure needs to be >100mmHg and <160mmHg 
on medications) 
EXC 3: Subject has severe stenosis of the aortic or mitral valve, defined as a valve area less than 
or equal to 1.0 cm2 or subject has severe regurgitation of the aortic or mitral valve. 
EXC 4: Subject has symptomatic COPD requiring oxygen 
EXC 5: Subject’s Pacemaker has less than 6 months of Pacemaker battery life 
EXC 6: Subject had an aortic valve replacement (surgical or TAVR) procedure less than 9 months 
prior to enrollment. 
EXC 7: Subject’s programmed upper rate limit is less than 100 bpm because of concerns of 
elevated pacing 
EXC 8: Subject is unable or unwilling to perform the 6 Minute Walk Test at all scheduled study 
visits 

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EXC 9: Subject is currently enrolled or planning to enroll in a potentially confounding trial during 
the course of the study (co-enrollment in concurrent studies is only allowed when documented 
pre-approval is obtained from the Medtronic study manager) 
EXC 10: Subject is pregnant  
EXC 11: Subject meets any exclusion criteria required by local law 
EXC 12: Subject’s life expectancy is less than 12 weeks 
EXC 13: Subject with medical condition that precludes the patient from participation in the 
opinion of the investigator 
EXC 14: Subject has known coronary disease with Class II angina 
9.5.   Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of bias. 
Methods incorporated in the study design to minimize potential bias include (but are not limited to): 
• 
Subjects will be evaluated at Baseline to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to randomization 
• 
Subjects will be randomly assigned to their treatment assignment 
• 
Subject demographics and medical history will be collected at Baseline and differences that may 
affect endpoints will be identified 
• 
Subjects will be blinded to their randomization assignment 
• 
Data collection requirements and study procedures will be standardized across all sites  
• 
All study site personnel and Medtronic personnel will be trained on their respective aspects of the 
study using standardized training materials, and required to follow the CIP 
• 
Monitoring visits will be conducted according to the study-specific monitoring plan. 
• 
A single Echocardiography Core Lab will be used to analyze the echo data, and members of the 
core lab will be blinded to subject’s randomization 
• 
A single Blood Core Lab will be used to analyze the blood data 
• 
Registration of the trial on ClinicalTrials.gov  
In summary, potential sources of bias that may be encountered in this clinical study have been 
considered and minimized by careful study design. 
10.   Study Procedures  
Prior to performing study related procedures, all sites must have IRB approval and documentation from 
Medtronic of site readiness. 
Medtronic representatives may perform the following activities at the study sites during the study, if 
appropriately trained and under supervision of the Principal Investigator: 
• 
Study training relevant and pertinent to the involvement of personnel conducting study activities 
and investigator responsibilities 
• 
Technical support at all visits (e.g. programming of the pacemakers according to study 
requirements, performing device interrogations/save-to-media, etc.), but no CRF data entry shall 
be performed by Medtronic personnel  
• 
Monitoring activities 

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At the request of the Principal Investigator or other authorized site personnel, Medtronic will use information 
from its device registration database to provide a study site a list of its patients whom the site had implanted 
with the Medtronic dual chamber pacemaker with Sleep Function, required by the inclusion criteria set out 
in Section 9.3.  Study site, if permitted by its IRB, could further review the records of such patients to 
determine if they may be eligible to participate in the study. 
10.1.    Study Personnel Requirements 
All clinical investigators managing the subject’s heart failure must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with heart failure.  
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
The principal investigator shall: 
• 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation 
• 
Be experienced in the field of application  
• 
Disclose potential conflicts of interest that interfere with the conduct of the clinical investigation 
or interpretation of results 
The principal investigator shall be able to demonstrate that the proposed investigational site: 
• 
Has the required number of eligible subjects needed within the recruitment period 
• 
Has a qualified investigational site team and adequate facilities available for the foreseen 
duration of the clinical investigation  
Site personnel training and delegation will be completed prior to participation in this clinical study.  
10.2.   Role of the Sponsor Representative  
Sponsor representatives may provide support as required for the study under supervision of the PI, 
including:  
• 
Provide study training relevant and pertinent to the involvement of personnel conducting study 
activities and Investigator responsibilities  
• 
Technical support at  all visits under the supervision of a study Investigator, but no data entry, 
shall be performed by Medtronic personnel or their representatives at sites  
• 
Monitoring activities  
10.3.   Site Activation 
During the activation process (prior to subject enrollment), Medtronic will train site personnel on the CIP, 
relevant standards and regulations, obtaining informed consent, and on data collection and reporting 
tools. If new members join the study site team, they will receive training on the applicable clinical study 
requirements relevant to their role before contributing to the clinical study. For new members, local IRB  
notification requirements must be met, as well as Medtronic requirements. 

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A Clinical Trial Agreement (CTA) or Work Order (WO) shall be entered into effect by Medtronic, the 
participating investigation site and/or the principal clinical investigator at each investigational site as per 
local legal requirements, and returned, fully executed, to Medtronic prior to the commencement of any 
study activities. Financial aspects of conducting and reporting a study will be specified in the agreement. 
By signing and dating the agreement the investigation site indicates approval of the CIP. 
Prior to performing study related activities, all sites must have IRB approval. 
All local and regional regulatory requirements will be fulfilled prior to site activation and enrollment of 
subjects into the study. Each study site must have written documentation from Medtronic of site and 
investigator readiness before beginning any study-related activities. Requirements for activation may 
include, but are not limited to the following:  
• 
Written documentation of IRB approval of the current version of the CIP, IC Form, Authorization 
to Use and Disclose Personal Health Information/Research Authorization/other privacy language 
(data protection authorization) as required by law, subject materials, and voting list (as required 
by local law)   
• 
Fully executed CTA or WO on file with the sponsor  
• 
Investigator Agreement 
• 
Current Curriculum Vitae (CV)  
• 
Financial Disclosure Agreement  
• 
Documentation of delegated tasks 
• 
Documentation of study site personnel training  
Additional requirements imposed by the IRB shall be followed, if applicable.  
Medtronic will provide each study site with documentation of study site/investigator readiness; this letter 
must be received prior to subject enrollment. 
10.4.   Equipment Requirements 
The following equipment must be available at each site to support study activities: 
• 
Medtronic market-released programmers 
• 
Echocardiography machine capable of recording and exporting echo data in digital format 
• 
Access to dry ice for shipment of blood samples 
• 
Computer with high speed internet access using a web browser compatible with the electronic 
data management system for electronic database entry 
The maintenance and calibration of the programmers used for this study will be assessed outside of this 
clinical study. Sites are responsible for maintaining and calibrating non-programmer equipment used in 
the course of this study in accordance with established site practice. Records should be kept and able to 
be provided upon request by the Sponsor or regulatory agency.  
10.5.   Schedule of Events 
Clinical data is collected at designated time points throughout the study as indicated in Table 4 below. 
Data will be collected using eCRFs, an electronic data management system for clinical studies. See 
Section 16.2.   Data Management for more information. At the baseline, 4 week,  8 week, and 12 week 
visits subjects are to fill out the MN Living with Heart Failure Questionnaire and perform a 6 Minute Walk 
Test.  At the same visits, an echocardiogram must be done, for which instructions are provided in an 
Echocardiography Handbook (provided under separate cover). A blood draw must also be done, 

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(instructions are provided under separate cover.) The device programming should occur after all other 
study procedures are complete, except for the final device interrogation and save-to-media. The EQ-5D-
5L Questionnaire will only be collected at the Baseline and 8 week visits. 
In addition to eCRF data, non-eCRF data will be collected to include device interrogation files/save-to-
media and digital echo data. 
Table 4: Study Procedures 
Study Procedure Enroll-
ment Baseline 
Telephone 
Call Follow Up 
Visits 
(24 Hour, 5 
days, 
2 weeks, 
6 weeks, 
10 weeks) 
4 week 
visit 
8 week 
visit 
12 week 
visit 
(Study 
Exit) 
Early 
Study  
Exit  
 
Unscheduled 
Visit 
Informed consent 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
x 
x 
 
 
 
 
 
 
Demographics 
 
x 
 
 
 
 
 
 
Medical History 
 
x 
 
 
 
 
 
 
Medications 
 
x 
X 
x 
X 
x 
X 
x** 
Physical 
Assessment 
 
x 
 
x 
X 
x 
 
x** 
NYHA class 
 
x 
 
x 
X 
x 
 
 
MN Living with 
Heart Failure 
Questionnaire 
 
x 
 
x 
X 
x 
 
 
EQ-5D-5L 
Questionnaire 
 
x 
 
 
X 
 
 
 
6 Minute Walk Test 
 
x 
 
x 
X 
x 
 
 
Echo 
 
x 
 
x 
X 
x 
 
x** 
Blood Draw 
 
x 
 
x 
X 
x 
 
x** 
Initial Device 
Interrogation/Save-
to-media 
 
x 
 
x 
X 
x 
x 
x** 
Device 
Programming 
 
x 
 
x* 
x* 
 
x** 
x** 
Final Device 
Interrogation/ 
Save-to-Media 
 
x 
 
x 
X 
x 
x 
x** 
At least 30 minute 
observation period 
post device 
programming 
 
x 
 
 
 
 
 
 
Symptom 
Assessment 
 
 
X 
x 
X 
x 
 
x** 

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Study Procedure Enroll-
ment Baseline 
Telephone 
Call Follow Up 
Visits 
(24 Hour, 5 
days, 
2 weeks, 
6 weeks, 
10 weeks) 
4 week 
visit 
8 week 
visit 
12 week 
visit 
(Study 
Exit) 
Early 
Study  
Exit  
 
Unscheduled 
Visit 
Heart Rate (using 
finger oximeter) 
 
 
X 
 
 
 
 
 
 
Crossover 
 
 
 
                              As they occur 
System 
modifications 
 
As they occur 
Adverse events 
(AEs)/Death 
 
As they occur 
Device Deficiencies 
 
As they occur 
Study deviations 
 
As they occur 
Study Exits 
As they occur 
 
* See programming recommendations for the follow up visit 
** If deemed necessary by the investigator 
Table 5 below specifies permitted time windows for the required subject visits. Should a subject miss a 
visit or the visit falls outside the pre-specified window, a study deviation must be reported and the 
original follow-up schedule maintained for subsequent visits. Data analyses will include follow-up visits, 
regardless of whether the visit occurs within the window. Therefore, a late visit is preferred over a missed 
visit but must be accompanied by a deviation. 
 
 

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Table 5: Visit windows 
Visit 
Must occur between 
After reference visit 
Baseline 
0 - 30 days 
Enrollment 
24 Hour Phone Call 
0-1 day 
Baseline 
5 Day Phone Call 
2 - 8 days 
Baseline 
2 Week Phone Call 
11 – 17 days 
Baseline 
Randomization – 4 week 
visit 
21 – 35 days 
Baseline 
6 Week Phone Call 
39 – 45 days 
Baseline 
8 Week Visit 
49 – 63 days 
Baseline 
10 Week Phone Call 
67 – 73 days 
Baseline 
12 Week Visit (Exit) 
77 - 91 days 
Baseline 
 
10.6.   Prior and Concomitant Medications 
There are no medication restrictions in the study unless they are investigational and may confound the 
study results, in which case, prior approval would be needed from Medtronic.  
At baseline, 4, 8, and 12 week follow up visits, all telephone call follow up visits, unscheduled visits, and 
early exit visits, cardiovascular medications and the use of insulin will be collected. Cardiovascular 
medications include: ACE inhibitors, ARBs, MRAs, antiarrhythmics, anti-coagulants and antiplatelets, 
antihypertensives, antilipidemics (incl. statins), ß-blockers, calcium channel blockers, diuretics, digitalis, 
inotropes, nitrates, digoxin, and vasodilators. 
10.7.   Subject Consent 
Informed consent is defined as a legally effective documented confirmation of a subject’s voluntary 
agreement to participate in a particular clinical study after information has been given to the subject on 
all aspects of the clinical study that are relevant to the subject’s decision to participate. This process 
includes obtaining an Informed Consent Form and an Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language (data protection authorization) as required by 
law that has been approved by the study site’s IRB, and Medtronic,  and signed and dated by the subject 
and the Principal Investigator or an authorized designee. A subject may only consent after information 
has been given to the subject on all aspects of the clinical study that are relevant to the subject’s decision 
to participate.  
Prior to enrolling subjects, each site must have documented IRB approval of the Informed Consent Form 
(IC Form) and an Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language (data protection authorization) as required by law. Any changes to a 
previously approved Informed Consent Form throughout the course of the study must be reviewed and 
approved by Medtronic and the IRB reviewing the application before being used to obtain consent or re-
consent a study subject. The document(s) must be controlled (i.e. versioned and dated) to ensure it is 
clear which version(s) were approved by Medtronic and the IRB. All important new information should be 
provided in written form to new and existing subjects throughout the study. If relevant, all affected 
subjects must be asked to confirm their continuing informed consent in writing.   

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Prior to initiation of any study-specific procedures, informed consent must be obtained from the subject. 
Likewise, privacy or health information protection regulation may require subjects to sign additional forms 
to authorize sites to submit subject information to the study sponsor. Obtaining informed consent must 
be conducted by the principal investigator or an authorized designee, and the Informed Consent Form 
and an Authorization to Use and Disclose Personal Health Information/Research Authorization/other 
privacy language (data protection authorization), as required by law, must be given to the subject in a 
language he/she is able to read and understand. 
The process of obtaining informed consent shall: 
• 
Ensure that the principal investigator or an authorized designee obtains the informed consent 
process. 
• 
Include all aspects of the clinical study that are relevant to the subject's decision to participate 
throughout the clinical study. 
• 
Avoid any coercion or undue improper influence on, or inducement of the subject to participate. 
• 
Not waive or appear to waive the subject’s legal rights. 
• 
Ensure the Informed Consent Form and an Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language, (data protection authorization) as 
required by law, are given to the subject in a non-technical language the subject is able to read 
and understand. 
• 
Provide ample time and opportunity for the subject to read and understand the Informed 
Consent Form to inquire about details of the study, and to consider participation. All questions 
about the study should be answered to the satisfaction of the subject. 
• 
Include a personally dated signature of the subject acknowledging that their participation in the 
study is voluntary. 
• 
Include a personally dated signature by the principal investigator or authorized designee 
responsible for obtaining the informed consent, as required by local law. 
• 
Provide the subject with a copy of the Informed Consent Form and an Authorization to Use and 
Disclose Personal Health Information/Research Authorization/other privacy language (data 
protection authorization) as required by law. 
• 
Ensure subjects are notified of any significant new findings about the study that become 
available during the course of the study which are pertinent to the safety and well-being of the 
subject, as this could impact a subject’s willingness to participate in the study. 
If the informed consent is obtained the same day the subject begins participating in study-related 
procedures, it must be documented that consent was obtained prior to participation in any study-related 
procedures. It is best practice for the process of obtaining the informed consent to be documented in the 
subject’s case history, regardless of circumstance. 
In the event the subject cannot read and/or write, witnessed (impartial third party) informed consent will 
be allowed, provided detailed documentation of the process of obtaining the informed consent is 
recorded in the subject’s case history and the witness signs and dates the Informed Consent Form. 
Informed consent shall be obtained through a supervised oral process. An independent witness must be 
present throughout the process. The IC Form and any other information must be read aloud and 
explained to the prospective subject, if allowed by local law. The witness signs and personally dates the 
Informed Consent Form attesting that the information was accurately explained and that informed 
consent was freely given. The subject should “make his mark” (sign or otherwise physically mark the 
document so as to indicate consent) on the Informed Consent Form as well. The Informed Consent Form 

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should document the method used for communication with the prospective subject and the specific 
means by which the prospective subject communicated agreement to participate in the study.  
The original of the signed Informed Consent Form must be filed in the hospital/clinical chart and/or with 
the subject’s study documents. 
The Informed Consent Form and an Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language (data protection authorization) as required by 
law, must be available for monitoring, auditing and regulatory inspections. Any Medtronic personnel who 
support the initial programming of the elevated night pacing must be able to review the subject’s signed 
and dated Informed Consent Form and verify its completeness prior to proceeding with the programming. 
In the event the designated Medtronic personnel identify the IC Form as being incomplete, the 
programming will not be allowed to occur until the consent of the subject can be adequately and 
appropriately obtained. 
10.8.   Enrollment 
A subject is considered enrolled when the Informed Consent Form has been signed and dated. The date 
the subject signed the Informed Consent Form and an Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language (data protection authorization) as required by 
law, must be documented in the subject’s medical records. Enrollment can be a stand-alone visit or can 
occur on the same day as the Baseline Visit. Once consent is obtained, report adverse events/deaths, 
study deviations and subject exits as they occur. 
10.9.   Baseline Visit 
The Baseline Visit must occur within 30 days after subject enrollment. The Baseline visit can be a stand-
alone visit or can be performed on the same day as consent is obtained and documented in the subject’s 
medical chart. If eligibility verification at the Baseline visit shows that the subject does not meet all 
inclusion and exclusion criteria the subject must be exited. The device programming should occur after all 
other study procedures are complete, except for the final device interrogation and save-to-media.  
The subject will be provided at the Baseline Visit with a finger pulse oximeter monitor to use at home 
during the telephone follow-up visits to measure their heart rate. The finger pulse oximeter should be 
returned to the site at the study exit visit. 
In the event a subject experiences symptoms at home after the Baseline visit, the subject will be 
instructed to seek medical help to determine the cause of the symptoms. 
The following information is required to be collected at the Baseline visit: 
• 
Verification of Inclusion/Exclusion criteria 
• 
Subject Demographics 
• 
Medical History 
• 
Medications 
• 
Physical Assessment (including height, weight, heart rate and blood pressure) 
• 
NYHA Class 
• 
MN Living with Heart Failure Questionnaire 
• 
EQ-5D-5L Questionnaire 
• 
6 Minute Walk Test 
• 
Echo*  
• 
Blood Draw** 

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• 
Device Interrogation (initial) 
• 
Save-to-Media (initial) 
• 
Device Programming, see Table 6. 
• 
Subject observation of at least 30 minutes to ensure the subject can tolerate 100 bpm pacing 
post programming 
• 
Device Interrogation (final) - this needs to be completed at the end of the visit after 
programming has been completed 
• 
Save-to-Media (final) 
*The Baseline echo must be sent to the Echocardiography Core Laboratory (echo core lab) for analysis, 
with a copy of the echo remaining at the site. Details of the echo core lab, type of echo to be performed, 
and the review process will be provided in an Echocardiography Handbook (provided under separate 
cover). 
** The baseline blood sample must be sent to the Blood Core Laboratory for analysis. Details of the 
blood core lab and the blood draw process will be provided under separate cover. 
10.9.1.   Programming Recommendations at Baseline  
Table 6 lists the programming recommendations applicable to all study subjects. At the Baseline visit, 
when the Sleep Function is turned ON, the pacing rate will remain at the 100 bpm setting until 5:00 am 
the next day. Use of AAI (R) programming is not recommended due to the possibility of AV block 
occurring at higher rate pacing. 
 
 

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Table 6: Programming Recommendations at Baseline 
Parameter 
Elevated Night Pacing ON  
Sleep function 
On† 
Sleep Rate  
Whatever was previously 
programmed as Lower Rate 
Bed Time 
05:00 (5am) †† 
Wake Time 
23:30 (11:30pm) †† 
Pacing Parameter: Lower Rate 
100 bpm 
Rate response 
ON (if previously programmed 
ON) 
ADL 
> 105 bpm 
Rate Profile Optimization 
Off 
ADL Setpoint 
Previously programmed value as 
ADL Setpoint plus 5 
UR Setpoint 
Previously programmed value as 
UR Setpoint plus 5 
† After the Sleep Function is turned ON, any telemetry activation, such as programming, magnet application or CareLink 
transmission – the ongoing sleep function will be terminated which means the programmed rate will jump to 100 bpm. 
If ERI is detected, the pacemaker will turn the Sleep function to Off and the Lower Rate will be reprogrammed to VVI 65 
automatically. 
††If the subject’s normal sleep hours are not during 11:30 pm – 5:00 am, adjust the Bed Time and Wake Time to keep the 5 hours 
of pacing aligned with the time that the subject will likely be sleeping. 
10.10.   Scheduled Follow-Up Phone Calls 
The participating investigator/study coordinator will attempt to reach the subject for phone calls at 
regular intervals after the Baseline visit (24 hours, 5 days, 2 weeks, 6 weeks, 10 weeks) to inquire about 
symptoms and medications. A standard set of questions to use when inquiring about symptoms and 
medications will be provided to the sites. Subjects will also be asked their heart rate, which the subject 
can read using a finger pulse oximeter monitor that will be given to them at Baseline to use. 
10.11.   Randomization (4 Week Follow-Up) 
Subjects will be assigned to a group at random during the randomization visit. Randomization will occur 
at 4 weeks. 
Subjects will be randomized in a 2:1 ratio to the Elevated Night Pacing ON or to the Elevated Night 
Pacing OFF group. 

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Sites will receive this randomization assignment from the randomization schedule, which is automatically 
populated on the eCRF. 
Procedures to be performed and data to be collected at Randomization include: 
• 
Physical Assessment (including weight, heart rate, symptoms, and blood pressure)  
• 
Medications 
• 
NYHA Class 
• 
MN Living with Heart Failure Questionnaire  
• 
6 Minute Walk Test  
• 
Echo* 
• 
Blood Draw** 
• 
Randomization assignment  
• 
Device Interrogation/ (initial) 
• 
Save-to-Media (initial) 
• 
Device Programming, see Table 7: Programming Recommendations at 4 Week Follow-Up 
• 
Device Interrogation (final) - this needs to be completed at the end of the visit after 
programming has been completed 
• 
Save-to-Media (final) 
• 
Adverse Events (report new/assess ongoing AEs), Study Deviations, System Modifications, Device 
Deficiencies, Crossovers (as they occur) 
*The echo must be sent to the Echo Core Laboratory for analysis, with a copy of the echo remaining at 
the site. Details of the Echo Core Laboratory, type of echo to be performed, and the review process will 
be provided in an Echocardiography Handbook (provided under separate cover). 
** The blood sample must be sent to the Blood Core Laboratory for analysis. Details of the blood core lab 
and the blood draw process will be provided under separate cover. 
For any subject who has an abnormal NT-proBNP, troponin or LVEF measurement as defined in the 
Safety Assessment (Section 10.19.   Assessment of Safety) and the investigator elects to discontinue 
elevated night pacing, a subsequent visit will be necessary for the elevated night pacing to be 
programmed OFF if the subject was randomized to the elevated pacing ON arm.  The subject should 
continue to be followed through the 12 week visit. 
10.11.1.   Blinding 
The study will be single blinded (i.e., subjects are blinded to their group) to reduce bias for the duration 
of the study. It is essential that sites, including echocardiography staff, take special precaution to 
maintain the blind for the entire portion of the subject’s participation in the study. Other options to 
maintain the blind may be applied per investigational site research procedure. Refer to the Randomization 
and Blinding Plan for specific details.  
10.11.2.   Programming Recommendations at 4 Week Follow-Up 
Table 7 lists the programming recommendations applicable to study subjects, according to their 
respective randomization assignment. 
 
 

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Table 7: Programming Recommendations at 4 Week Follow-Up 
Parameter 
Elevated Night Pacing ON  
Elevated Night Pacing OFF  
Sleep function 
ON† 
 
Per physician discretion 
Sleep Rate  
Whatever was previously 
programmed as Lower Rate 
Per physician discretion 
Bed Time 
05:00 (5am) †† 
Per physician discretion 
Wake Time 
23:30 (11:30pm) †† 
Per physician discretion 
Pacing Parameter: Lower Rate 
100 bpm 
Per physician discretion 
Rate response 
ON (if previously programmed 
ON) 
Per physician discretion 
ADL 
> 105 bpm 
Per physician discretion 
 
Rate Profile Optimization 
OFF 
Per physician discretion 
 
ADL Setpoint 
Previously programmed value as 
ADL Setpoint plus 5 
Per physician discretion 
UR Setpoint 
Previously programmed value as 
UR Setpoint plus 5 
Per physician discretion 
† After the Sleep Function is turned ON, any telemetry activation, such as programming, magnet application or CareLink 
transmission – the ongoing sleep function will be terminated which means the programmed rate will jump to 100 bpm. 
If ERI is detected, the pacemaker wil automatically turn the Sleep function to Off and program the pacing mode and rate to VVI 65. 
††If the subject’s normal sleep hours are not during 11:30 pm – 5:00 am, adjust the Bed Time and Wake Time to keep the 5 hours 
of pacing aligned with the time that the subject will likely be sleeping. 
 
10.12.   8 Week Follow-Up 
The following procedures must be performed / data are required to be collected at the 8 week visit: 
• 
Physical Assessment (including weight, heart rate, symptoms and blood pressure) 
• 
Medications 
• 
NYHA Class 
• 
MN Living with Heart Failure Questionnaire 
• 
EQ-5D-5L Questionnaire 
• 
6 Minute Walk Test 
• 
Echo* 
• 
Blood Draw** 

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• 
Device Interrogation (initial) 
• 
Save to media (initial) 
• 
Device Programming, see Table 8. 
• 
Device Interrogation (final) - this needs to be completed at the end of the visit after 
programming has been completed 
• 
Save-to-Media (final) 
• 
Adverse Events (report new/assess ongoing AEs), Study Deviations, System Modifications, Device 
Deficiencies, Crossovers (as they occur) 
*The echo must be sent to the Echo Core Laboratory for analysis, with a copy of the echo remaining at 
the site. Details of the Echo Core Laboratory, type of echo to be performed, and the review process will 
be provided in an Echocardiography Handbook (provided under separate cover). 
** The blood sample must be sent to the Blood Core Laboratory for analysis. Details of the blood core lab 
and the blood draw process will be provided under separate cover. 
 10.12.1.   Programming Recommendations 
Table 8 lists the programming recommendations applicable to study subjects who still have elevated 
night pacing ON. (All subjects should have elevated night pacing OFF by the end of the 8 week visit.) 
Table 8: Programming Recommendations at 8 Week Follow-Up 
Parameter 
Elevated Night Pacing OFF  
Sleep function 
 
Per physician discretion 
Sleep Rate  
Per physician discretion 
Bed Time 
Per physician discretion 
Wake Time 
Per physician discretion 
Pacing Parameter: Lower Rate 
Per physician discretion 
Rate response 
Per physician discretion 
ADL 
Per physician discretion 
Rate Profile Optimization 
Per physician discretion 
 
ADL Setpoint 
Per physician discretion 
UR Setpoint 
Per physician discretion 

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10.13.   Unscheduled Follow-Up Visits 
An unscheduled visit is defined as any unplanned visit by the subject to the study site. Routine visits or 
other planned visits are not collected.  
The following information is recommended to be collected at an unscheduled follow-up visit at the 
discretion of the investigator if deemed necessary: 
• 
Physical Assessment (including weight, heart rate, symptoms and blood pressure) 
• 
Medication changes 
• 
Echo* 
• 
Blood draw** 
• 
Device Interrogation (initial) 
• 
Save-to-Media (initial) 
• 
Program the Sleep Function and parameters to protocol 
• 
Device Interrogation (final) - this needs to be completed at the end of the visit after 
programming has been completed 
• 
Save to Media (final) 
 
The following is required: 
 
• 
Adverse Events (report new/assess ongoing AEs) 
• 
Study Deviations 
• 
System Modifications 
• 
Device Deficiencies 
• 
Crossovers 
*The echo must be sent to the Echo Core Laboratory for analysis, with a copy of the echo remaining at 
the site. Details of the Echo Core Laboratory, type of echo to be performed, and the review process will 
be provided in an Echocardiography Handbook (provided under separate cover). 
** The blood sample must be sent to the Blood Core Laboratory for analysis. Details of the blood core lab 
and the blood draw process will be provided under separate cover. 
10.14.  12 Week Visit (Study Exit) 
At the completion of the 12 week follow-up visit, subjects will be exited from the study since this is the 
final visit. The 12 week follow-up visit and exit visit should be combined, and both a 12 week follow-up 
eCRF and a Study Exit eCRF need to be completed.The following procedures must be performed / data 
are required to be collected at the 12 week visit: 
• 
Medications 
• 
Physical Assessment (including weight, heart rate, symptoms and blood pressure) 
• 
NYHA Class 
• 
MN Living with Heart Failure Questionnaire 
• 
6 Minute Walk Test  
• 
Echo* 
• 
Blood Draw** 
• 
Device Interrogation (initial) 
• 
Save to Media (initial) 
• 
Program the sleep function and pacing parameters to elevated night pacing OFF (see Table 8) for 
subjects who still have their pacemaker programmed to elevated night pacing ON.  

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• 
Device Interrogation (final) - this needs to be completed at the end of the visit after 
programming has been completed 
• 
Save-to-Media (final) 
• 
Adverse Events (report new/assess ongoing AEs), Study Deviations, System Modifications, Device 
Deficiencies 
* The echo must be sent to the Echo Core Laboratory for analysis, with a copy of the echo remaining at 
the site. Details of the Echo Core Laboratory, type of echo to be performed, and the review process will 
be provided in an Echocardiography Handbook (provided under separate cover). 
** The blood sample must be sent to the Blood Core Laboratory for analysis. Details of the blood core lab 
and the blood draw process will be provided under separate cover. 
10.15.   Study Exit 
Subjects will be exited from the study for any of the following situations: 
• 
Study completed 
• 
Subject death 
• 
Subject lost to follow-up 
• 
Subject chooses to exit (i.e. revokes informed consent) 
• 
Investigator withdraws subject  
• 
Subject has intolerable symptoms that cannot be alleviated by reprogramming 
A Study Exit eCRF needs to be completed for all subjects with the date and reason for the exit. The 
following should also be collected if applicable: 
• 
Scheduled/Unscheduled Follow Up eCRF, if applicable 
• 
Adverse Events, Study Deviations, System Modifications, Device Deficiencies  
The finger pulse oximeter should be returned to the stie at the study exit visit. After all study tests and 
procedures have been completed and just prior to subject exit from the study, the subject may be 
informed (verbally or in written form) of the subject’s randomization assignment. 
Following exit, subjects will continue to receive standard medical care and should be managed and 
followed per physician discretion. There will be no further required study-related follow-up visits for these 
subjects.  
10.15.1.   Lost to Follow-Up 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two attempts 
to contact the subject, and the method of attempt (e.g., one letter and one phone record, or two letters) 
must be recorded.  
10.15.2.   Subject Does Not Meet Eligibility Criteria 
If eligibility is not met, the subject must be exited prior to study procedures and device programming.  
10.15.3.   Subject chooses to exit (i.e. revokes informed consent) 
A subject can withdraw from the study at any time. If the subject wishes to exit from the study (i.e. the 
subject revokes informed consent), the site is required to document the reason for exit on the Study Exit 
eCRF.  

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10.15.4.   Investigator Withdraws Subject 
No subjects should be withdrawn by investigators unless compelling medical justification is present. It is 
recommended investigators discuss any withdrawals with the study team prior to exiting subjects. If the 
subject was randomized, it is preferred to keep the subject in the study and perform study procedures / 
collect data to the extent possible. If an Investigator withdrawal is necessary, the site is required to 
document the reason for exit on the Study Exit eCRF. 
10.16.   Device Interrogation / Save-to-Media 
For the Baseline, Randomization and in clinic follow-up visits, an initial interrogation and final device 
interrogation file (since last session) must be obtained (.pdd) and saved in a digital format (Save-to-
Media). Store one copy of the save-to-media at the site and send a copy to Medtronic. It is recommended 
that data are not cleared during any interrogation. 
An initial interrogation and final device interrogation (since last session) and Save-to-Media should also 
be completed at the time of study exit, for a crossover, a system modification, and in the case of a death 
(where possible).  
10.17.   System Modification 
A system modification will be reported in the event the device and/or leads require invasive modification 
(e.g. generator or lead explant, generator or lead replacement, lead repositioning, etc.). In the event of a 
system modification, regardless of outcome of the modification, subjects should remain in the study when 
possible and the follow-up visit schedule for the subject will remain unchanged. For a system modification 
the following information/activities are required to be collected: 
• Report the reason for the system modification 
• Report the details of the system modification procedure 
• Device interrogation (initial and final) 
• Save-to-Media (a copy of the interrogation files must be sent to Medtronic with a copy also being 
maintained at the site) 
• Report the associated AE or Device Deficiency, if applicable 
It is recommended that all explanted Medtronic products (device, leads, etc.) are returned to Medtronic 
for analysis per local process and when permissible by local laws and regulations. 
In the event that subject has a re-attempt after a previous unsuccessful system modification, the 
subsequent attempt(s) must be reported via eCRF as separate system modifications. 
10.18.   Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the Clinical 
Investigation Plan or the Clinical Trial Agreement. 
Prior approval by Medtronic is expected in situations where the investigator anticipates, contemplates, or 
makes a conscious decision to deviate. Prior approval is not required when a deviation is necessary to 
protect the safety, rights or well-being of a subject in an emergency or in unforeseen situations beyond 
the investigator’s control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of data 
due to computer malfunction, inability to perform required procedures due to subject illness, blood 
sample or echo lost at Core Lab). 

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For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward. 
This may also apply for other unforeseen situations (e.g. the subject permanently refuses to complete a 
study required procedure and the data will not contribute to the primary end point analysis). However, 
prior approval from Medtronic is required for such situations. 
All study deviations must be reported to Medtronic regardless of whether they are medically justifiable, 
pre-approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency. 
The deviation must be recorded in Oracle Clinical (see Section 10.18.   Deviation Handling) with an 
explanation for the deviations. 
In the event the deviation involves a failure to obtain a subject’s informed consent, or is made to protect 
the life or physical well-being of a subject in an emergency, the deviation must be reported to the IRB as 
well as Medtronic as soon as possible but no later than five (5) working days, or according to local 
requirements.  Reporting of all other study deviations should comply with the IRB policies and/or local 
laws and deviations must be reported to Medtronic as soon as possible upon the site becoming aware of 
the deviation. 
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the Clinical Investigation Plan, conduct 
additional training, terminate the study). Repetitive or serious investigator compliance issues may result 
in initiation of a corrective action plan with the investigator and site, and in some cases, necessitate 
suspending enrollment until the problem is resolved or ultimately terminating the investigator's 
participation in the study. Medtronic may provide site-specific reports to investigators summarizing 
information on deviations that occurred at the investigational site on a periodic basis. 
10.19.   Assessment of Safety 
As a feasibility study, the primary objective is to assess the feasibility of using elevated night pacing as a 
therapy for heart failure with preserved ejection fraction.  This includes assessing the safety and 
tolerability of elevated night pacing, as described in Section 5.1.   Background. Subjects who experience 
intolerable symptoms from the elevated pacing therapy and whose symptoms cannot be reconciled by 
reprogramming may have the elevated night pacing programmed OFF.  NT-proBNP, troponin, assessed 
from peripheral blood samples and LVEF, as assessed by the echo, will be collected at Baseline and at the 
4 week visit. Subjects with increases in NT-proBNP and troponin from Baseline to the 4 week visit should 
be monitored by the investigator for accompanying symptoms, including worsening heart failure and 
cardiac ischemia.  Symptoms should be reported as adverse events and subjects will be considered for 
withdrawal from the study, at the discretion of the investigator.  Subjects with 4 week LVEF < 45% 
whose baseline LVEF was at least 55% may also be considered for withdrawal from the study at the 
discretion of the investigator.  NT-proBNP, troponin and LVEF will be further assessed as discussed in 
Section 10.11.   Randomization (4 Week Follow-Up) and Section 14.1.2.   Ancillary Safety Endpoint – NT-
proBNP, troponin, LVEF. Further information on the collection of Adverse Events is discussed in Section 
12.5.   Reporting of Adverse Events. 
10.20.   Assessment of Efficacy 
Assessment of efficacy will be done on an exploratory basis.  Quality of life, mobility and echo 
measurements will be collected and assessed as discussed in Sections 6.1   Objectives and 14.1.   
Endpoint Definitions. 

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10.21.   Recording Data 
The study will collect data using Oracle Clinical, an electronic data management system for clinical 
studies. Sites will enter data onto eCRFs within an Oracle Clinical database.  
Data reported on the eCRFs shall be derived from source documents, which may include worksheets, 
QOL questionnaires, patient medical records, echo data, blood lab data, programmer printouts and device 
interrogation/save-to-media files. These source documents must be created and maintained by the 
investigational site team. Further detail on data management is provided in Section 16.2.   Data 
Management.   
11.1.  Potential Risks 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life of the product, 
from the research and development phase through the study phase and market release. 
There are risks associated with the elevated night pacing: 
Table 9: Risks Related to Elevated Pacing 
Risk 
Potential Patient Harm 
Mitigation 
Pacing at a sustained 
elevated rate that causes 
symptoms during the day 
or night 
Increased risk of 
Dizziness, palpitations, 
heart racing, shortness of 
breath, difficulty sleeping 
At the time of enrollment, subjects 
will be evaluated to whether they 
can tolerate a pacing rate of 
100bpm 
Subjects will be instructed to call 
study team if they are experiencing 
symptoms 
Symptoms will be gathered from 
subjects using phone calls following 
enrollment, 4 week, and 8 week 
clinic visits 
A programming checklist will be 
used at enrollment, 4 week, 8 
week, and Exit visits to ensure 
appropriate programming of the 
Sleep Function parameters 
Pacing at a sustained 
elevated rate may initiate 
or make heart failure or 
AF or ischemia worse 
Increased risk of chest 
pain, atrial arrhythmia, or 
ischemia 
We are monitoring troponin and 
NT-proBNP levels for worsening 
heart failure and troponin for 
ischemia.  If levels worsen the 
subject will have their elevated 
pacing therapy programmed Off 
Mode-switch during atrial 
arrhythmia results in a 
higher ventricular non-
tracking pacing rate 
because the lower rate is 
programmed to 100bpm 
Increased risk of 
Dizziness, palpitations, 
heart racing, shortness of 
breath 
Symptoms will be gathered from 
subjects using phone calls following 
enrollment, 4 week, and 8 week 
clinic visits 
 

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Pacing at a sustained 
elevated rate that causes 
symptoms following 
unscheduled clinic visits. 
(Any minor telemetry 
activation, such as 
reprogramming, magnet 
application, or CareLink 
transmission will suspend 
the Sleep Function and 
the pacer will start pacing 
at the programmed Lower 
Rate.) 
Increased risk of 
Dizziness, palpitations, 
heart racing, shortness of 
breath 
Subjects will be instructed to call 
study team if they are experiencing 
symptoms 
Subjects will also be asked their 
heart rate, which the subject can 
read using a finger pulse oximeter 
monitor that will be given to them 
at Baseline to use  
Centers will be trained to instruct 
subjects to come to center for 
unscheduled visits 
Misleading information 
that could reasonably lead 
to incorrect pacing 
therapy. (Rate histograms 
will show a higher 
percentage of pacing at 
100bpm.  Clinicians not 
aware of the subject’s 
participation in the study 
may program the Lower 
Rate back to pre-study 
values.) 
No risk to the patient.  
May result in loss of 
usable data for the study. 
 
Subjects will be given a REVAMP 
study ID card 
Negative impact to device 
longevity due to change 
in the pacing rate to 100 
bpm 
Failure to come in for exit 
visit for device 
reprogramming may 
negatively impact device 
longevity by 20% over 
remaining lifetime of 
device.  Premature 
battery depletion which 
could lead to early 
Explant/ revision 
procedure related 
harm (Infection, 
Thrombus, Embolus, 
Hematoma, 
Stroke,Pneumothorax, 
Hemothorax, Nerve 
Damage) 
  
The Patient informed Consent will 
include warnings about the impact to 
battery life of the device, if the patient 
does not adhere to thestudy protocol 
for the 12 week follow up and exit visit 
Missing or Misleading 
information leading to 
adverse operation of the 
device when used in 
combination with other 
features or devices within 
its system 
Risk of additional 
unnecessary elevated 
pacing rates. 
The Clinical Investigation Protocol  and 
training material will include details 
about the device interactions and 
programming recommendations for this 
study 

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Additional information can be found in the Foreseeable Adverse Event List (FAL) in APPENDIX C. 
Subjects who are pregnant are excluded from study participation. If a subject becomes pregnant during 
the study, she must notify the physician immediately. 
There may be other discomforts and risks related to elevated night pacing and this study that are not 
foreseen at this time. The adverse event collection requirements in this study will ensure that risks 
associated with the study are adequately monitored. 
11.2.   Risk Minimization 
Medtronic has minimized the risks to the subject by the following: 
• 
Performing required laboratory and pre-clinical testing prior to the REVAMP clinical study. 
• 
Implementing quality control measures into development and production processes. 
• 
Providing guidelines for subject selection and evaluation, and subject inclusion and exclusion 
criteria. 
• 
Providing adequate instructions and training. 
• 
Selecting investigators that have demonstrated previous experience with the programming, 
interrogation, and monitoring of pacemaker devices. 
• 
After enrollment in the REVAMP clinical study, at each protocol required follow-up, the 
investigator must evaluate the subject’s health, assess for any adverse events, and interrogate 
the study device to verify appropriate study device function. 
11.3.   Potential Benefits 
Elevated pacing rates may offer no benefit. The potential benefits of having the elevated pacing ON for 
this 12 week study include: 
• 
Improvement in exercise capacity 
• 
Improvement in symptoms 
Additionally, information collected from this study may assist in the design of new product(s)/therapy(ies) 
and/or instructions for use. 
11.4.   Risk-Benefit Rationale 
The risk for harm is minimal with this study as the pacing rate is within the FDA-approved programmable 
parameters of the Lower Rate and the Sleep Function, and pacing rates of 100 bpm can occur with 
activities of daily living. There are potential benefits to the subject, as listed in Section 11.3.   Potential 
Benefits. Therefore, the study risk-benefit is acceptable. 
12.   Adverse Event Assessments 
Timely, accurate, and complete reporting and analysis of safety information for clinical studies are crucial 
for the protection of subjects. Medtronic has established procedures to ensure appropriate reporting of 
safety information. 

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 12.1.   Adverse Events 
Adverse Event definitions are provided in Table 10. To ensure that all AEs that are potentially relevant are 
collected, the following will be collected throughout the study duration, starting at the time of signing the 
Informed Consent Form: 
• 
All system related AEs  
• 
All programming related AEs 
• 
All cardiovascular related AEs 
• 
All Serious Adverse Events (SAEs), regardless of relatedness 
In order to fully understand intolerable symptoms and mitigate any safety concerns about elevated night 
pacing, for any subject that exits the study because of intolerable symptoms, the enrolling site should 
report any associated programming related AEs. Reporting of these events to Medtronic will occur on an 
Adverse Event (AE) eCRF. Documented pre-existing conditions are not considered AEs unless the nature 
or severity of the condition has worsened. 
For AEs that require immediate reporting (see Table 12), initial reporting may be done by phone, fax, or 
on the eCRF completing as much information as possible. The original completed AE eCRF must be 
submitted to Medtronic as soon as possible. 
Each adverse event must be reported separately. Any medication, whether cardiovascular or not, 
associated with the treatment of an adverse event must be reported. 
Subject deaths are also required to be reported. Refer to Section 12.6.   Subject Death for Subject Death 
collection and reporting requirements. 
12.2.   Device Deficiencies 
Device Deficiency is defined as an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device Deficiencies will need to be collected in the study. 
Device Deficiency information will be collected throughout the study and reported to Medtronic. 
12.3.   Processing Updates and Resolution 
For any changes in status of a previously reported adverse event (i.e. change in actions taken, change in 
outcome, change in relatedness), information needs to be updated on, or added to the original AE eCRF. 
All adverse events must be followed until the adverse event has been resolved, is unresolved with no 
further actions planned, the subject dies or exits the study, or until study closure, whichever occurs first. 
At the time of study exit, all collected adverse events with an outcome of “Unresolved” must be reviewed 
and an update to the original AE eCRF must be reported. At a minimum, if there are no changes to the 
description, relatedness, test and procedures or actions taken, the outcome must be updated to reflect 
“Unresolved at time of study exit”. 
 
 

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12.4.   Definitions/Classifications 
Where the definition indicates “device”, it refers to any device used in the study. 
Table 10: Adverse Event and Device Deficiency Definitions 
General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory findings) 
in subjects, users or other persons, whether or not related to the 
investigational medical device 
 
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. 
(ISO 14155:2011, 3.2) 
Adverse Device Effect (ADE) 
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. (ISO 14155:2011, 3.1) 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors and 
inadequate labeling (ISO 14155:2011, 3.15) 
Relatedness 
System Related 
 
 
 
An adverse event that results from the presence or performance 
of any component of the system. 
 
Device-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the device.  
RA lead-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the RA lead.  
RV lead-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the RV lead.  
 
Programming Related 
An adverse event that results from the CIP required programming 
for elevated night pacing therapy. 
Cardiovascular Related 
 
 
 
 
An Adverse Event relating to the heart and the blood vessels or 
the circulation, e.g. Atrial Fibrillation, Myocardial Infarction, 
stroke, perivascular disease. 
 
 
 

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Seriousness 
Serious Adverse Event (SAE) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that 
either resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body 
function, 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) led to fetal distress, fetal death or a congenital abnormality 
or birth defect 
 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event. 
(ISO 14155:2011, 3.37) 
 
Unanticipated Adverse Device Effect 
(UADE) 
 
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 a nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan 
or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects. (21 CFR 812.3(s)) 
12.5.   Reporting of Adverse Events 
12.5.1.   Adverse Event and Device Deficiency Classification 
All reported Adverse Events and Device Deficiencies will be reviewed by a Medtronic representative. AEs 
will be classified according to the definitions provided. 
Upon receipt of Adverse Events at Medtronic, a Medtronic representative will review the Adverse 
Event/Device Deficiency for completeness and accuracy and when necessary will request clarification 
and/or additional information from the Investigator. Medtronic will utilize MedDRA, the Medical Dictionary 
for Regulatory Activities, to assign a MedDRA term for each adverse event based on the information 
provided by the investigator. 
Regulatory reporting of AEs and Device Deficiencies will be completed according to local regulatory 
requirements. Refer to Table 12 for a list of required investigator and Medtronic reporting requirements 
and timeframes. It is the responsibility of the investigator to abide by any additional AE reporting 
requirements stipulated by the IRB responsible for oversight of the study. 
APPENDIX C contains the Foreseeable Adverse Event List (FAL), which is a list of adverse events that 
may be experienced by subjects. This list may help to assess if an adverse event is unanticipated in 
nature. 
For emergency contact regarding a UADE, contact a clinical study representative immediately (refer to 
the study contact list provided in the site’s study documents binder/investigator site file or refer to the 
Sponsor Contact Information section provided in the CIP). 

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Adverse Events and Deaths will be classified according to the standard definitions as outlined below: 
Table 11: Adverse Event Classification Responsibilities 
What is 
classified?  
Who 
classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, RA Lead, RV Lead, Programming, Cardiovascular 
Sponsor 
Device, RA Lead, RV Lead, Programming 
Seriousness 
Investigator 
SAE  
Sponsor 
SAE, UADE 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other 
supporting data 
Sponsor 
MedDRA term assigned based on the data provided by 
Investigator 
Death Classification Investigator 
Sudden Cardiac, Non-sudden Cardiac, Non-Cardiac, 
Unknown 
12.5.2.  Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs and device deficiencies will be recorded and reported according to local 
regulatory requirements. It is the responsibility of the Investigator to abide by the adverse event 
reporting requirements stipulated by local law and the site’s IRB. 
Table 12: Reporting Requirements 
Unanticipated Adverse Device Effects (UADEs)  
Investigator submit to: 
Medtronic 
Submit as soon as possible, but no later than within 10 working days after the investigator 
first learns of the event. (21 CFR 812.150(a)(1)) 
IRB 
Submit as soon as possible, but no later than within 10 working days after the investigator 
first learns of the event. (21 CFR 812.150(a)(1)) 
Sponsor submit to: 
Regulatory 
authorities 
 
Submit as soon as possible, but no later than within 10 working days after the sponsor first 
learns of the event. (21 CFR 812.150(b)(1))  
IRB 
Submit as soon as possible, but no later than within 10 working days after the sponsor first 
learns of the event. (21 CFR 812.150(b)(1))  
Investigators Submit as soon as possible, but no later than within 10 working days after the sponsor first 
learns of the event. (21 CFR 812.150(b)(1))  

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12.6.   Subject Death 
12.6.1.   Death Data Collection 
All subject deaths must be reported by the investigator to Medtronic on an Adverse Event eCRF (AE with 
outcome of death) as soon as possible after the investigator first learns of the death.  In case of death, 
there should be one AE with the outcome of death. 
In the event of a subject’s death, it is recommended that the implanted system be explanted and 
returned to Medtronic for analysis whenever possible per local process. Local laws and procedures must 
be followed where applicable. 
System Interrogation Data Recommendations: 
• 
After the subject has died but prior to explant, it is strongly recommended that the system be 
interrogated and a full summary interrogation (Interrogate All) performed when possible, and 
saved in a digital format (Save-to-Media). Store one copy of the save-to-media at the site and 
send a copy to Medtronic. 
• 
Make the device interrogation/save-to-media file before any programming to prevent overwriting 
information in the device’s memory and/or distinguishing between events detected during versus 
before the explant procedure. 
• 
Recommend obtaining the exact date and time of death as lower temperatures after death can 
cause ERI and other “event flags” to be stored in the device memory. 
A copy of the death certificate, if available and allowed by state/local law, should be sent to the 
Medtronic clinical study team. When a death occurs in a hospital, a copy of the death summary report 
and all relevant hospital records should be sent to the Medtronic clinical study team, if available. If an 
autopsy is conducted, the autopsy report should also be sent to the Medtronic clinical study team if 
available and allowed by state/local law. When the death occurs at a remote site, it is the investigative 
site’s responsibility to attempt retrieval of information about the death. Additionally, device disposition 
information should be updated. In summary, the following data will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to system and/or procedure 
• 
Device interrogation and Save-to-Media (if available) 
• 
Device disposition information 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and allowed by state/local law) 
12.6.2.  Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s death. The Investigator 
shall classify each subject death per the following definitions: 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the heart. 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; preexisting heart disease may have been 
known to be present, but the time and mode of death are unexpected. If time of onset cannot be 

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determined, SCD will alternatively be defined as any unexpected cardiac death occurring out of the 
hospital or in the emergency room as dead on arrival. 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, including all 
cardiac deaths of hospitalized subjects on inotropic support. 
Non-cardiac Death: A death not classified as a cardiac death. 
Unknown Classification: Unknown death classification is intended for use only when there is insufficient or 
inadequate information to classify the death. 
Table 13: Subject Death Classification Responsibilities 
What is 
classified?  
Who 
classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, RA Lead, RV Lead, Programming 
Death Classification Investigator 
Sudden Cardiac, Non-sudden Cardiac, Non-cardiac, 
Unknown 
Regulatory reporting of Subject Deaths will be completed according to local regulatory requirements. 
12.7.   Product Complaint Reporting 
All devices used in the study will be market released at study start. Therefore, product complaint 
reporting is applicable and AEs related to any market-released device during the study must be reported. 
The reporting of product complaints is not part of the clinical study and should be done in addition to the 
Adverse Event reporting requirements.  Refer to local regulations for reporting requirements. 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness or performance of a medical device that has 
been placed on the market. 
13.   Data Review Committees 
13.1.   Echocardiography Core Laboratory 
The study will utilize an Echocardiography Core Laboratory (echo core lab). The echo core lab will 
complete data analysis on all study echoes required to be performed (Baseline, 4 week, 8 week, and 12 
week). An echocardiogram will be performed as described in the Echocardiography Handbook (provided 
under separate cover).   
The echo core lab will be blinded to subjects’ randomization assignment. Echoes sent to the core lab for 
analysis will be labeled in such a way to maintain the blind and not provide information that would inform 
which visit the echo was collected. 
13.2.   Blood Core Laboratory 
The study will utilize a Blood Core Laboratory (blood core lab). The blood core lab will complete data 
analysis on all study blood samples required to be performed (Baseline, 4 week, 8 week, and 12 week). 
Details of the blood core lab and the blood draw process will be provided under separate cover. 

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14.   Statistical Design and Methods 
This feasibility study is not powered to formally test a hypothesis.  However, it is expected that a sample 
of up to 30 subjects will be sufficient to determine whether this approach warrants further study.  The 4 
week safety and tolerability objective described in Section 14.1.1.   Ancillary Safety and Tolerability 
Endpoint will help determine whether to move forward with this therapy.  Figure 3 indicates that 
improvements in the confidence interval width at various proportions of subjects meeting the 4 week 
safety and tolerability endpoint beyond 30 subjects are relatively small. 
 
 

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Figure 3: 95% Confidence Interval Widths for Various Proportions of 4 Week Safety 
and Tolerability Endpoint 
 
 
C.I. Width vs N with C.L.=0.95 P=0.500 C.I. One
Proportion
C.I. Width
N
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0
10
20
30
40
50
C.I. Width vs N with C.L.=0.95 P=0.700 C.I. One
Proportion
C.I. Width
N
0.1
0.2
0.3
0.4
0.5
0
10
20
30
40
50

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This section presents statistical considerations for the study design and provides a high-level description 
of planned analysis and reporting. More details will be given in a separate Statistical Analysis Plan (SAP) 
that will be completed before data freeze and unblinding for the primary objective analysis. Any deviation 
to the pre-specified statistical analyses will be noted in the study report. 
As part of the exploratory/ancillary safety, tolerability and efficacy effects described in 10.20.   
Assessment of Efficacy, it will be of interest to characterize changes in collected measurements from 
baseline to 4 weeks, compare changes in collected measurements at 4 weeks to 8 weeks in the subjects 
randomized to the elevated night pacing ON arm to subjects randomized to the elevated night pacing 
OFF arm and compare changes in collected measurements at 12 weeks to Baseline, 4 and 8 weeks to see 
whether any therapeutic improvements are sustained after the therapy is discontinued. 
The 4 week endpoints will characterize the magnitude of change as a result of the therapy.  For MNLWHF 
and the 6 Minute Walk Test, positive changes could be due to placebo-related effects, since this phase of 
the study is single arm and unblinded.  Efficacy changes from the 4 week to the 8 week visit in the ON 
arm versus the OFF arm would be indicative of actual therapeutic effects of elevated night pacing, as 
blinding would help mitigate any placebo effect. Safety and tolerability changes from the 4 week to the 8 
week visit in the ON arm versus the OFF arm would be indicative of long term safety and tolerability of 
elevated night pacing for subjects for which the first 4 weeks of therapy were safe and tolerable. 
If there are changes in any of the efficacy measurements from baseline to week 4 and/or improvements 
in any of the efficacy measurements in the ON arm compared to the OFF arm from week 4 to week 8, 
there may be additional analyses on the extracellular matrix biomarkers to correlate to the efficacy 
improvements. 
C.I. Width vs N with C.L.=0.95 P=0.900 C.I. One
Proportion
C.I. Width
N
0.0
0.1
0.2
0.3
0.4
0.5
0
10
20
30
40
50

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14.1.   Endpoint Definitions 
14.1.1.   Ancillary Safety and Tolerability Endpoint  
Safety and Tolerability – 4 weeks 
 
Hypothesis 
A 4 week period of elevated night pacing is safe and tolerable.   
 
Analysis Methods 
The proportion of subjects who remain in the study up until the 4 week visit without exiting 
due to intolerable symptoms, increase in NT-proBNP levels, decrease in LVEF or increase in 
troponin will be calculated along with the lower bound of the one-sided 95% confidence 
interval 
 
Determination of Subjects for Analysis 
All enrolled subjects that are programmed with elevated night pacing. 
 
Safety and Tolerability – 8 weeks 
 
Hypothesis 
Following a 4 week period of elevated night pacing, compare the safety and tolerability of 
subjects in the ON and OFF arm for an additional 4 weeks of elevated night pacing 
 
Analysis Methods 
The proportion of subjects who remain in the study from the 4 week visit to the 8 week visit 
without exiting due to intolerable symptoms, increase in NT-proBNP levels, decrease in LVEF 
or increase in troponin will be calculated along with the lower bound of the one-sided 95% 
confidence interval for both arms (elevated night pacing left ON versus elevated night pacing 
programmed OFF). 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this analysis. 
14.1.2.   Ancillary Safety Endpoint – NT-proBNP, troponin, LVEF 
NT-proBNP, troponin, LVEF – 4 weeks 
 
Hypothesis 
For each of the main safety measures (NT-proBNP, troponin and LVEF), comparisons will be 
done to see if there are changes from baseline after a 4 week period of elevated night 
pacing. 
Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A two-sided paired t-test will be performed testing the 
hypothesis 
Ho:  = 0 
 
 
Ha:  ≠ 0 
 
 
Where = difference in measurement from baseline to week 4 visit 

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Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
NT-proBNP, troponin, LVEF – 8 weeks 
Hypothesis 
For each of the main safety measures (NT-proBNP, troponin and LVEF), it will be assessed 
whether there is a difference in the change of the measurement following an additional 4 
week period of elevated night pacing after an initial 4 week period of elevated night pacing 
compared to that period of 4 weeks with the elevated night pacing programmed OFF after 
the initial 4 weeks period of elevated night pacing. 
Analysis Methods 
A paired comparison of the measurement at the 8 week visit compared to the scored at the 4 
week visit period compared to the value at the start of the period will be calculated.  A two-
sided paired t-test will be performed testing the hypothesis 
Ho:  = OFF 
 
 
Ha: ≠ OFF 
Where = difference in NT-proBNP, troponin or LVEF from week 4 to week 8 for subjects 
in the ON arm and OFF= difference in those measurements in subjects in the OFF arm 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  NT-proBNP, troponin or LVEF 
at time of exit will be used for subjects that do not complete the full 4 weeks of participation 
in the study from week 4 to week 8. 
14.1.3.   Ancillary Safety Endpoint – Adverse Events 
Adverse Events – 4 weeks 
 
Hypothesis 
Not applicable.  This endpoint is to characterize adverse events during the first 4 weeks of 
elevated night pacing. 
Analysis Methods 
Summarization of adverse events by MedDRA preferred term.  Summarization may include 
pertinent subgroups, including all potentially related events and all CV-related events. 
Determination of Subjects for Analysis 
All adverse events reported for subjects actively receiving elevated night pacing will be 
included. 
Adverse Events – 8 weeks 
Hypothesis 
There are differential rates of adverse event reporting between subjects randomized to 
receive elevated night pacing and subjects randomized to elevated night pacing OFF.  In 
addtion, adverse events for subjects continuing to receive elevated night pacing will be 
characterized and extended from the AE’s collected during the first 4 weeks. 
Analysis Methods 
The adverse reporting rate during the period from week 4 to week 8 in subjects in the ON 
arm and OFF arm will be compared and characterized. 

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Determination of Subjects for Analysis 
Rates of adverse events for subjects randomized to OFF will be calculated over the full period 
of follow-up, while rates of adverse events for subjects randomized to ON will be calculated 
only during the period that subjects were actually receiving elevated night pacing. 
14.1.4.   Ancillary Efficacy Endpoint - Quality of Life  
MNLWHF Questionnaire – 4 weeks 
 
Hypothesis 
There is an improvement in quality of life from baseline after a 4 week period of elevated 
night pacing, as assessed by the MNLWHF Questionnaire. 
Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A one-sided paired t-test will be performed testing the 
hypothesis 
Ho:  ≤ 0 
 
 
Ha:  > 0 
 
 
Where = difference in MNLWHF score from baseline to week 4 visit 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
MNLWHF Questionnaire – 8 weeks 
Hypothesis 
There is an improvement in quality of life of an additional 4 week period of elevated night 
pacing after an initial 4 week period of elevated night pacing compared to that period of 4 
weeks with the elevated night pacing programmed OFF after the initial 4 weeks period of 
elevated night pacing, as assessed by the MNLWHF Questionnaire. 
Analysis Methods 
A paired comparison of the scores at the 8 week visit compared to the scores at the 4 week 
visit period will be calculated.  A one-sided paired t-test will be performed testing the 
hypothesis 
Ho: ≤ OFF 
 
 
Ha:  > OFF 
 
 
Where  = difference in MNLWHF score from week 4 to week 8 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  MNLWHF score at time of exit 
will be used for subjects that do not complete the full 4 weeks of participation in the study 
from week 4 to week 8. 
EQ-5D-5L Questionnaire – 8 weeks 
Hypothesis 
There is an improvement in quality of life from baseline after an 8 week period of elevated 
night pacing, as assessed by the EQ-5D-5L Questionnaire.  This assumes the effect is the 
same whether or not elevated nice pacing is turned off at week 4. 
 

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Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A one-sided paired t-test will be performed testing the 
hypothesis 
Ho:  ≤ 0 
 
 
Ha:  > 0 
 
 
Where = difference in EQ-5D-5L score from baseline to week 8 visit 
Determination of Subjects for Analysis 
All subjects that completed 8 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis.  EQ-5D-5L score at time of exit will be 
used for subjects that do not complete the full 4 weeks of participation in the study from 
week 4 to week 8. 
Hypothesis 
There is more of an improvement in quality of life after an 8 week period of elevated night 
pacing than for a 4 week period of elevated night pacing followed by 4 weeks with the 
elevated night pacing programmed OFF after the initial 4 weeks period of elevated night 
pacing, as assessed by the EQ-5D-5L Questionnaire. 
Analysis Methods 
A paired comparison of the scores at the 8 week visit compared to the scored at the baseline 
visit will be calculated.  A one-sided paired t-test will be performed testing the hypothesis 
Ho: ≤ OFF 
 
 
Ha:  > OFF 
 
 
Where  = difference in EQ-5D-5L score from baseline to week 8 
Determination of Subjects for Analysis 
All subjects that completed 8 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis.  EQ-5D-5L score at time of exit will be 
used for subjects that do not complete the full 4 weeks of participation in the study from 
week 4 to week 8. 
14.1.5.   Ancillary Efficacy Endpoint - Mobility and Activity 
 
6 Minute Walk Test Distance – 4 weeks 
Hypothesis 
There is an improvement in the 6 Minute Walk Test distance from baseline after a 4 week 
period of elevated night pacing. 
Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A one-sided paired t-test will be performed testing the 
hypothesis 
Ho:  ≤ 0 
 
 
Ha:  > 0 
 
 
Where µ = difference in 6 Minute Walk Test distance from baseline to week 4 visit  
  

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Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
 
6 Minute Walk Test Distance – 8 weeks 
Hypothesis 
There is an improvement in the 6 Minute Walk Test distance from an additional 4 week 
period of elevated night pacing after an initial 4 week period of elevated night pacing 
compared to that period of 4 weeks with the elevated night pacing programmed OFF after 
the initial 4 weeks period of elevated night pacing. 
Analysis Methods 
A paired comparison of the scores at the 8 week visit compared to the scored at the 4 week 
visit period compared to the value at the start of the period will be calculated.  A one-sided 
paired t-test will be performed testing the hypothesis 
Ho:  ≤ OFF 
 
 
Ha:  > OFF 
Where  = difference in MNLWHF score from week 4 to week 8 in subjects 
randomized to the ON arm and OFF  = difference in 6 Minute Hall Walk Test distance 
from week 4 to week 8 in subjects randomized to the OFF arm 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  6 Minute Walk Test distance at 
time of exit will be used for subjects that do not complete the full 4 weeks of participation in 
the study from week 4 to week 8. 
 
 
Device-measured activity levels – 4 weeks 
Hypothesis 
There is an improvement in daytime activity levels from baseline over a 4 week period of 
elevated night pacing. 
Analysis Methods 
Activity levels over time will be characterized over time from baseline to the 4 week visit. 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
 
Device-measured activity levels – 8 weeks 
Hypothesis 
There is an improvement in daytime activity levels over an additional 4 week period of 
elevated night pacing after an initial 4 week period of elevated night pacing compared to that 
period of 4 weeks with the elevated night pacing programmed OFF after the initial 4 weeks 
period of elevated night pacing. 
 
 

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Analysis Methods 
Activity levels over time will be characterized over time from the 4 week visit to the 8 week 
visit and compared between the subjects with the elevated pacing programmed ON versus 
OFF. 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Daytime activity levels up to 
time of exit will be used for subjects that do not complete the full 4 weeks of participation in 
the study from week 4 to week 8. 
14.1.6.   Ancillary Efficacy Endpoint – Echo Measurements 
Echo measurements – 4 weeks 
 
Hypothesis 
All echo measurements will be assessed to see if there are changes from baseline after a 4 
week period of elevated night pacing. 
Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A two-sided paired t-test will be performed testing the 
hypothesis 
Ho:  = 0 
 
 
Ha:  ≠ 0 
 
 
Where = difference in measurement from baseline to week 4 visit 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
 
Echo measurements – 8 weeks 
 
Hypothesis 
All echo measurements will be assessed to determine whether there is a difference in the 
change of the measurement following an additional 4 week period of elevated night pacing 
after an initial 4 week period of elevated night pacing compared to that period of 4 weeks 
with the elevated night pacing programmed OFF after the initial 4 weeks period of elevated 
night pacing. 
Analysis Methods 
A paired comparison of the measurement at the 8 week visit compared to the scored at the 4 
week visit period compared to the value at the start of the period will be calculated.  A two-
sided paired t-test will be performed testing the hypothesis 
Ho:  = OFF 
 
 
Ha:  ≠ OFF 
Where  = difference in echo measurement from week 4 to week 8 in subjects 
randomized to the ON arm and OFF  = difference in echo measurement from week 4 to 
week 8 in subjects randomized to the OFF arm 
 
 

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Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Echo measurement at time of 
exit will be used for subjects that do not complete the full 4 weeks of participation in the 
study from week 4 to week 8. 
14.1.7.   Ancillary Efficacy Endpoint – Collagen Degradation Biomarker 
Measurements 
Biomarker measurements – 4 weeks 
 
Hypothesis 
If the results of the safety, tolerability and efficacy of elevated night pacing appear to be 
promising, additional work may be done to assess collagen degradation biomarker 
measurements  to see if there are changes from baseline after a 4 week period of elevated 
night pacing. 
Analysis Methods 
A paired comparison of the value at the end of the period compared to the value at the start 
of the period will be calculated.  A two-sided paired t-test will be performed testing the 
hypothesis 
Ho:  = 0 
 
 
Ha:  ≠ 0 
 
 
Where = difference in measurement from baseline to week 4 visit 
Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Subjects that were unable to 
tolerate or withdrew from the treatment during the first 4 weeks because of safety or other 
issues will not be included in this efficacy analysis. 
 
Biomarker measurements – 8 weeks 
 
Hypothesis 
If the results of the safety, tolerability and efficacy of elevated night pacing appear to be 
promising, additional work may be done to determine whether there is a difference in the 
change in the collagen degradation biomarker measurements following an additional 4 week 
period of elevated night pacing after an initial 4 week period of elevated night pacing 
compared to that period of 4 weeks with the elevated night pacing programmed OFF after 
the initial 4 weeks period of elevated night pacing. 
Analysis Methods 
A paired comparison of the measurement at the 8 week visit compared to the scored at the 4 
week visit period compared to the value at the start of the period will be calculated.  A two-
sided paired t-test will be performed testing the hypothesis 
Ho:  = OFF 
 
 
Ha:  ≠ OFF 
Where  = difference in collagen degradation biomarker measurement from week 4 
to week 8 in subjects randomized to the ON arm andOFF  = difference in collagen 
degradation biomarker measurement from week 4 to week 8 in subjects randomized to 
the OFF arm 

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Determination of Subjects for Analysis 
All subjects that completed 4 weeks of elevated night pacing.  Biomarker measurement at 
time of exit will be used for subjects that do not complete the full 4 weeks of participation in 
the study from week 4 to week 8. 
14.1.8.   Ancillary Efficacy Endpoint – Sustained effects of elevated night pacing 
Hypothesis 
it will be explored whether there are sustained effects of elevated night pacing. 
Analysis Methods 
These analyses will be exploratory in nature, involving characterizing changes from baseline 
and end of therapy to the last follow-up visit. 
Determination of Subjects for Analysis 
All subjects that have follow-up visits after elevated night pacing was programmed OFF.  This 
will include subjects completed 12 weeks of follow-up and subjects that had elevated night 
pacing programmed OFF at 4 weeks and completed 8 weeks of follow-up. 
15.   Ethics 
15.1.   Statement(s) of Compliance  
REGULATORY COMPLIANCE 
This REVAMP study will be conducted in compliance with international ethical and scientific quality 
standards, known as good clinical practice (GCP). The study was designed to reflect the GCP principles 
outlined in ISO 14155:2011. GCP includes review and approval by an independent IRB before initiating 
and obtaining and documenting the freely given patient informed consent of a subject before initiating 
the study. 
The study will be conducted according to federal, national and local laws, regulations, standards, and 
requirements where the study is being conducted. The principles of the Declaration of Helsinki have been 
implemented through the patient informed consent process, IRB approval, study training, clinical trial 
registration, preclinical testing, risk-benefit assessment and publication policy. 
The REVAMP study will be conducted as a Non-Significant Risk (NSR) IDE study. The study will be 
conducted in compliance with 21 CFR Parts 11, 50, 56, 812.2(b)(1). This study does not require an IDE 
submission to FDA.  
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act FDAAA and Declaration of Helsinki on http://www.clinicaltrials.gov (PL 
110-85, section 810(a)). 
Approval of the CIP and CIP amendments is required from the following groups prior to any study 
procedures at a study center: 
• 
Medtronic 
• 
An Institutional Review Board at each individual study center 
Similarly, approval of subsequent revisions to the CIP is required at each study center from the above 
mentioned groups prior to implementation of the revised CIP at that center. 
 

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16.   Study Administration 
16.1.   Monitoring  
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  Trained Medtronic 
personnel or delegates appointed by Medtronic may perform study monitoring at the study site in order 
to ensure that the study is conducted in accordance with the CIP, the Clinical Trial Agreement or Work 
Order, and applicable regulatory and local requirements. Medtronic, or delegates, must therefore be 
allowed access to the subjects’ case histories (clinic and hospital records, and other source 
data/documentation) upon request as per the Informed Consent Form and Authorization to Use and 
Disclose Personal Health Information/Research Authorization/other privacy language (data protection 
authorization) as required by law and Clinical Trial Agreement or Work Order.  The principal investigator 
should also be available during monitoring visits. 
Monitoring for the study will be done in accordance to the study-specific monitoring plan. 
Monitoring visits may be conducted periodically to assess site study progress, the investigator’s 
adherence to the CIP, regulatory compliance including but not limited to IRB approval and review of the 
study, maintenance of records and reports, and review of source documents against subject eCRFs. 
Monitors review site regulatory and study compliance by identifying findings of non-compliance and 
communicating those findings along with recommendations for preventative/corrective actions to site 
personnel.  Monitors may work with study personnel to determine appropriate corrective action 
recommendations and to identify trends within the study or at a particular site. Regulatory documents 
may be reviewed at each study site. 
Frequency of monitoring visits may be based upon subject enrollment, duration of the study, study 
compliance, number of adverse events, number of deviations, findings from previous monitoring visits 
and any suspected inconsistency in data that requires investigation. 
16.2.   Data Management 
Data will be collected using Oracle Clinical, an electronic data management system for clinical studies.  
CRF data will be stored in a secure, password-protected database which will be backed up nightly.  Data 
will be reviewed using programmed and manual data checks.  Data queries will be made available to sites 
for resolution.  Study management reports may be generated to monitor data quality and study progress.  
At the end of the study, the data will be frozen and will be retained indefinitely by Medtronic. 
All records and other information about subjects participating in this study will be treated as confidential. 
Data will be transferred and processed by Medtronic or a third party designated by Medtronic in a key 
coded form, unless it’s impossible to make it anonymous, for instance, where the subject’s name cannot 
be removed from the data carrier. 
Procedures in the CIP require source documentation.  Source documentation will be maintained at the 
site. Source  may include worksheets, patient medical records, echo data, programmer printouts, device 
interrogation files, and certain CRF fields which must be created and maintained by the investigational 
site team. 
The data reported on the eCRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing. Save-to-media data collected at 

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office visits will be sent to Medtronic.  Upon receipt, device data will be maintained within a Medtronic 
device database and retrieved for analysis and reporting. 
16.3.   Direct Access to Source Data/Documents  
The sponsor or a regulatory authority may audit or inspect the study site to evaluate the conduct of the 
study. The clinical investigator(s)/institution(s) shall allow study related monitoring, audits, IRB review 
and regulatory inspection by providing direct access to source data/documents. 
16.4.   Confidentiality 
All records and other information about subjects participating in this study will be treated as confidential. 
See Section 16.2.   Data Management for further information. 
16.5.   CIP Amendments 
Approval of subsequent revisions to the CIP is required at each study site from the following groups prior 
to implementation of the revised CIP at the site: 
• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
An independent institutional review board. 
If a CIP amendment occurs, site personnel will need to be re-trained as necessary, and will need to 
submit any changes to their IRB. 
16.6.   Warranty/Insurance Information 
16.6.1.   Warranty 
Warranty information is provided in the product packaging for the commercially released pacemaker 
devices and leads, and additional copies are available upon request. 
16.7.   Record Retention 
16.7.1.   Investigator Records 
The investigator is responsible for the preparation and retention of the records including, but not limited 
to, those cited below. All of the below records, with the exception of case history records and case report 
forms, should be kept in the Investigator Site File (i.e., the study binder provided to the investigator) or 
Subject Study Binder. eCRFs must be maintained and signed electronically by an investigator within the 
electronic data capture system during the study. The following records are subject to inspection and must 
be retained for a period of two years (or longer as local law/regulation or hospital administration 
requires) after product approval. Measures shall be taken to avoid loss or premature destruction. 
• 
All correspondence between the IRB, sponsor, monitor, and/or the investigator that pertains to 
the investigation, including required reports. 
• 
Subject’s case history records, including:  
o 
Signed and dated Informed Consent Form, in accordance with local requirements 

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o 
Observations of adverse events/adverse device effects/device deficiencies 
o 
Medical history 
o 
Baseline and follow-up data (if applicable) 
o 
Documentation of the dates and rationale for any deviation from the protocol 
• 
Electronically signed and dated eCRFs and a blank set of eCRFs where required by local law 
• 
All approved versions of the CIP and IC Form 
• 
Signed and dated Clinical Trial Agreement or Work Order 
• 
IRB approval documentation. Written information that the investigator or other study staff, when 
member of the IRB, did not participate in the approval process. Approval documentation must 
include the IRB composition, where required per local law.   
• 
List of investigation sites 
• 
Randomization list 
• 
Current curriculum vitae of principal investigators  
• 
Documentation of delegated tasks 
• 
Study training records for site staff  
• 
Final Study Report including the statistical analysis 
16.7.2.   Investigator Reports 
The investigator is responsible to prepare and submit the following complete, accurate, and timely 
reports: 
Table 14: Investigator Reports for the United States 
Report  
Submit to 
Description/Constraints 
Unanticipated 
adverse device 
effects 
Sponsor and 
IRB/MEC 
The investigator shall submit to the sponsor and reviewing 
IRB as soon as possible, but no later than 10 working days 
after the investigator first learns of the effect. (21 CFR 
812.150 (a)(1)) 
Withdrawal of 
IRB/MEC approval 
(either suspension or 
termination) 
Sponsor 
The investigator must report a withdrawal of approval by 
the reviewing IRB/MEC of the investigator’s part of the 
investigation within 5 working days. (21 CFR 
812.150(a)(2)) 
Failure to obtain 
informed consent  
IRB 
Investigator’s report will be submitted to IRB within five 
working days of notification.  (21 CFR 812.150(a)(5)) 
Other 
IRB/MEC and FDA 
An investigator shall, upon request by a reviewing 
IRB/MEC, FDA or any other regulatory agency, provide 
accurate, complete, and current information about any 
aspect of the investigation. (21 CFR 812.150(a)(7)) 
 
Reports are subject to inspection and to the retention requirements as described above for investigator 
records. 
Investigator reporting requirements for safety data are listed in Section 12.   Adverse Event Assessments. 
 
 

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16.7.3.   Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records that includes, but is not 
limited to: 
• 
All correspondence which pertains to the clinical study 
• 
Executed Clinical Trial Agreement 
• 
Randomization List 
• 
Current curriculum vitae of principal investigators  
• 
Electronically signed and dated eCRFs 
• 
All approved informed consent templates, and other information provided to the subjects and 
advertisements, including translations 
• 
Copies of all IRB approval letters and relevant IRB correspondence and IRB voting 
list/roster/letter of assurance 
• 
Names of the institutions in which the clinical study will be conducted 
• 
Names/contact addresses of monitors 
• 
Monitoring reports (interim monitoring visit reports, follow-up letters and close-out visit reports) 
• 
Site qualification visit reports 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the clinical study 
• 
The approved Clinical Investigation Plan, study related reports, and revisions 
• 
Documentation of delegated tasks 
• 
Study training records for site personnel and Medtronic personnel involved in the study 
• 
Sample of CRFs 
• 
Any other records that local regulatory agencies require to be maintained 
16.7.4.   Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in the 
tables below. In addition to the reports listed below, Medtronic shall, upon request of reviewing IRB or 
FDA, provide accurate, complete and current information about any aspect of the clinical study. Safety 
data Medtronic reporting requirements are listed in Section 12.   Adverse Event Assessments. 
 
 

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Table 15: Sponsor Reports for the United States 
Report  
Submit to 
Description/Constraints 
Withdrawal of IRB 
approval 
Investigators, IRB 
 
Notification within five working days after receipt of the 
withdrawal of approval.  (21 CFR 812.150(b)(2))   
Progress Reports 
IRB 
 
Progress reports will be submitted at least annually.  (21 
CFR 812.150(b)(5), 812.36(f)   
Failure to obtain 
informed consent 
MDT, IRB 
Investigator’s report will be submitted to IRB within five 
working days of notification.  (21 CFR 812.150(b)(8)) 
Final report 
Investigators and 
IRB 
A final report will be submitted to investigators, and 
IRBs/MECs within six months after completion or 
termination of this study.  (21 CFR 812.150(b)(7)) 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and 
the final report of the clinical investigation.  
Site specific study deviations will be submitted to 
investigators periodically.   
 
Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in secured file cabinets at Medtronic 
during the course of this study. After closure of the study Medtronic will archive records and reports as 
required by applicable regulations. 
16.8.   Publication and Use of Information 
Publications from the REVAMP clinical study will be handled according to Medtronic Policies and Standard 
Operating Procedures and as indicated in the Clinical Trial Agreement or Work Order. 
16.8.1.   Publication Committee 
The REVAMP clinical study will utilize a Publication Committee which will include the Steering Committee 
members as well as Medtronic personnel. This committee will manage study publications with the goal of 
publishing findings from the data. The Publication Committee may develop the final Publication Plan as a 
separate document. 
The Publication Committee’s role is to: 
• 
manage elements addressed in the publication plan as outlined in this section 
• 
develop the final Publication Plan under separate cover, as needed 
• 
execute the Publication Plan 
• 
oversee the publication of primary, secondary and ancillary study results 
• 
review and prioritize publication proposals 
• 
provide input on publication content, and  
• 
determine authorship 
In addition, the committee will apply and reinforce the authorship guidelines set forth in the Publication 
Plan. Membership in the Publication Committee does not guarantee authorship. The committee will meet 
as needed. 

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16.8.2.   Management of Primary, Secondary, and Ancillary Publications 
The Publication Committee reviews, prioritizes and manages all publications including primary, secondary 
and ancillary publications. Primary and secondary publications are those that address analyses of any or 
all primary objectives or secondary/ancillary objectives, respectively, as specified in the Clinical 
Investigation Plan. An ancillary publication is any publication that does not address the study objectives 
identified in the Clinical Investigation Plan. They include publications proposed and developed by other 
Medtronic departments or entities, clinicians participating in this clinical study and clinicians not 
participating in this clinical study. The committee will work with Medtronic to ensure that requests do not 
present conflicts with other proposals, are not duplicative and to determine which ancillary publication 
proposals, if any, will be supported. 
The committee may decide that no publications, including abstracts, will be published prior to the end of 
the study or with individual site data. Requests for publications on study objectives utilizing subset data 
(e.g., regional) will be evaluated for scientific validity and the ability of Medtronic to provide resources.  
16.8.3.   Criteria for Determining Authorship  
Publications will adhere to authorship criteria defined by the International Committee of Medical Journal 
Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, www.icmje.org).  
Individual authorship criteria defined by the target journal or conference will be followed when it differs 
from ICMJE criteria. 
Authors, including Medtronic personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contribution to conception and design, or acquisition of data, or analysis and 
interpretation of data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
Decisions regarding authorship and contributor-ship will be made by the publication committee. The 
selected authors will be responsible for drafting the publication. All selected authors must fulfill the 
authorship conditions stated above to be listed as authors, and all contributors who fulfill the conditions 
must be listed as authors. 
All investigators not listed as co-authors will be acknowledged as the “Medtronic REVAMP Clinical Study 
Investigators” and will be individually listed according to the guidelines of the applicable scientific journal 
when possible. Any other contributors will be acknowledged by name with their specific contribution 
indicated. 
16.8.4.   Transparency 
Transparency of study results will be maintained by the following means: 
• 
a final report, describing the results of all objectives and analysis, will be distributed to all 
investigators and IRBs. 
• 
registering and posting the study results on ClinicalTrials.gov based on the posting rules 
stipulated  
• 
submitting for publication the primary study results after the study ends  
• 
disclosing conflicts of interest (e.g. financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences  

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• 
making an individual sites study data accessible to the corresponding investigator after the 
completion of the study, if requested  
16.9.   Suspension or Early Termination 
16.9.1.   Planned Study Closure 
Study Closure is a process initiated by distribution of a study closure letter. Study closure is defined as 
closure of a clinical study that occurs when Medtronic and/or regulatory requirements have been satisfied 
per the Clinical Investigation Plan and/or by a decision by Medtronic or regulatory authority, whichever 
occurs first. The study closure process is complete upon distribution of the Final Report or after final 
payments, whichever occurs last. Ongoing IRB oversight is required until the overall study closure 
process is complete. Upon study closure, subjects should be managed and followed per physician 
discretion. 
16.9.2.   Early Termination or Suspension 
Early Termination of the Study is the closure of a clinical study that occurs prior to meeting defined 
endpoints. This is possible for the whole study or a single site. Study Suspension is a temporary 
postponement of study activities related to enrollment and distribution of the product. This is possible for 
the whole study or a single site. In the event the whole study or a single site is terminated, subjects will 
be exited.  
Study-Wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study include but are not limited 
to: 
• 
Adverse events associated with the system or product under investigation which might endanger 
the safety or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic  
Investigator/Site Termination or Suspension 
Possible reasons for clinical investigator or site termination or suspension include but are not limited to: 
• 
Failure to obtain initial IRB approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement or Work Order (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 suspension of the site 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations) 
• 
Investigator request (e.g. no longer able to support the study) 
 
 

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16.9.3.   Procedures for Termination or Suspension 
Medtronic-Initiated and Regulatory Authority-Initiated 
• 
Medtronic will promptly inform the clinical investigators of the (early) termination or suspension 
and the reasons and inform the regulatory authority(ies) where required 
• 
In the case of study termination or suspension for reasons other than a temporary IRB approval 
lapse, the investigator will promptly inform the IRB  
• 
In the case of study termination, the investigator must inform the subjects and may inform the 
personal physician of the subjects to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the suspension is lifted by 
Medtronic 
• 
In the case of a study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare 
Investigator-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension 
• 
The investigator will promptly inform the institution (where required per regulatory requirements)  
• 
The investigator will promptly inform the IRB 
• 
The investigator will promptly inform the subjects and/or the personal physician of the subjects 
to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subjects enrolled should continue to be followed out of 
consideration of their safety, rights and welfare 
IRB-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with IRB policy or its 
determination that an overriding safety concern or ethical issue is involved 
• 
The investigator will inform his/her institution (where required per local requirements)  
• 
The investigator will promptly inform the subjects, and/or the personal physician of the subjects, 
with the rationale for the study termination or suspension 
 
 

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17.   Appendices  
APPENDIX A: DATA COLLECTION ELEMENTS (ELECTRONIC CASE REPORT FORMS) 
Electronic Case Report Forms for the REVAMP clinical study will be provided under separate cover. Final 
eCRFs will be provided to sites via the electronic data management system after the site has fulfilled all 
requirements for database access. 
 
APPENDIX B: INFORMED CONSENT TEMPLATE(S) 
Informed Consent Form templates will be provided under separate cover. 
 
APPENDIX C: FORESEEABLE ADVERSE EVENT LIST 
The information provided in this section pertains to foreseeable adverse events that may be observed in 
the REVAMP Study and may assist in identifying those events that are unexpected in nature. Potential 
risks and associated adverse events related to the patients implanted market-released device are in 
alignment with the product labeling. This section address in more detail those events that are foreseeable 
due to participation in the REVAMP Study in those patients with a dual chamber pacemaker.    
 
Potential risks associated with elevated night pacing as well as risk minimization are discussed within 
Section 11.  Treatment required for programming related adverse events may include device 
reprogramming, medications, or other surgical and medical remedies.  The foreseeable adverse event 
information includes rates of adverse events reported from previous Medtronic studies evaluating 
traditional pacemaker systems.  Evaluation of potentially anticipated events may involve data in this 
Clinical Investigation Plan as well as a thorough review of all available information (e.g. labeling, current 
event reporting, published data, etc.).   
 
Adverse Events Reported in Previous Clinical Studies with Dual Chamber Pacing Systems 
 
Table 16 provides examples of adverse events associated with the use of traditional dual chamber 
pacemaker systems reported in six previous Medtronic studies between 1999 and 2012.  The six 
predicate Medtronic studies include the EnRhythm pre-market evaluation study, 3830 IDE study, 5076 
IDE study, EnRhythm MRI IDE study, Advisa MRI IDE study, and the SAVEPACe post-market study.  
These six studies collected all adverse events and include data from 2667 subjects that underwent a 
device implant.  The average follow-up time across the six studies ranged from 5.9 to 30.8 months.  
Table 16 displays the adverse event rates classified as related to the implanted system and/or procedure.    
Kaplan-Meier estimates and associated 95% confidence intervals of the adverse event rates are provided 
in the table below at 30-days and 12-months (365 days) post-implant to characterize both peri-
procedural and long-term adverse events related to the procedure or implanted system. 
 
Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
ADVERSE DRUG REACTION 
9 (9, 0.34%) 
0.18% - 0.65% 
10 (10, 0.39%) 
0.21% - 0.72% 
ADVERSE DRUG REACTION 
9 (9, 0.34%) 
0.18% - 0.65% 
10 (10, 0.39%) 
0.21% - 0.72% 
AIR EMBOLISM 
4 (4, 0.15%) 
0.06% - 0.40% 
4 (4, 0.15%) 
0.06% - 0.40% 

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Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
AIR EMBOLISM 
4 (4, 0.15%) 
0.06% - 0.40% 
4 (4, 0.15%) 
0.06% - 0.40% 
ANAEMIA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
ANEMIA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
ANXIETY 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
ANXIETY 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
ATELECTASIS 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
ATELECTASIS 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
ATRIAL FIBRILLATION 
59 (59, 2.25%) 
1.75% - 2.90% 
63 (63, 2.43%) 
1.90% - 3.10% 
ATRIAL FIBRILLATION 
54 (54, 2.06%) 
1.58% - 2.68% 
57 (57, 2.18%) 
1.69% - 2.82% 
PAROXYSMAL ATRIAL FIBRILLATION 
5 (5, 0.19%) 
0.08% - 0.46% 
6 (6, 0.25%) 
0.11% - 0.55% 
ATRIAL FLUTTER 
9 (9, 0.35%) 
0.18% - 0.66% 
9 (9, 0.35%) 
0.18% - 0.66% 
ATRIAL FLUTTER 
8 (8, 0.31%) 
0.15% - 0.61% 
8 (8, 0.31%) 
0.15% - 0.61% 
PAROXYSMAL ATRIAL FLUTTER 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
ATRIAL TACHYCARDIA 
11 (11, 0.42%) 
0.23% - 0.76% 
11 (11, 0.42%) 
0.23% - 0.76% 
ATRIAL TACHYCARDIA 
11 (11, 0.42%) 
0.23% - 0.76% 
11 (11, 0.42%) 
0.23% - 0.76% 
ATRIOVENTRICULAR BLOCK FIRST 
DEGREE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
ATRIOVENTRICULAR BLOCK FIRST DEGREE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
BASILAR MIGRAINE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
BASILAR MIGRAINE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
CARDIAC FAILURE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.31% 
DECOMPENSATED HEART FAILURE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.31% 
CARDIAC FAILURE CONGESTIVE 
13 (11, 0.42%) 
0.23% - 0.76% 
17 (15, 0.61%) 
0.37% - 1.02% 
CONGESTIVE HEART FAILURE 
13 (11, 0.42%) 
0.23% - 0.76% 
17 (15, 0.61%) 
0.37% - 1.02% 
CARDIAC PERFORATION 
14 (14, 0.53%) 
0.31% - 0.89% 
15 (15, 0.58%) 
0.35% - 0.96% 
CARDIAC PERFORATION 
14 (14, 0.53%) 
0.31% - 0.89% 
15 (15, 0.58%) 
0.35% - 0.96% 
CARDIAC TAMPONADE 
5 (5, 0.19%) 
0.08% - 0.45% 
5 (5, 0.19%) 
0.08% - 0.45% 
CARDIAC TAMPONADE 
5 (5, 0.19%) 
0.08% - 0.45% 
5 (5, 0.19%) 
0.08% - 0.45% 
CARDIOMYOPATHY 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.31% 
CARDIOMYOPATHY 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.31% 
CAROTID ARTERY DISEASE 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
CAROTID ARTERY DISEASE 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
CELLULITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.31% 
CELLULITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.31% 
CHEST DISCOMFORT 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
CHEST PRESSURE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 

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Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
CHEST PAIN 
11 (10, 0.38%) 
0.20% - 0.71% 
14 (13, 0.52%) 
0.30% - 0.90% 
CHEST PAIN 
11 (10, 0.38%) 
0.20% - 0.71% 
12 (11, 0.42%) 
0.23% - 0.76% 
RETROSTERNAL PAIN 
0 (0, 0%) 
-- 
1 (1, 0.06%) 
0.01% - 0.42% 
THORACIC PAIN 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
CHRONOTROPIC INCOMPETENCE 
3 (3, 0.12%) 
0.04% - 0.36% 
4 (4, 0.16%) 
0.06% - 0.42% 
CHRONOTROPIC INCOMPETENCE 
3 (3, 0.12%) 
0.04% - 0.36% 
4 (4, 0.16%) 
0.06% - 0.42% 
COMPLICATION OF DEVICE INSERTION 
17 (17, 0.64%) 
0.40% - 1.02% 
17 (17, 0.64%) 
0.40% - 1.02% 
COMPLICATION OF DEVICE INSERTION 
17 (17, 0.64%) 
0.40% - 1.02% 
17 (17, 0.64%) 
0.40% - 1.02% 
CONFUSIONAL STATE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
CONFUSION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
CORONARY ARTERY DISEASE 
11 (11, 0.42%) 
0.23% - 0.76% 
11 (11, 0.42%) 
0.23% - 0.76% 
CORONARY ARTERY DISEASE 
11 (11, 0.42%) 
0.23% - 0.76% 
11 (11, 0.42%) 
0.23% - 0.76% 
DEVICE CAPTURING ISSUE 
16 (16, 0.61%) 
0.37% - 0.99% 
22 (22, 0.90%) 
0.59% - 1.36% 
LOSS OF CAPTURE 
16 (16, 0.61%) 
0.37% - 0.99% 
22 (22, 0.90%) 
0.59% - 1.36% 
DEVICE COMPUTER ISSUE 
4 (4, 0.15%) 
0.06% - 0.41% 
9 (7, 0.28%) 
0.13% - 0.59% 
INAPPROPRIATE DEVICE PROGRAMMING 
4 (4, 0.15%) 
0.06% - 0.41% 
9 (7, 0.28%) 
0.13% - 0.59% 
DEVICE CONNECTION ISSUE 
5 (5, 0.19%) 
0.08% - 0.46% 
5 (5, 0.19%) 
0.08% - 0.46% 
CONNECTOR BLOCK PROBLEM 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
INADEQUATE LEAD CONNECTION 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
DEVICE DAMAGE 
5 (5, 0.19%) 
0.08% - 0.45% 
5 (5, 0.19%) 
0.08% - 0.45% 
CATHETER DAMAGE 
5 (5, 0.19%) 
0.08% - 0.45% 
5 (5, 0.19%) 
0.08% - 0.45% 
DEVICE DISLOCATION 
63 (59, 2.26%) 
1.75% - 2.91% 
84 (78, 3.06%) 
2.46% - 3.81% 
DEVICE MIGRATION 
0 (0, 0%) 
-- 
2 (2, 0.08%) 
0.02% - 0.32% 
LEAD DISLODGEMENT 
63 (59, 2.26%) 
1.75% - 2.91% 
82 (76, 2.98%) 
2.39% - 3.72% 
DEVICE EXTRUSION 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
DEVICE PROTRUSION 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
DEVICE INTOLERANCE 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.32% 
DEVICE INTOLERANCE 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.32% 
DEVICE ISSUE 
4 (3, 0.12%) 
0.04% - 0.36% 
4 (3, 0.12%) 
0.04% - 0.36% 
DEVICE ISSUE 
4 (3, 0.12%) 
0.04% - 0.36% 
4 (3, 0.12%) 
0.04% - 0.36% 
DEVICE LEAD DAMAGE 
2 (2, 0.07%) 
0.02% - 0.30% 
3 (3, 0.13%) 
0.04% - 0.39% 
DEVICE LEAD DAMAGE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
DEVICE LEAD FRACTURE 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.36% 
LEAD INSULATION FAILURE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
DEVICE MALFUNCTION 
2 (2, 0.07%) 
0.02% - 0.30% 
3 (3, 0.12%) 
0.04% - 0.37% 
DEVICE MALFUNCTION 
2 (2, 0.07%) 
0.02% - 0.30% 
3 (3, 0.12%) 
0.04% - 0.37% 

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Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
DEVICE PACING ISSUE 
27 (25, 0.95%) 
0.65% - 1.41% 
63 (57, 2.41%) 
1.86% - 3.12% 
ELEVATED PACING THRESHOLD 
27 (25, 0.95%) 
0.65% - 1.41% 
63 (57, 2.41%) 
1.86% - 3.12% 
DEVICE POWER SOURCE ISSUE 
0 (0, 0%) 
-- 
3 (3, 0.12%) 
0.04% - 0.39% 
DEVICE POWER SOURCE ISSUE 
0 (0, 0%) 
-- 
3 (3, 0.12%) 
0.04% - 0.39% 
DEVICE STIMULATION ISSUE 
14 (14, 0.53%) 
0.32% - 0.90% 
19 (17, 0.66%) 
0.41% - 1.06% 
INAPPROPRIATE DEVICE STIMULATION OF 
MUSCLE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
INAPPROPRIATE EXTRA-CARDIAC DEVICE 
STIMULATION 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
INAPPROPRIATE PECTORAL MUSCLE 
STIMULATION 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.33% 
INAPPROPRIATE PHRENIC NERVE 
STIMULATION 
5 (5, 0.19%) 
0.08% - 0.46% 
7 (7, 0.27%) 
0.13% - 0.57% 
INAPPROPRIATE STIMULATION OF 
DIAPHRAGM 
7 (7, 0.27%) 
0.13% - 0.56% 
8 (7, 0.27%) 
0.13% - 0.56% 
DIARRHOEA 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
DIARRHEA 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
DIZZINESS 
4 (4, 0.15%) 
0.06% - 0.41% 
7 (7, 0.29%) 
0.14% - 0.62% 
DIZZINESS 
4 (4, 0.15%) 
0.06% - 0.41% 
7 (7, 0.29%) 
0.14% - 0.62% 
DRESSLER'S SYNDROME 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
DRESSLER'S SYNDROME 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
DYSPNOEA 
1 (1, 0.04%) 
0.01% - 0.28% 
3 (3, 0.12%) 
0.04% - 0.38% 
DYSPNEA 
1 (1, 0.04%) 
0.01% - 0.28% 
3 (3, 0.12%) 
0.04% - 0.38% 
ECCHYMOSIS 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
ECCHYMOSIS 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
EJECTION FRACTION DECREASED 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.36% 
EJECTION FRACTION DECREASED 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.36% 
ERYTHEMA MIGRANS 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
ERYTHEMA CHRONICUM MIGRANS 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
EXTRAVASATION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
EXTRAVASATION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
FALL 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
FALL 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
FATIGUE 
2 (2, 0.08%) 
0.02% - 0.31% 
3 (3, 0.12%) 
0.04% - 0.37% 
FATIGUE 
2 (2, 0.08%) 
0.02% - 0.31% 
3 (3, 0.12%) 
0.04% - 0.37% 
HAEMATOMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HEMATOMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HAEMOGLOBIN DECREASED 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 

056-F275, Clinical Investigation Plan Template, Version 2.0 
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Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
HEMOGLOBIN DECREASED 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HEART RATE INCREASED 
0 (0, 0%) 
-- 
2 (2, 0.08%) 
0.02% - 0.33% 
HEART RATE HIGH 
0 (0, 0%) 
-- 
2 (2, 0.08%) 
0.02% - 0.33% 
HEART RATE IRREGULAR 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HEART RATE IRREGULAR 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HEPARIN-INDUCED THROMBOCYTOPENIA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HEPARIN-INDUCED THROMBOCYTOPENIA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
HYPERTENSION 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
HYPERTENSION 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
HYPOTENSION 
7 (7, 0.27%) 
0.13% - 0.56% 
7 (7, 0.27%) 
0.13% - 0.56% 
HYPOTENSION 
7 (7, 0.27%) 
0.13% - 0.56% 
7 (7, 0.27%) 
0.13% - 0.56% 
IMPAIRED HEALING 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
WOUND HEALING DELAYED 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
IMPLANT SITE DISCHARGE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
IMPLANT SITE DISCHARGE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
IMPLANT SITE HAEMATOMA 
21 (21, 0.80%) 
0.52% - 1.22% 
23 (23, 0.88%) 
0.59% - 1.32% 
IMPLANT SITE HEMATOMA 
21 (21, 0.80%) 
0.52% - 1.22% 
23 (23, 0.88%) 
0.59% - 1.32% 
IMPLANT SITE INFECTION 
18 (18, 0.69%) 
0.44% - 1.10% 
27 (26, 1.01%) 
0.69% - 1.48% 
IMPLANT SITE INFECTION 
7 (7, 0.27%) 
0.13% - 0.56% 
9 (8, 0.31%) 
0.15% - 0.62% 
IMPLANT SITE POCKET INFECTION 
11 (11, 0.42%) 
0.23% - 0.76% 
18 (18, 0.70%) 
0.44% - 1.11% 
IMPLANT SITE PAIN 
9 (9, 0.35%) 
0.18% - 0.66% 
19 (19, 0.81%) 
0.51% - 1.27% 
IMPLANT SITE PAIN 
2 (2, 0.08%) 
0.02% - 0.30% 
3 (3, 0.12%) 
0.04% - 0.36% 
IMPLANT SITE POCKET PAIN 
7 (7, 0.27%) 
0.13% - 0.57% 
16 (16, 0.69%) 
0.42% - 1.13% 
IMPLANT SITE PARAESTHESIA 
0 (0, 0%) 
-- 
3 (3, 0.12%) 
0.04% - 0.38% 
IMPLANT SITE PARAESTHESIA 
0 (0, 0%) 
-- 
3 (3, 0.12%) 
0.04% - 0.38% 
IMPLANT SITE SWELLING 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
IMPLANT SITE SWELLING 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
IMPLANT SITE WARMTH 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
IMPLANT SITE WARMTH 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
INCISION SITE COMPLICATION 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
INCISION SITE INFLAMMATION 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
INCISION SITE ERYTHEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
INCISION SITE ERYTHEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
INCISION SITE HAEMORRHAGE 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
INCISION SITE BLEEDING 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
INCISION SITE PAIN 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.32% 

056-F275, Clinical Investigation Plan Template, Version 2.0 
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REVAMP Clinical Investigation Plan 
 
27 APR 2018 
Medtronic Confidential 
 
Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
INCISION SITE PAIN 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.32% 
INCISIONAL DRAINAGE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
INCISIONAL DRAINAGE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
INFECTION 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.32% 
INFECTION 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.32% 
INTENTIONAL DEVICE MISUSE 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.35% 
INAPPROPRIATE DEVICE THERAPY FOR 
ATRIAL ARRHYTHMIA 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.35% 
INTRACARDIAC THROMBUS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
INTRACARDIAC THROMBUS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
JOINT RANGE OF MOTION DECREASED 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
JOINT RANGE OF MOTION DECREASED 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
LEAD DISLODGEMENT 
7 (6, 0.23%) 
0.10% - 0.51% 
15 (14, 0.56%) 
0.33% - 0.94% 
LEAD DISLODGEMENT 
7 (6, 0.23%) 
0.10% - 0.51% 
15 (14, 0.56%) 
0.33% - 0.94% 
LOSS OF CONSCIOUSNESS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
LOSS OF CONSCIOUSNESS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
MEDICAL DEVICE DISCOMFORT 
3 (2, 0.08%) 
0.02% - 0.30% 
3 (2, 0.08%) 
0.02% - 0.30% 
MEDICAL DEVICE DISCOMFORT 
3 (2, 0.08%) 
0.02% - 0.30% 
3 (2, 0.08%) 
0.02% - 0.30% 
MEDICAL DEVICE SITE REACTION 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
TISSUE BREAKDOWN ASSOCIATED WITH 
DEVICE 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.29% 
MUSCULOSKELETAL PAIN 
3 (3, 0.11%) 
0.04% - 0.35% 
4 (4, 0.15%) 
0.06% - 0.41% 
SHOULDER PAIN 
3 (3, 0.11%) 
0.04% - 0.35% 
4 (4, 0.15%) 
0.06% - 0.41% 
MYOCARDIAL INFARCTION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
MYOCARDIAL INFARCTION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NAUSEA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NAUSEA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NECK PAIN 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
NECK PAIN 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
NIPPLE PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NIPPLE PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NON-CARDIAC CHEST PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
NON-CARDIAC CHEST PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
OEDEMA 
6 (6, 0.23%) 
0.10% - 0.51% 
6 (6, 0.23%) 
0.10% - 0.51% 
EDEMA 
6 (6, 0.23%) 
0.10% - 0.51% 
6 (6, 0.23%) 
0.10% - 0.51% 
ORTHOSTATIC HYPOTENSION 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
ORTHOSTATIC HYPOTENSION 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 

056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 78 of 90 
Version 3.0 
REVAMP Clinical Investigation Plan 
 
27 APR 2018 
Medtronic Confidential 
 
Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
POSTURAL HYPOTENSION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
OVERSENSING 
0 (0, 0%) 
-- 
4 (4, 0.18%) 
0.07% - 0.48% 
OVERSENSING 
0 (0, 0%) 
-- 
4 (4, 0.18%) 
0.07% - 0.48% 
PACEMAKER GENERATED ARRHYTHMIA 
3 (3, 0.11%) 
0.04% - 0.35% 
4 (4, 0.16%) 
0.06% - 0.42% 
PACEMAKER MEDIATED TACHYCARDIA 
3 (3, 0.11%) 
0.04% - 0.35% 
4 (4, 0.16%) 
0.06% - 0.42% 
PACEMAKER SYNDROME 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PACEMAKER SYNDROME 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.31% 
PAIN 
1 (1, 0.04%) 
0.01% - 0.27% 
2 (2, 0.08%) 
0.02% - 0.31% 
PAIN IN EXTREMITY 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
PAIN IN ARM 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
PAIN OF EXTREMITIES 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PALPITATIONS 
10 (10, 0.38%) 
0.21% - 0.71% 
12 (12, 0.48%) 
0.27% - 0.85% 
HEART RACING 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PALPITATIONS 
9 (9, 0.35%) 
0.18% - 0.66% 
11 (11, 0.44%) 
0.24% - 0.80% 
PANIC ATTACK 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PANIC ATTACK 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PERICARDIAL EFFUSION 
18 (17, 0.65%) 
0.40% - 1.04% 
20 (19, 0.73%) 
0.46% - 1.14% 
CARDIAC PERFORATION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PERICARDIAL EFFUSION 
17 (16, 0.61%) 
0.37% - 0.99% 
19 (18, 0.69%) 
0.43% - 1.09% 
PERICARDITIS 
4 (4, 0.15%) 
0.06% - 0.41% 
5 (4, 0.15%) 
0.06% - 0.41% 
PERICARDITIS 
4 (4, 0.15%) 
0.06% - 0.41% 
5 (4, 0.15%) 
0.06% - 0.41% 
PLEURAL EFFUSION 
11 (11, 0.42%) 
0.23% - 0.75% 
11 (11, 0.42%) 
0.23% - 0.75% 
PLEURAL EFFUSION 
11 (11, 0.42%) 
0.23% - 0.75% 
11 (11, 0.42%) 
0.23% - 0.75% 
PNEUMONIA 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
PNEUMONIA 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
PNEUMOTHORAX 
43 (43, 1.62%) 
1.20% - 2.18% 
43 (43, 1.62%) 
1.20% - 2.18% 
PNEUMOTHORAX 
43 (43, 1.62%) 
1.20% - 2.18% 
43 (43, 1.62%) 
1.20% - 2.18% 
POSTOPERATIVE WOUND COMPLICATION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
POSTOPERATIVE WOUND COMPLICATION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
POSTOPERATIVE WOUND INFECTION 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.39% 
SUTURE LINE INFECTION 
0 (0, 0%) 
-- 
1 (1, 0.05%) 
0.01% - 0.39% 
PRESYNCOPE 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
NEAR SYNCOPE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
VASOVAGAL REACTION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PRURITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 

056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 79 of 90 
Version 3.0 
REVAMP Clinical Investigation Plan 
 
27 APR 2018 
Medtronic Confidential 
 
Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
PRURITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PULMONARY EMBOLISM 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PULMONARY EMBOLUS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PULMONARY OEDEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PULMONARY EDEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
PYREXIA 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
FEVER 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 
RASH 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
RASH 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
RENAL FAILURE 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
RENAL INSUFFICIENCY 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
RESTLESSNESS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
RESTLESSNESS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
SINUS TACHYCARDIA 
1 (1, 0.04%) 
0.01% - 0.27% 
3 (3, 0.13%) 
0.04% - 0.42% 
SINUS TACHYCARDIA 
1 (1, 0.04%) 
0.01% - 0.27% 
3 (3, 0.13%) 
0.04% - 0.42% 
SUBCLAVIAN ARTERY STENOSIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
SUBCLAVIAN ARTERY STENOSIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
SUBCLAVIAN VEIN THROMBOSIS 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
SUBCLAVIAN VEIN THROMBOSIS 
1 (1, 0.04%) 
0.01% - 0.28% 
1 (1, 0.04%) 
0.01% - 0.28% 
SUBCUTANEOUS EMPHYSEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
SUBCUTANEOUS EMPHYSEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
SUPRAVENTRICULAR EXTRASYSTOLES 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
PREMATURE ATRIAL CONTRACTION 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
SUPRAVENTRICULAR TACHYCARDIA 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
SUPRAVENTRICULAR TACHYCARDIA 
3 (3, 0.11%) 
0.04% - 0.35% 
3 (3, 0.11%) 
0.04% - 0.35% 
SUTURE RELATED COMPLICATION 
1 (1, 0.04%) 
0.01% - 0.28% 
2 (2, 0.08%) 
0.02% - 0.31% 
SUTURE RELATED COMPLICATION 
1 (1, 0.04%) 
0.01% - 0.28% 
2 (2, 0.08%) 
0.02% - 0.31% 
SWELLING 
0 (0, 0%) 
-- 
2 (2, 0.08%) 
0.02% - 0.33% 
SWELLING 
0 (0, 0%) 
-- 
2 (2, 0.08%) 
0.02% - 0.33% 
SYNCOPE 
4 (4, 0.15%) 
0.06% - 0.40% 
5 (5, 0.20%) 
0.08% - 0.47% 
SYNCOPE 
4 (4, 0.15%) 
0.06% - 0.40% 
5 (5, 0.20%) 
0.08% - 0.47% 
THROMBOPHLEBITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
THROMBOPHLEBITIS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
THROMBOSIS 
2 (2, 0.08%) 
0.02% - 0.31% 
4 (4, 0.18%) 
0.07% - 0.47% 
THROMBOSIS 
2 (2, 0.08%) 
0.02% - 0.31% 
4 (4, 0.18%) 
0.07% - 0.47% 
TRANSIENT ISCHAEMIC ATTACK 
2 (2, 0.08%) 
0.02% - 0.30% 
2 (2, 0.08%) 
0.02% - 0.30% 

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Table 16: Previous Clinical Study Data - System and/or Procedure Related Adverse Events (n=2667) 
 
Within 30-days of Implant 
Within 12-months of Implant 
MedDRA Preferred Term 
  Lowest Level Term 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
No. Events 
(No. Subjects, 
%)1 
95% CI1 
TRANSIENT ISCHAEMIC ATTACK 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
TRANSIENT ISCHEMIC ATTACKS 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
UNDERSENSING 
9 (9, 0.34%) 
0.18% - 0.65% 
13 (13, 0.53%) 
0.31% - 0.92% 
LOSS OF SENSING 
2 (2, 0.07%) 
0.02% - 0.30% 
3 (3, 0.11%) 
0.04% - 0.35% 
UNDERSENSING 
7 (7, 0.27%) 
0.13% - 0.56% 
10 (10, 0.42%) 
0.22% - 0.78% 
VASCULAR PSEUDOANEURYSM 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
VASCULAR PSEUDOANEURYSM 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
VENOUS INSUFFICIENCY 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
VENOUS EDEMA 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
VENOUS THROMBOSIS 
8 (8, 0.31%) 
0.15% - 0.61% 
8 (8, 0.31%) 
0.15% - 0.61% 
VENOUS THROMBOSIS 
8 (8, 0.31%) 
0.15% - 0.61% 
8 (8, 0.31%) 
0.15% - 0.61% 
VENTRICULAR EXTRASYSTOLES 
10 (10, 0.38%) 
0.21% - 0.71% 
11 (11, 0.42%) 
0.23% - 0.76% 
FUSION BEAT 
0 (0, 0%) 
-- 
1 (1, 0.04%) 
0.01% - 0.28% 
PREMATURE VENTRICULAR CONTRACTIONS 
10 (10, 0.38%) 
0.21% - 0.71% 
10 (10, 0.38%) 
0.21% - 0.71% 
VENTRICULAR TACHYCARDIA 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
VENTRICULAR TACHYCARDIA 
2 (2, 0.08%) 
0.02% - 0.31% 
2 (2, 0.08%) 
0.02% - 0.31% 
VIRAL INFECTION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
VIRAL INFECTION 
1 (1, 0.04%) 
0.01% - 0.27% 
1 (1, 0.04%) 
0.01% - 0.27% 
 
APPENDIX D: PARTICIPATING INVESTIGATORS AND INSTITUTIONS 
 A complete list of participating investigators and institutions (including names, titles/professional 
positions, address(es), and telephone numbers) where study activities will be conducted will be provided 
upon request under a separate cover.  
 
APPENDIX E: ETHICS COMMITTEE (IRB) 
 A complete list of participating IRB and the Chairperson(s) will be distributed under separate cover when 
available upon request. 
 
APPENDIX F: LABELING 
Labeling and packaging for all products used in this study will follow the local regulatory requirements. 
Labeling for all system components market released at study start in the respective geographies can be 
found with each package insert and/or will be available on http://manuals.medtronic.com. In the event a 
non-Medtronic lead is used, governing labeling for that lead should be consulted.  
 

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APPENDIX G: CIP Change History 
Table 17: Change History CIP V1.0 to CIP V2.0 
Applicable Sections 
Change 
Rationale 
Title Page, Appendix D & E, 
header/footer 
Update to Version 2.0 from 1.0 
Updated date to April 2017  
from Dec 2016 
CIP update 
Sponsor Contact Information 
Clinical Study Leader now 
Andrea DeRoche, 
previously Scott Sarazin 
Role change 
CROs/Core Laboratories 
Added The Ohio State 
University as the 
echocardiographu core lab 
and ACM Glabal Central 
Lanoratory as the blood core 
lab 
Formally adding contact 
information of the core 
laboratories 
1. Version History 
Added version 2.0 
CIP Update 
4. Synopsis 
Removed “Ensura MRI” in 
the Product Name section 
Available OUS only 
4. Synopsis; Exclusion Criteria, 
9.4  
Changed criteria from “Subject 
has permanent AF or AF at 
time of enrollment visit” to 
Subject has permanent AF or 
AF noted on baseline 
interrogation rhythm strip” 
Provide clairifcation to criteria 
4. Synopsis; Exclusion Criteria, 
9.4 
Added “ prior to enrollment” 
for exclusion criteria regarding 
aortic valve replacement 
procedure less than 1  year  
Provide clairifcation to criteria 
4. Synopsis; Exclusion Criteria, 
9.4 
Added “Subject has 
know coronary disease 
with Class II angina”   
Added per Steering Committee 
recommendation  
4. Synopsis; Study Procedures 
and Assessments, 10.8 
Added “Subject observation 
of at least 30 minutes to 
ensure that they can tolerate 
100 bpm pacing post 
programming”  
Added per Steering Committee 
recommendation 
4. Synopsis; Study Procedures 
and Assessments, 10.9 
Added a 24 Hour Telephone 
call Follow-Up Visit 
Added per Steering Committee 
recommendation 
 
 

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Applicable Sections 
Change 
Rationale 
7. Study Design 
Removed “This study is a 
Non-Significant Risk (NSR) 
Investigational Device 
Examption (IDE) study as 
subjects will already have 
implanted market-approved 
Medtronic pacemakers that 
have the Sleep Function.” 
And added “The REVAMP 
study will be conducted as a 
Non-Significant Risk (NSR) 
IDE study. The REVAMP 
Research System does not 
include an investigational 
device; the ability to program 
a lower rate of 100 bpm is 
available in market-released 
pacemakers, and the Sleep 
function (which allows a 
different rate to be 
programmed for part of a 24 
hour clock) is an approved 
feature in market-released 
pacemakers that will be used 
in the clinical study. The 
study will be conducted in 
compliance with 21 CFR Parts 
11, 50, 56, 812.2 (b)(1). This 
study does not require an 
IDE submission to FDA.” 
Provide further clearity around 
the meaning of a Non-
Significant Risk IDE study 
7.1 Duration 
Removed sentence regarding 
study start date 
Not required  
8.3 Study Componets, 10.3  
Added “Access to dry ice to 
ship blood samples” 
Provide clarity around shipping 
samples  
 
 

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Applicable Sections 
Change 
Rationale 
10. Study Procedures 
Added the following “At the 
request of the Principal 
Investigator or other 
authorized site personnel, 
Medtronic will use 
information from its device 
registration database to 
provide a study site a list of 
its patients whom the site 
had implanted with the 
Medtronic dual chamber 
pacemaker with Sleep 
Function, required by the 
inclusion criteria set out in 
Section 9.3.  Study site, if 
permitted by its IRB, could 
further review the records of 
such patients to determine if 
they may be eligible to 
participate in the study.” 
To allow Medtronic access to 
potential study subjects at the 
study site using device 
database 
10.2 Site Activation  
Added a bullet to include 
Financial Disclosure 
Agreement 
To include all required 
documents 
10.4 Schedule of Events 
Added the 24 hour post 
baseline call, medications to 
be collected at the early 
study visit, and at least 30 
minute observation person 
post programming 
Added per Steering Committee 
recommendation 
10.5 Prior and Concomitant 
Medications 
Added “all telephone call 
follow up visits” to the second 
sentence in the paragraph 
To be consistant with schedule 
of events table  
10.8 Baseline Visit 
Added “In the event a subject 
experiences symptoms once 
sent home after the Baseline 
visit, the subject should be 
instructd to seek medical help 
for device reprogramming if 
they cannot or do not 
tolerate elevated pacing.”  
Added per Steering Committee 
recommendation 
10.10.1 Blinding 
Added “Refer to the 
Randomization and Blinding 
Plan for specific details.” 
Provide further clearity as to 
where to find this detailed 
information 
 
 

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Applicable Sections 
Change 
Rationale 
10.12 unscheduled Follow-Up 
Visits 
Changed “An unscheduled 
visit is defined as a visit not 
required by the follow up visit 
schedule in the CIP.” To now 
read “An unscheduled visit is 
defined as any unplanned 
visit by the subject to the 
study site. Routine visits or 
other planned visits are not 
collected.”  
Provide clearity for how this 
visit is defined 
10.13 12 Week Visit (Study 
Exit) 
Added “NYHA” as a bullet 
To be consistant with schedule 
of events table 
15.1 Statement(s) of 
Compliance 
Added the following sentence 
“ The study was designed to 
reflect the GCP principles 
outlined in ICO 14155:2011.” 
Required per Medtroinc CIP 
checklist 
16.1 Monitoring 
Changed “Monitoring for the 
study, including site initiation 
visits, interim monitoring 
visits, and closeout visits, will 
be done in accordance to the 
study-specific plan.” To now 
read “Monitoring for the study 
will be done in accordance to 
the study-specific plan 
Specific details to be outlined in 
the Monitoring Plan 
 
 

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Applicable Sections 
Change 
Rationale 
16.2 Data Management 
Revised this paragraph from 
“Procedures in the CIP require 
source documentation.  Source 
documentation will be 
maintained at the site. Source 
documents, which may include 
worksheets, patient medical 
records, echo data, 
programmer printouts, device 
interrogation files, must be 
created and maintained by the 
investigational site team.” To 
“Procedures in the CIP require 
source documentation.  Source 
documentation will be 
maintained at the site. Source 
may include worksheets, patient 
medical records, echo data, 
programmer printouts, device 
interrogation files, and certain 
CRF fields which must be 
created and maintained by the 
investigational site team.”  
Provide clearity that only certain 
CRF fields will need source 
documents created 
 
 
 

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Table 18: Change History CIP V2.0 to CIP V3.0 
Applicable Sections 
Change 
Rationale 
1. Version History 
Added Version 3.0 
Table 18 
CIP Update 
 
 
1. Version History 
Added Table 17 to V2.0 
Clarification of changes 
3.  Glossary 
Added ADL (Activities of Daily 
Living) and UR (Upper Rate) 
Consistency within protocol 
4.   Synopsis; Sample Size 
Increased number of subjects 
from 40 to 50 and number of 
sites from approximately 5 sites 
to 10 sites 
Recommended by Steering 
Committee 
4. Synopsis;  
Inclusion/Exclusion Criteria and 
9. Selection of Subjects 
   9.3. Inclusion Criteria 
 
Changed Subject has had a 
marked released dual chamber 
Medtronic Pacemaker with 
Sleep Function for at 6 months 
to for at least 3 months.  
Change recommended by 
Steering Committee 
4.  Synopsis; 
Inclusion/Exclusion Criteria and 
9.  Selection of Subjects 
    9.3. Inclusion Criteria 
Changed from Subject has 
dyspnea with exertion to 
Subject has dyspnea with 
exertion or diagnosed as NYHA 
Class II or III heart Failure 
Clarification recommended by 
Steering Committee 
4.  Synopsis; 
Inclusion/Exclusion Criteria and 
9. Selection of Subjects 
  9.4. Exclusion Criteria 
Changed from Subject has 
more than moderate valve 
disease to Subject has severe 
stenosis of the aortic or mitral 
valve, defined as a valve area 
less than or equal to 1.0cm² or 
subject has severe 
regurgitation of the aortic or 
mitral valve. 
Clarification recommended by 
Steering Committee 
 

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Applicable Sections 
Change 
Rationale 
4.  Synopsis; 
Inclusion/Exclusion Criteria  
9. Selection of Subjects 
  9.4. Exclusion Criteria 
Changed from Subject has had 
an aortic valve replacement 
(surgical or TAVR) procedure 
less than 1 year to Subject has 
had an aortic valve 
replacement (surgical or TAVR) 
procedure less than 9 months. 
Recommended by Steering 
Committee 
Section 7. Study Design 
7.1. Duration 
Increased duration of study 
from 12 months to 24 months 
Necessary for additional site 
selections and enrollments 
5.1 Background and 
8.4 Product Use 
Added acronym or definition of 
acronym first time used 
Consistency within protocol 
7.  Study Design 
Sites and Subjects 
7.2. Rationale 
Increased number of subjects 
from 40 to 50 
Recommended by Steering 
Committee 
14.  Statistical Design and 
Methods 
Removed list of analyses 
Removal of redundant 
information; can see in Section 
14.1 Endpoint Definitions 
14.1 Endpoint Definitions 
14.1.2. Ancillary Safety 
Endpoint – NT-proBNP, 
troponin, LVEF 
14.1.4. Ancillary Efficacy 
Endpoint – Quality of Life 
14.1.5. Ancillary Efficacy 
Endpoint – Mobility and Activity 
14.1.6. Ancillary Efficacy 
Endpoint – Echo Measurements 
14.1.7. Ancillary Efficacy 
Endpoint – Collagen Degration 
Biomarker Measurements 
Updated symbols to show µ 
instead of a square 
Consistency within protocol 
14.1.4. Ancillary Efficacy 
Endpoint – Quality of Life 
Added EQ-5D-5L Questionnaire 
– 8 weeks section 
Clarify the quality of life 
analyses 
14.1.5. Ancillary Efficacy 
Endpoint – Mobility and Activity 
Updated ‘:’ to ‘-‘ in section 
header; Updated MNLWHF for 
week 8 to 6 Minute Hall Walk 
Test distance 
Consistency within protocol 

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Applicable Sections 
Change 
Rationale 
14.1.7. Ancillary Efficacy 
Endpoint – Collagen 
Degradation Biomarker 
Measurements 
Updated echo to collagen 
degration biomarker at week 8 
Consistency within protocol 
10.  Study Procedure 
10.2. Rose of Sponsor 
Representative  
Added to specify MDT field role  Clarify MDT field role  
Appendix G:  CIP Change  
Table 17 
History V1 to V2 
Inclusion updated to Exclusion Consistency within protocol 
Sponsor Contact 
Sponsor’s Medical Expert 
David Steinhaus removed 
Robert Kowal added 
Change in staff 
Table of Contents 
Added Table 18 
CIP Changes V2 to V3 
Capture changes in CIP 
Appendix G:  CIP Change 
Added Table 18 
CIP Changes V2 to V3 
Addition of Table of Changes 
Capture changes V2 to V3 
Throughout CIP 
Formatting & grammatical  
changes  
Format change & grammatical 
errors 
Table 15: Sponsor Reports for 
the United States 
Removed:  
Recall and Disposition 
Other 
Not required for NSR IDE 
APPENDIX D:  Participating 
Investigators and Institutions 
APPENDIX E:  Ethics Committee 
(IRB) 
Removed: 
At the time of REVAMP CIP V2 
completion were not finalized 
Site selections have been made 
for 5 sites since V2 
10: Study Procedure 
10.9.1.   Programming 
Recommendations at Baseline  
Added: Use of AAI (R) 
programming is not 
recommended due to the 
possibility of AV block occurring 
Clarifying Programming 
recommendation 
 
 

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