Micra Atrial TRacking Using A Ventricular AccELerometer 2
Phase: NA
Conditions: Atrioventricular Conduction Block
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

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Clinical Investigation Plan
Clinical Investigation Plan/Study Title 
Micra Atrial TRacking Using A Ventricular 
AccELerometer 2
Abbreviated Name: MARVEL 2 study
Clinical Investigation Plan Identifier
MARVEL 2 study
Study Product Name
MARVEL 2 Research System
Sponsor
United States
Nicole Wood, Principal Clinical Research 
Specialist
Medtronic, Inc. 
8200 Coral Sea Street NE
Mounds View, MN U.S.A. 55112
Phone: +1-800-328-2518
Local Sponsor
Europe Middle East, Africa (EMEA)
Nina Kristiansen, Senior Clinical Research 
Specialist 
Medtronic, Bakken Research Center B.V.
Endepolsdomein 5,
6229 GW Maastricht
The Netherlands
Phone:+31-433-566-566
Local Sponsor
Southeast Asia 
Sheikh Abdul-Aziz, Principal Clinical Research 
Specialist 
Medtronic Malaysia Sdn Bhd
B-23-1, Level 23 The Ascent, Paradigm No 1 Jalan 
SS7/26A Kelana Jaya 
47301 Petaling Jaya, 
Selangor
Malaysia
Phone: +603-7883-8000
Local Sponsor
Hong Kong
Sheikh Abdul-Aziz, Principal Clinical Research 
Specialist 
Medtronic Hong Kong Medical Ltd. 1104-11, 
11/F, Tower 1, 

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The Gateway, 
Harbour City, Kowloon, 
Hong Kong SAR, China
Phone: +852-2919-1300
Document Version
Version 2.0
Document Reference Number
MDT18024
Lead Principal Investigator(s)
United States:
Europe:
 
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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1 Investigator Statement
Study product Name
MARVEL 2 Research System 
Sponsor
Medtronic, Inc.
8200 Coral Sea Street NE
Mounds View, MN U.S.A. 55112
Phone: +1-800-328-2518
Local Sponsor
Medtronic, Bakken Research Center B.V.
Endepolsdomein 5,
6229 GW Maastricht,  The Netherlands
Phone: +31-43-35-66-566
Local Sponsor
Medtronic Malaysia Sdn Bhd
B-23-1, Level 23 The Ascent, Paradigm No 1 Jalan
SS7/26A Kelana Jaya
47301 Petaling Jaya,
Selangor, Malaysia
Phone: +603-7883-8000
Local Sponsor
Medtronic Hong Kong Medical Ltd
1104-11, 11/F, Tower 1, 
The Gateway, 
Harbour City, Kowloon, 
Hong Kong SAR, China
Phone: +852-2919-1300
Manufacturer
Medtronic, Inc.
710 Medtronic Parkway
Minneapolis, MN U.S.A. 55432
Phone: +1-800-328-2518
Clinical Investigation Plan Identifier
MARVEL 2 clinical study
Version Number/Date 
Version 2.0/ 01NOV2018
I have read the protocol, including all appendices, and I agree that it contains all necessary details for 
me and my staff to conduct this study as described. I will conduct this study as outlined herein and will 
make a reasonable effort to complete the study within the time designated.
I agree to comply with Declaration of Helsinki, Clinical Investigation Plan, Good Clinical Practice and to 
the national and local laws, regulations, standards, and requirements. I agree to ensure that the 
confidential information contained in this document will not be used for any purpose other than the 
evaluation and conduct of the clinical investigation without the prior written consent of Medtronic.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Medtronic. I will discuss this material with them to ensure that they are fully 
informed about the products and the study.

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Investigator’s Signature:
Investigator’s Name:
Institution:
Date:

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2 Table of Contents
1 Investigator Statement.......................................................................................................... 3
2 Table of Contents ................................................................................................................... 5
3 Table of Tables ..................................................................................................................... 11
4 Table of Figures.................................................................................................................... 11
5 Glossary................................................................................................................................ 12
6 Synopsis ............................................................................................................................... 14
7 Introduction ......................................................................................................................... 20
Background.............................................................................................................................20
Purpose ..................................................................................................................................21
8 Objectives and Endpoints..................................................................................................... 22
Objectives...............................................................................................................................22
8.1.1 Primary Objective(s)...................................................................................................................22
8.1.2 Secondary Objective ..................................................................................................................22
Endpoints................................................................................................................................23
8.2.1 Primary Endpoint(s) ...................................................................................................................23
8.2.2 Secondary Endpoint...................................................................................................................26
9 Study Design ........................................................................................................................ 27
9.1.1 De Novo Subjects .......................................................................................................................29
9.1.2 Reenrollment of MARVEL Study Subjects..................................................................................31
Duration..................................................................................................................................31
Rationale.................................................................................................................................31
Minimization of Bias.................................................................................................................32
10 Product Description............................................................................................................ 32
General .................................................................................................................................32
10.1.1 Micra Implantable Device........................................................................................................33

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10.1.2 Medtronic Carelink Programmer (2090), 2090 Programmer Desktop Software, and Micra 
Software (SW022)...............................................................................................................................33
10.1.3 MARVEL 2 Software .................................................................................................................34
10.1.4 Extended Range Holter Monitor System .................................................................................34
Dosage Form and Route of Administration...............................................................................35
Manufacturer.........................................................................................................................35
Packaging .............................................................................................................................35
Intended Population...............................................................................................................35
Equipment.............................................................................................................................35
Product Use...........................................................................................................................35
Product Training Requirements...............................................................................................36
Product Receipt and Tracking .................................................................................................36
Product Storage...................................................................................................................36
Product Return ....................................................................................................................36
Product Accountability..........................................................................................................36
11 Selection of Subjects.......................................................................................................... 37
Study Population....................................................................................................................37
Subject Enrollment.................................................................................................................37
Inclusion Criteria....................................................................................................................37
Exclusion Criteria ...................................................................................................................37
Enrollment Strategy ...............................................................................................................38
12 Study Preparation .............................................................................................................. 38
Investigator/Investigation site selection ..................................................................................38
Site activation........................................................................................................................38
13 Study Procedures ............................................................................................................... 39
Schedule of Events ................................................................................................................39
Role of the Sponsor Representatives.......................................................................................41
Subject Screening..................................................................................................................41
Prior and Concomitant Medications .........................................................................................41
Subject Consent ....................................................................................................................41
Randomization and Treatment Assignment..............................................................................43
Study Procedure Visit .............................................................................................................43

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13.7.1 Study Procedure Visit...............................................................................................................43
13.7.2 Eligibility Assessment...............................................................................................................43
13.7.3 Demographics and Pacing Indication.......................................................................................43
13.7.4 Medical History........................................................................................................................44
13.7.5 Cardiovascular Medications.....................................................................................................44
13.7.6 Physical Exam...........................................................................................................................44
13.7.7 12-Lead Electrocardiogram......................................................................................................44
13.7.8 X-Ray (if available)....................................................................................................................44
13.7.9 Initial Device Interrogation ......................................................................................................44
13.7.10 Download the MARVEL 2 Software........................................................................................44
13.7.11 Holter Monitor / ECG Setup...................................................................................................45
13.7.12 Auto-Setup Phase / Parameter Settings Evaluation ..............................................................45
13.7.13 Evaluation Phase / Resting Period .........................................................................................45
13.7.14 Evaluation Phase / Posture and Activity................................................................................45
13.7.15 Echocardiogram .....................................................................................................................46
13.7.16 Accelerometer Characterization............................................................................................46
13.7.17 Remove the MARVEL 2 Software and Holter.........................................................................47
13.7.18 Final Device Interrogation......................................................................................................47
13.7.19 Implant Assessment (de novo subjects only).........................................................................47
13.7.20 Post-Implant Assessment (de novo subjects only).................................................................47
13.7.21 One-Month Post-Implant Visit (de novo subjects only).........................................................48
13.7.22 System Modification (de novo subjects only)........................................................................48
Treatment Compliance ...........................................................................................................48
Assessment of Efficacy...........................................................................................................48
Assessment of Safety ...........................................................................................................48
Recording Data....................................................................................................................49
Deviation Handling...............................................................................................................49
Subject Withdrawal or Discontinuation ..................................................................................50
13.13.1 Subject Exit.............................................................................................................................51
14 Risks and Benefits.............................................................................................................. 51

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Potential Risks .......................................................................................................................51
Potential Benefits...................................................................................................................56
Risk-Benefit Rationale ............................................................................................................56
15 Adverse Events and Device Deficiencies............................................................................ 56
Adverse Event and Device Deficiency Assessment....................................................................56
15.1.1 Adverse Events.........................................................................................................................56
15.1.2 Device Deficiencies ..................................................................................................................56
15.1.3 Event Updates and Resolution.................................................................................................57
Definitions/Classifications .......................................................................................................57
Reporting of Adverse Events...................................................................................................62
15.3.1 Adverse Events and Device Deficiency Classification ..............................................................62
15.3.2 Adverse Events and Device Deficiency Reporting Requirements............................................63
Subject Death........................................................................................................................65
16 Data Review Committees................................................................................................... 66
Clinical Event Committee (CEC) ..............................................................................................66
Data Monitoring Committee (DMC) .........................................................................................66
CRO/Core Labs ......................................................................................................................66
17 Statistical Design and Methods.......................................................................................... 67
General Considerations ..........................................................................................................67
17.1.1 Description of Baseline Variables ............................................................................................67
Type I Error Control...............................................................................................................67
Usable Holter Datasets...........................................................................................................68
Classification of Predominant Heart Rhythm During Holter Monitoring .......................................68
Primary Efficacy Objective ......................................................................................................68
17.5.1 Hypothesis................................................................................................................................68
17.5.2 Performance Requirement ......................................................................................................68
17.5.3 Sample Size ..............................................................................................................................69
17.5.4 Analysis Methods.....................................................................................................................70
17.5.5 Determination of Subjects and Data for Analysis....................................................................71
17.5.6 Missing Data and Sensitivity Analyses .....................................................................................72

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Primary Safety Objective ........................................................................................................73
17.6.1 Hypothesis................................................................................................................................73
17.6.2 Performance Requirement ......................................................................................................73
17.6.3 Sample Size ..............................................................................................................................73
17.6.4 Analysis Methods.....................................................................................................................74
17.6.5 Determination of Subjects and Data for Analysis....................................................................75
17.6.6 Missing Data and Sensitivity Analyses .....................................................................................75
Secondary Objective ..............................................................................................................75
17.7.1 Hypothesis................................................................................................................................75
17.7.2 Performance Requirement ......................................................................................................75
17.7.3 Power Calculation ....................................................................................................................76
17.7.4 Analysis Methods.....................................................................................................................78
17.7.5 Determination of Subjects and Data for Analysis....................................................................79
17.7.6 Missing Data and Sensitivity Analyses .....................................................................................79
18 Ethics.................................................................................................................................. 85
Statement(s) of Compliance ...................................................................................................85
19 Study Administration ......................................................................................................... 87
Monitoring.............................................................................................................................87
Data Management .................................................................................................................87
Direct Access to Source Data/Documents ................................................................................88
Confidentiality .......................................................................................................................88

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Liability .................................................................................................................................89
19.5.1 Insurance (EMEA).....................................................................................................................89
19.5.2 Insurance (Malaysia)................................................................................................................89
19.5.3 Insurance (Hong Kong).............................................................................................................89
19.5.4 Insurance (US)..........................................................................................................................90
CIP Amendments...................................................................................................................90
Record Retention...................................................................................................................90
19.7.1 Investigator Records ................................................................................................................90
19.7.2 Investigator Reports.................................................................................................................91
19.7.3 Sponsor records .......................................................................................................................94
19.7.4 Sponsors reports......................................................................................................................95
Publication and Use of Information .......................................................................................100
19.8.1 Publication Committee ..........................................................................................................100
19.8.2 Management of publications.................................................................................................100
19.8.3 Criteria for Determining Authorship......................................................................................101
19.8.4 Transparency..........................................................................................................................101
Suspension or Early Termination...........................................................................................102
19.9.1 Planned study closure............................................................................................................102
19.9.2 Early termination or suspension............................................................................................102
19.9.3 Procedures for termination and suspension .........................................................................103
20 References ....................................................................................................................... 104
21 Appendices ....................................................................................................................... 105
APPENDIX A: DATA COLLECTION ELEMENTS (ELECTRONIC CASE REPORT FORMS) .......................105
APPENDIX B: INFORMED CONSENT TEMPLATE(S) ........................................................................106
APPENDIX C: FORESEEABLE ADVERSE EVENT LIST.......................................................................106
APPENDIX D: PARTICIPATING INVESTIGATORS AND INSTITUTIONS.............................................108
APPENDIX E: ETHICS COMMITTEE...............................................................................................109
APPENDIX F: LABELING...............................................................................................................109
APPENDIX G: PRE-CLINICAL TESTING..........................................................................................109
APPENDIX H: PREVIOUS CLINICAL STUDIES ................................................................................109

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APPENDIX I: ADDITIONAL INFORMATION FOR SITES BY COUNTRY ..............................................110
22 Version History................................................................................................................. 110
3 Table of Tables
Table 1:  MARVEL 2 Research System.........................................................................................................33
Table 2:  Summary of Study Procedures.....................................................................................................40
Table 3: 1 Month Visit Window ..................................................................................................................48
Table 4. Potential Risks and Minimizations ................................................................................................52
Table 5:  Adverse Event and Device Deficiency Definitions........................................................................57
Table 6:  Adverse Event Classification Responsibilities...............................................................................63
Table 7:  Reporting Requirements..............................................................................................................63
Table 8:  CRO and Core Laboratory Information.........................................................................................67
Table 9: Power to Reject the Null Hypothesis for the Secondary Objective ..............................................78
Table 10:  Investigator reports applicable for all geographies per Medtronic requirements ....................92
Table 11:  Investigator reports applicable to EMEA per ISO 14155............................................................92
Table 12:  Investigator reports applicable to the United States per FDA regulations................................93
Table 13:  Sponsor Reports for EMEA.........................................................................................................96
Table 14. Sponsor Reports for Malaysia .....................................................................................................97
Table 15. Sponsor Reports for Hong Kong..................................................................................................98
Table 16:  Sponsor Reports for United States.............................................................................................99
Table 17:  Summary of System Related AEs by Severity and MedDRA Term (Micra IDE Clinical Study)..107
Table 18: Summary of Procedure Related AEs by Severity and MedDRA Term (Micra IDE Clinical Study)
..................................................................................................................................................................107
4 Table of Figures
Figure 1: Atrioventricular Pacing Percentage versus Components of AV Synchrony.................................25
Figure 2: MARVEL 2 Study Flow..................................................................................................................28
Figure 3: Additional Study Procedures for De Novo Subjects.....................................................................30
Figure 4:  Medtronic Application Login.......................................................................................................34
Figure 5: AV Synchronous Pacing Percentage Observed in the MARVEL Study by Predominant Rhythm.70
Figure 6: LVOT VTI (cm) During VVI Mode and MARVEL Adaptive Mode (MARVEL Study) .......................77

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SW022
MicraTM
Application Software
(Medtronic)
Commercially available in applicable geographies
MRVL2
MARVEL 2 Software Rev.1.0
(Medtronic)
Investigational
9986
2090 Programmer Baseline 
Operating System Software
(Medtronic)
Commercially available in applicable geographies
2090
Medtronic Carelink
Programmer
(Medtronic)
Commercially available in applicable geographies
Model 
ER220 
Extended 
Range Holter 
Monitor**
ERX10 Extended Range Tel-B 
Antenna (Medtronic)
Investigational 
DR220 Holter (NorthEast 
Monitoring, Inc)
Commercially available in applicable geographies
*The MicraTM Model MC1VR01 device will be considered investigational the moment the MARVEL 2 
software is downloaded and will no longer be investigational when the MARVEL 2 software is 
removed. Commercially available devices listed in the table above will be used inside the approved 
indications, except the Micra device.
**When permanently attached together, the DR220 Holter and ERX10 Extended Range Tel-B 
Antenna become ER220 Extended Range Holter Monitor and will be considered investigational.  
Primary Objective(s)
Primary Efficacy Objective
Demonstrate the superiority of the MARVEL 2 features to provide 
atrioventricular synchronous pacing relative to Micra VVI pacing in 
subjects with normal sinus node function and persistent 3rd degree AV 
node block at rest.
Primary Safety Objective
Demonstrate that the MARVEL 2 features provide pacing as intended.
Secondary Objective(s)
Secondary Objective
Demonstrate an increase in stroke volume, as measured by left 
ventricular outflow tract velocity time integral, with the MARVEL 2 
features compared to VVI pacing in subjects with normal sinus node 
function and persistent 3rd degree AV node block.
 
 
 

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Study Design
The MARVEL 2 study is an acute, prospective, global, multi-center, 
software-download clinical study.  The study is planned to be conducted 
in US, Europe, and Asia.  The study is expected to be conducted at
approximately 15-20 centers in up to 100 subjects to obtain at least 70 
usable Holter datasets to meet the objectives of the study.  The 
expected total study duration (from first subject enrollment to the exit 
of the last subject) is approximately 6-months; this represents the time 
necessary to enroll the target sample size of at least 70 subjects with 
usable Holter datasets. Software will be downloaded into patients 
implanted with a Micra device to allow the new algorithm performance 
to be measured in patients where a Micra device has already been 
chosen as most appropriate for the patient.  
Most enrolled subjects will complete the study procedures during a 
single study visit.  However, subjects enrolling in the study at the time of 
their Micra implant (anticipated to be approximately 10 subjects) will 
have the investigational algorithm downloaded following Micra implant, 
prior to hospital discharge, and approximately 1-month post-implant.  
This subset of subjects with de novo Micra implants will allow the 
MARVEL 2 features to be tested at multiple points in the device life 
cycle.   
Since the download algorithm running in a Micra device significantly 
increases current drain, a 2-4 hour acute study is used to limit the 
reduction in device longevity.  
Sample Size
A sample size of at least 70 subjects with usable Holter datasets
following MARVEL 2 software download is required to test the study’s 
primary objectives. This includes at least 35 subjects with a 
predominant heart rhythm of normal sinus node function and persistent 
3rd degree AV block to provide at least 90% power to test the study’s 
primary efficacy objective.  Since all subjects may not have usable Holter 
data, up to 100 subjects may be enrolled to achieve the goal of 70 
usable Holter datasets.  Enrollment may end once the target number of 
usable Holter datasets has been obtained.

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There is no minimum number of subjects required to be enrolled at a 
center.  However, to ensure a widespread distribution of data and 
minimize center bias in study results, the maximum number of enrolled 
subjects at a single site is 20. 
Enrollment Strategy
The intent is to ensure subjects enrolled early in the study contribute to 
the primary efficacy and secondary objectives, specifically subjects with 
normal sinus node function and persistent 3rd degree AV node block.  
Once at least 35 of these subjects have been enrolled, other subjects 
with a history of AV block may be enrolled to demonstrate the safety 
and utility of the MARVEL 2 algorithm in patients with other forms of AV 
block.  These include subjects who may have predominantly intact AV 
conduction or AV block with sinus node dysfunction, and/or atrial 
arrhythmias. More than 35 subjects meeting the criteria for the primary 
efficacy objective may be enrolled.  It is preferable to enroll subjects 
with de novo Micra implants early in the study since they will have a 1-
month follow-up.  
The enrollment strategy and current target patient population available 
for enrollment to address the primary efficacy and secondary study 
objectives will be communicated to the study centers.
Inclusion/Exclusion 
Criteria
Inclusion Criteria

Subject has been implanted with a Micra TPS (Model 
MC1VR01) with remaining device longevity of 6 years or more 
or is expected to be implanted with a Micra TPS.

Subject has history of AV block*

Subject is ≥ 18 years old and as per required local law.

Subject (and/or witness as applicable per local regulations) 
provides signed and dated authorization and/or consent per 
institution and local requirements.

Subject is willing and able to comply with the protocol.
*This includes subjects with normal sinus function and persistent 3rd degree AV 
block and subjects with other forms of AV block.
Exclusion Criteria

Subject is currently enrolled or planning to participate in a 
potentially confounding drug or device trial during the study.  
Co-enrollment in concurrent trials is only allowed when 
documented pre-approval is obtained from the Medtronic 
Clinical Research Specialist.

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
Subject is pregnant (if required by local law, women of child-
bearing potential must undergo a pregnancy test within seven 
days prior to MARVEL 2 study procedures).

Subject meets any exclusion criteria required by local law (age 
or other).
Study Procedures and 
Assessments
After consent, enrollment, baseline data collection, and initial MicraTM
TPS device interrogation, the investigational MARVEL 2 software will be 
downloaded into an implanted Micra device and a customized Holter 
monitor will be placed on the subject. The Holter will record surface 
ECG, EGM, accelerometer signals, and device and MARVEL 2 algorithm 
markers. The subject will sit or lie while an automatic setup is 
performed to determine the optimal accelerometer vector and sensing 
parameters.  Following the automatic setup, the MARVEL 2 features will 
be evaluated at rest.  Subsequently, the subject will perform a series of 
posture maneuvers and exercises.  Subjects will have an 
echocardiogram performed while the MARVEL 2 features are 
programmed to adaptive mode (VDD pacing) and programmed to 
monitor mode (VVI pacing). After all study procedures have been 
completed, the MARVEL 2 software will be removed, a final Micra TPS 
device interrogation performed, the Micra TPS device will be 
programmed to its intended permanent device settings, and the subject 
will be exited. The in-office testing is expected to last 2-4 hours.    
It is expected that approximately 10 subjects with de novo Micra 
implants (i.e. those enrolling at the time of their Micra implant) may 
enroll in the MARVEL 2 study.  Studying subjects with de novo implants
ensures some accelerometer signals will be collected 
during/immediately after the implant procedure.  In addition, studying 
these subjects prior to hospital discharge and at 1-month provides 
information on the evolution of the accelerometer signal and AV 
synchrony.
Safety Assessments
All adverse events (AEs) that occur from the time of enrollment through 
study exit will be collected and reported to Medtronic during the study.  
Additionally, any device deficiencies related to the Micra device or 
MARVEL 2 software will be collected.  
All Holter recordings will be evaluated for the presence of pauses 
exceeding two cardiac cycles and oversensing induced tachyarrhythmias 
(OIT) exceeding 100 bpm.
Statistics
A sample size of at least 70 subjects with usable Holter datasets 
following MARVEL 2 software download is required. This includes at 
least 35 subjects with a predominant heart rhythm of normal sinus node 

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rows of Figure 1 display the relationship between AV synchrony percentage and median P-V interval 
(top row), interquartile range for the P-V interval (middle row), and the number of episodes of 
dyssynchrony exceeding 5 consecutive beats (bottom row).  The columns of Figure 1 display the 
relationships for the 33 MARVEL subjects with a predominant rhythm of high-grade AV block (left 
column) and 31 MARVEL subjects with a predominant rhythm of intact AV conduction.  The red dashed 
vertical line indicates 70% AV synchrony on each plot.
Careful examination of Figure 1 indicates that subjects with >70% AV synchrony had a median P-V 
interval of 225 ms or lower, and this was true for all subjects with >70% AV synchrony regardless of 
predominant rhythm.  The middle row of Figure 1 shows that all the 9 subjects (100%) with high-grade 
AV Block and <70% AV synchrony had an interquartile range or their P-V intervals exceeding 200 ms 
while 22 or the 23 (96%) of the subjects with high-grade AV block and >70% AV synchrony had a P-V 
interval interquartile range less than 200 ms.  Similarly, for the subjects with intrinsic AV conduction, the 
two subjects with <70% AV synchrony had P-V interval interquartile ranges exceeding 200 ms, while all 
29 subjects with >70% synchrony had P-V interval interquartile ranges less than 200 ms.  Finally, the 
bottom row of Figure 1 shows that none of the 23 subjects with high-grade AV block and none of the 29 
subjects with intact AV conduction and >70% AV synchrony had more than 15 instances of more than 5 
consecutive beats of dyssynchrony.   This analysis further suggests that the requirement for at least 70% 
AV synchrony is appropriate.

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Figure 1: Atrioventricular Pacing Percentage versus Components of AV Synchrony
SAS Program: V:\MARVEL\Reports\Final_Report\AdHocDataRequests\MARVEL2\summarizeAsynchronousBeats.sas
R Program: V:\MARVEL\Reports\Final_Report\AdHocDataRequests\MARVEL2\plotAsynchronyDistribution.R

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8.2.1.2 Primary Safety Endpoint
A subject will meet the primary endpoint if they are free from the following MARVEL 2 software related 
events during the entire Holter monitoring period where the MARVEL 2 features are enabled:
1.
Pauses lasting longer than two cardiac cycles (where cardiac cycle length is defined by 
the programmed lower rate interval), AND
2.
Episodes of oversensing induced tachycardia exceeding 3-minutes, defined as 
oversensing accelerometer signal leading to a heart rate exceeding 100 BPM
Rationale for Endpoint
The primary safety endpoint will ensure that the pacing functionality of the MARVEL 2 features 
are safe (i.e. the MARVEL 2 algorithm does not interfere with the Micra device’s ability to 
provide pacing support).  Specifically, the primary safety endpoint will allow the MARVEL 2 study 
to demonstrate that the MARVEL 2 features 1) provide adequate rate support and 2) do not 
pace too fast due to oversensing.
8.2.2 Secondary Endpoint
The secondary endpoint is left ventricular outflow tract (LVOT) velocity time integral (VTI) as obtained 
from echocardiogram while the MARVEL 2 features are in adaptive mode (VDD pacing) and while the 
MARVEL 2 features are in monitor mode (VDI pacing which is effectively VVI pacing).  This will be 
measured by the echo core laboratory.
Rationale for Endpoint
LVOT VTI is a measure of stroke volume and correlated with cardiac function.  Traditional dual chamber 
pacemakers (with a lead in both the right atrium and right ventricle) have been shown to improve stroke 
volume compared to VVI pacing.  Demonstrating a significant increase in LVOT VTI in the study will show 
that the MARVEL 2 features also improve stroke volume compared to VVI pacing.9
 
 
 
 
 
 
 
 

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9 Study Design 
The MARVEL 2 study is an acute, prospective, global, multi-center, software-download clinical study to 
evaluate the performance of the MARVEL 2 software, which includes a comprehensive set of the 
anticipated Micra AV features.  The study is planned to be conducted in the US, Europe, and Asia.  In the 
United States, the study is being conducted under an Investigational Device Exemption (IDE).  Overall, 
the study is expected to be conducted at approximately 15-20 centers and will enroll up to 100 subjects 
to obtain at least 70 usable Holter datasets to meet the sample size required to test the primary
objectives of the study.  Holter datasets will be considered usable if there is readable telemetry signal as 
determined by Medtronic personnel experienced in the review of Holter recordings.  
The expected total study duration (from first subject enrollment to the exit of the last subject) is 
approximately 6-months with the proposed start date of January 2019.  This represents the time 
necessary to enroll the target sample size of at least 70 subjects. A download study into patients with an 
existing Micra device allows the new algorithm performance to be measured in patients where a Micra 
device has already been chosen as most appropriate for the patient.   Most enrolled subjects will 
complete the study procedures at a single 2 to 4-hour study visit.  However, a subset of subjects who 
enroll in the study at the time of their Micra implant (anticipated to be approximately 10 subjects) will 
have the investigational algorithm downloaded following Micra implant, one day post-implant, and at 
approximately 1-month post-implant.  Studying these subjects with de novo Micra implants will allow 
the MARVEL 2 software features to be tested at multiple points in the device life cycle.
Additionally, study centers that participated in the MARVEL study may enroll up to three randomly 
selected subjects with normal sinus node function and persistent 3rd degree AV node block that 
participated in the MARVEL study.  Allowing subjects enrolled in the MARVEL study to participate in the 
MARVEL 2 study will enable an assessment of AV synchrony at multiple points in time.
Because the download algorithm running in Micra device significantly increases current drain, a 2 to 4-
hour acute study is used to limit the reduction in device longevity.  
There is no minimum number of subjects required to be enrolled at a center.  However, to ensure a 
widespread distribution of data and minimize center bias in study results, the maximum number of 
enrolled subjects at a single site is 20.
Figure 2 displays the MARVEL 2 study flow for all study subjects.

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9.1.1 De Novo Subjects
De Novo subjects are those subjects that enroll in the MARVEL 2 study at the time of their Micra 
implant.  Note that these will be subjects where the clinician and patient have determined that a Micra 
device is the most appropriate therapy for the patient’s condition.  It is expected that approximately 10 
de novo subjects will enroll in the MARVEL 2 study.  Studying these subjects with de novo Micra implants 
ensures some accelerometer signals are collected during or immediately after the implant procedure.  In 
addition, studying these subjects prior to hospital discharge and at 1-month provides information on the 
evolution of the accelerometer signal and AV synchrony.
Specifically, following Micra implant and initial device interrogation, the investigational MARVEL 2 
software will be downloaded into the Micra, and a custom Holter monitor will be placed on the subject.  
The Holter monitor will record surface ECG, EGM, accelerometer signals, and device and MARVEL 2 
algorithm markers.  The subject should be in a sitting or supine position while the automatic setup runs 
for approximately 20 minutes.  Once completed, the MARVEL 2 software will be removed from the 
Micra, and the Holter monitor will be removed from the subject.  Note that the MARVEL 2 software will 
be in monitor mode (VDI mode with no atrial tracking) on the day of the Micra implant.  Prior to hospital 
discharge and at approximately 1-month post-implant de novo subjects will perform the MARVEL 2 
study procedures as described in Figure 2 (however, the subject should not be exited after completing 
the study procedures at their pre-hospital discharge post-implant visit).   Figure 3 describes the 
additional study procedures required for de novo subjects.
Thus, de novo subjects will be exposed to the investigational MARVEL 2 algorithm for a total of 
approximately 4.5 to 8 hours.

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The investigator must notify the subject of any significant new findings about the study that become 
available during 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 relevant, approval may be requested from 
subjects to confirm their continued participation. ICF templates will be provided under a separate cover.
Prior to initiation of any study-specific procedures, IC must be obtained from the subject. Likewise, 
privacy or health information protection regulation may require subjects to sign additional forms to 
authorize centers to submit subject information to the study sponsor. The IC process must be conducted 
by the principal investigator or an authorized designee, and the ICF and other privacy language, as 
required by law, must be given to the subject in a language he or she is able to read and understand. 
The process of IC must be conducted without using coercion or undue improper influence on or 
inducement of the subject to participate by the investigator or other center personnel. The IC process 
shall not waive or appear to waive subject’s legal rights. The language used shall be as non-technical as 
possible and must be understandable to the subject and the impartial witness, where applicable.
The subject must have ample time and opportunity to read and understand the ICF, to inquire about 
details of the study, and to decide whether to participate in the clinical study. All questions about the 
study should be answered to the satisfaction of the subject.
When the subject decides to participate in the clinical study, the ICF must be signed and personally 
dated by the subject and investigator or authorized designee, as required by the ICF.
If the IC is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any 
study-related procedures. It is best practice for the IC process to be documented in the subject’s case 
history, regardless of circumstance.
In the event the subject cannot read and/or write and if allowed by local law the IC process shall be 
obtained through a supervised oral process. An independent witness (if applicable as per local 
regulation) must be present during this process. The ICF and any other information must be read aloud 
and explained to the prospective subject, and whenever possible, either shall sign and personally date 
the ICF attesting that the information was accurately explained and that ICF was freely given. The source
documentation should provide 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 ICF must be filed in the hospital/clinical chart and/or with the subject’s study 
documents.
A copy of the ICF and other privacy language as required by law, signed and dated if required by local 
law, must be provided to the subject.
The ICF and other privacy language as required by law must be available for monitoring and auditing. 
Any Medtronic field personnel who support the study procedure must be able to review the subject’s 
signed and dated ICF and verify its completeness prior to proceeding with the study procedure. In the 
event the Medtronic Field personnel identify ICF as being incomplete, the study procedure will not be 
allowed to occur until the consent of the subject can be adequately and appropriately obtained.  

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13.7.4 Medical History
The subjects’ medical history will be obtained and recorded.  For de novo subject medical history, in 
addition to collection of medical history at baseline, will also be collected at the pre-hospital discharge 
and 1-month study visits.
13.7.5 Cardiovascular Medications
The cardiovascular medications prescribed to the subjects will be recorded.  For de novo subjects the 
cardiovascular medications will be recorded at implant and at the pre-hospital discharge and 1-month 
study visits.
13.7.6 Physical Exam
A basic physical exam will be performed, including height and weight (if not in the subject’s medical 
chart) and blood pressure.  For de novo subjects a physical exam should be performed at implant and at 
the pre-hospital discharge and 1-month study visits.
13.7.7 12-Lead Electrocardiogram
A 12-lead electrocardiogram from the subject will be recorded.  The recording of this electrocardiogram 
should be within seven days prior to the study procedure visit.  For de novo study subjects, an 
electrocardiogram should be recorded prior to the implant procedure, at pre-hospital discharge, and 1-
month study visits.
13.7.8 X-Ray (if available)
X-ray images documenting the implant location of the Micra will be collected, if available.  If not 
available, no new x-ray image will be requested.
13.7.9 Initial Device Interrogation
An interrogation of the Micra device will be performed to verify device longevity is at least 6 years and 
saved on a USB drive or on a diskette.  Device interrogation data (.pdd file) should be sent to Medtronic 
using a secure, electronic transfer. Missed device interrogations are considered a protocol deviation and 
must be documented in the protocol deviation CRF.
13.7.10 Download the MARVEL 2 Software 
Details of the procedure for downloading the MARVEL 2 software into the Micra device are documented 
in the MARVEL 2 User Manual.
Upon downloading the MARVEL 2 software into the Micra device, the Micra device becomes 
investigational as described in Table 1: MARVEL 2 Research System.
As outlined in the MARVEL 2 User Manual, when the MARVEL 2 software is turned to adaptive mode, 
the algorithm will acquire the Micra accelerometer signal and begin tracking the A4 signal (the 

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accelerometer signal corresponding to atrial contraction).  Ventricular pacing will then be initiated by 
the device if an intrinsic R wave is not observed between A4 detection and the programmable A4-VP 
interval.
13.7.11 Holter Monitor / ECG Setup
The ER220 Holter monitor will be placed on the subject per the instructions for use. 
In addition to the ECG cable for the Holter monitor, an ECG cable from the Medtronic Carelink 
Programmer will be connected to the subject.  If P-waves are not visible on the Medtronic Carelink 
Programmer, the ECG connections should be repositioned until P-waves are visible.
13.7.12 Auto-Setup Phase / Parameter Settings Evaluation
During the auto-setup phase, the subject should remain in a consistent supine or sitting position.  Prior 
to initiation of the auto-setup, the pacing mode will be programmed to VDI mode with a lower rate of 
50 bpm.  The auto-setup feature will be initiated from the Medtronic Carelink Programmer.  After 
approximately 20 minutes, the auto-setup feature will complete, and programming recommendations 
will be displayed.  Data collected during the auto setup phase will contribute to the VVI phase of the for 
the primary efficacy objective evaluation as the device will be programmed to a non-atrial tracking 
mode (i.e. VDI which is effectively VVI pacing).
Following the auto setup phase, proper operation of the auto-setup recommended settings will be 
verified first in VDI pacing mode (non atrial tracking mode) and then in VDD pacing mode (atrial tracking 
mode).  
13.7.13 Evaluation Phase / Resting Period
Data collected during the resting period will contribute to the primary efficacy objective.  The duration 
of the resting period will be approximately 20 minutes.  During the resting period, the subject should 
remain in a consistent supine or sitting position.  The pacing mode will be set to VDD (atrial tracking 
mode).   
13.7.14 Evaluation Phase / Posture and Activity 
During the posture and activity evaluation the subject will perform the following maneuvers. The times 
for each maneuver will be recorded on the MARVEL 2 procedure worksheet:

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
Have the subject lie on their back for approximately 2 minutes

Have the subject lie on their right side for approximately 2 minutes

Have the subject lie on their left side for approximately 2 minutes

Have the subject sit for approximately 2 minutes

Have the subject stand for approximately 2 minutes

Have the subject walk at a normal (comfortable) pace for approximately 2 minutes

Have the subject walk at a vigorous pace for approximately 2 minutes with the goal of having 
the subject achieve a maximum heart rate of at least 100 bpm
Subjects will be allowed to have recovery time after the walking maneuvers as needed.
13.7.15 Echocardiogram
An echocardiogram (echo) will be performed both when the MARVEL 2 algorithm is programmed to 
Monitor and Adaptive modes.
The echocardiogram should be performed in accordance with the study required echo protocol. The 
echo views and measurements that will be collected include, but are not limited to, apical 4-chamber, 
left atrial volume, LVOT VTI, Mitral VTI, Mitral flow including E and A wave measurements.  The original 
recording will be sent to the Echo Core Lab for analysis either by mailing the electronic storage medium 
or through electronic transfer.  A copy must be maintained at the center with the subject’s records.  It is 
recommended that echo recordings are sent to the Echo Core lab as soon as possible after obtaining the 
echocardiogram.  The Echo Core Lab will conduct a quality review of all echoes and provide feedback to 
study centers as needed. 
Randomly generated numbers will be assigned to label the echo recording medium and link the echo 
core lab results to an individual study center and subject.  Additionally, study sites will be randomized to 
perform the echo while the MARVEL 2 algorithm is programmed to Adaptive mode first followed by 
Monitor Mode second or while the MARVEL 2 algorithm is programmed to Monitor mode first followed 
by Adaptive mode.  Note that this strategy will blind the echo core lab personnel to study site, subject, 
and pacing mode.  The MARVEL 2 study worksheets will indicate the MARVEL 2 programmed mode 
sequence in which the echo images should be acquired.
 
 
 
 

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13.7.17 Remove the MARVEL 2 Software and Holter
Details of the procedure for removing the MARVEL 2 software from the Micra device is documented in 
the MARVEL 2 User Manual.  
The ER220 Holter will be removed from the subject.  The data recorded on the SD card from the Holter
monitor should be sent to Medtronic for evaluation.
The Micra device is to be programmed to its intended permanent settings for VVI(R) mode for the 
subject.
13.7.18 Final Device Interrogation
Before performing a final device interrogation and exiting the subject, the Micra device should be 
verified that it has been reprogrammed to its intended permanent settings.  An interrogation of the 
Micra device should be saved on a USB drive or on a diskette.  Device interrogation data (.pdd file) 
should be sent to Medtronic using a secure, electronic transfer utility.  Missed device interrogations are 
considered a protocol deviation and must be documented in the protocol deviation CRF.
13.7.19 Implant Assessment (de novo subjects only)
De novo subjects will be enrolled prior to their Micra implant. The de novo subjects will be studied at 
three time points.  The first study of a de novo subject will be immediately following the implant of the 
subject’s Micra device.  A Holter monitor will be placed on the subject (see Section 3.7.7) and the 
MARVEL 2 software will be downloaded into the subject’s Micra (see Section 3.7.6). The auto-setup 
evaluation will then be performed (see Section 3.7.8).  Following the auto-setup evaluation, the MARVEL 
2 software will be removed from the subject’s Micra and the Holter will be removed from the subject 
(see Section 3.7.12).  Note, at this time point, the MARVEL 2 algorithm will not be programmed to 
adaptive mode (i.e. there will be no atrial tracking). This assessment would ideally be performed in the 
implant procedure room but could be performed in a recovery room.
If a de novo subject has an unsuccessful Micra implant attempt where an operating Micra device does 
not remain in the right ventricle following groin access site closure, the subject should be exited from 
the study following the resolution of any adverse events.  Note that an unsuccessful implant is not an 
adverse event.  However, all adverse events that occur during an unsuccessful implant procedure should 
be reported.
13.7.20 Post-Implant Assessment (de novo subjects only)
The second time the de novo subjects are studied is prior to discharge for their Micra implant.  At this 
time point, all MARVEL 2 in-clinic study procedures will be performed (Sections 13.7.4 through 13.7.18).  
Note, that the MARVEL 2 software will be removed from the subject’s Micra at the end of these study 
procedures.

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
The event is not a known side effect of the product category 
the device belongs to or of similar devices and procedures;

The event has no temporal relationship with the use of the 
device or the procedures.

The serious event does not follow a known response pattern 
to the medical device (if the response pattern is previously 
known) and is biologically implausible.

The discontinuation of medical device application or the 
reduction of the level of activation/exposure – when clinically 
feasible – and reintroduction of its use (or increase of the 
level of activation/exposure) do not impact the serious event.

The event involves a body-site or an organ not expected to be 
affected by the device or procedure.

The serious event can be attributed to another cause (e.g., an 
underlying or concurrent illness/clinical condition, an effect of 
another device, drug, treatment, or other risk factors).

The event does not depend on a false result given by the 
device used for diagnosis (when applicable).

Harms to the subject are not clearly due to use error.
In order to establish the non-relatedness, not all the criteria listed 
above might be met at the same time, depending on the type of 
device/procedures and the event.
Unlikely
The relationship with the use of the device seems not relevant and/or 
the event can be reasonably explained by another cause, but 
additional information may be obtained.
Possible
The relationship with the use of the investigational device is weak but 
cannot be ruled out completely. Alternative causes are also possible 
(e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also 
be classified as possible.
Probable
The relationship with the use of the investigational device seems 
relevant and/or the event cannot be reasonably explained by another 
cause, but additional information may be obtained. 
Causal Relationship
The event is associated with the device or study procedures beyond 
reasonable doubt when:

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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)
Serious Adverse Device Effect 
(SADE) 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event.
(ISO 14155:2011, 3.36)
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))
Unanticipated Serious Adverse 
Device Effect (USADE)
Serious adverse device effect which by its nature, incidence, severity 
or outcome has not been identified in the current version of the risk 
analysis report
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been 
identified in the risk analysis report.
(ISO 14155:2011, 3.42)
Complication
An Adverse event that includes the following is considered a 
complication:
a) Results in death,
b) Involves any termination of significant device function, or
c) Requires an invasive intervention
Non-invasive (FDA, CFR 21; 812.3 (k)): when applied to a 
diagnostic device or procedure, means one that does not by 
design or intention:  Penetrate or pierce the skin or mucous 
membranes of the body, the ocular cavity, or the urethra, or 
enter the ear beyond the external auditory canal, the nose 
beyond the nares, the mouth beyond the pharynx, the anal 
canal beyond the rectum, or the vagina beyond the cervical os
NOTE: Only system or procedure related AEs will be classified as 
complications or observations

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Meeting the performance requirement for the primary efficacy objective will demonstrate that the
MARVEL 2 features provide high rates of atrioventricular synchronous pacing and greatly exceed rates 
observed with VVI pacing in the patient population expected to benefit the most from atrioventricular 
synchronous pacing.
17.5.3 Sample Size
A sample size of at least 35 subjects with normal sinus node function and persistent 3rd degree AV block
and a sufficient number of evaluable cardiac cycles  during the vector setup and 20-minute resting 
period will provide greater than 90% power to reject the null hypothesis based on the following 
assumptions:
1.
Two-sided type I error rate = 0.05
2.
Single analysis after all enrolled subjects have had an opportunity to complete the MARVEL 2 
study procedures and have had their Holter data evaluated
3.
Each subject will have at least 500 evaluable beats* during the auto-setup phase (VVI pacing)
period and during VDD pacing during the 20-minute resting period
4.
The proportion of subjects meeting the primary efficacy endpoint in one pacing mode, but not 
the other (i.e. proportion of discordant pairs) will exceed 50%
5.
At least 90% of discordant subjects will favor the MARVEL 2 features
*Note: An evaluable beat is defined as an observable P-wave on the Holter ECG followed by at 
least 300 ms of drop-out free Holter telemetry data or a Micra ventricular event marker.
Justification of Sample Size Assumptions
Figure 5 displays the AV synchronous pacing percentage observed in the MARVEL study by predominant 
rhythm.  The average AV synchronous pacing percentage among the 33 subjects with a predominant 
rhythm of high-grade AV block was 80.0% during MARVEL adaptive mode (VDD pacing) compared to 
37.5% during VVI pacing (P<0.001).   Among the 33 subjects with a predominant rhythm of high-grade 
AV block, 72.7% of subjects (24 of 33) had an AV synchronous pacing rate exceeding 70% while in 
MARVEL adaptive mode compared to 6.1% (2 of 33) during MARVEL monitor mode (VVI pacing).

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Figure 5: AV Synchronous Pacing Percentage Observed in the MARVEL Study by Predominant 
Rhythm
17.5.4 Analysis Methods
Following download of the investigational MARVEL 2 software, a Holter monitor will be placed on the 
subjects.  The Holter monitor will record surface ECG, EGM, accelerometer signals, and device and 
MARVEL 2 algorithm markers.  Specifically, the Holter will record whether the MARVEL 2 features senses
an atrial contraction (A4 signal representing active ventricular filling detected on the accelerometer 
waveform), delivers a pacing spike, or inhibits a pacing spike based on a sensed intrinsic R-wave.
For each subject, the VVI pacing control period will occur shortly following investigational software 
download during the approximately 20-minute algorithm auto-setup phase where the MARVEL 2
programmable parameters are setup to enable optimal tracking of the A4 signal.  The auto-setup phase 
will occur while the MARVEL 2 features are in monitor mode (i.e. VDI pacing, which is effectively VVI 
pacing).  For purposes of evaluating the primary efficacy objective, the 20-minute resting period while 
the MARVEL 2 features are programmed to adaptive mode and providing VDD pacing will serve as each 
subject’s treatment period. 
Note that a randomized crossover design will not be used to compare AV synchronous pacing 
percentage between the MARVEL 2 pacing mode and VVI pacing for the following reasons: 1) knowledge 
of pacing mode is unlikely to influence AV synchronous pacing rate as such knowledge is unlikely to 
influence right atrial contractility, 2) the auto-setup phase will provide an opportunity to assess the AV 
synchronous pacing percentage during VVI pacing, 3) carryover effects are not possible since as soon as 
the MARVEL 2 features are programmed to adaptive mode atrial tracking will commence, and
 

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Similar to the original MARVEL study, Holter files will be processed and reviewed by Medtronic 
personnel experienced in the review of Holter recordings using Holter and MATLAB utilities.  A human 
overread will also be used to truth each P-wave.  Device and MARVEL 2 markers will not be used by the 
MATLAB scripts or human overread to identify P-waves.  Finally, a MATLAB script will collate the 
identified P-waves, times corresponding to distinct study procedures, and MARVEL 2 markers in a .csv 
format file.  This .csv file will indicate the time after each P-wave a ventricular pace or intrinsic sensed R-
wave occurred.  Comparison of this P-R interval to 300 ms will determine whether a beat was 
synchronous.  If at least 70% of beats are considered synchronous during the VVI or MARVEL 2 adaptive 
pacing mode during resting, then the subject will be considered to have met the primary efficacy 
endpoint during the VVI or MARVEL 2 adaptive pacing mode during rest respectively.  McNemar’s test 
for paired proportions will be used to test the primary efficacy objective hypothesis.
The following pre-specified subgroups will be evaluated: sex, geography (US versus outside of US), and 
participation in the MARVEL study (yes versus no).  A repeated measures logistic regression model 
utilizing generalized estimating equations will be used to evaluate the homogeneity of the MARVEL 2
adaptive pacing mode effect on the primary efficacy endpoint by subgroup. For this model, the response 
will be the primary endpoint status (1=met primary endpoint, 0=did not meet) and the independent 
variables will be the pacing mode (VVI pacing or MARVEL 2 adaptive mode), subgroup status, and a 
subgroup status by pacing mode interaction.
Additionally, the proportion of subjects meeting the primary efficacy endpoint will be summarized and 
compared between VVI pacing and MARVEL 2 adaptive pacing using the methods described above in the 
following subsets of subjects with normal sinus node function and persistent 3rd degree AV block:
1.
Those subjects exhibiting low PVC burden
2.
Those subjects exhibiting low PVC burden with a mitral valve doppler echo E/A ratio of 1.5 or 
less
17.5.5 Determination of Subjects and Data for Analysis
All subjects with normal sinus node function and persistent 3rd degree AV block during Holter
monitoring with at least 500 evaluable beats during VVI pacing and at least 500 evaluable beats during
MARVEL 2 adaptive pacing in which the device is providing VDD pacing1 will be included in the primary 
analysis for this objective. For de novo subjects, only data collected during the 20-minute resting period 
at pre-hospital discharge will contribute to the analysis of the primary objective.  (Note that ancillary 
objective number five will compare the atrioventricular synchronous pacing rates observed at pre-
hospital discharge and at 1-month post-implant.)  However, if a de novo subject does not have usable 
Holter data at pre-hospital discharge, their Holter data approximately 1-month post-implant will be used
in the analysis, if available.
                                                          
1 Cardiac cycles during MARVEL 2 adaptive mode pacing that occur during an AV conduction test will not be 
considered evaluable as the pacing mode is set temporarily to VVI40 while the device checks for intrinsic AV 
conduction.  

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Loss of communication between the Holter and the implanted Micra device, called telemetry dropout, 
can lead to loss of the marker indicating a ventricular event was sensed or a ventricular pace was 
delivered.  Therefore, beats with no ventricular sense or pace markers and indication of telemetry 
dropout in the first 300 ms after a P-wave will be discarded (i.e. they are not evaluable beats).
17.5.6 Missing Data and Sensitivity Analyses
Missing Data
Given the relatively short duration of the study, missing data is not expected to be a serious issue. Since 
telemetry dropout may influence the number of evaluable beats for a subject during both VVI pacing 
and MARVEL 2 adaptive pacing, the total number of heart beats and total number of evaluable beats will 
be summarized.
If any subjects with normal sinus node function and persistent 3rd degree AV block do not have usable 
Holter data during the study, the reason the Holter data was not usable will be discussed.  Additionally, 
to address concerns with missing data that may arise, sensitivity analyses will be performed to assess 
the robustness of the observed statistical inference with respect to the missing data. 
The first sensitivity analysis will be to include all subjects with normal sinus node function and persistent 
3rd degree AV block that had some usable Holter data during both 20-minute resting period (MARVEL 2
adaptive pacing) and VVI pacing control period (i.e. auto-setup phase) regardless of the number of 
evaluable beats in each phase.  
The second sensitivity analysis will include all subjects who had the MARVEL 2 software downloaded and
had a Holter monitor placed on them that were classified as having a predominant rhythm of persistent 
3rd degree AV block with normal sinus function or who did not have their rhythm classified.  This 
sensitivity analysis will incorporate a tipping point methodology.  Specifically, all subjects with missing 
data will be included as meeting the primary efficacy endpoint during MARVEL 2 adaptive pacing and 
not meeting it during VVI pacing (i.e. discordant in favor of MARVEL 2 adaptive pacing) and then 
iteratively changed to not meeting the endpoint during MARVEL 2 adaptive pacing and meeting it during 
VVI pacing (i.e. discordant in favor of VVI pacing pacing).  The tipping point will be defined as the 
number of subjects of the total with missing data that would have to shift from being discordant in favor 
of MARVEL 2 pacing to discordant in favor of VVI pacing to change the statistical inference.  Stochastic 
methods may be used to aid in interpreting the likelihood of meeting or exceeding the tipping point.
Other Sensitivity Analyses
Since de novo subjects may have more than one visit in which both the AV synchronous pacing 
percentage is evaluated in both VVI and MARVEL 2 adaptive mode, the primary efficacy endpoint will
also be compared utilizing usable Holter data from all study visits for subjects with normal sinus node 
function and persistent 3rd degree AV block.  Specifically, a logistic regression model utilizing GEE to 
account for correlation in outcomes within subject will be used to estimate the effect of MARVEL 2
adaptive pacing on the primary efficacy endpoint.  Specifically, the response for this model will be the 
primary efficacy endpoint status (1=met primary efficacy endpoint, 0=did not meet primary efficacy 
endpoint) and the independent variable will be pacing mode (VVI or MARVEL 2 adaptive mode).  An 
exchangeable working correlation matrix will be employed with subjects considered repeated across 
study visit.

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3.
The proportion of subjects meeting the primary endpoint in the MARVEL 2 pacing mode will 
exceed 98%.
Justification of Sample Size Assumptions
It is expected that all (100%) subjects will meet the primary safety endpoint.  Specifically, in the MARVEL 
study, no pauses exceeding two cardiac cycles (as defined by the lower pacing rate interval) and no 
oversensing induced tachycardia exceeding three minutes were observed.
17.6.4 Analysis Methods
A Holter monitor will be placed on all study subjects during the MARVEL 2 study procedures.  The Holter 
continuously records ECG and data telemetered from the implanted Micra device.  The telemetered 
data includes ventricular electrograms reflecting ventricular activation and marker channel.  The marker 
channel includes the ventricular sensed and paced event markers as well as markers unique to the 
MARVEL 2 features including whether the MARVEL 2 features sense an atrial beat (A4 signal).  In 
addition, the Holter records supplemental marker data including V-V interval, pacing rate, pacing mode, 
pacing amplitude, pacing pulse width, R-wave amplitude, and sensor counts.
Each Holter dataset will be reviewed by Medtronic personnel experienced in the review of Holter 
recordings to determine the recording time, quality of the recording, and confirm correct MARVEL 2
feature operation.  Holter datasets will be further analyzed manually and using programmed scripts to 
extract information related to:

Ventricular sensing (including V-V interval)

A4 detection
All available Holter recordings (including multiple recordings for subjects evaluated at multiple visits 
following initial Micra implant) will be used to determine if a subject meets the primary safety endpoint.  
First, the ventricular markers from the Micra device will be searched for long intervals.  For each of 
these identified long intervals, the surface ECG signal will be manually reviewed to determine if they are 
true pauses or due to telemetry dropout.  For any true pauses, the surface ECG signal, accelerometer 
signal, and device markers will be examined to determine if the pause was related to the MARVEL 2 
algorithm or for another reason (e.g. T-wave oversensing).  To identify any potential oversensing 
induced tachycardia the ventricular markers from the Micra will be searched for indication of a heart 
rate above 100 BPM exceeding 3 minutes.  If high heart rates exceeding this criterion are identified, the 
surface ECG, the accelerometer signal, and MARVEL 2 markers will be examined to determine if the high 
heart rates were due to MARVEL 2 algorithm oversensing.  Subjects free from pauses and oversensing 
induced tachycardia exceeding 3 minutes related to the MARVEL 2 algorithm will be considered to have 
met the primary safety endpoint.
An exact binomial test will be used to test the primary safety hypothesis.  Specifically, the numerator will 
be the number of subjects meeting the primary safety endpoint.  The denominator will be the number 
of subjects with Holter recordings with usable telemetry while the MARVEL 2 algorithm is programmed 
to adaptive mode (i.e. atrial tracking mode).   
The following pre-specified subgroups will be evaluated if there are two or more subjects who do not 
meet the primary safety objective: sex, geography (US versus outside of US), and predominant heart 

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17.7.3 Power Calculation
Background 
The MARVEL study demonstrated a mean increase in LVOT VTI of 2.1 (cm) [95% CI: 0.7 – 3.5 cm] with 
associated standard deviation of 3.8 cm in MARVEL 2 adaptive pacing relative to VVI pacing in 31 
subjects with high-grade AV block and with paired echocardiogram data.  Specifically, as displayed in 
Figure 6, mean LVOT VTI increased from an average of 21.8 cm to 23.9 cm.  The left panel of Figure 6
displays the LVOT VTI values for individual subjects (gray lines) and on average (dark blue lines) for the 
31 subjects with high-grade AV block subjects in MARVEL with paired echo assessments in both pacing 
modes.  The right-hand plot in Figure 6 displays the absolute change in LVOT VTI for MARVEL 2 adaptive 
pacing relative to the VVI pacing mode for individual subjects (red circles) and on average (blue circle).  
The right-hand plot also indicates that the lower 95% confidence interval for the mean change in LVOT 
VTI exceeded zero. 
The increase of 2.1 cm in LVOT VTI observed in the MARVEL study with MARVEL adaptive mode relative 
to VVI pacing is consistent with historical studies during the 1980s evaluating cardiac output between 
DDD and VVI pacing modes.  See for example, Labovitz, et al9, who observed a mean increase in LVOT 
VTI of approximately 2 cm with DDD pacing relative to VVI pacing in 26 patients with paired 
echocardiogram data in both DDD and VVI pacing modes.

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Figure 6: LVOT VTI (cm) During VVI Mode and MARVEL Adaptive Mode (MARVEL Study)
Note: Error bars represent 95% confidence intervals for mean LVOT VTI by pacing mode (right panel) or in mean paired LVOT 
VTI value differences during MARVEL adaptive pacing relative to VVI pacing. 
Power Calculation
As the sample size for the primary efficacy objective determines the number of subjects with normal 
sinus node function and persistent 3rd degree AV block with usable Holter data that are required for the 
study (at least 35 subjects), the power to reject the null hypothesis for the secondary objective was 
determined for a number of sample sizes as the protocol does not preclude study investigators from 
enrolling a higher number of subjects with normal sinus node function and persistent 3rd degree AV 
block nor account for the potential of missing echocardiogram data due to reasons such as improper 

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echocardiogram image acquisition, equipment malfunction, or subject refusal. The following 
assumptions were made for all power calculations:
1.
Two-sided type I error rate = 0.05
2.
Single analysis after all enrolled subjects have had an opportunity to complete the MARVEL 2 
study procedures and have had their Holter data evaluated
3.
Each subject will have paired echocardiogram available for analysis in both the MARVEL 2
adaptive mode and in VVI mode.
4.
The paired difference in LVOT VTI is normally distributed with a mean of 2.1 cm and a standard 
deviation of 3.8 cm in the population of potential patients with normal sinus node function and 
persistent 3rd degree AV block.
5.
A paired t-test will be the primary test statistic.
Table 9 displays the study power for both the paired t-test and for the Wilcoxon Signed-Rank test when 
there are 30, 35, and 40 subjects with normal sinus node function and persistent 3rd degree AV block
observed during Holter monitoring.  Although the pre-specified analytical method to evaluate the null 
hypothesis will be the paired t-test, the Wilcoxon Signed-Rank test may be used as a sensitivity analysis 
if there is strong evidence the difference in LVOT VTI is not normally distributed.
Table 9: Power to Reject the Null Hypothesis for the Secondary Objective
Sample Size1
Statistical Method2
Power (%)
30
Paired t-test
83.3
Wilcoxon Signed-Rank
80.5
35
Paired t-test
88.8
Wilcoxon Signed-Rank
86.8
40
Paired t-test
92.6
Wilcoxon Signed-Rank
91.3
1Number of subjects with paired LVOT VTI data available for analysis.
2Power for Wilcoxon Singed-Rank test based on the population LVOT VTI having an underlying normal 
distribution.
17.7.4 Analysis Methods
Echocardiograms will be collected for each subject during MARVEL 2 adaptive pacing and during VVI 
pacing. To ensure that the echo core lab is blinded to subject and programmed pacing mode, randomly 
generated numbers will be used to label the echo recording medium. Specifically, a random 5-digit 
number (“echo id”) will be assigned to label the echo recording medium and link the echo core lab 
results to an individual study subject.  Additionally, study sites will be randomized to perform the echo 
while the MARVEL 2 algorithm is programmed to Adaptive mode first followed by Monitor Mode second 

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or while the MARVEL 2 algorithm is programmed to Monitor mode first followed by Adaptive mode.  
This strategy will blind the echo core lab personnel to study site, subject, and pacing mode and allow the 
“echo id” to link to the appropriate center, subject, and pacing mode.
Since subject is the experimental unit, a paired t-test will be used to test the null hypothesis.   
The following pre-specified subgroups will be evaluated using an analysis of variance (ANOVA) model: 
sex, geography (US versus outside of US), and participation in the original MARVEL study (yes versus no).  
For each ANOVA model the response will be the change in LVOT VTI between MARVEL 2 adaptive pacing 
and VVI pacing.  The independent variable will be an identifier for subgroup.
If graphical assessments (e.g. Q-Q plots) of the distribution of change in LVOT VTI strongly suggest a 
deviation from normality, the Wilcoxon Signed-Rank test may be used as a sensitivity analysis.
17.7.5 Determination of Subjects and Data for Analysis
All subjects with normal sinus node function and persistent 3rd degree AV block during Holter 
monitoring and with paired LVOT VTI measurements during MARVEL 2 adaptive pacing and VVI pacing 
will be included in the analysis.  Note that so long as a subject’s predominant rhythm can be determined 
from the Holter recording, the subject may be included in this analysis as determination of predominant 
rhythm does not require device marker channel.
For de novo subjects, only echocardiogram data collected at pre-hospital discharge will contribute to the 
analysis of the secondary objective.  However, if a de novo subject is missing paired echocardiogram on 
the day following their Micra procedure but have paired LVOT VTI data from their 1-month visit, the 1-
month data will be used in the analysis if available.
17.7.6 Missing Data and Sensitivity Analyses
Missing Data
Given the relatively short duration of the study, missing data is not expected to be a serious issue.  
However, missing data may arise if a subject does not perform the echocardiogram or the 
echocardiogram is uninterpretable by the echo core lab. Note that both reasons for missing data may 
plausibly be considered independent to change in LVOT VTI.
If the level of missing data is an issue, tipping point methodology will be employed to evaluate the
sensitivity of the statistical inference to the missing data.  Additionally, stochastic methods may be 
employed to aid in interpreting the likelihood the tipping point would be met or exceeded.
Additional Sensitivity Analysis
Since de novo subjects may have more than one visit in which echocardiograms are obtained, the 
secondary objective will also be evaluated utilizing all available echocardiogram data.  Specifically, a
mixed effects linear regression model will be used account for correlation in outcomes within subject to 
determine the effect of MARVEL 2 pacing on change in LVOT VTI.  For this model, change in LVOT VTI will 
be the response and the model will incorporate an intercept and a random effect for subject.  The fixed 
effects for the intercept term will be used to quantify the effect of MARVEL 2 adaptive pacing on LVOT 
VTI.

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The MARVEL 2 study is designed to reflect the GCP principles outlined in ISO 14155:2011 and other 
international clinical requirements outlined below. These include the protection of the rights, safety and 
well-being of human subjects, controls to ensure the scientific conduct and credibility of the clinical 
investigation and the definition of responsibilities of the sponsor and investigators. In accordance with 
ISO 14155:2011, the sponsor shall avoid improper influence on, or inducement of, the subject, monitor, 
any investigator(s) or other parties participating in, or contributing to, the clinical investigation. All 
investigators shall avoid improper influence on or inducement of the subject, sponsor, monitor, other 
investigator(s) or other parties participating in or contributing to the clinical investigation. Adverse Event 
and Device Deficiency handling in the MARVEL 2 study is ISO 14155:2011 compliant for all participating
geographies.
Ultimately, all sites in all geographies will follow and comply with:
• Principles of Declaration of Helsinki
• 21 CFR Part 11 (Electronic Records, Electronic Signatures)
• The Clinical Trial Agreement
• The procedures described within this CIP
• Local Ethics Board Requirements
In addition to the regulatory requirements outlined above, the study will be conducted according to 
federal, national and local laws, regulations, standards, and requirements of the countries/geographies 
where the study is being conducted. These include but are not limited to the following: 
In the United States, the study will be conducted under an FDA IDE in compliance with 21 CFR Parts:
• 50: Protection of Human Subjects
• 56: Institutional Review Boards
• 812: Investigational Device Exemptions
In EMEA, the study will be conducted in compliance with:

ISO 14155:2011

Active Implantable Medical Device Directive (AIMDD)

Declaration of Helsinki version 2013.
In Hong Kong and Malaysia, the study will be conducted in compliance with:

ISO 14155:2011, with exception of a formal site initiation visit / visit report (All activation related 
requirements will be conducted / collected in separate parts).

Declaration of Helsinki 2013.  
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://clinicaltrials.gov (PL 110-
85, section 810(a)). In addition, the study may be registered in local regulatory databases where 
required by local law. 

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
Correspondence between the IRB/EC, sponsor, monitor, regulatory authority 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 
o
Observations of adverse events/adverse device effects/device deficiencies
o
Medical history
o
Baseline, Study procedure and follow-up data (if applicable)
o
Documentation of the dates and rationale for any deviation from the protocol

Electronically signed and dated e-CRFs and a blank set of CRFs where required by local law

All approved versions of the CIP, ICF and Investigator’s Brochure

Fully executed Clinical Trial Agreement

Ethics Committee approval documentation.  Written information that the investigator or other 
study staff, when member of the Ethics Committee, did not participate in the approval process. 
Approval documentation must include the Ethics Board composition, where required per local 
law.  

Regulatory authority notification, correspondence and approval, where required per local law.
List of investigation sites: This list is not yet final at the time of CIP development.  The list will be 
provided under a separate cover and will be maintained by the sponsor.

Subject Identification & Enrollment Log

Device accountability logs and internal tracking of investigational products

Current curriculum vitae (signed and dated) of principal investigators and key members of 
investigation site team (for EMEA only)

Current curriculum vitae of principal investigators (US and Malaysia)

Documentation of delegated tasks

Study training records for investigation site team

Insurance certificates

Any other records that FDA and local regulatory agencies required to be maintained (e.g. Ethics 
Committee Roster, study equipment calibration information)

Final Study Report including the statistical analysis
19.7.2 Investigator Reports
The investigator is responsible for the preparation (review and signature) and submission to the sponsor 
of all case report forms, adverse events and adverse device effects (reported per the country-specific 
collection requirements), device deficiencies, deaths, and any deviations from the clinical investigation 
plan.  If any action is taken by an Ethics Board with respect to this clinical study, copies of all pertinent 
documentation must be forwarded to Medtronic in a timely manner. Reports are subject to inspection 
and to the retention requirements as described above for investigator records. 
Safety data investigator reporting requirements are listed in Section 15.3.2 of the Adverse Event 
section. The investigator shall prepare and submit in a complete, accurate and timely manner the 
reports listed in this section.

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19.7.3 Sponsor records
Medtronic shall maintain the following accurate, complete, and current records that includes, but is not 
limited to:
• Correspondence which pertains to the MARVEL 2 Study
• Executed Clinical Trial Agreement
• Current curriculum vitae (signed and dated) of principal investigators and key members of 
investigation site team (EMEA only)
•Current curriculum vitae of principal investigators (US and Malaysia)
• Device accountability logs and internal tracking of investigational products 
• Electronically signed and dated e-CRFs
• All approved informed consent templates, and other information provided to the subjects and 
advertisements, including translations
• Copies of all Ethics Committee approval letters and relevant Ethics Committee correspondence 
and Ethics Committee voting list/roster/letter of assurance
• List of names, addresses, and professional position of the clinical investigators and coordinating 
clinical, if appointed. 
• Names and addresses of the institutions in which the MARVEL 2 study will be conducted: This 
list is not yet final at the time of CIP development. The list will be provided under a separate 
cover and will be maintained by the sponsor.
• Regulatory authority correspondence, notification and approval as required by national 
legislation
• Insurance certificates 
• 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 MARVEL 2 study
• The approved Clinical Investigation Plan, Investigator’s Brochure and 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

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19.7.4 Sponsors reports
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in the 
tables below (by geography).  In addition to the reports listed below, Medtronic shall, upon request of 
reviewing Ethics Board, regulatory agency or FDA, provide accurate, complete and current information 
about any aspect of the investigation. Safety data Medtronic reporting requirements are listed in Table 7
of the Adverse Event section.  

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19.8.2 Management of publications
A 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 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 center 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.
19.8.3 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

Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Decisions regarding authorship and contributor-ship will be made by the 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 MARVEL 2 Clinical 
Study Investigators” and will be individually listed according to the guidelines of the applicable scientific 
journal when possible and affiliation. Any other contributors will be acknowledged by name with their 
specific contribution indicated.
19.8.4 Transparency
Transparency of study results will be maintained by the following means:

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19.9.2 Early termination or suspension
Early Termination is the closure of a clinical study that occurs prior to meeting defined endpoints. This is 
possible for the whole study or a single center. 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 center. 
Study 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 or regulatory body (where the study is operating under regulatory body               
authority) 

Technical issues during the manufacturing process
Investigator/center termination or suspension
Possible reasons for clinical investigator or center termination or suspension include but are not limited 
to:

Failure to obtain initial Ethics Board approval or annual renewal of the study

Persistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria) 

Lack of enrollment

Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. failure to 
submit data in a timely manner, failure to follow-up on data queries and monitoring findings in a 
timely manner, etc.) 

Ethics Board suspension of the center

Fraud or fraudulent misconduct is discovered (as defined by local law and regulations) 
Investigator request (e.g. no longer able to support the study)
19.9.3 Procedures for termination and suspension
Medtronic-initiated and regulatory authority-initiated

Medtronic will promptly inform the clinical investigators of the 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 Ethics 
Committee approval lapse, the investigator will promptly inform the Ethics Committee along 
with the reason(s) for termination or suspension 

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 

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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 Ethics Committee and provide detailed explanation of 
termination/suspension”

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
For regions following ISO only: the investigator will promptly inform the regulatory authorities
Ethics Board-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 Ethics Committee 
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 the personal physician of the subjects, 
with the rationale for the study termination or suspension
For regions following ISO only: the sponsor (and investigator, if required by local law) will promptly 
inform the regulatory authorities 
20 References
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Lloyd M, Roberts PR, Sagi V, Hummel J, Bongiorni MG, Knops RE, Ellis CR, Gornick CC, Bernabei MA, 
Laager V, Stromberg K, Williams ER, Hudnall JH, Ritter P; Micra Transcatheter Pacing Study Group. A 
Leadless Intracardiac Transcatheter Pacing System. N Engl J Med. 2016 Feb 11;374(6):533-41. Doi: 
10.1056/NEJMoa1511643. Epub 2015 Nov 9. 
2 Duray GZ, Ritter P, El-Chami M, Narasimhan C, Omar R, Tolosana JM, Zhang S, Soejima K, Steinwender 
C, Rapallini L, Cicic A, Fagan DH, Liu S, Reynolds D; Micra Transcatheter Pacing Study Group. Long-term 
performance of a transcatheter pacing system: 12-Month results from the Micra Transcatheter Pacing 
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real-world setting: The Micra Transcatheter Pacing System Post-Approval Registry. Heart Rhythm. 2017 
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4 Lloyd M, Reynolds D, Sheldon T, Stromberg K, Hudnall JH, Demmer WM, Omar R, Ritter P, Hummel J, 
Mont L, Steinwender C, Duray GZ. Rate adaptive pacing in an intracardiac pacemaker. Heart Rhythm. 
2017 Feb;14(2):200-205. Doi: 10.1016/j.hrthm.2016.11.016. Epub 2016 Nov 15.
5 Gillis AM, Russo AM, Ellenbogen KA, Swerdlow CD, Olshansky B, Al-Khatib SM, Beshai JF, McComb JM, 
Nielsen JC, Philpott JM, Shen WK. HRS/ACCF expert consensus statement on pacemaker device and 
mode selection. J Am Coll Cardiol. 2012 Aug 14;60(7):682-703. Doi: 10.1016/j.jacc.2012.06.011. Epub 
2012 Jul 30.
6 Chinitz L, Ritter P, Khelae SK, Iacopino S, Garweg C, Grazia-Bongiorni M, Neuzil P, Johansen JB, Mont L, 
Gonzalez E, Sagi V, Duray GZ, Clementy N, Sheldon T, Splett V, Stromberg K, Wood N, Steinwender C.
Accelerometer-based atrioventricular synchronous pacing with a ventricular leadless pacemaker: Results 
from the Micra atrioventricular feasibility studies. Heart Rhythm. 2018 May 11. Pii: S1547-
5271(18)30470-3. Doi: 10.1016/j.hrthm.2018.05.004.
7 Sweeney MO, Bank AJ, Nsah E, Koullick M, Zeng QC, Hettrick D, Sheldon T, LamasGA; Search AV 
Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) Trial. 
Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med. 2007 Sep
6;357(10):1000-8.
8 Toff WD, Camm AJ, Skehan JD; United Kingdom Pacing and Cardiovascular Events Trial Investigators. 
Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med. 2005 Jul 
14;353(2):145-55.
9 Labovitz AJ, Williams GA, Redd RM, Kennedy HL. Noninvasive assessment of pacemaker 
hemodynamics by Doppler echocardiography: importance of left atrial size. J Am Coll Cardiol. 1985 
Jul;6(1):196-200.
21 Appendices 

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APPENDIX A: DATA COLLECTION ELEMENTS (ELECTRONIC CASE 
REPORT FORMS)
Electronic Case Report Forms for the MARVEL 2 clinical study will be provided under separate cover. 
Final e-CRFs 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)
Geography-specific Informed Consent 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 MARVEL 2 Study and may assist in identifying those events that are unexpected in nature. Potential 
risks and associated adverse events related to the patient’s implanted Micra device are in alignment 
with the product labeling. 
Potential risks associated with the Marvel 2 software as well as risk minimization are discussed within 
Section 14. Treatment required for MARVEL 2 software related adverse events may include device 
reprogramming, medications, or other surgical and medical remedies.  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.).  
Potential adverse events related to participation in the MARVEL 2 study include:

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
Inadequate rate adaptive pacing during study participation 

Unintended loss of capture

Loss of pacing

Skin rash/irritation, or allergic reaction

Discomfort during exercise maneuvers

Reduced device longevity resulting in early replacement procedure could result in complications 
from replacement procedure

Dizziness

Palpitations

Fatigue

Shortness of breath

Difficulty sleeping

Syncope

Decreased heart rate

Arrhythmia

Asystole

Syncope/fainting

Death
Table 17 provides examples of adverse events associated with the presence or performance of the Micra 
Transcatheter Pacing System that reported in the Micra IDE Clinical Study.
Table 17: Summary of System Related Aes by Severity and MedDRA Term (Micra IDE Clinical 
Study)
Number of Events (Number, % Subjects)
(Denominator = 726 Subjects with Implant Attempt)
Adverse Event Keyterm
Event
Serious Event
Complication
Total Adverse Events
65 (60, 8.3%)
38 (37, 5.1%)
32 (30, 4.1%)
Cardiac arrhythmias
17 (16, 2.2%)
7 (7, 1.0%)
6 (6, 0.8%)
  Atrioventricular block complete
8 (8, 1.1%)
5 (5, 0.7%)
5 (5, 0.7%)
  Bundle branch block right
4 (4, 0.6%)
1 (1, 0.1%)
0 (0, 0.0%)
  Sinus node dysfunction
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Ventricular fibrillation
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Ventricular tachycardia
3 (3, 0.4%)
0 (0, 0.0%)
0 (0, 0.0%)
Traumatic Cardiac Injury
13 (13, 1.8%)
12 (12, 1.7%)
12 (12, 1.7%)
  Cardiac perforation
3 (3, 0.4%)
3 (3, 0.4%)
3 (3, 0.4%)
  Pericardial effusion
10 (10, 1.4%)
9 (9, 1.2%)
9 (9, 1.2%)
Pacing Issues
9 (9, 1.2%)
4 (4, 0.6%)
2 (2, 0.3%)
  Device dislocation
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Device pacing issue
8 (8, 1.1%)
3 (3, 0.4%)
1 (1, 0.1%)
Other
26 (25, 3.4%)
15 (15, 2.1%)
12 (12, 1.7%)
  Angina pectoris
3 (3, 0.4%)
0 (0, 0.0%)
0 (0, 0.0%)
  Cardiac failure
7 (7, 1.0%)
7 (7, 1.0%)
6 (6, 0.8%)

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Number of Events (Number, % Subjects)
(Denominator = 726 Subjects with Implant Attempt)
Adverse Event Keyterm
Event
Serious Event
Complication
  Chest pain
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Non-cardiac chest pain
5 (5, 0.7%)
1 (1, 0.1%)
1 (1, 0.1%)
  Pacemaker syndrome
5 (5, 0.7%)
3 (3, 0.4%)
2 (2, 0.3%)
  Pericarditis
2 (2, 0.3%)
1 (1, 0.1%)
1 (1, 0.1%)
  Presyncope
2 (2, 0.3%)
2 (2, 0.3%)
1 (1, 0.1%)
  Syncope
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
It is expected that approximately 10 subjects may enroll in the study at the time of their Micra implant.  
Thus, Table 18 provides a summary of procedure related adverse events by MedDRA keyterm that 
occurred during the Micra IDE clinical study.
Table 18: Summary of Procedure Related Aes by Severity and MedDRA Term (Micra IDE 
Clinical Study)
Number of Events (Number, % Subjects)
(Denominator = 726 Subjects with Implant Attempt)
Adverse Event Keyterm
Event
Serious Event
Complication
Total Adverse Events
117 (100, 13.8%)
48 (44, 6.1%)
50 (45, 6.2%)
Cardiac arrhythmias
17 (16, 2.2%)
8 (8, 1.1%)
7 (7, 1.0%)
  Atrioventricular block complete
8 (8, 1.1%)
5 (5, 0.7%)
5 (5, 0.7%)
  Bundle branch block right
4 (4, 0.6%)
1 (1, 0.1%)
0 (0, 0.0%)
  Ventricular fibrillation
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Ventricular tachycardia
4 (4, 0.6%)
1 (1, 0.1%)
1 (1, 0.1%)
Embolism and thrombosis
5 (5, 0.7%)
3 (3, 0.4%)
3 (3, 0.4%)
  Deep vein thrombosis
4 (4, 0.6%)
2 (2, 0.3%)
2 (2, 0.3%)
  Pulmonary embolism
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
Events at Groin Puncture Site
51 (49, 6.7%)
11 (11, 1.5%)
11 (11, 1.5%)
  Arterial injury
5 (5, 0.7%)
0 (0, 0.0%)
1 (1, 0.1%)
  Arteriovenous fistula
5 (5, 0.7%)
4 (4, 0.6%)
4 (4, 0.6%)
  Impaired healing
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Incision site complication
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Incision site haematoma
8 (8, 1.1%)
0 (0, 0.0%)
1 (1, 0.1%)
  Incision site haemorrhage
18 (17, 2.3%)
3 (3, 0.4%)
2 (2, 0.3%)
  Incision site infection
2 (2, 0.3%)
0 (0, 0.0%)
0 (0, 0.0%)
  Incision site pain
3 (3, 0.4%)
0 (0, 0.0%)
0 (0, 0.0%)
  Incisional drainage
6 (6, 0.8%)
2 (2, 0.3%)
2 (2, 0.3%)
  Vascular pseudoaneurysm
2 (2, 0.3%)
2 (2, 0.3%)
1 (1, 0.1%)
Traumatic Cardiac Injury
13 (13, 1.8%)
12 (12, 1.7%)
12 (12, 1.7%)
  Cardiac perforation
3 (3, 0.4%)
3 (3, 0.4%)
3 (3, 0.4%)
  Pericardial effusion
10 (10, 1.4%)
9 (9, 1.2%)
9 (9, 1.2%)
Pacing Issues
2 (2, 0.3%)
2 (2, 0.3%)
2 (2, 0.3%)
  Device dislocation
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Device pacing issue
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
Other
29 (28, 3.9%)
12 (12, 1.7%)
15 (15, 2.1%)

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Number of Events (Number, % Subjects)
(Denominator = 726 Subjects with Implant Attempt)
Adverse Event Keyterm
Event
Serious Event
Complication
  Acute myocardial infarction
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Angina pectoris
3 (3, 0.4%)
0 (0, 0.0%)
0 (0, 0.0%)
  Back pain
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Chest pain
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Dysuria
1 (1, 0.1%)
0 (0, 0.0%)
0 (0, 0.0%)
  Hypotension
3 (3, 0.4%)
1 (1, 0.1%)
3 (3, 0.4%)
  Medication error
2 (2, 0.3%)
1 (1, 0.1%)
2 (2, 0.3%)
  Metabolic acidosis
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Non-cardiac chest pain1
6 (6, 0.8%)
1 (1, 0.1%)
1 (1, 0.1%)
  Osteoarthritis
1 (1, 0.1%)
0 (0, 0.0%)
1 (1, 0.1%)
  Pericarditis
2 (2, 0.3%)
1 (1, 0.1%)
1 (1, 0.1%)
  Presyncope
5 (5, 0.7%)
5 (5, 0.7%)
3 (3, 0.4%)
  Syncope
1 (1, 0.1%)
1 (1, 0.1%)
1 (1, 0.1%)
  Urinary retention
1 (1, 0.1%)
0 (0, 0.0%)
1 (1, 0.1%)
1One event of non-cardiac chest pain was considered to have an unknown relationship to the Micra procedure.
APPENDIX D: PARTICIPATING INVESTIGATORS AND 
INSTITUTIONS
At the time of MARVEL 2 CIP Version 2.0 completion, site confirmation was not finalized. 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 distributed under a separate 
cover when available. Approval of the MARVEL 2 CIP will be documented by signing the Clinical Trial 
Agreement or a separate investigator agreement.
APPENDIX E: ETHICS COMMITTEE
At the time of MARVEL 2 CIP Version 2.0 completion, site confirmation was not yet finalized. Therefore, 
a complete list of participating Ethics Committee 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. 

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2.0
Changed Version number and date. 
Section 19.3 Direct Access to 
Source Data/Documents.
added (geographies following 
ISO14155)
and removed the clause “For EMEA 
only” 
Nicole Wood, Principal Clinical 
Research Specialist 
Kurt Stromberg, Sr. Prin Statistician