Aveir Dual-Chamber Leadless i2i IDE Study
Phase: NA
Conditions: Cardiac Pacemaker, Artificial, Cardiac Rhythm Disorder, Bradycardia
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
 
 
 
 
87173 CIP Posting Cover Page Ver C 
Template 
Page 1 of 1 
 
NCT Number: NCT05252702 
AveirTM DR i2i Study 
Aveir Dual-Chamber Leadless i2i IDE Study 
Study Document No: ABT-CIP-10416 
Version C 
Date: 28-JUL-2022 
 
 
Sponsor  
 
 
Abbott Medical 
        
 
 
 
Cardiac Rhythm Management 
15900 Valley View Court 
Sylmar, CA  91342 
U.S. 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 1 of 96 
 
ABT-CIP-10416 
CRD 1023 
“AveirTM DR i2i Study” 
Aveir Dual-Chamber Leadless i2i IDE Study 
 
 
Version Number 
C 
 
Date 
July 28, 2022 
 
 
National Coordinating Clinical 
Investigators             
 (U.S. and Canada) 
 (Europe and Asia Pacific) 
Steering Committee 
 
 
 
 
 
 
 
 
 
 
 
 
Planned Number of Sites and 
Region(s) 
85 sites worldwide (U.S., Canada, Europe, and Asia-Pacific) 
Clinical Investigation Type 
Prospective, multi-center, international, single-arm, pivotal 
investigational study.  
Medical Expert 
 
 
 
 
Sponsor 
Abbott Medical  
Cardiac Rhythm Management 
15900 Valley View Court 
Sylmar,  CA  91342 
U.S. 
 
Electronic Data Capture Software 
 
 
Core Laboratory 
 
 
CIP Author of Current Version  
  
 
Sr. Scientist, Clinical Research 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 2 of 96 
 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
Template: 86357 Rev. J 
Page 3 of 96
NATIONAL COORDINATING CLINICAL INVESTIGATOR 
SIGNATURE PAGE 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
Coordinating Clinical Investigator – U.S. and Canada 
Printed name: 
Signature: 
Date: 
Coordinating Clinical Investigator – Europe and Asia-Pacific 
Printed name: 
Signature: 
Date: 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 4 of 96 
 
TABLE OF CONTENTS 
 
1.0 
INTRODUCTION ............................................................................................................. 8 
1.1 
Background and Rationale ......................................................................................................... 8 
2.0 
CLINICAL INVESTIGATION OVERVIEW ...................................................................... 10 
2.1 
Clinical Investigation Objective ................................................................................................. 10 
2.2 
Device(s) Used in the Clinical Investigation ............................................................................. 11 
3.0 
CLINICAL INVESTIGATION DESIGN ........................................................................... 22 
3.1 
Clinical Investigation Procedures and Follow-up Schedule ...................................................... 23 
3.2 
Measures Taken to Avoid and Minimize Bias ........................................................................... 25 
3.3 
Suspension or Early Termination of the Clinical Investigation .................................................. 25 
4.0 
ENDPOINTS .................................................................................................................. 26 
4.1 
Primary Endpoints and Rationale ............................................................................................. 26 
4.2 
Other Secondary Endpoint ....................................................................................................... 28 
4.3 
Additional Data ......................................................................................................................... 28 
5.0 
SUBJECT SELECTION AND WITHDRAWAL ............................................................... 30 
5.1 
Subject Population.................................................................................................................... 30 
5.2 
Subject Recruitment/Screening and Informed Consent ........................................................... 30 
5.3 
Eligibility Criteria ....................................................................................................................... 32 
5.4 
Subject Enrollment ................................................................................................................... 34 
5.5 
Subject Withdrawal and Discontinuation .................................................................................. 35 
5.6 
Number of Subjects .................................................................................................................. 36 
5.7 
Total Expected Duration of the Clinical Investigation ............................................................... 37 
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS ..................................................... 37 
6.1 
Baseline Assessment ............................................................................................................... 37 
6.2 
Implant Procedure .................................................................................................................... 38 
6.3 
System Revision with a Replacement Aveir LP ........................................................................ 42 
6.4 
System Revision without a Replacement Aveir LP ................................................................... 43 
6.5 
Pre-Discharge (In-hospital) ....................................................................................................... 44 
6.6 
Follow-up Assessments ............................................................................................................ 45 
6.7 
Schedule of Events ................................................................................................................... 53 
6.8 
Requirement for Core Laboratories .......................................................................................... 55 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 5 of 96 
 
7.0 
ADVERSE EVENTS ...................................................................................................... 55 
7.1 
Definition................................................................................................................................... 55 
7.2 
Device Relationship .................................................................................................................. 56 
7.3 
COVID-19 Relationship and Assessment Log .......................................................................... 56 
7.4 
Adverse Event and Device Deficiency/Device Malfunction Reporting ...................................... 57 
8.0 
STATISTICAL CONSIDERATIONS ............................................................................... 59 
8.1 
Analysis Populations ................................................................................................................ 60 
8.2 
Statistical Analyses................................................................................................................... 60 
8.3 
Sample Size Calculation ........................................................................................................... 63 
8.4 
Planned Interim Analysis .......................................................................................................... 64 
8.5 
Timing of Analysis .................................................................................................................... 65 
8.6 
Subgroup Analysis .................................................................................................................... 65 
8.7 
Multiplicity ................................................................................................................................. 65 
8.8 
Procedures for Accounting for Missing Data ............................................................................ 65 
8.9 
Deviations from Statistical Plan ................................................................................................ 65 
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................. 65 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 66 
10.1 
Selection of Clinical Sites and Investigators ............................................................................. 66 
10.2 
Clinical Investigation Finances and Agreements ...................................................................... 66 
10.3 
CIP Amendments ..................................................................................................................... 66 
10.4 
Training..................................................................................................................................... 66 
10.5 
Monitoring ................................................................................................................................. 67 
10.6 
Deviations from CIP .................................................................................................................. 67 
10.7 
Quality Assurance Audit ........................................................................................................... 68 
10.8 
Sponsor Auditing ...................................................................................................................... 68 
10.9 
Committees .............................................................................................................................. 68 
11.0 DATA HANDLING AND RECORD KEEPING ................................................................ 70 
11.1 
Protection of Personally Identifiable Information ...................................................................... 70 
11.2 
Data Management Plan ............................................................................................................ 71 
11.3 
Source Documentation ............................................................................................................. 71 
11.4 
Case Report Form Completion ................................................................................................. 71 
11.5 
Record Retention ...................................................................................................................... 72 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 6 of 96 
 
11.6 
Investigational Devices Accountability ...................................................................................... 72 
12.0 ETHICAL CONSIDERATION ......................................................................................... 72 
12.1 
Institutional Review Board/Medical Ethics Committee Review and Approval .......................... 72 
13.0 CLINICAL INVESTIGATION CONCLUSION ................................................................. 73 
14.0 PUBLICATION POLICY ................................................................................................. 73 
15.0 RISK ANALYSIS ............................................................................................................ 74 
15.1 
Anticipated Clinical Benefits ..................................................................................................... 74 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ................................... 74 
15.3 
Residual Risks Associated with the Device Under Investigation, as Identified in the Risk 
Management Report / Risk Analysis Report ....................................................................................... 74 
15.4 
Risks Associated with Participation in this Clinical Investigation .............................................. 75 
15.5 
Steps Taken to Control or Mitigate Risks ................................................................................. 75 
15.6 
Risk to Benefit Rationale .......................................................................................................... 75 
16.0 APPENDICES ................................................................................................................ 76 
17.0 References .................................................................................................................... 95 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 7 of 96 
 
COMPLIANCE STATEMENT: 
 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the 
Declaration of Helsinki, applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 
21 CFR Part 56, 21 CFR Part 812, 21 CFR Part 54, 21 CFR Part 11, and OUS ISO14155:2020) and 
the appropriate local legislation(s). The most stringent requirements, guidelines or regulations must 
always be followed. The conduct of the clinical investigation will be approved by the appropriate 
Institutional Review Board (IRB)/Ethics Committee (EC) of the respective investigational site and by the 
applicable regulatory authorities (e.g., FDA, PMDA, MHRA, etc.). 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 8 of 96 
 
1.0 
INTRODUCTION 
This clinical investigation is intended to evaluate the safety and effectiveness of the AveirTM 
Dual-Chamber (DR) Leadless Pacemaker (LP) system in patients indicated for a DDD(R) 
pacemaker to support regulatory approval for the Aveir DR LP system for DDD(R) pacing 
indications and the Aveir atrial LP for AAI(R) pacing indications.  This clinical investigation will 
be conducted under an investigational device exemption (IDE) and is intended to support 
market approval worldwide.  This clinical investigation is sponsored by Abbott Medical. 
This clinical investigation will be conducted in accordance with this clinical investigation plan 
(CIP). All investigators involved in the conduct of the clinical investigation will be qualified by 
education, training, or experience to perform their tasks and this training will be documented 
appropriately. 
1.1 
Background and Rationale 
 Background 
Cardiac pacing has been an established therapy for patients with bradyarrhythmia for over 
50 years. However, this life-improving therapy is still associated with significant 
complications, primarily related to the transvenous lead and the subcutaneous pulse generator 
pocket. Short-term complication rates as high as 8% to 12% have been reported, and 
include pneumothorax, cardiac tamponade, pocket hematoma, and lead dislodgement.1, 2, 3  
In the long term, these leads are also prone to insulation breaks and conductor fracture, 
requiring re-intervention that puts the patient at risk for significant morbidity.4  Furthermore, 
0.7% to 2.4% of patients encounter serious complications related to the subcutaneously placed 
pulse generator that include skin erosion, pocket infection, and septicemia.5 
The complications associated with the conventional transvenous pacemaker design have 
triggered the clinical need to eliminate the pacemaker lead, pockets and connectors 
through a fully self-contained leadless pacemaker system that can be implanted 
percutaneously with a steerable catheter, thus offering patients a less-invasive approach as 
compared to conventional pacemaker procedures that require more extensive surgery. The 
leadless concept was also designed to improve patient comfort by eliminating the visible lump 
and scar at a conventional pacemaker’s pectoral implant site and by removing the need 
for activity restrictions to prevent dislodgement or damage of a conventional lead. 
As of the end of 2020, only two single-chamber leadless pacemaker models are commercially 
available while others are in development or under clinical investigation. The MicraTM 
Transcatheter Pacing System VR and AV models (TPS; Medtronic, Minneapolis, Minnesota) 
are the only market-approved leadless pacemaker systems capable of providing single-
chamber right ventricular pacing, sensing, and delivery of rate response in VVI(R) or VDD 
pacing modes, respectively. Patients implanted with a Micra VR experienced a 48% reduction 
in the risk of major complications at 12 months compared to patients with transvenous 
systems from a historical control group, resulting in 82% fewer system revisions and 47% 
fewer hospitalizations.6 
Despite the cardiac rhythm management advances demonstrated from conventional 
transvenous pacemaker to single chamber leadless pacemaker systems, most patients 
require dual chamber pacing because of their clinical presentation. In the U.S. market, less 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 9 of 96 
 
than 20% of patients who require permanent pacemakers receive traditional single-chamber 
devices while the remaining 80% receive traditional dual-chamber devices. 7 Therefore, most of 
the U.S. pacemaker population is represented by a need for dual-chamber pacing therapy. 
Currently, over 700,000 pacemakers are implanted annually worldwide for the treatment 
of bradyarrhythmias. A bradyarrhythmia may be due to disease in the heart’s electrical system 
such as problems with the sinoatrial (SA) node or some interruption in conduction through 
the natural electrical pathways of the heart. High degree AV block and sick sinus syndrome 
are the major indications for the implantation of dual-chamber cardiac pacemakers.  
Patients who are indicated for dual-chamber pacing would benefit from a dual-chamber 
leadless pacemaker system that provides atrial and ventricular bradycardia therapy while 
eliminating the long-term complications associated with the surgical pocket and transvenous 
atrial and ventricular leads that are associated with conventional pacing systems. In the 
FOLLOWPACE Study in a pacemaker population (n=1517) where 68.8% were implanted with 
dual-chamber devices, 140 patients (9.2%) experienced a complication after 2 months with 
conventional pacing systems. Of those, most were lead-related (n=84).2  
Currently, there are no leadless pacing systems capable of DDD(R) pacing. The Aveir DR LP 
system is a promising new technology that can deliver DDD(R) pacing therapy while also 
offering advantages over transvenous dual-chamber pacemakers for the treatment of 
bradyarrhythmias.  This technology has the same design advantages as single-chamber LP 
systems which have led to the better comparative clinical outcomes previously described. The 
Aveir DR LP system is expected to provide comparable bradycardia treatment as transvenous 
dual-chamber pacemakers for patients indicated for similar conditions. 
The Aveir DR LP system is a programmable system comprising of two implanted leadless 
pacemakers that provide dual chamber rate-responsive bradycardia pacing therapy.  A 
ventricular LP is intended for direct permanent implantation into the right ventricle, and an atrial 
LP is intended for direct implantation into the right atrium.  Each leadless pacemaker is 
delivered to the target heart chamber percutaneously via the femoral vein.   
Abbott Medical’s Aveir leadless pacemaker technology also offers other clinical features 
including device retrievability and device upgradability from a single chamber leadless 
configuration to a dual chamber leadless configuration. The Aveir DR LP system is designed to 
be retrievable,  where individual LPs of the implanted system can be removed and replaced at 
end of service by a dedicated retrieval catheter. 
 Rationale for Conducting this Clinical Investigation 
The Aveir DR i2i study will be the first in-human evaluation of the Aveir DR LP system.  
The purpose of this clinical investigation is to evaluate the clinical safety and effectiveness 
of the Aveir DR LP system in a patient population indicated for a DDD(R) pacemaker.  The 
results of this clinical investigation will support regulatory pre-market submissions for the 
Aveir DR LP system for DDD(R) pacing indications and the Aveir atrial LP for AAI(R) 
pacing indications in various geographies as outlined below. 
To support the Aveir DR LP system for DDD(R) pacing indications, the primary safety 
endpoint will evaluate the dual-chamber system complication-free rate at 3 months post 
implant. The primary effectiveness endpoint #1 will evaluate atrial sensing/pacing, and the 
primary effectiveness endpoint #2 will evaluate AV synchrony performance at 3 months 
post implant.  The ventricular LP (model LSP202V) in the Aveir DR LP system is the same 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 10 of 96 
 
as the ventricular LP (model LSP112V) evaluated in the Leadless II IDE study (Phase II) 
(NCT04559945). This study included the evaluation of the ventricular sensing/pacing 
performance of the LSP112V within a single-chamber leadless system.  The ventricular 
sensing/pacing performance is not affected by the ventricular LP’s integration from a 
single-chamber leadless system into a dual-chamber leadless system. Therefore, this 
clinical investigation does not need to re-evaluate acceptable ventricular sensing/pacing of 
the ventricular LP (model LSP202V).      
Clinical data from subjects implanted with the Aveir DR LP system will be leveraged to 
support the use of the Aveir atrial LP for AAI(R) pacing indications through the collective 
evaluation of its safety and performance through three endpoints: the primary effectiveness 
endpoint #1, a secondary safety endpoint, and a secondary effectiveness endpoint.  
The secondary safety endpoint will evaluate the atrial-only complication-free rate at 3 
months post-implant.  The primary effectiveness endpoint #1 will evaluate the atrial 
sensing and pacing performance at 3 months post-implant, and the secondary 
effectiveness endpoint will evaluate the atrial rate response while programmed to AAI(R) 
mode during graded exercise testing. Rate response pacing is based on temperature 
measures from the atrial LP while programmed to AAIR mode only. 
 
 
 
 
       
 
 
 
 
 
..   
2.0 
CLINICAL INVESTIGATION OVERVIEW 
2.1 
Clinical Investigation Objective 
 Primary Objectives 
The primary objectives of this study are to evaluate the safety and effectiveness of the Aveir DR 
LP system through 3 months post-implant in a subject population indicated for a DDD(R) 
pacemaker system.   
 Secondary Objectives 
The secondary objectives of this study are to evaluate the safety and effectiveness of the Aveir 
atrial LP through 3 months post-implant in a subject population indicated for a DDD(R) 
pacemaker system to support an indication for AAI(R) pacing.   

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 13 of 96 
 
The LP and all its accessories (except for the Link Module) are single-procedure devices and 
are furnished sterile.  Detailed information regarding the Aveir™ DR LP system can be found in 
the Instructions for Use for each device.  
2.2.3.1 Aveir LP  
Intended Use:  The Aveir™ LP (model LSP201A - right atrial and LSP202V - right ventricular) 
is designed to provide bradycardia pacing as a pulse generator with built-in battery and 
electrodes for implantation in the right ventricle and/or right atrium. The LP is intended to 
provide sensing of cardiac signals and delivery of cardiac pacing therapy within the implanted 
chamber for the target treatment group. The LP is also intended to operate optionally with 
another co-implanted LP to provide dual-chamber pacing therapy.     
 
As a leadless device, the Aveir LP does not need a connector, pacing lead, or pulse generator 
pocket.  The LP is delivered to the target heart chamber percutaneously via the femoral vein 
through an Aveir Introducer and Aveir Delivery Catheter.  The proximal end of the LP has a 
feature for docking to delivery and retrieval catheters, providing for repositioning and retrieval 
capability.  A distal non-retractable, helix affixes the LP to the endocardium of the target heart 
chamber.  Three additional features on the outside of the LP nosecone are designed to 
provide secondary fixation securement.   
 
Sensing and pacing occur between a distal electrode near the fixation helix and the external 
can of the LP.  The tip electrode includes a single dose of dexamethasone sodium phosphate 
(DSP), intended to reduce inflammation.  The distal tip electrode is a titanium-nitride coated, 
platinum-iridium disc located at the center of the fixation helix. The ring electrode is the 
uncoated proximal part of the titanium pacemaker case.    
 
The LP senses local blood pool temperature to provide rate modulated pacing with changes in 
metabolic demand. 
 
Communication Between Co-Implanted Leadless Pacemakers 
To allow dual-chamber synchronous sensing and pacing to occur, each LP communicates 
bidirectionally with the programmer system and also beat-to-beat with a paired, co-implanted 
LP.  Through i2i™ (implant-to-implant) communication via two electrodes on each LP, 
electrical signals are output with data encoded in a series of short pulses delivered 
concurrently with each local paced or sensed event.   
Generally, in a dual-chamber operating mode, the RV-implanted LP manages overall pacing 
and timing functions, while the pacing and timing functions of the RA-implanted LP are 
managed indirectly by the RV-implanted LP.  The RV-implanted LP’s activity sensor 
determines the target sensor-indicated rate to be used by both LPs and the rate is set (or 
updated) through i2i communication.   
In the event of a sustained disruption in communication between the co-implanted LPs, the 
system will automatically revert to ventricular-only pacing mode until communication is 
restored. 
 
Communication Between Leadless Pacemaker and Programmer 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 14 of 96 
 
Each LP communicates bi-directionally with the external Aveir Link Module in conjunction with 
a Merlin Patient Care System (PCS) Model 3650 programmer to interrogate and program the 
LP and to monitor electrocardiogram (ECG) waveforms for observing LP function.   
 
The Link Module provides an interface between the Merlin Programmer and standard ECG 
electrodes placed on the subject’s torso, for two-way communication with the implanted LP(s) 
and acquisition of the surface ECG. The Programmer transmits signals to an implanted LP via 
conducted communication with sub-threshold electrical pulses applied via skin electrodes.   
 
Consequently, the LP transmits signals using circuits and electrodes already provided for 
pacing, with data encoded in pulses delivered during the heart’s refractory period.  This 
conducted communication allows data to be communicated between the LP and surface 
electrodes at a low current that does not affect pacing or sensing functions. The LP also has a 
commanded electrogram (EGM) for current of injury assessment. An EGM shows the heart's 
electrical activity as sensed by the pacing system. The current of injury is a measure intended 
to assess implant integrity during the implant procedure, like conventional transvenous leads. 
 
Each Aveir LP is supplied contained inside a Loading Tool to hold the LP until the implantation 
procedure. The Loading Tool with the LP facilitates connection of the LP to the Delivery 
Catheter. The Loading Tool does not have direct patient contact.  Figure 1 and Table 2 below 
show the Loading Tool and features of both Aveir LPs.   
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 16 of 96 
 
Volume 
1.0 cm3  
1.1 cm3  
Mass 
2.1 grams  
2.4 grams  
Fixation Mechanism 
Distal non-retractable helix  
Distal non-retractable helix  
Fixation Depth 
Approximately 1.63 mm  
Approximately 1.63 mm  
Electrode Tip  
Helical 
Domed 
Electrode spacing 
≥ 24 mm 
≥ 24 mm 
Ring electrode geometric 
surface area 
~124 mm2 
~244 mm2 
 
Please refer to the Aveir LP Instructions for Use for a complete listing of the LP materials in 
contact with blood or tissue and other technical specifications.  
 
2.2.3.2 Aveir Delivery Catheter 
Intended Use:  The Aveir Delivery Catheter is intended to be used in the peripheral 
vasculature and the cardiovascular system to deliver and manipulate an LP.  Delivery and 
manipulation include implanting an LP within the target chamber of the heart. 
The AveirTM Delivery Catheter includes a steerable delivery catheter, an integrated guiding 
catheter with a protective sleeve designed to protect an attached LP’s fixation helix and 
electrode, and a valve bypass tool to dilate the 25 Fr inner diameter introducer sheath 
hemostasis valve and advance the system into the femoral vein.  
The delivery catheter system provides a means to perform these actions during the 
implantation procedure: 
• Attach and dock a separate LP pre-loaded in the loading tool 
• Position the protective sleeve over the LP’s fixation helix and lock the sleeve into place 
• Advance the Aveir LP from an access site in the groin (utilizing minimally invasive 
techniques) through the femoral vein into the target heart chamber 
• Hand inject contrast solution through the guide catheter flush port to its distal tip 
• Pull back the protective sleeve to expose the flexible section of the delivery catheter  
• Map the endocardium with the docked LP to assess appropriateness of implant site 
• Position the LP and rotate it to affix the LP helix to the endocardium 
• Undock the LP from the delivery catheter system leaving the LP tethered to the delivery 
catheter to measure thresholds with minimal force transmission from the delivery catheter  
• Re-dock to the delivery catheter, unscrew and reposition the LP if necessary for 
acceptable thresholds 
• Disconnect the LP from the tethers of the delivery catheter system, leaving the LP 
implanted in the endocardium 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 17 of 96 
 
Apart from the docking mechanism, the delivery catheter and its control system (handle) have 
the same operating principle as a conventional steerable catheter and control system.  
The delivery catheter has an effective length of 105 cm (41.3 inches).   
For further information refer to the Instructions for use for the AveirTM Delivery Catheter. 
Figure 2 below shows mechanical characteristics of the delivery catheter:  
 
Figure 2– AveirTM Delivery Catheter 
 
 
 
2.2.3.3 Aveir Link Module and Programmer Software 
Intended Use:  The Aveir Link Module is intended for use in conjunction with a MerlinTM PCS 
Model 3650 programmer to interrogate and program an Aveir LP and to monitor LP function 
during an implant, retrieval, or follow-up procedure.  
The Aveir™ Link Module communicates with an implanted Aveir™ LP via conducted 
communication through the St. Jude Medical™ Patient Cable and skin electrodes. Safe, high 
frequency electrical pulses are sent between the LP and programmer system to interrogate 
and program the LP. The Link Module also uses the Patient Cable and skin electrodes to 
acquire a patient’s ECG waveform. The Link Module is powered via a USB port of the 
Merlin™ PCS Model 3650.  
The Aveir™ Link Module connected to a Merlin™ PCS (Model 3650, P030054/S8) enables non-
invasive communication with the implanted medical device allowing the user to retrieve device 
diagnostics and customize the device parameters to meet the patient needs without requiring 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 19 of 96 
 
2.2.3.4 Aveir Introducer 
Intended Use:  The Aveir Introducer is intended to provide a conduit into the venous system 
for insertion of diagnostic and other interventional devices. 
The Introducer is designed to perform as a guiding sheath for introduction of diagnostic or 
interventional devices.  The Aveir™ Introducer is compatible with the Aveir™ Delivery 
Catheter and Aveir™ Retrieval Catheter. 
The Introducer is comprised of an introducer sheath with a flush port and three-way stopcock 
and a dilator. The AveirTM Introducer has a 25F inner diameter and comes in two lengths, 
measured by introducer sheath length – 30 cm (Model LSN25301) and 50 cm (Model 
LSN25501). 
The introducer sheath is coated with a hydrophilic lubricious coating. The introducer sheath is 
fitted with a hemostasis valve to minimize air introduction and maintain hemostasis during 
insertion and/or exchange, a sideport with a three-way stopcock, and a suture loop. The 
introducer sheath features a radiopaque tip marker incorporated within the sheath material to 
identify the location of the distal tip of the sheath.   
For further information refer to the Instructions for use for the AveirTM Introducer. 
 
 
 
 
 
 
 
Figure 4 below shows the mechanical characteristics of the 25F introducer: 
 
 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 21 of 96 
 
The Retrieval Catheter uses a tri-loop snare to grasp the docking feature on the proximal end 
of an Abbott Medical LP, mate the LP to the retrieval catheter, unscrew the LP, and retrieve 
the LP.   
The retrieval catheter system is intended to be manipulated by a single operator and allows 
the operator to perform these actions: 
• Advance the retrieval catheter system from an access site in the groin (utilizing minimally 
invasive techniques) through the femoral vein into the heart 
• Steer and position the snare toward the docking button of the LP 
• Snare the docking button of the LP  
• Dock the retrieval catheter to the LP 
• Rotate the LP to unscrew the LP helix from the endocardium  
• Protect the LP helix and electrode during retrieval 
• Extract the LP through the access site in the groin 
Apart from the docking mechanism, the retrieval catheter and its control system (handle) have 
the same operating principle as a conventional steerable catheter and control system. The 
system includes a valve bypass tool, a steerable retrieval catheter, an integrated guiding 
catheter with a protective sleeve, and a tri-loop snare.  
 
For further information refer to the Instructions for use for the AveirTM Retrieval Catheter. 
 
Figure 5 below shows the mechanical characteristics of the Retrieval Catheter.  
 
Figure 5 – AveirTM Retrieval Catheter 
 
 
Catheter effective length = 105 cm (41.3 inches) 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 22 of 96 
 
 
 
 
 
Snare loop inner diameter = 16.5 mm (0.65 inch) 
 
 
 
 Device Handling 
The Sponsor requires clinical sites to store all investigational products according to the labeling 
and Instructions for Use in a secure area to prevent unauthorized access or use. 
  
3.0 
CLINICAL INVESTIGATION DESIGN 
This is a prospective, multi-center, international, single-arm, pivotal investigational study 
designed to evaluate the safety and effectiveness of the Aveir DR LP system in a subject 
population indicated for a DDD(R) pacemaker.    
The clinical investigation will enroll up to 550 subjects from up to 85 participating centers from 
the United States, Canada, Europe, and Asia Pacific.  The Sponsor may approach centers in 
other countries for participation in the clinical investigation as needed.   
Subjects participating in the clinical investigation will be followed through at least 12 months with 
data collected at baseline, implant procedure, pre (hospital) discharge, and follow-up at 1 
month, 3 months, 6 months, 12 months and every 6 months thereafter until study completion.  
 
 
 
 
  
 
 
 
. 
 
The Sponsor has designed this clinical investigation to involve as little pain, discomfort, fear, 
and any other foreseeable risk as possible for subjects. Refer to the Risks Analysis section of 
this clinical investigation plan for details. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 23 of 96 
 
3.1 
Clinical Investigation Procedures and Follow-up Schedule 
The flowchart and the follow-up requirements of this clinical investigation are described below. 
Subjects will be screened for study eligibility by the investigator and/or research staff per the 
inclusion and exclusion criteria listed in Section 5.3.  Subjects that do not meet the inclusion and 
exclusion criteria will be exited from the study as a screen failure. 
Clinical study assessments will occur at baseline, implant procedure, pre-discharge, 1 month, 3 
months, 6 months, 12 months, and every 6 months thereafter until study completion.   
Follow-up visits will be conducted in-person at the investigational site and will include a 
combination of standard of care and study-specific testing.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 24 of 96 
 
Figure 6: Clinical Investigation Flowchart 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 25 of 96 
 
3.2 
Measures Taken to Avoid and Minimize Bias 
Multiple measures will be taken to avoid and minimize bias in this clinical investigation.  This is a 
prospective clinical investigation in which the outcome is unknown at the time of enrollment and 
all subjects must meet the defined eligibility criteria to minimize selection bias.  The Sponsor will 
provide guidance to sites regarding data collection for post-procedure follow-up visits.  
Additionally, the Sponsor will provide case report forms for data collection to sites, which will 
minimize inter-observer variability.   
An independent Clinical Events Committee (CEC) will perform an evaluation of primary safety 
endpoint data . Additionally, an independent core laboratory will evaluate collected Holter data 
from sites to determine AV synchrony performance in subjects.   
The Sponsor will use a CEC made up of physicians who are not investigators to adjudicate all 
adverse events (AEs) determined by the Sponsor’s Safety group to potentially meet the criteria 
of 1) a serious AE and/or 2) an AE related to the investigational devices or procedures. To 
minimize bias, only the CEC’s adjudication of the collected data will be used for the analysis of 
the primary safety endpoint. 
Protocols are also in place to minimize subjects who are lost-to-follow-up (Section 5.5).  
Sensitivity analyses will be performed to evaluate the impact that missing data may have on the 
clinical investigation. 
The Sponsor will establish an independent Data and Safety Monitoring Board (DSMB) (Section 
10.9.3) that will serve in an advisory role to ensure safety by reviewing cumulative data from the 
clinical investigation at prescribed intervals for the purpose of safeguarding the interests of 
enrolled subjects and those patients yet to be enrolled, as well as the continuing validity and 
scientific merit of the clinical investigation. 
3.3 
Suspension or Early Termination of the Clinical Investigation 
The CIP does not define a formal statistical rule for early termination of the clinical investigation 
for insufficient effectiveness of the device under investigation. However, the Sponsor reserves 
the right to discontinue the clinical investigation at any stage or reduce the follow-up period with 
suitable written notice to the investigator. Possible reason(s) may include, but are not limited to: 
• 
Unanticipated adverse device effect (e.g., UADE) occurs and it presents an 
unreasonable risk to the participating subjects 
• 
Serious health threat  
• 
An oversight committee, (i.e. DSMB) makes a recommendation to stop or terminate the 
clinical investigation (such as higher frequency of anticipated adverse device effects) 
• 
Further product development is cancelled 
 
 Subject Follow-up in cases of early termination or suspension 
Should the Sponsor discontinue the clinical investigation, sites will follow subjects per routine 
hospital practice with device-related AEs reported to the Sponsor as per vigilance/commercial 
reporting requirements. The investigator shall return all clinical investigation materials (including 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 26 of 96 
 
devices) to the Sponsor and provide a written statement to the IRB/EC (if applicable). All 
applicable clinical investigation documents shall be subject to the same retention policy as 
detailed in Section 11.5 of the CIP.  
 
If the Sponsor suspends or prematurely terminates the clinical investigation at an individual site 
in the interest of safety, the Sponsor will inform all other Principal Investigators. 
 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the CIP and existing agreements for following the 
subjects enrolled in the clinical investigation, and the Principal Investigator or authorized 
designee will promptly inform the enrolled subjects at his/her site, if appropriate. 
 
A Principal Investigator, IRB/EC, or regulatory authority may also suspend or prematurely 
terminate participation in the clinical investigation at the investigational site(s) for which they are 
responsible. The investigators will follow the requirements specified in the Clinical Trial 
Agreement.  
 
If a suspended investigation is to be resumed, a prior approval should be obtained from the 
EC/IRB and a notification should be sent to the regulatory bodies. 
 
4.0 
ENDPOINTS  
The primary and secondary endpoint analyses will be based on newly enrolled (de novo) 
subjects in the investigation who have an attempted implant. De novo subjects are defined as 
subjects that do not have an implanted pacemaker on the date of consent through the date of 
the Aveir LP implant.  
4.1 
Primary Endpoints and Rationale 
 Primary Safety Endpoint 
The primary safety endpoint evaluates the 3-month Aveir DR LP system complication-free-rate 
in de novo subjects based on CEC adjudication of adverse events.  
A complication is defined as a device-or-procedure-related serious adverse event (SADE), 
including those that prevent initial implantation (includes both Atrial LP and Ventricular LP 
related complications and implant procedure-related complications). 
4.1.1.1 Rationale for Selection of the Primary Safety Endpoint 
The primary safety endpoint evaluates a device- or procedure-related SADE rate which is an 
appropriate measure for safety and consistent with the primary safety endpoints used in the 
Leadless II IDE trial (Phase 1: NCT02030418 and Phase 2: NCT04559945) and multiple pre-
market leadless pacemaker trials.  The 3-month timepoint for assessing the primary safety 
endpoint is an appropriate time period as outlined in FDA’s Executive Summary on leadless 
pacemaker devices (February 2016): “based on publicly available clinical data for leadless 
pacemaker devices, it is known that the overwhelming majority of complications occur within 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 28 of 96 
 
clinical presentation of symptoms for patients with AV conduction abnormalities with PR 
intervals greater than 300 ms. Patients with marked prolongation of the PR interval >300 ms 
exhibit symptoms similar to those with pacemaker syndrome that is due to loss of AV 
synchrony and atrial contraction against closed atrioventricular valves14.  The evaluation of AV 
synchrony at rest while seated and the definition of success with at least 70% of evaluable 
cardiac cycles is based on similar, predicate device studies for market approval. 15 
 Secondary Safety Endpoint 
The secondary safety endpoint evaluates the 3-month Aveir atrial LP complication free rate in 
de novo subjects based on CEC adjudication of adverse events. 
An atrial LP complication is defined as an atrial device- or procedure-related SADE, including 
those that prevent initial LP implantation. Complications that are exclusively related to the 
ventricular LP or its delivery/retrieval will not be considered atrial LP complications and will be 
excluded from this evaluation. Complications that cannot be exclusively determined to be 
related to the ventricular or atrial LP will be considered atrial LP complications (e.g. femoral 
access complications, embolism, etc.).  
4.2 
Other Secondary Endpoint 
 Secondary Effectiveness Endpoint 
The secondary effectiveness endpoint evaluates the appropriate and proportional rate response 
of the atrial LP in de novo subjects during graded exercise testing (CAEP protocol). 
4.3 
Additional Data  
The clinical investigation will collect and report the following additional data descriptively using 
only summary statistics. The Sponsor will not perform hypothesis tests with pre-specified criteria 
on this additional data collected.   
 
• 
Demographics: gender, age, ethnicity/race (if provided), indication for pacemaker 
implant 
o Comparisons of demographics between the study population to the existing dual-
chamber pacemaker population by region 
• 
Medical history 
• 
Use of beta blocker, ACE, ARB, anti-coagulation, anti-arrhythmic, and anti-platelet 
medications 
• 
All adverse events, and whether or not each is device-related or procedure-related 
• 
Implant success rate and reasons for unsuccessful implant 
• 
Device handling characteristics at implant 
• 
Number of device repositionings at time of implantation 
• 
Implant duration, fluoroscopy duration, and time from implant to hospital discharge 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 29 of 96 
 
• 
Optional: Pre-procedure (i.e. MRI, CT, X-ray) and procedural imaging (i.e. ICE) 
measures to evaluate the right atrium and/or the atrial LP based on any imaging data 
provided to the Sponsor 
• 
Final location of LP placement 
• 
Remaining device longevity at the six-month visit, as displayed by the programmer 
based on delivered therapy, programmed settings, percent pacing, and measured 
pacing impedance   
• 
Average base rate, impedance, pulse amplitude, pulse duration, and percentage pacing 
at all visits 
• 
Hospitalizations  
• 
Mortality 
• 
Upgradeability of the Aveir ventricular LP (VR) into the Aveir DR LP system summarized 
by: 
o Success rate of VR to DR upgrades and reasons for unsuccessful upgrades.   
o Summary of adverse events related to upgrades 
o Summary of device measurements for subjects with an upgrade  
• 
AV synchrony (at various positions and activity levels) 
• 
EQ-5D Health-Related Quality of Life Analysis 
 
 24-hour Holter Monitor Data Analysis 
All capable de novo subjects will be asked to wear a 24-hour Holter monitor and complete a 
symptom diary, until 50 subjects provide data contributing to the analysis.  The test may be 
performed any time after the beginning of the 3-month visit window. The preferred window to 
perform the 24- hour Holter test is between the 3-month and 6-month visit.  These data will be 
examined for appropriate sensing, pacing, AV Synchrony during the activities of daily living for 
each subject.  In addition, these data will be evaluated for any correlation between any subject 
symptoms with losses of AV synchrony, if present. 
 
The investigational plan does not require inclusion of pacer-dependent subjects to assess the 
device’s pacing capabilities because it is expected that approximately 65% of subjects will have 
>60% pacing, based on data from transvenous pacemakers (for 1,395 subjects with a mean 
follow-up of 5.8 years, 74% dual-chamber pacemakers), provided below: 16 
 
Histogram of percentage pacing: 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 30 of 96 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Sponsor will provide a 24-hour Holter summary report to the respective in-country 
regulatory agency, 
 which includes the 
following for each subject: 
 
• 
Minimum, maximum, and average heart rate 
• 
Percent atrial pacing 
• 
A telemetry strip of the minimum heart rate and a telemetry strip during pacing (the pacing 
strip may be the same as the minimum heart rate strip, but is not required). 
• 
Number of pauses seen (defined as RR interval greater than or equal to 2 sec or < 30 bpm) 
• 
All telemetry strips of a pause greater than the programmed lower rate limit after accounting 
for any hysteresis programming 
• 
All telemetry strips showing evidence of atrial oversensing, undersensing, or loss of capture 
• 
Programmed parameters (which are necessary to assess if the pauses or minimum heart 
rate seen on Holter are appropriate or not) 
• 
AV Synchrony 
• 
Appropriate Automatic Mode Switching (AMS) due to atrial arrhythmias 
• 
Reported adverse events and/or subject symptoms with diary entry that is timed and dated 
to correlate Holter findings with events and/or symptoms. 
 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This clinical investigation will enroll subjects of all genders over the age of 18 years who are 
indicated for a DDD(R) pacemaker.  Patients must meet all general eligibility criteria and provide 
written informed consent prior to sites conducting any investigation-specific procedures not 
considered standard of care.  
5.2 
Subject Recruitment/Screening and Informed Consent 
 Subject Recruitment and Screening 
The following assessments are performed as part of the subject recruitment process prior to 
obtaining informed consent: 
• 
Demographics (age on consent date, gender) 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 31 of 96 
 
• 
Medical history screening (including major cardiovascular, vascular, and other coexisting 
medical conditions associated with eligibility criteria) 
 
A member of the site’s clinical investigation team previously trained to the CIP must evaluate 
patients for the general clinical investigation eligibility criteria and will enter all screened patients 
into a site-specific recruitment/screening log.  A patient who does not satisfy all general eligibility 
criteria prior to informed consent is considered a recruitment failure and should not be enrolled 
in the clinical investigation. 
 
Sites will ask patients meeting general inclusion criteria and no general exclusion criteria to sign 
an Informed Consent form following the established Informed Consent process (described in 
Section 5.2.2) if they wish to participate in the clinical investigation. Sites will enter these 
patients into the recruitment/screening log.   
 
Patients who have signed an informed consent and are subsequently found not to meet 
eligibility criteria prior to an attempted implant are considered screen failures and should be 
withdrawn.  
 
 Informed Consent 
The Investigator or his/her authorized designee will conduct the Informed Consent process, as 
required by applicable regulations and the center’s IRB/EC. This process will include a verbal 
discussion with the patient on all aspects of the clinical investigation that are relevant to the 
patient’s decision to participate, such as details of clinical investigation procedures, anticipated 
benefits, and potential risks of clinical investigation participation. Sites must inform patients 
about their right to withdraw from the clinical investigation at any time and for any reason 
without sanction, penalty, or loss of benefits to which the patient is otherwise entitled. 
Withdrawal from the clinical investigation will not jeopardize their future medical care or 
relationship with the investigator.  
 
During the discussion, the Principal Investigator or his/her authorized designee will avoid any 
improper influence on the patient and will respect the patient’s legal rights. Financial incentives 
will not be given to patients. However, patients may be compensated for time and travel directly 
related to the participation in the clinical investigation. The site shall provide the patient with the 
Informed Consent form (ICF) written in a language that is understandable to the patient and that 
has been approved by the center’s IRB/EC. The patient shall have adequate time to review, ask 
questions, and consider participation. The Principal Investigator or his/her authorized designee 
will make efforts to ensure that the patient understands the information provided. If the patient 
agrees to participate, they must sign and date the Informed Consent form, along with the person 
obtaining the consent prior to any clinical investigation-specific procedures. The site will file the 
signed original in the patient’s hospital or research charts and provide a copy to the patient. The 
dated signatures can be electronic. The site will follow local hospital and local EC/IRB 
provisions for documenting electronic ICF signature.   
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 32 of 96 
 
Sites should report any failure to obtain informed consent from a patient to the Sponsor within 5 
working days and to the reviewing center’s IRB/EC according to the IRB’s/ EC’s reporting 
requirements. 
 
Subjects must provide written informed consent prior to any clinical investigation-related 
procedure.  If, during the clinical investigation, new information becomes available that can 
significantly affect a subject's future health and medical care, the Principal Investigator or 
his/her authorized designee (if applicable) will provide this information to the subject. If relevant, 
sites will ask the subject to confirm their continuing informed consent in writing. 
5.2.2.1 Special Circumstances for Informed Consent  
This clinical investigation excludes individuals unable to make the decision to participate in a 
clinical investigation on their own or who are unable to fully understand all aspects of the 
investigation that are relevant to the decision to participate, or who could be manipulated or 
unduly influenced as a result of a compromised position, expectation of benefits or fear of 
retaliatory response. 
 
This clinical investigation excludes individuals under the age of 18 or age of legal consent 
from the clinical investigation population. 
 
The clinical investigation excludes individuals unable to read or write. 
 
The clinical investigation excludes pregnant or breastfeeding women. 
 
All other aspects of the Informed Consent process will follow Section 5.2.2. 
In addition, US sites must obtain an authorization for use and disclosure of the subject’s 
protected health information, in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA), from the subject.  
 
For live case presentations or live case remote observations, the patient needs to sign a 
specific Live Case ICF, approved by the IRB/EC and by the Sponsor, as well as by the 
respective regulatory or competent authorities, as applicable. The investigator must request 
Sponsor approval prior to performing a Live Case.  
 
5.3 
Eligibility Criteria 
 General Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and interview 
with a candidate patient. Patients must meet ALL general inclusion criteria to participate in the 
clinical investigation. If ANY general exclusion criteria are met, the patient is excluded from the 
clinical investigation and cannot be enrolled. 
 
If any clinical and/or laboratory tests are required for patient screening and are not included in a 
site’s standard tests, they must be completed after written informed consent is obtained.  

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 33 of 96 
 
 Inclusion Criteria 
5.3.2.1 General Inclusion Criteria 
1. Subject must have at least one of the clinical indications before device implant in 
adherence with ACC/AHA/HRS/ESC dual chamber pacing guidelines 
2. Subject is ≥ 18 years of age or age of legal consent, whichever age is greater 
3. Subject has a life expectancy of at least one year 
4. Subject is willing to comply with clinical investigation procedures and agrees to return to 
clinic for all required follow-up visits, tests, and exams 
5. Subject has been informed of the nature of the clinical investigation, agrees to its 
provisions and has provided a signed written informed consent, approved by the IRB/EC 
 Exclusion Criteria 
5.3.3.1 General Exclusion Criteria 
1. Subject is currently participating in another clinical investigation that may confound the 
results of this study as determined by the Sponsor 
2. Subject is pregnant or nursing and those who plan pregnancy during the clinical 
investigation follow-up period 
3. Subject has presence of anatomic or comorbid conditions, or other medical, social, or 
psychological conditions that, in the investigator’s opinion, could confound the assessment 
of the investigational device and/or implant procedure, limit the subject’s ability to 
participate in the clinical investigation or to comply with follow-up requirements of the 
clinical investigation results 
4. Subject has a known allergy or hypersensitivity to < 1 mg of dexamethasone sodium 
phosphate or any blood or tissue contacting material listed in the IFU 
5. Subject has an implanted vena cava filter or mechanical tricuspid valve prosthesis 
6. Subject has pre-existing, permanent endocardial pacing or defibrillation leads (does not 
include lead fragments) 
7. Subject has current implantation of either conventional or subcutaneous implantable   
cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device 
8. Subject has an implanted leadless cardiac pacemaker (except for an Aveir ventricular LP) 
9. Subject is implanted with an electrically-active implantable medical device with stimulation 
capabilities (such as neurological or cardiac stimulators)* 
10. Subject is unable to read or write 
*NOTE: Does not apply to a medical device with no known impact to the Aveir Leadless Pacemaker 
System, including the Aveir Link Module. Patient evaluation and the decision to implant the LP should 
take into account the presence of other active implantable devices and should include consultation with 
the Sponsor and/or manufacturer of the co-existing device.  
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 34 of 96 
 
5.4 
Subject Enrollment 
A patient is considered enrolled in the clinical investigation from the moment the patient 
provides written informed consent. 
 
All enrolled subjects who meet eligibility criteria should undergo an attempted implant. A subject 
may withdraw or be withdrawn prior to the implant attempt. If an enrolled subject does not 
undergo an attempted implant, the subject should be withdrawn as soon as possible.   
 
If subjects receive a device without meeting all the conditions listed above, they should still 
complete all follow-up requirements. These subjects are considered CIP deviations. 
 
 Enrollment of Medicare Beneficiaries (US Sites Only)  
This clinical investigation will enroll Medicare beneficiaries and therefore conforms to all 
standards of Medicare coverage requirements. The Risks and Benefits section describes how 
all enrolled subjects, including Medicare beneficiaries, may be affected by the device under 
investigation. 
The Sponsor expects subjects enrolled in the clinical investigation to be consistent with the 
Medicare population based on age range, demographic characteristics, and cardiovascular risk 
factors representative of the Medicare patient population.  As such, the Sponsor expects the 
clinical investigation results to be generalizable to the Medicare population. 
 
 Historically Under-Represented Demographic Subgroups 
The Sponsor intends to implement FDA's guidance on sex-specific data in medical device 
clinical investigations to ensure adequate representation of women and other traditionally under-
represented demographic subgroups in this clinical investigation.  As noted in the guidance, 
some barriers to participation of women and ethnic minorities in clinical investigations have 
traditionally been: 
• 
Lack of understanding about main obstacles to participation of such subgroups in 
clinical research  
• 
Inclusion/exclusion criteria potentially not needed to define the clinical investigation 
population may unintentionally exclude specific subgroups  
• 
Under diagnosis of disease etiologies and pathophysiology leading to under referral of 
demographic subgroups  
• 
Avoidance of specific subgroups by investigators and Sponsors due to the perception 
that it takes more time and resources to recruit them  
• 
Fear of fetal consequences (for female participants)  
• 
Family responsibilities limiting women's ability to commit time for follow-up requirements 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 35 of 96 
 
Historically, Phase 1 of the Leadless II IDE trial, mainly in the US, included 38% females, an 
average age of 75.8 years, and 9% non-white ethnic minorities1.  This clinical investigation will 
also enroll subjects in the US and has identical criteria on the enrollment of female and minority 
ethnicity.  As such, Abbott expects similar proportions of female and minority ethnicity for this 
study.  The traditional barriers for female enrollment (such as fear or fetal consequence, family 
plan of new pregnancies that may limit the ability of time commitment to  follow-up) are not 
applicable to this clinical investigation due to the expected average age of the patient 
population. Therefore, the eligibility criteria of this clinical study do not introduce gender or racial 
bias 
The Sponsor will take the following steps to ensure adequate representation of women and 
racial or ethnic minorities in this clinical investigation:  
1. The Sponsor will provide training to investigational site personnel to ensure adequate 
representation of these demographic subgroups  
2. The Sponsor will regularly review enrollment data to investigate whether there is under-
representation of these demographic subgroups  
3. The Sponsor will regularly review withdrawal rates for under-represented subgroups and 
compare these rates with that in the overall clinical investigation population 
4. As appropriate and necessary, the Sponsor will retrain sites on the importance of 
recruiting and retaining subjects in the clinical investigation 
5. The Sponsor will approach sites without bias or consideration for specific demographic 
subgroups  
6. The Sponsor will have informed consent materials in alternative languages and will work 
with sites and IRBs/ECs on recruitment materials  
5.5 
Subject Withdrawal and Discontinuation 
Each subject meeting all general and screening eligibility criteria shall remain in the clinical 
investigation until completion of the required follow-up period; however, a subject’s participation 
in any clinical investigation is voluntary and the subject has the right to withdraw at any time 
without penalty or loss of benefit. Conceivable reasons for discontinuation may include, but are 
not limited to, the following: 
• 
Subject death 
• 
Subject voluntary withdrawal  
• 
Subject lost-to-follow-up  
• 
Subject’s follow-up is terminated according to Section 3.3 
• 
Unsuccessful Implant 
• 
LP explanted and not re-implanted 
 
 
1 Vivek Y. Reddy, et al. Percutaneous Implantation of an Entirely Intracardiac Leadless Pacemaker. NEJM. 2015; 
373:1125-1135. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 36 of 96 
 
• 
LP abandoned and Aveir LP not re-implanted   
 
Sites must notify the Sponsor of the reason(s) for subject discontinuation. Investigators must 
also report this to their respective IRB/EC as defined by their institution’s procedure(s).  
 
No additional follow-up is required or data recorded from subjects once withdrawn from the 
clinical investigation, except for the status (deceased/alive). 
 
However, if a subject withdraws from the investigation due to problems related to the safety or 
performance of the device under investigation, the investigator shall ask for the subject's 
permission to follow his/her status/condition outside of the clinical investigation according to 
standard of care. 
 
Lost-to-Follow-up 
 
If the subject misses two consecutive scheduled follow-up time points and the attempts at 
contacting the subject detailed below are unsuccessful, then the subject is considered lost-to-
follow-up. Site personnel shall make all reasonable efforts to locate and communicate with the 
subject (and document these efforts in the source documents), including the following, at each 
contact time point: 
• 
A minimum of two telephone calls on different days over the specified follow-up windows 
to contact the subject should be recorded in the source documentation, including date, 
time and initials of site personnel trying to make contact. 
• 
If these attempts are unsuccessful, the site should send a certified letter to the subject. 
• 
If a subject misses one or more non-consecutive follow-up contact time points, it will be 
considered a missed visit. The subject may then return for subsequent visits. If the 
subject misses two consecutive time points and the above-mentioned attempts at 
communicating with the subject are unsuccessful, the subject will be considered lost-to-
follow-up.  
 
Note: Telephone contact with a General Practitioner, non-clinical investigation cardiologist or 
relative without the presence of the subject or indirect documentation obtained via discharge 
letters will not be considered as subject contact. 
5.6 
Number of Subjects  
The clinical investigation will enroll up to 550 subjects at up to 85 sites worldwide to analyze the 
primary endpoints that is based on the following: 
• 
300 de novo subjects to evaluate the primary endpoints, including attrition 
• 
Up to 200 de novo subjects 
 
  
• 
Up to 50 subjects to assess the upgradeability to a Aveir DR LP system in subjects 
previously implanted with the Aveir VR LP single chamber system  

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 37 of 96 
 
 
 
 
   
Subjects previously implanted with an Aveir VR LP who are enrolled to assess the 
upgradeability to an Aveir DR LP system (up to 50) will be concurrently enrolled with the de 
novo subjects but will not contribute toward the evaluation of the primary and secondary 
endpoints. 
No site may enroll more than 15% of the total subjects required to evaluate the primary 
endpoints.   
5.7 
Total Expected Duration of the Clinical Investigation 
The expected duration of each subject’s participation in the clinical study is 1 year including the 
scheduled visits and data collection as listed in Section 6.6.  All enrolled subjects will be 
followed through subject withdrawal or study closure, whichever occurs first. Study closure will 
not begin until all active subjects have completed their 12-month follow up visits or the 12-month 
visit window has passed. For more information about the clinical investigation conclusion and 
site closure, see Section 13.0.   
 
 
 
 
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS 
6.1 
Baseline Assessment 
Investigators will document each subject’s demographics including age at consent, sex, height, 
weight, and race/ethnicity (if applicable). Investigators will also document each subject’s 
baseline medical history, including cardiopulmonary history, patient LP status (e.g. de novo or 
pre-existing Aveir LP), and cardiac medications. Investigators will document the cardiac drug 
categories for the cardiac medications (e.g. beta blockers, ACE inhibitors, ARBs, anti-
coagulants, anti-platelets, anti-arrhythmics) as well as any changes to these medications during 
the follow-up period.   
Investigators will obtain a 12-lead ECG only if one has not already been recorded within the last 
30 days prior to the implant date. Investigators will administer an EQ-5D 5L quality of life survey 
to each subject prior to implant and record the responses.  All subjects will undergo routine 
laboratory assessment per the site’s standard of care.   
For female subjects of childbearing age, investigators will document a pregnancy assessment 
according to the site’s standard test method, which may include obtaining a blood sample for 
conducting a pregnancy test. Any pregnancy test must be done after the subject signs an ICF.  
A negative pregnancy test result must be obtained within 7 days prior to the index procedure. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 38 of 96 
 
 Data Submission 
Once the site has collected the required information and completed the required testing, the site 
will complete and submit the following case report forms to Abbott Medical using the EDC 
system:  
• 
Enrollment Form 
• 
Medical History Forms 
• 
Quality of Life Assessment (EQ-5D 5L)  
• 
Adverse Event Form, if applicable 
• 
Deviation Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
6.2 
Implant Procedure 
Please refer to the IFU for instructions on handling and preparation of the Aveir DR LP system.  
All Investigators must read and understand the IFU and Investigator Brochure (IB), as 
applicable.  Sponsor representatives may also assist the team in equipment setup prior to and 
during a procedure. 
 Medications  
Investigators will administer all medications per hospital standard of care for pacemaker implant 
and femoral venous catheterization procedures.  Use of anticoagulation medications is not 
required with the implantation of the Aveir LP and is left to the investigator’s discretion. During 
the procedure, appropriate anticoagulant therapy should be considered to reduce potential 
thrombus formation.  Investigators will record any cardiac medications given prior to and during 
the implant procedure including beta blockers, ACE inhibitors, ARB, anti-coagulants, anti-
platelets, and anti-arrhythmics. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 39 of 96 
 
 Imaging 
At a minimum, proper equipment must be available for high resolution fluoroscopy to assist with 
delivery and implantation of the LPs. The fluoroscopy must have the ability to record and save 
images, to zoom, and to obtain images in multiple projections, in accordance with the 
manufacturer’s IFU. 
Optional Imaging to Characterize Right Atrium  
Investigators are also encouraged to use any other appropriate imaging modalities available at 
their sites during the procedure that can help characterize the right atrium/appendage and 
evaluate how the atrial LP is positioned relative to the local anatomy. Imaging modalities may 
include intraprocedural intracardiac echocardiography (ICE). Use of any supplemental imaging 
modalities is optional and is left to the investigator’s discretion. 
In addition, any pre-existing imaging of a subject’s right atrium/appendage, such as pre-
procedural MRI or CT, should be submitted to the Sponsor.  
All imaging data obtained for the purpose of right atrial characterization should be de-identified 
and submitted to the Sponsor. 
 Femoral Vein Assessment and Access 
The Sponsor supports using either ultrasound or fluoscopic guidance techniques for assessing 
femoral vein access-site location, including evaluation of the size and presence of any disease. 
However, investigators will use medical judgment and follow institutional standards of care when 
accessing the femoral vein for catheter-based procedures. Only approved investigators will 
perform femoral vein access.   
Investigators will insert and remove any investigational introducer sheaths in accordance with 
the manufacturer’s IFU.   
 LP Preparation and Implant 
Investigators will prepare and implant the Aveir LPs in accordance with the manufacturer’s IFU.  
Consult the IFU for implantation guidelines and general handling information.  Only approved 
investigators will perform the implant procedure, including placement of the Aveir device.  
If both atrial and ventricular LPs are implanted, pairing in dual-chamber mode and establishing 
i2i communication must be attempted at the end of the procedure to verify that the system can 
be programmed in a dual-chamber pacing mode. If verified, subjects should be discharged and 
remain in a dual-chamber pacing mode throughout the study period. Investigators are permitted 
to change the pacing mode at any time if clinically appropriate.   
Following the placement of both LP devices, investigators should obtain a cinefluoroscopy for at 
least 2 cardiac cycles in orthogonal views to evaluate final LP placement. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 40 of 96 
 
 LP Assessment and Programming 
Investigators and/or Sponsor representatives will interrogate the Aveir DR LP system using the 
market-approved St. Jude Medical™ Merlin™ Patient Care System (Model 3330) with the Aveir 
Link Module (Model LSL02).   
 
Sponsor representatives may assist investigators in assessing pacemaker effectiveness (for 
example pacing, sensing, and rate response effectiveness), downloading diagnostic information, 
and programming pacemaker parameters.   
Investigators will measure and record the following parameters: 
• 
Atrial and Ventricular LP Capture threshold at 0.4 ms pulse duration* 
• 
Atrial and Ventricular LP Impedance 
• 
Atrial and Ventricular LP Sense Amplitude*  
• 
Atrial and Ventricular i2i throughput 
• 
Atrial and Ventricular i2i setting level 
• 
Battery Voltage**  
• 
Device Longevity and Remaining Capacity to recommended replacement time (RRT)** 
* Atrial and Ventricular sense amplitude measurements are not required if the subject’s 
intrinsic rate has been established to be below 30 beats per minute.  Atrial capture 
threshold and sense amplitudes are not required if the subject is in atrial fibrillation or 
atrial flutter.  Ventricular capture thresholds are not required if a high ventricular rate is 
present.  
**Not required at implant or pre-discharge visits.  
To avoid potential complications associated with undersensing, Investigators shall program a 
sensing margin of at least two times the intrinsic cardiac amplitude (e.g. for an intrinsic R-wave 
of 4 mV, program the R-sensitivity ≤2 mV). 
 LP Repositioning and/or Release 
Once the investigator implants an Aveir LP and successfully demonstrates acute effectiveness, 
the investigator may release the Aveir LP.  When the investigator has released the Aveir LP, 
s/he will use fluoroscopy to assess positioning of the implanted LP. 
Investigators may reposition the Aveir LP, if determined necessary.  For release and 
repositioning procedures, refer to the IFU.   
Once the Aveir LP has been released, investigators will use an Aveir Retrieval Catheter for 
removal, if needed (Refer to the Aveir Retrieval Catheter IFU).  Once the LP has been removed, 
investigators may attempt to implant another Aveir LP, or instead, choose to implant a different 
market-approved pacemaker.   
 Subjects with two (2) LPs implanted 
Investigators will follow subjects who leave an attempted de novo implant procedure with two 
Aveir LPs implanted through a minimum of 12-months post-implant according to the clinical 
investigation flowchart described in Figure 6. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 41 of 96 
 
   
 Subjects with one (1) LP implanted 
De Novo Subjects 
 
Investigators will follow subjects who leave an attempted de novo implant procedure with one 
Aveir LP implanted through a minimum of 12-months post-implant according to the clinical 
investigation flowchart described in Figure 6.  
 
The investigator must document the nature of and reasons for the unsuccessful LP implant on 
the Implant Form.  Subjects who leave an index procedure with one LP implanted will not be 
eligible for re-implantation attempts of a second LP in a different chamber at a later date during 
the study period. 
 
Upgrade Subjects 
 
Investigators will follow subjects who leave an attempted upgrade procedure with an 
unsuccessfully implanted atrial LP for a period of at least 30 days to evaluate for adverse 
events.  At the end of the 30 days, the investigator will withdraw the subject.   
 
The investigator must document the nature of and reasons for the unsuccessful implant on the 
Implant Form.  Subjects who have an unsuccessful upgrade will not be eligible for re-
implantation attempts of an atrial LP at a later date during the study period. 
 
 Subjects without any LPs implanted 
Investigators will follow subjects who leave an attempted de novo implant procedure without any 
implanted Aveir LPs for a period of at least 30 days to evaluate for adverse events.  At the end 
of the 30 days, the investigator will withdraw the subject.   
 
The investigator must document the nature of and reasons for the unsuccessful implant on the 
Implant Form.  Subjects who have an unsuccessful implant will not be eligible for re-implantation 
attempts of any Aver LPs at a later date during the study period. 
 
 Healthcare Utilization 
Procedural and post-procedural healthcare utilization information will primarily be used for 
health economics and reimbursement research purposes. All inpatient hospitalizations, 
outpatient services, emergency room and urgent care visits for cardiac or non-cardiac reasons, 
including any associated with LP system revision procedure(s) should be reported to the 
Sponsor via a Healthcare Utilization Form. Any supporting documentation (i.e., 
Admission/Discharge Summary) that is available should also be submitted to the Sponsor via 
the EDC system.  
Healthcare utilization data to be collected includes the type, a subject’s final primary diagnosis, 
any procedures performed, and billing information (if applicable). Submission of a Healthcare 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 42 of 96 
 
Utilization Form for the index LP implant procedure itself, without associated adverse events, is 
optional. 
 
 Data Submission 
Once the site has collected the required information and completed the required testing, the site 
will complete and submit the following case report forms to Abbott Medical using the EDC 
system:  
• 
Implant Forms  
• 
Aveir LP Assessment and Programming Form (Implant) with device session print out 
PDFs 
• 
Device Accountability Log 
• 
Healthcare Utilization Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 
All imaging data obtained for the purpose of right atrial characterization (e.g. ICE) should be de-
identified and submitted to the Sponsor. 
Any cinefluoroscopy imaging should be de-identified and submitted to the Sponsor upon 
Sponsor request.  
6.3 
System Revision with a Replacement Aveir LP 
In the event an Aveir LP must be replaced during the follow-up period, investigators may opt to 
replace the first Aveir LP with a new Aveir LP in one of the following ways: 
• 
Retrieve the first Aveir LP and implant a new Aveir LP  
• 
Deactivate the first Aveir LP and implant a second Aveir LP in close proximity to the first  
When considering Aveir LP retrieval and replacement, investigators will refer to the respective 
IFUs.  Sponsor representatives may also assist the team in equipment setup prior to and during 
a procedure. If the subject receives a new Aveir LP, the subject must continue with his/her 
ongoing follow-up schedule. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 43 of 96 
 
 Data Submission 
The site will complete and submit the following case report forms and device print outs to Abbott 
Medical using the EDC system:  
• 
System Revision Form 
• 
Device Accountability Log 
• 
Healthcare Utilization Form 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
6.4 
System Revision without a Replacement Aveir LP 
In the event an Aveir LP must be replaced during the follow-up period, investigators may opt to 
revise the Aveir LP without a replacement Aveir LP in one of the following ways: 
• 
Retrieve the Aveir LP and implant a commercially available pacemaker, CRT device,  
ICD, or not opt for a replacement device. 
• 
Deactivate the Aveir LP and implant a commercially available pacemaker, CRT device, 
ICD, or not opt for a replacement device. 
When considering Aveir LP retrieval, investigators will refer to the respective IFUs.  Sponsor 
representatives may also assist the team in equipment setup prior to and during a procedure. 
If the subject has all Aveir LPs removed or deactivated at any time during the clinical 
investigation, and the subject will not receive a replacement Aveir LP, the site will follow the 
subject for at least 30 days. At the end of the 30 days, the investigator will withdraw the subject.    
If the subject has at least one active Aveir LP after a system revision procedure, the subject 
must continue with his/her ongoing follow-up schedule.  
 
 Data Submission 
The site will complete and submit the following case report forms to Abbott Medical using the 
EDC system: 
• 
System Revision Form   
• 
Device Accountability Log 
• 
Healthcare Utilization Form 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 44 of 96 
 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Study Withdrawal Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
6.5 
Pre-Discharge (In-hospital)  
 Access-site Management During Hospital Stay 
Investigators will manage vascular-access sites per standard of care for procedures using large 
bore venous access.  Investigators will assess and document any post-procedural access-site 
bleeding events based on the following grading system. 
ACCESS-SITE OOZING:  Superficial bleeding of a cutaneous or subcutaneous origin 
characterized by diffuse localized bleeding and controlled with minimal care (e.g., application of 
manual pressure, application of sandbag or other pressure dressing as per standard of care). 
ACCESS-SITE HEMATOMA:  A localized collection of extravasated blood in subcutaneous 
tissue at the access site that does not require intervention. A metric ruler should be used to 
measure the widest portion of the hematoma. 
ACCESS-SITE HEMATOMA REQUIRING INTERVENTION:  A localized collection of 
extravasated blood in subcutaneous tissue at the access site that requires intervention including 
wound exploration (e.g., acutely expanding hematoma, acute leg pain/numbness/swelling) 
and/or prolongation of hospital stay. 
 Pre-Discharge Assessment 
Investigators will assess all subjects at the implant center prior to hospital discharge, or within 2-
days post implant, whichever is shorter.  The clinical investigation team will: 
• 
Assess for adverse events and deviations from investigation plan 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 
• 
Measure and record Aveir LP performance, as described in Section 6.2.5 LP 
Assessment and Programming  
• 
Program Aveir LP per physician discretion 
• 
Obtain a 12-lead ECG with pacing ON 
• 
Obtain a posterior/anterior (P/A) and lateral view chest x-ray to assess final LP position 
• 
Investigator will use medical judgment and provide institutional standard of care for post-
pacemaker-implant monitoring 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 45 of 96 
 
 
 Data Submission 
The site will complete and submit the following case report forms and device print outs to Abbott 
Medical using the EDC system:  
• 
Pre-Discharge Form (includes medication changes) 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Healthcare Utilization Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
Device Accountability Log, if applicable 
• 
System Revision Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 
Any post-procedure chest X-ray imaging should be de-identified and submitted to the Sponsor 
upon Sponsor request.  
6.6 
Follow-up Assessments  
The site will perform the required clinical follow-up at the following intervals for all subjects 
implanted with an Aveir DR LP system: 
• 
1 month (± 15 days) follow-up site visit  
• 
3 month (± 30 days) follow-up site visit  
• 
6 month (± 30 days) follow up site visit 
• 
12 month (±45 days) follow up site visit 
• 
Every 6 months thereafter until study closure (±45 days) 
 
Dates for follow-up visits will be calculated from the date of the implant procedure.  Follow-up 
assessments can be performed at any point within the pre-specified follow-up visit window. 
Every effort should be made by the site personnel to have the subject return to the 
investigational site for all follow-up visits. If, despite all efforts, the subject is unable to return to 
the site during a follow-up window, subjects may undergo a remote follow-up assessment to 
collect applicable non-device performance data.  Remote assessments should include 
telephone contact with the subject and/or a visit to a medical facility with all data that can be 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 46 of 96 
 
reasonably and legally collected remotely on the study subject.  Follow-up visits occurring at 
non-study sites will be limited to standard of care data collection only. Authorization for the 
release of medical records from a non-study facility is the responsibility of the investigational 
site. Any missed testing will be considered a protocol deviation. 
An enrolled subject may only be followed at another investigational site with prior agreement 
from that site’s Investigator and from the Sponsor. 
 1-Month Follow-Up Visit 
The 1-month follow-up visit will occur 30 days (±15 days) post-implant procedure and will 
include the following assessments:   
• 
Assess for adverse events and deviations from investigation plan 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 
• 
Assess Quality of Life (EQ-5D 5L) 
• 
Measure and record LP performance, as described in Section 6.2.5 LP Assessment and 
Programming 
• 
Program Aveir LP and adjust programmable parameters of LP, as needed 
• 
Optional: 6-Minute Walk Test (6MWT) only for those capable de novo subjects who 
may be appropriately programmed temporarily in AAIR mode and who have a tolerance 
of high sensor-driven rates2  
• 
Administer the 6MWT with the rate-response feature in AAIR ON or Passive mode 
using the Rate Response Optimization function of the programmer for the Aveir 
atrial LP (Refer to the 6MWT protocol in Appendix V).  
• 
Assess Magnet Mode in AAIR ON or Passive 
• 
After completing the 6MWT, use the Rate Response Optimization function of the 
programmer to model the response of the algorithm to the 6MWT protocol so that a 
peak sensor rate of approximately 100 beats/min is achieved.  The results of this 
Rate Response Optimization will be used to adjust programmable sensor 
parameters of the Aveir atrial LP in preparation for the CAEP protocol to be 
administered in a subsequent visit. 
6.6.1.1 Data submission 
The site will complete and submit the following case report forms and device print outs to 
Abbott Medical using the EDC system:  
• 
Follow-up Visit Form (includes medication changes) 
 
 
2 Administration of the 6MWT can be done any time between the 1-month and 3-month follow-up visit until 30 
subjects contribute to the analysis. Subjects  

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 47 of 96 
 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Quality of Life Assessment (EQ-5D 5L) 
• 
6 Minute Walk Test Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
Device Accountability Log, if applicable 
• 
System Revision Form, if applicable 
• 
Healthcare Utilization Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 
All source documentation associated with the 6MWT, including device session printouts, source 
worksheets, and LP data files should be de-identified and submitted to the Sponsor.  
 
 3-Month Follow-Up Visit 
The 3-month follow-up visit will occur 90 days (±30 days) post-implant procedure and will 
include the following assessments:   
• 
Assess for adverse events and deviations from investigation plan 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 
• 
Assess Quality of Life (EQ-5D 5L) 
• 
Measure and record LP performance, as described in Section 6.2.5 LP Assessment and 
Programming 
• 
Measure and perform in-clinic AV Synchrony Assessment only for de novo subjects 
programmed in a dual-chamber pacing mode as described in Section 6.6.2.1 
• 
Program Aveir LP and adjust programmable parameters of LP, as needed 
• 
Optional: CAEP Protocol only for those capable de novo subjects who may be 
appropriately programmed temporarily in AAIR pacing mode and who have a tolerance 
of high sensor-driven rates3  
 
 
3 Administration of the CAEP protocol can be done any time between the 3- month and 6-month follow-up visit 
until 30 subjects contribute to the analysis 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 48 of 96 
 
o If the 6MWT is conducted the same day as the CAEP protocol, wait at least 1 hour 
after the 6MWT has been completed prior to starting the CAEP protocol.  
o The optimized sensor parameters resulting from the 6MWT are advised for the 
CAEP protocol, however, the physician has discretion to alter these parameters.  
Administer the CAEP protocol with rate-response feature in AAIR ON mode (refer 
to the CAEP protocol in Appendix V). 
o After completing the CAEP protocol, program Aveir LP and adjust programmable 
parameters of the LP, as needed. 
• 
Optional: 24-hour Holter data collection and patient diary4 only for de novo subjects 
programmed to DDD(R) mode and who demonstrate at least 25% atrial pacing during 
the most recent device interrogation  
6.6.2.1 AV Synchrony Assessment – In-Clinic  
Subject Population  
All de novo subjects who can be programmed to a dual chamber pacing mode will be 
administered the in-clinic AV Synchrony Assessment.   
Setup 
After the 3-month LP Assessment and Programming is performed and device session 
printouts obtained, the site will clear the device diagnostics prior to starting the in-clinic AV 
Synchrony Assessment.  
A Holter monitor will be setup and worn by the subject according to the instructions provided 
by the Sponsor and/or Core Lab. The setup may include adjusting the clock times on the 
Holter Monitor or Merlin Programmer so that the beginning and end of each position/activity 
can be identified on both devices.  
The subject will also be connected to the Merlin Programmer at certain periods during the 
assessment. The investigator may also need to reprogram the base rate to improve the 
likelihood of atrial pacing for select patients.  LP interrogation and Holter recording should not 
take place simultaneously to minimize device artifacts or noise on the Holter.  
The site will be trained to properly set up the Holter and Merlin Programmer for the in-clinic AV 
Synchrony Assessment through separate instructional materials.  
AV Synchrony Assessment For Primary Effectiveness Endpoint #2: 
While wearing the Holter monitor, the subject should remain in a seated position at rest for 5 
minutes while the Holter will record the subject’s cardiac rhythm. The site will record the Holter 
start and stop recording times on the AV Synchrony Assessment CRF and then interrogate 
the LP.  At the end of the assessment period, the site will obtain a device session printout.  
 
 
4 Holter data collection can be done any time between the 3- month and 6-month follow-up visit. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 49 of 96 
 
The site will be trained to administer the in-clinic AV Synchrony Assessment and send the 
Holter data to the Core Lab for AV Synchrony analysis.  
 
The Sponsor will evaluate the data from this assessment for the primary effectiveness 
endpoint #2. 
Additional AV Synchrony Assessment in Various Positions/Activity Levels: 
While wearing the Holter monitor, the subject’s cardiac rhythm wil be recorded while the 
subject assumes the following positions and activity levels in the following order for 2 minutes 
each: 
• 
Supine  
• 
Left Lateral 
• 
Right Lateral 
• 
Standing 
• 
Normal Walk 
• 
Fast Walk 
 
Prior to each 2-minute assessment, the site will interrogate the LP system using the Merlin 
programmer and clear the device diagnostics.  The site will record the Holter start and stop 
recording times for each 2-minute assessment on the AV Synchrony Assessment CRF.  At the 
end of each 2-minute assessment, the site will obtain a device session printout. The site will 
be trained to administer the in-clinic AV Synchrony Assessment and send the Holter data to 
the Core Lab for AV Synchrony analysis.  
 
The AV Synchrony analysis under these positions and activity levels will not contribute toward 
the primary effectiveness endpoint #2 but will be reported separately.   
 
6.6.2.2 AV Synchrony Assessment – 24 Hours  
Fifty (50) de novo subjects will be selected by investigators to wear a Holter monitor and 
complete a symptom diary for at least 24 hours. The assessment may be performed any time 
after the beginning of the 3-month visit window. The preferred window to perform the 24-hour 
Holter test is between the 3-month and 6-month visit.  These recorded data will be examined 
for appropriate sensing, pacing, and AV synchrony during the activities of daily living for each 
subject.  In addition, these data will be evaluated for any correlation between any subject 
symptoms and losses of AV synchrony, if present. 
 
A 24-hour Holter will only be worn for subjects who can be programmed to DDD(R) mode and 
who demonstrate at least 25% atrial pacing on the most recent device interrogation. The site 
will connect each capable subject to a 24-hour Holter monitor until 50 subjects contribute to 
the analysis.  
 
The site will be trained to administer the 24-Hour AV Synchrony Assessment and send the 
Holter data to the Core Lab for AV Synchrony analysis. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 50 of 96 
 
6.6.2.3 Data Submission 
The site will complete and submit the following case report forms and device print outs to 
Abbott Medical using the EDC system:  
 
• 
Follow-up Visit Form (includes medication changes) 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
AV Synchrony Assessment Form (In-clinic) with device session print out PDFs 
• 
Quality of Life Assessment (EQ-5D 5L) 
• 
24 Hour AV Synchrony Assessment Form, if applicable 
• 
6 Minute Walk Test Form, if applicable 
• 
CAEP Exercise Test Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
Device Accountability Log, if applicable 
• 
System Revision Form, if applicable 
• 
Healthcare Utilization Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 
Any in-clinic Holter data or 24-Hour Holter data (if collected) should be de-identified and 
submitted to the Core Lab according to the instructions to be provided separately.  
 
All source documentation associated with the AV Synchrony Assessment (In-Clinic and 24 
Hour),  6MWT, and CAEP, including device session printouts, source worksheets, and LP data 
files (if applicable) should be de-identified and submitted to the Sponsor.  
 
 
 6-Month Follow-Up Visit 
The 6-month follow-up visit will occur 180 days (±30 days) post-implant procedure and will 
include the following assessments:   
• 
Assess for adverse events and deviations from investigation plan 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 51 of 96 
 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 
• 
Assess Quality of Life (EQ-5D 5L) 
• 
Measure and record LP performance, as described in Section 6.2.5 LP Assessment and 
Programming 
• 
Program Aveir LP and adjust programmable parameters of LP, as needed 
6.6.3.1 Data submission 
The site will complete and submit the following case report forms and device print outs to 
Abbott Medical using the EDC system:  
• 
Follow-up Visit Form (includes medication changes) 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Quality of Life Assessment (EQ-5D 5L) 
• 
CAEP Exercise Test Form, if applicable 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
Device Accountability Log, if applicable 
• 
System Revision Form, if applicable 
• 
Healthcare Utilization Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 
All source documentation associated with the CAEP, including device session printouts, source 
worksheets, and LP data files should be de-identified and submitted to the Sponsor.  
 
 12-Month Follow-Up Visit and Each Follow-up Visit Every Subsequent 6 Months until 
Study Completion 
The 12-month follow-up visit will occur 365 days (±45 days) and subsequently every 180 days 
(±45 days) post-implant procedure and will include the following assessments:   
• 
Assess for adverse events and deviations from investigation plan 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 52 of 96 
 
• 
Assess Quality of Life (EQ-5D 5L) - 12 month visit only 
• 
Measure and record LP performance, as described in Section 6.2.5 LP Assessment and 
Programming 
• 
Program Aveir LP and adjust programmable parameters of LP, as needed 
6.6.4.1 Data submission 
The site will complete and submit the following case report forms and device print outs to 
Abbott Medical using the EDC system:  
• 
Follow-up Visit Form (includes medication changes) 
• 
Aveir LP Assessment and Programming Form (Follow-Up) with device session print out 
PDFs 
• 
Quality of Life Assessment (EQ-5D 5L) – 12 month visit only 
• 
Adverse Event Form, if applicable 
• 
Device Deficiency Form, if applicable  
• 
Deviation Form, if applicable 
• 
Device Accountability Log, if applicable 
• 
System Revision Form, if applicable 
• 
Healthcare Utilization Form, if applicable 
• 
COVID-19 Assessment Log, if applicable 
• 
Study Withdrawal Form, if applicable 
 Unscheduled Follow-Up Visits 
If a subject returns to the investigational site for a visit that is related to the device or implant 
procedure, the site will assess the following at the unscheduled visit:   
• 
Assess for adverse events and deviations from investigation plan 
• 
Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-
arrhythmics 
• 
Measure and record LP performance, as described in Section 6.2.5 LP Assessment and 
Programming 
• 
Program Aveir LP and adjust programmable parameters of LP, as needed 
6.6.5.1 Data submission 
The site will complete and submit the following case report forms and device print outs to 
Abbott Medical using the EDC system:  
•  Follow-up Visit Form (includes medication changes) 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 53 of 96 
 
•  Aveir LP Assessment and Programming Form (Follow-Up) with device session print 
out PDFs 
•  Adverse Event Form, if applicable 
•  Device Deficiency Form, if applicable  
•  Deviation Form, if applicable 
•  Device Accountability Log, if applicable 
•  System Revision Form, if applicable 
•  Healthcare Utilization Form, if applicable 
•  COVID-19 Assessment Log, if applicable 
•  Study Withdrawal Form, if applicable 
 Patient Reported Outcome (PRO) Measures  
The Coordinator or designee will administer the patient-reported outcome questionnaires, via 
paper for later transcription to EDC, or electronically. If the patient reported outcome 
questionnaire is given to the patient electronically, the source data will be available in the EDC 
system for the site’s records.  It is important that the subject understands the meaning of all 
words and instructions in the questionnaires. The Coordinator or designee should instruct the 
subject to ask any questions about the questionnaires if further explanation is needed. Once the 
questionnaires are completed, the Coordinator or designee will review for completeness to 
verify that all questions have been answered according to the directions provided.  
 
The CIP requires collecting the EQ-5D 5L as a PRO measure: 
 
The EQ-5D Questionnaire version 5L is a widely used validated questionnaire that provides an 
indicator of overall health status. The self-administered/electronic questionnaire consists of 2 
parts:  a 5 item description of one dimension (Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, and Anxiety/Depression) and a thermometer-like visual analogue scale ranging 
from 0 to 100 (EQ-VAS) assessing overall state of health.   Self-ratings on the five levels in the 
five dimensions (items) can be summarized to produce 3125 health states, also known as a 
health profile. Health profiles can be assigned index values derived from econometric 
techniques to elicit societal preference weights. These index values can then be used in 
economic evaluation of health programs.  The questionnaire takes a few minutes to complete.  
6.7 
Schedule of Events 
CIP Activity 
Screening/ 
Enrollment 
Baseline 
 
Implant 
Procedure 
 
Pre-
Discharge 
(0-2 days) 
1 Month 
(±15 days) 
3 Month 
 (±30 days) 
6 Month 
(±30 days) 
12 Month and 
Every 6 months 
until study 
completion 
(±45 days) 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
Informed Consent 
Process 
X 
 
 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 54 of 96 
 
CIP Activity 
Screening/ 
Enrollment 
Baseline 
 
Implant 
Procedure 
 
Pre-
Discharge 
(0-2 days) 
1 Month 
(±15 days) 
3 Month 
 (±30 days) 
6 Month 
(±30 days) 
12 Month and 
Every 6 months 
until study 
completion 
(±45 days) 
Screening Log 
X 
 
 
 
 
 
 
 
Pregnancy Test 
 
X† 
 
 
 
 
 
 
Demographics and  
Medical History  
 
X 
 
 
 
 
 
 
RA Characterization 
Imaging 
 
Y 
Y 
 
 
 
 
 
Changes in 
Medication 
 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
X 
 
X 
 
 
 
 
Cine of Final LP 
Placement 
 
 
X 
 
 
 
 
 
Chest X-ray of LP 
 
 
 
X 
 
 
 
 
Aveir Assessment 
and Programming 
 
 
X 
X 
X 
X 
X 
X 
In-clinic Holter AV 
Synchrony Protocol 
 
 
 
 
 
X* 
 
 
Sensor optimization 
exercise test 6MWT 
 
 
 
 
X** 
X** 
 
 
Graded exercise test 
CAEP Protocol  
 
 
 
 
 
X** 
X** 
 
24 hour Holter 
monitor with patient 
diary 
 
 
 
 
 
X** 
X** 
 
EQ-5D 5L patient 
survey 
 
X 
 
 
X 
X 
X 
X*** 
Device 
Accountability Log 
 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
Adverse Event 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Deviation 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Device Deficiency 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
System Revision 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Withdrawal 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
COVID-19 
Assessment log 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Healthcare 
Utilization 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
X = Required for all subjects 
X† = For female subjects of childbearing age  

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 55 of 96 
 
X* = For de novo subjects only 
X** = For select appropriate de novo subjects only. CIP activity only needs to be done once among designated visits.  
X*** = EQ-5D 5L patient survey required at 12-month visit only 
(X) = If applicable for all subjects 
Y = Optional, if available. Imaging at baseline visit applies to pre-existing subject imaging only (e.g. MRI, CT). 
 
6.8 
Requirement for Core Laboratories  
The Sponsor will utilize an independent core laboratory for evaluating ECGs collected in the 
clinical investigation. Each investigational site will submit ECGs to the core laboratory for 
evaluation. The core laboratory will provide the required interpretation and documentation of 
each data submission according to their standard operating procedures and investigation-
specific charter. 
The Sponsor will use the data obtained from the core laboratory readings for clinical 
investigation purposes only and not for clinical treatment of the subject. The Sponsor will use 
the data provided by the core laboratory in data analyses, where measurements were collected 
by the core laboratory.  
7.0 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical investigation adverse event 
reporting, the Sponsor has adopted uniform and worldwide applicable standard definitions and 
reporting timelines to be used and adhered to by the investigators.  
7.1 
Definition 
 Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the medical device under investigation. 
 
As part of ISO14155 Section 3.2, the Adverse Event definition has the following notes: 
 
Note 1: This definition includes events related to the medical device under investigation or the 
comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to medical 
devices under investigation or comparator. 
 Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 56 of 96 
 
a) Led to a death, 
b) Led to a serious deterioration in health of the subject, that either resulted in  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalization or prolongation of existing hospitalization, or 
4. medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
5. chronic disease  
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect including 
physical or mental impairment. 
 
Note: A planned hospitalization for a pre-existing condition, or a procedure required by the CIP 
without a serious deterioration in health, is not considered to be an SAE. 
 
 Device Deficiency/Device Malfunction 
Device deficiency is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, usability, safety or performance, such as malfunction, misuse or use error 
and inadequacy in the information supplied by the manufacturer including labeling. This includes 
the failure of the device to meet its performance specifications or otherwise perform as 
intended.  
 
Note 1: performance specifications include all claims made in the labeling of the device.  
Note 2: the definition includes device deficiencies related to investigational medical device or 
the comparator. 
 
A device malfunction is the failure of a device to meet its performance specifications or 
otherwise perform as intended, when used in accordance with the instructions for use or CIP. 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or 
device under investigation caused or contributed to an AE is to be determined by the 
Investigator and recorded on the appropriate CRF form. Determination should be based on the 
assessment of temporal relationships, evidence of alternative etiology, medical/biologic 
plausibility and patient condition (pre-existing condition). 
 
7.3 
COVID-19 Relationship and Assessment Log 
 
Determination of whether there is a reasonable possibility that COVID-19 caused or contributed 
to an AE is to be determined by the Investigator and recorded on the Adverse Event form. If 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 57 of 96 
 
an adverse event is determined to be related to COVID-19, the investigator must complete the 
COVID-19 Assessment Log to confirm the positive test result. Any COVID-19 assessment done 
by the investigative site as part of diagnostic tests for any adverse event should also be 
documented on the COVID-19 Assessment Log.  
 
 Unanticipated (Serious Adverse) Device Effect [UADE/USADE]  
Unanticipated serious adverse device effect (UADE/USADE) refers to any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated with, 
a device, if that effect, problem or death was not previously identified in nature, severity, or 
degree of incidence in the 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. 
 
 Serious Health Threat 
Serious Health Threat is a signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in subjects, users or other 
persons, and that requires prompt remedial action for other subjects, users or other persons 
Note: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring 
at short intervals. 
7.4 
Adverse Event and Device Deficiency/Device Malfunction Reporting 
 Adverse Event Reporting 
Safety surveillance and reporting starts as soon as the patient is enrolled in the clinical study.  
Safety surveillance and reporting will continue until sites perform the last follow-up visit, the 
subject is deceased, the subject concludes participation in the clinical investigation, or the 
subject withdraws from the clinical investigation.  Sites will collect all adverse event data, 
including deaths and device deficiency data, throughout the period defined above and will report 
these events to the Sponsor on a CRF. Sites should update additional information regarding an 
adverse event on the appropriate CRF.  
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be 
reported.  
 
Unavoidable AEs are not reportable unless the condition worsens or continues beyond the time 
frame listed below.  Unavoidable AEs, listed below, do not need to be reported if they are 
resolved within the time frame specified. 
 
Unavoidable AEs related to the Implant Procedure 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 61 of 96 
 
P-wave sensitivity 
P-wave amplitude ≥ 1.0 mV 
 
 
The primary effectiveness endpoint #1 hypothesis is: 
 
H0:   RateEP ≤ 82.5%    vs.   H1:   RateEP > 82.5% 
where 82.5% is the PG 
 
The RateEP is the proportion of subjects who have met success criteria in the primary 
effectiveness endpoint #1.  
 
Success Criteria: A subject will meet the primary effectiveness endpoint #1 endpoint if: pacing 
threshold voltage ≤ 3.0 V at 0.4 ms at the 3-month visit and the sensed P-wave amplitude is ≥ 
1.0 mV at the 3-month visit. 
 
The RateEP will be estimated as a binomial proportion and the 97.5% LCB of the RateEP will be 
calculated using the normal approximation. The null hypothesis is rejected at the 2.5% 
significance level if the LCB exceeds the PG of 82.5%. The p-value for the one-sided Z-test will 
be calculated and compared to the 2.5% significance level. 
 
The Sponsor will analyze the primary effectiveness endpoint #1 on 
 the full analysis 
(primary analysis) 
 populations. In the full analysis population, subjects 
withunsuccessful implants due to reasons other than atrial pacing/sensing (e.g. cardiac 
anatomy) will be excluded from the analysis. Subjects who don’t meet pacing/sensing success 
criteria at 3 months or subjects with unsuccessful implant solely due to unacceptable atrial LP 
pacing or sensing will be counted as failures. Additionally, for subjects with missing 3-month 
pacing threshold or P-wave amplitude data, a multiple imputation analysis will be used to impute 
the missing outcomes. 
 Primary Effectiveness Endpoint #2 Analyses  
The primary effectiveness endpoint #2 evaluates the 3-month AV synchrony success rate 
(RateAV) at rest/seated using a Holter monitor in-clinic. AV synchrony success is defined as 
subjects with a paced or sensed ventricular beat within 300 ms following a paced or sensed 
atrial beat for at least 70% of evaluable cardiac cycles. The primary effectiveness endpoint #2 
hypothesis is: 
 
H0: RateAV ≤ 83% vs. H1: RateAV > 83% 
where 83% is the PG 
 
The RateAV is the proportion of subjects who have met success criteria in the primary 
effectiveness endpoint #2.  
 
The RateAV will be estimated as a binomial proportion and the 97.5% LCB of the RateAV will be 
calculated using the normal approximation. The null hypothesis is rejected at the 2.5% 
significance level if the LCB exceeds the PG of 83%. The p-value for the one-sided Z-test will be 
calculated and compared to the 2.5% significance level.  

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
Template: 86357 Rev. J 
Page 62 of 96
The Sponsor will analyze primary effectiveness endpoint #2 on the full analysis (primary 
analysis) population. In the primary analysis, subjects who don’t meet AV synchrony success 
criteria at 3 months or subjects with an unsuccessful implant solely due to a failure to establish 
i2i communication at the end of implant procedure will be imputed as endpoint failures. Subjects 
with unsuccessful implants due to reasons other than AV synchrony (e.g., cardiac anatomy) will 
be excluded from the analysis. 
Secondary Safety Endpoint Analyses 
The Sponsor will test the secondary safety endpoint if the primary endpoints are met. This 
endpoint evaluates the 3-month Aveir Atrial LP related CFR based on CEC adjudication of 
adverse events. An atrial LP complication is defined as an atrial device- or procedure-related 
SADE, including those that prevent initial LP implantation. Complications that are exclusively 
related to the ventricular LP or its delivery/retrieval will not be considered atrial LP complications 
and will be excluded from this evaluation. Complications that cannot be exclusively determined 
to be related to the ventricular or atrial LP will be considered atrial LP complications (e.g. 
femoral access complications, embolism, etc.). The secondary safety endpoint hypothesis is: 
H0: CFRA ≤ 84% vs. H1: CFRA > 84% 
where 84% is the PG 
The CFRA will be estimated as a binomial proportion and 97.5% LCB of CFRA will be calculated 
using the normal approximation. The null hypothesis is rejected at the 2.5% significance level if 
the LCB exceeds the PG of 84%. The p-value for the one-sided Z-test will be calculated and 
compared to the 2.5% significance level.  
The Sponsor will analyze the secondary safety endpoint based on the full analysis population. 
Secondary Effectiveness Endpoint Analyses 
The secondary effectiveness endpoint includes evaluation of a CAEP exercise protocol for the 
atrial LP. The secondary effectiveness endpoint will be tested if all the primary endpoints are 
met and the secondary safety endpoint is also met. The following CAEP hypothesis will be 
evaluated: 
H0:    Mean Slope < 0.65 or Mean Slope > 1.35 
H1:    0.65 ≤ Mean Slope ≤ 1.35. 
6 Minute Walk Test (6MWT) 
All capable subjects will be asked to perform a minimal effort 6MWT simulating daily walking to 
identify the appropriate sensor parameters for each subject prior to conducting the CAEP 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
Template: 86357 Rev. J 
Page 63 of 96
exercise protocol.  After completion of the 6MWT, the site will program the appropriate sensor 
parameters into the Aveir device for use in the subsequent CAEP protocol. 
CAEP exercise protocol 
All capable subjects who have completed the 6MWT protocol will be asked to perform a 
maximal effort CAEP exercise protocol to demonstrate an appropriate and proportional 
response of sensor-indicated rate in graded exercise tests. Subjects will undergo the CAEP 
exercise test any time after the beginning of their 3-month visit window and before the end of 6-
month visit window. Each subject will undergo this test at a single visit. 
The analysis will include data from subjects who have completed the 6MWT protocol and have 
completed at least stage 3 of the CAEP exercise protocol, or 3.6 metabolic equivalent of task 
(METs).  Any CAEP assessments performed which substantially deviate from the CAEP 
exercise protocol (See Appendix V) or where insufficient data is available will be excluded from 
the analysis. However, the results of subjects who did not meet the analysis criteria will still be 
reported. Up to thirty subjects among the implanted population will provide data contributing to 
the analysis.  
A mixed effects model for repeated measures will be used to estimate the mean slope (through 
origin) and standard error of mean slope across N subjects. A no intercept model with 
unstructured covariance matrix for the random effect (subject) will be used for this analysis. A 
95% confidence interval for the mean slope will be provided and if this interval falls within the 
equivalence bounds of (0.65,1.35), the null hypothesis is rejected.  
Based on recently reported studies of marketed rate-responsive pacemakers the expected 
slope for similar devices, including the Aveir device, is estimated to be approximately 77%, with 
an associated standard deviation of 14%.  It is estimated based on these data that a sample 
size of 8 subjects would be sufficient to demonstrate that the lower and upper 95% confidence 
bounds meet the success criterion, based on a normally distributed random variable.  To ensure 
that a robust cross-section of subjects is evaluated, however, up to 30 subjects will undergo this 
assessment. 
Descriptive Analyses 
Summary statistics will be presented for the descriptive endpoints. Continuous variables will be 
summarized using mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using counts and percentages. Time-to-event variables will be 
analyzed using the Kaplan-Meier method, if applicable. The 95% confidence intervals for each 
type of data will be provided as appropriate. Difference between groups will be summarized using 
descriptive statistics including 95% confidence intervals, if applicable. 
8.3 
Sample Size Calculation 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 64 of 96 
 
  
 
  
 
 276 evaluable subjects will provide 
 
to meet a performance goal of 78% and reject the null hypothesis at a 2.5% one-sided 
significance level. 
 
 300 subjects will be 
enrolled. 
 
Power calculation for the primary effectiveness endpoint #1 at 3 months (RateEP):  
 
 267 evaluable subjects 
 
 will provide 
 to meet a PG of 82.5% and reject the null hypothesis at a 
2.5% one-sided significance level. 
 
 
 
Power calculation for the primary effectiveness endpoint #2 at 3 months (RateAV):  
 
 267 evaluable subjects 
 
 will provide 
 to meet a PG of 83% and reject the null hypothesis at a 
2.5% one-sided significance level. 
 
 
 
Power calculation for the secondary safety endpoint (CFRA):  
 276 evaluable subjects (
 
will provide 
 to meet a PG of 84% and reject the null hypothesis 
at a 2.5% one-sided significance level. 
 
 
The Sponsor performed the sample size and power calculations using PASS 15 (NCSS, LLC). 
8.4 
Planned Interim Analysis 
 
 
 
  
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 65 of 96 
 
8.5 
Timing of Analysis 
 
 
 
 
8.6 
Subgroup Analysis  
Subgroup analyses such as by age and sex will be considered. Details will be described in the 
Statistical Analysis Plan. 
8.7 
Multiplicity  
 
 
. 
 
  
 
 
  
8.8 
Procedures for Accounting for Missing Data  
Every effort will be made to collect all required data. All available safety and effectiveness data 
will be used in the analysis. Sensitivity analysis will be performed to evaluate the potential impact 
of the missing data on the primary safety and effectiveness endpoints. The details of missing data 
handling will be described in the Statistical Analysis Plan.  
8.9 
Deviations from Statistical Plan 
The Sponsor will document any major changes to the statistical plan in an amendment to the 
statistical plan and any less significant changes to the planned analyses in the final report.  
  
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents for performing 
clinical investigation-related monitoring, audits, IRB/EC review and regulatory inspections. 
 
Subjects providing informed consent are agreeing to allow clinical investigation monitors or 
regulatory authorities, including foreign countries, to review in confidence any records identifying 
the subjects in this clinical investigation. This information may be shared with regulatory 
agencies; however, the Sponsor undertakes not to otherwise release the subject's personal and 
private information. 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 66 of 96 
 
 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Selection of Clinical Sites and Investigators 
The Sponsor will select investigators qualified by training and experience to participate in the 
clinical investigation. Sites will be selected based upon review of a recent site assessment, if 
applicable, and the qualifications of the investigators who will participate in the clinical 
investigation.  
10.2 Clinical Investigation Finances and Agreements 
Abbott will finance the clinical investigation and will compensate investigational sites for 
participation in the clinical investigation per the conditions of agreement between Abbott and the 
investigational site. 
10.3 CIP Amendments  
The Sponsor will provide approved CIP amendments to the Investigators prior to implementing 
the amendment. The Principal Investigator is responsible for notifying the IRB/EC or equivalent 
committee of the CIP amendment (administrative changes) or obtaining IRB’s/EC’s approval of 
the CIP amendment (changes in subject care or safety), according to the instructions provided 
by the Sponsor with the CIP amendment.   
 
Sites must document in writing acknowledgement/approval of the CIP amendment by the 
IRB/EC prior to implementation of the CIP amendment. Sites must also provide copies of this 
documentation to the Sponsor. 
10.4 Training 
 Site Training 
All Investigators and clinical investigation personnel are required to attend Sponsor training 
sessions, which may be conducted at an Investigator's meeting, a site initiation visit, or other 
appropriate training sessions. Over-the-phone or self-training may take place as required. 
Training of Investigators and clinical investigation personnel will include, but is not limited to, the 
CIP requirements, investigational device usage, electronic case report form completion, and 
clinical investigation personnel responsibilities. All Investigators and clinical investigation 
personnel that are trained must sign a training log (or an equivalent) upon completion of the 
training. Prior to signing the training log, Investigators and clinical investigation personnel must 
not perform any CIP-related activities that are not considered standard of care at the site.  
 Training Required for the Use of the Device  
The Sponsor will train implanting physicians on the Aveir™ DR LP system prior to their first 
case in accordance with the appropriate training plan(s).  The Sponsor will manage proof of 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 67 of 96 
 
training records as controlled documents in an appropriate archiving system. If updates are 
made to the training plan, physicians will be required to complete the revised training plan prior 
to their next case. 
10.5 Monitoring  
Sponsor and/or designee will monitor the clinical investigation over its duration according to the 
CIP-specific monitoring plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following 
criteria are met:  
 
• 
The investigator understands and accepts the obligation to conduct the clinical 
investigation according to the CIP and applicable regulations and has signed the 
Investigator Agreement.  
• 
The Investigator and his/her staff should have sufficient time and facilities to conduct the 
clinical investigation and should have access to an adequate number of appropriate 
subjects to conduct the clinical investigation.  
• 
Sites must have source documentation (including original medical records) to 
substantiate proper informed consent procedures, adherence to CIP procedures, 
adequate reporting and follow-up of adverse events, accuracy of data collected on case 
report forms, and device information.  
• 
The Investigator/site will permit access to such records and will maintain a monitoring 
visit sign-in log at the site. The Investigator will agree to dedicate an adequate amount of 
time to the monitoring process. The Investigator and/or research coordinator will be 
available for monitoring visits. It is expected that the Investigator will provide the monitor 
with a suitable working environment for review of clinical investigation-related 
documents. 
10.6 Deviations from CIP 
The Investigator should not deviate from the CIP for any reason except in cases of medical 
emergencies when the deviation is necessary to protect the rights, safety, and well-being of the 
subject, or to eliminate an apparent immediate hazard to the subject. In that event, the 
Investigator will notify Sponsor immediately by phone or in writing.  
 
The Sponsor will not grant any waivers for CIP deviations.  Sites must report all deviations to 
the Sponsor using the Deviation CRF. The Sponsor will monitor the occurrence of CIP for 
evaluation of investigator compliance to the CIP and regulatory requirements and handle 
according to written procedures. Investigators will determine the cause on deviations and inform 
their IRB/EC or equivalent committee of all CIP deviations in accordance with their specific 
IRB/EC or equivalent committee reporting policies and procedures.  
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 68 of 96 
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or 
company representative will attempt to secure compliance by one or more of the following (and 
not limited to):  
• 
Visiting the investigator and/or delegate 
• 
Telephoning the investigator and/or delegate 
• 
Corresponding with the investigator and/or delegate 
 
The investigator will be requested to implement corrective actions to address the events of non-
compliance.  Repeated non-compliance with the signed agreement, the CIP, or any other 
conditions of the clinical investigation may result in further escalation in accordance with the 
Sponsor’s written procedures, including securing compliance or, at its sole discretion, the 
Sponsor may terminate the investigator's participation in the clinical investigation.   
10.7 Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical investigation records, 
including source documentation, for inspection during a Quality Assurance audit.  
 
If an investigator is contacted by a Regulatory Agency in relation to this clinical investigation, the 
Investigator will notify the Sponsor immediately. The Investigator and Research Coordinator 
must be available to respond to reasonable requests and audit queries made during the audit 
process. The Investigator must provide the Sponsor with copies of all correspondence that may 
affect the review of the current clinical investigation (e.g., Form FDA 483, Inspectional 
Observations, Warning Letters, Inspection Reports, etc.). The Sponsor may provide any needed 
assistance in responding to regulatory audits. 
10.8 Sponsor Auditing 
Sponsor audits may be conducted for the clinical investigation in accordance with the below 
requirements: 
1. The Sponsor shall prepare an audit plan as well as the operating procedures for the related 
duties and conduct audits in accordance with the audit plan and the operating procedures. 
2. Individuals engaged in auditing (hereinafter referred to as "auditor") shall be different than 
those in charge of medical device development or monitoring. 
3. The auditor shall prepare an audit report documenting the matters confirmed in the audit to 
certify and verify that the audit has been conducted and submit them to the Sponsor. 
10.9 Committees  
 Steering Committee  
The Steering Committee is assigned by the Sponsor and consists of investigators. The Sponsor 
will also be represented on the committee. A core laboratory representative and other sponso 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 69 of 96 
 
personnel may also participate in the Committee meetings if appropriate. Meeting minutes from 
this committee will be filed with the sponsor. 
The Steering Committee is responsible for overseeing the scientific and operational aspects of 
the clinical investigation. This committee will meet regularly to monitor subject enrollment, 
general data collection and non-compliance with the CIP at individual centers, to review and act 
upon recommendations of the Data and Safety Monitoring Board (DSMB), to review operational 
issues that may arise and warrant a CIP amendment or other corrective action, and to 
determine policy regarding any publications arising from data generated from the performance 
of the clinical investigation. 
 Publication Committee 
 
A Publication Committee shall be established to oversee clinical investigations publications, 
including publication planning and authorship determinations. Publication Committee 
membership may include members of the Steering Committee, Principal Investigators, a 
representative of the Sponsor, and a statistician. The Publication Committee will determine 
policy and strategies regarding individual presentations and/or publications arising from clinical 
investigation generated data. The committee will also review all external requests for accessing 
clinical investigation-related data and strategies aligning with the Sponsor’s presentation and 
publication team expectations. The committee will also follow the Sponsor’s applicable policies 
and Standard Operating Procedures. 
 Data and Safety Monitoring Board (DSMB) 
The DSMB is an independent multidisciplinary group restricted to individuals free of apparent 
significant conflicts of interest. The source of these conflicts may be financial, scientific, or 
regulatory in nature. The DSMB is typically composed of at least two physicians with experience 
relevant to the clinical investigation and a biostatistician.   
The DSMB will serve in an advisory role to the Sponsor to ensure safety by reviewing 
cumulative data from the clinical investigation at prescribed intervals for safeguarding the 
interests of enrolled subjects and those patients yet to be enrolled, as well as the continuing 
validity and scientific merit of the clinical investigation. The composition, frequency of the 
meetings, and the statistical monitoring guidelines are described in detail in the DSMB charter. 
 
The DSMB may consider a recommendation for modifications or termination of the clinical 
investigation based on any perceived safety concerns regardless of statistical significance. The 
recommendations of the DSMB are not binding, and all final decisions related to clinical 
investigations modifications rest with the Sponsor.  
 Clinical Events Committee (CEC) 
The CEC is an independent adjudication body comprised of qualified physicians who are not 
participants in the clinical investigation. The CEC will review and adjudicate pre-specified events 
reported by investigators or identified by Safety personnel for the clinical investigation as 
defined in the CEC charter and according to definitions provided in this CIP.   

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 70 of 96 
 
11.0 DATA HANDLING AND RECORD KEEPING 
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in 
data collection for the duration of the clinical investigation.  
 
CRF data collection will be performed through a secure web portal and only authorized 
personnel will access the EDC system using a unique username and password to enter, review 
or correct data. Passwords and electronic signatures will be strictly confidential.   
 
The data will be subjected to consistency and validation checks within the EDC system and 
supplemental review by the Sponsor.    
 
At the end of the clinical investigation, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if 
applicable) will be provided to the investigational sites, if requested.  
 
For the duration of the clinical investigation, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical investigation progress 
records, laboratory reports, CRFs, signed ICFs, device accountability records (if applicable), 
correspondence with the IRB/EC and clinical investigation monitor/Sponsor, adverse event 
reports, and information regarding subject discontinuation or completion of the clinical 
investigation. 
11.1 Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained 
for this clinical investigation.  
 
The Sponsor implements technical and physical access controls to ensure that Personal 
Information is accessible only to and processed only on a ‘need to know’ basis, including 
periodic review of access rights, and revocation of access when an individual’s employment is 
terminated or the individual transitions to a role that does not require access to Personal 
Information, and appropriate restrictions on physical access to premises, facilities, equipment, 
and records containing Personal Information. 
 
The Sponsor requires the investigational sites to enter only pseudonymous Personal 
Information (key-coded) necessary to conduct the clinical investigation, such as the patient’s 
medical condition, treatment, dates of treatment, etc., into Sponsor’s data management 
systems. The Sponsor discloses as part of the clinical investigation informed consent process 
that some Sponsor representatives still may see Personal Information at the participating sites 
for technical support of the participating physicians on the device implant or procedures, 
monitoring and quality control purposes. All parties will observe confidentiality of Personal 
Information always throughout the clinical investigation. All reports and data publications will 
preserve the privacy of each subject and confidentiality of his/her information. 
 
The Sponsor data management systems and processes were designed, developed, and tested 
according to industry standards to appropriately safeguard Confidential Information (including 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 71 of 96 
 
any Personal Information) against unauthorized access and/or interference by third parties, 
intrusion, theft, destruction, loss or alteration. Clinical Investigation data are encrypted in transit 
and at rest.  
 
The Sponsor maintains a Privacy Incident procedure that complies in all respects with 
Applicable Law and industry best practices. 
11.2 Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, 
issuing and resolving data discrepancies, and database locking. If appropriate, the Sponsor may 
update the DMP throughout the duration of the clinical investigation. The Sponsor will track and 
document control all revisions. 
11.3 Source Documentation  
Regulations and GCP require the Investigator to maintain information in the subject’s original 
medical records that corroborates data collected on the CRFs. To comply with these regulatory 
requirements/GCP, sites should include the following information in the subject record at a 
minimum and if applicable to the clinical investigation: 
• 
Medical history/physical condition of the subject before involvement in the clinical 
investigation sufficient to verify CIP entry criteria 
• 
Dated and signed notes on the day of entry into the clinical investigation referencing the 
Sponsor, CIP number, subject ID number, and a statement that informed consent was 
obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and 
exams) 
• 
AEs reported and their resolution, including supporting documents, such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including 
documentation of site awareness of SAEs and of investigator assessment of device 
relationship for SAEs. 
• 
Subject’s condition upon completion of or withdrawal from the clinical investigation 
• 
Any other data required to substantiate data entered into the CRF 
• 
Patient reported outcome measures may be completed using CRF worksheets. This 
serves as source documentation. 
11.4 Case Report Form Completion  
Site research personnel trained on the CIP and CRF completion will perform the primary data 
collection clearly and accurately based on source-documented hospital and/or clinic chart 
reviews. The investigator will ensure accuracy, completeness, legibility, and timeliness of the 
data reported to the Sponsor on the CRFs and in all required reports. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 72 of 96 
 
Sites will collect data on all subjects enrolled into the clinical investigation.   
Only authorized site personnel will be permitted to enter the CRF data through the EDC system 
deployed by the Sponsor.  The Sponsor will use an electronic audit trail to track any subsequent 
changes of the entered data. 
11.5 Record Retention 
The Sponsor and Investigator/Site will archive and retain all documents pertaining to the clinical 
investigation as per the applicable regulatory record retention requirements. The Investigator 
must obtain permission from Sponsor in writing before destroying or transferring control of any 
clinical investigation records. 
11.6 Investigational Devices Accountability 
The Sponsor ships investigational products only to the Principal Investigator (the responsible 
leader of the investigational site) or his/her legal designee of each site, after sites receive 
documentation of site activation and shipping authorization is complete.   
 
The Investigator or an authorized designee must maintain adequate records of the receipt and 
disposition of each investigational device, including part number, batch/lot number, and serial 
number (if applicable), date used, subject identification, and treating physician. 
 
Storage locations for the devices at investigational sites must be locked with access restricted 
only to investigators and authorized personnel.  
 
Sites must return all investigational devices associated with a device failure or device deficiency 
immediately to the Sponsor.  
 
The clinical investigation will use an Inventory (Device) Accountability Log supplied by the 
Sponsor for device accountability. The Inventory Accountability Log must document the 
disposition of all investigational devices including those that have been returned to Sponsor. 
12.0 ETHICAL CONSIDERATION 
12.1 Institutional Review Board/Medical Ethics Committee Review and Approval 
The Principal Investigator at each investigational site will obtain IRB/EC approval for the CIP 
and ICF/other written information provided to the patient prior to consenting and enrolling 
patients in this clinical investigation. The site must receive the approval letter prior to the start of 
this clinical investigation and provide a copy to the Sponsor.  
 
Sites will submit any amendments to the CIP as well as associated ICF changes to the IRB/EC 
and written approval obtained prior to implementation, according to each institution’s IRB/EC 
requirements.  
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 73 of 96 
 
No changes will be made to the CIP or ICF or other written information provided to the patient 
without appropriate approvals, including IRB/EC, the Sponsor, and the regulatory agencies (if 
applicable).  
 
Until the clinical investigation is completed, the Investigator will advise his/her IRB/EC of the 
progress of this clinical investigation, per IRB/EC requirements. Written approval must be 
obtained from the IRB/EC yearly to continue the clinical investigation, or according to each 
institution’s IRB/EC requirements.  
 
Sites will not perform any investigative procedures, other than those defined in this CIP, on the 
enrolled subjects without the written agreement of the IRB/EC and the Sponsor. 
13.0 CLINICAL INVESTIGATION CONCLUSION 
Site closure for enrolling centers will not begin until at least all active subjects have completed 
their 12-month follow up visits or the 12-month visit window has passed and approval for 
commercial use is received from local regulatory agencies. 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical investigation closure. 
 
Upon completion of the study, a final report will be generated and submitted to all sites and all 
IRBs/ECs within one year of the end of the study.  For sites in the United States, the final report 
will be submitted to the FDA and reviewing IRBs within 6 months of study completion per 21 
CFR 812.150. 
14.0 PUBLICATION POLICY 
The data and results from the clinical investigation are the sole property of the Sponsor. The 
Sponsor shall have the right to access and use all data and results generated during the clinical 
investigation. Investigators will not use clinical investigation-related data without the written 
consent of the Sponsor for any purpose other than for clinical investigation completion or for 
generation of publication materials, as referenced in the Clinical Trial Agreement. Single-center 
results are not allowed to be published or presented before the multi-center results. The 
Sponsor must review and approve any proposals for publications or presentations by the 
investigators in a timely manner in compliance with the Sponsor’s publication policy set forth in 
the Clinical Trial Agreement. 
 
Upon receiving IDE approval from the FDA, the Sponsor will be responsible for registering this 
clinical investigation on ClinicalTrials.gov website, in accordance with the International 
Committee of Medical Journal Editors guidelines, or any other applicable guidelines. Sponsor 
shall be responsible for any such registration and results posting as required by the 
ClinicalTrials.gov website. Institution and/or Principal Investigator(s) shall not take any action to 
register the clinical investigation. A full report of the pre-specified outcomes, regardless of the 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 74 of 96 
 
results, will be made public through the ClinicalTrials.gov website no later than 12 months after 
clinical investigation completion, as required by section 801 of the FDA Amendments Act. If this 
clinical investigation is terminated early, the Sponsor will make every effort to hasten the release 
of the pre-specified outcomes through the ClinicalTrials.gov website.  
15.0 RISK ANALYSIS 
15.1 Anticipated Clinical Benefits 
Implantation of the LP for cardiac pacing could offer certain advantages as compared to a 
transvenous pacemaker. Specifically, the benefits that are associated with the use of the LP 
could include: 
• 
Percutaneous procedure with no incision or generator pocket needed; 
• 
Eliminates the need for lead (no risk of lead fracture, lowers risk of infection); 
• 
Eliminates the need for a pocket (no scar and/or evidence of the presence of a 
pacemaker); 
• 
Eliminates the need for connectors (eliminates connector complications); 
• 
Eliminates the visible scar at the pectoral implant site used for transvenous implants; 
• 
May reduce  the need for activity restrictions of the left upper extremity after transvenous 
pacemaker implantation; 
15.2 Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Risks associated with the specified device and procedure, together with their likely incidence, 
are described in the IB.  There may be risks related to the device under investigation that are 
unknown at present.  Likewise, the exact frequency of the risk may be unknown.  A list of 
foreseeable adverse events and anticipated adverse device effects can be found in Appendix 
IV.  
15.3 Residual Risks Associated with the Device Under Investigation, as Identified in 
the Risk Management Report / Risk Analysis Report 
Risk analysis of the Aver DR LP system has been performed in accordance with the Risk 
Analysis Plan, Failure Mode Effect Analysis), and Hazard Analysis to systemically identify 
potential hazards associated with the design and use of this device. Based upon bench testing 
and prior Abbott sponsored clinical study data, all risks have been identified and mitigated as far 
as possible through application of appropriate controls and inspections and determined to be 
within acceptable levels.   
Residual risks are likewise disclosed in the IFU in the form of clear instructions of what actions 
to take or to avoid, to avoid a hazardous situation of harm from occurring (contra-indications, 
warnings, and precautions). The anticipated AEs disclosed in the IFU (and Appendix IV) provide 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 75 of 96 
 
further information to enable the user, and potentially the patient, to make an informed decision 
that weighs the residual risk against the benefit of using the device. 
15.4 Risks Associated with Participation in this Clinical Investigation 
Protocol-required assessments are summarized in Section 6.7. Possible risks and discomforts 
associated with participation in the study will be similar to those associated with any routine 
dual-chamber pacemaker implantation procedure and related follow-up procedures.  
Study-specific assessments that are not considered standard of care include femoral vein 
access instead of subclavian vein access, six-minute walk test and treadmill tests for rate 
response evaluation, in-clinic AV Synchrony assessments, 24-hour Holter monitoring, and EQ-
5D quality of life assessment.  A subject may experience fatigue, shortness of breath, chest pain 
and/or leg cramps during six minute walk and treadmill tests; this is mitigated by performing this 
test under the supervision of a trained professional and in a testing area where medical care is 
immediately available.   
15.5 Steps Taken to Control or Mitigate Risks 
In-depth recommendations, special precautions, and instructions regarding patient selection, 
vessel sizing, device handling, device placement and system removal are included in the 
IFU/IB.   
 
The IFU/IB also states that the devices can only be used by physicians who have received 
appropriate training on how to use the device.  This statement is interpreted to mean that the 
physician users are expected to be aware of the known and foreseeable safety risks associated 
with the use of the devices including the surgical and/or non-surgical treatment of these 
conditions. 
 
Risks associated with the use of the device under investigation are minimized through device 
design, investigator selection and training, pre-specified patient eligibility requirements, study 
monitoring to ensure adherence to the protocol, and the use of a DSMB.   
 
Sites will report all adverse events and device deficiencies to the Sponsor and the Sponsor will 
monitor internally for safety surveillance purposes. 
15.6 Risk to Benefit Rationale 
It is concluded from preclinical data (risk analysis and literature review) that clinical risks are 
comparable to those associated with currently available therapy (transvenous dual-chamber 
pacing).  Uncertainty exists in relation to risks associated with novel features (percutaneous 
delivery via a femoral vein and the possibility dislodgement or migration). These residual risks 
cannot be estimated with confidence without data from a clinical investigation.  Taking into 
account the nature of the possible harm that could arise from these device-related risks and the 
assurance provided by pre-clinical data, the risk-benefit balance associated with the use of the 
LP in a clinical trial is considered to be favorable.   
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 76 of 96 
 
16.0 APPENDICES 
APPENDIX I: ABBREVIATIONS AND ACRONYMS 
Abbreviation 
Definition 
 
Abbreviation 
Definition 
 
 
 
 
 
LP 
Leadless Pacemaker 
 
ICF 
Informed Consent Form 
 
 
 
 
 
DR 
Dual-Chamber 
 
EC 
Ethics Committee 
 
 
 
 
 
CIP 
Clinical Investigational Plan 
 
IFU 
Instructions for Use 
 
 
 
 
 
VR 
Single-Chamber 
(Ventricular) 
 
ICD 
Implantable cardioverter defibrillator 
 
 
 
 
 
i2i 
Implant-to-implant 
 
CRT 
Cardiac resynchronization therapy 
 
 
 
 
 
RA 
Right Atrium 
 
ICE 
Intracardiac Echocardiography 
 
RV 
 
Right Ventricle 
 
 
 
 
 
 
RRT  
Recommended Replacement Time 
ECG 
Electrocardiogram 
 
 
PG 
 
Performance Goal 
 
 
 
 
 
 
EGM 
Electrogram 
 
EDC 
Electronic Data Capture 
 
 
 
 
 
CFR 
Complication Free Rate 
 
CAEP 
Chronotropic Assessment Exercise 
Protocol 
 
 
 
 
 
CEC 
Clinical Events Committee 
 
6MWT 
Six-Minute Walk Test 
 
 
 
 
 
DSMB 
Data Safety Monitoring 
Board 
 
CRF 
Case Report Form 
 
 
 
 
 
SADE 
Serious Adverse Device 
Effect 
 
SAE 
Serious Adverse Event 
 
 
 
 
 
AV 
Atrioventricular 
 
UADE 
Unanticipated Adverse Device 
Effect 
 
 
 
 
 
AMS 
Automatic Mode Switching 
 
LCB  
Lower Confidence Bound 
 
 
 
 
 
IB 
Investigator Brochure 
 
HRS 
Heart Rhythm Society 
 
 
 
 
 
ESC 
European Society of 
Cardiology 
 
AHA 
American Heart Association 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 77 of 96 
 
 
APPENDIX II: DEFINITIONS 
 
Adverse Event:  An adverse event (AE) is any untoward medical occurrence, unintended disease 
or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the medical device under investigation. 
 
As part of ISO14155 Section 3.2, the Adverse Event definition has the following notes: 
 
Note 1: This definition includes events related to the medical device under investigation or the 
comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to medical devices 
under investigation. 
 
Attempted Implant: An implant procedure when the Aveir Introducer Sheath or Aveir dilator is 
inserted through the skin of the access site.  
 
Complication:  A device- or procedure-related serious adverse event, including any adverse event 
that prevents initial implantation. 
 
Cardiac Tamponade:  Confirmed or suspected accumulation of fluid in the pericardial space. 
 
Cardiac Perforation:  An excursion of the LP through the cardiac muscle.  Signs and symptoms of 
a perforation by LP may include radiographic evidence of excursion of the LP into the pericardial 
sac, abnormal echocardiography indicative of a perforation, the accumulation of fluid in the 
pericardium, cardiac tamponade, or subject symptoms such as chest pain and discomfort. 
 
De Novo: Subjects who do not have an implanted pacemaker on the date of consent through the 
date of the Aveir LP implant.  
 
Device deficiency:  Any inadequacy in the identity, quality, durability, reliability, usability, safety or 
performance of an investigational device, including malfunction, use errors or inadequacy in 
information supplied by the manufacturer including labelling. 
 
Device-malfunction:  the failure of a device to meet its performance specifications or otherwise 
perform as intended.  Performance specifications include all claims made in the labeling for the 
device.  The intended performance of a device refers to the intended use for which the device is 
labeled or marketed.  
 
Diaphragmatic/Phrenic Nerve Stimulation:  Electrical activation of the diaphragm muscle by the 
device output pulse.  The abrupt diaphragmatic contraction is noted clinically as hiccups 
associated with each pacing stimulus.  The pacing stimulus may stimulate the diaphragm either 
directly or indirectly via the phrenic nerve. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 78 of 96 
 
Dislodgement:  The LP  separates from the endocardium after the implant procedure has been 
completed. 
 
Elevated Pacing Thresholds (RV):  Pacing thresholds > 2.5 V at 0.4 ms at implant.  Following 
lead maturation at 6-8 weeks, an increase in pacing thresholds of 1.2 V at 0.4 ms or greater 
between visits.  This definition is intended to serve as a guideline and it is understood that 
individual subjects may have unique situations.  
 
Elevated Pacing Thresholds (RA): Atrial pacing thresholds > 4.0 V at 0.4ms on or after the pre-
discharge assessment, or if there is an increase in atrial pacing thresholds of 1.2V at 0.4 ms or 
greater between visits. This definition is intended to serve as a guideline and it is understood that 
individual subjects may have unique situations. 
 
Established i2i Communication: A situation at the end of an implant procedure where non-zero 
i2i throughput in either LP transmission direction (i.e. A2V or V2A) has been demonstrated. If any 
of the following situations occur, i2i communication will NOT be considered established:  
a) Implanter decides to retrieve 1 or 2 LPs and not replace them exclusively due to 
unacceptable i2i communication; OR 
b) Implanter deliberately programs the LPs to a non-dual chamber pacing mode due to 
unacceptable i2i communication; OR 
c) There is zero i2i throughput in both LP transmission directions (i.e. atrial LP to 
ventricular LP AND ventricular LP to atrial LP)   
 
Intermittent or loss of i2i communication: When the subject either (a) has their Aveir DR 
system programmed to a non-dual chamber pacing mode at the end of any pre-discharge or 
follow-up visit solely due to unsatisfactory i2i communication even in the absence of untoward 
clinical signs, or (b) undergoes a system revision intervention due to unsatisfactory i2i 
communication.  
 
Implant procedure duration:  Defined as the time from delivery catheter and LP insertion to 
removal. 
 
Implant success rate:  Defined as the number of de novo subjects leaving the implant procedure 
with both implanted and functioning LP devices, divided by the number of subjects in whom 
implantation is attempted. 
 
Inadequate Fixation:  When an LP separates from the endocardium after being released from the 
Delivery Catheter during the implant procedure. 
 
Loss of Capture:  The inability of the device’s output pulse to result in depolarization and 
contraction of the ventricle. Causes include insufficient stimulus strength, separation of the 
electrode from the myocardium and placement of the stimulating electrode in contact with a non-
responsive portion of the myocardium such as scar tissue. Delivery of an output pulse at a time 
when the myocardium is physiologically refractory is not loss of capture, since capture is not 
physiologically feasible. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 79 of 96 
 
Loss of Sensing:  A condition in which the pulse generator is unable to sense intrinsic cardiac 
signals. 
 
Migration:  The movement of the LP to a different position outside the right ventricle and RVOT 
(for ventricular LP) or right atrium (for atrial LP). 
 
Oversensing:  The detection of inappropriate electrical signals by the pulse generator’s sense 
amplifier.  These signals, such as myopotentials, electromagnetic interference, or T waves must be 
of sufficient duration to interfere with normal device function.  
 
Premature Deployment:  When an LP completely separates from the Delivery Catheter before 
the LP was intended to be released by the implanter during the implant procedure 
 
Procedure duration:  Defined as the time from femoral introducer insertion to removal. 
 
       Serious Adverse Event (SAE):  Any untoward medical occurrence that: 
       a.   Led to death,        
       b.   Led to serious deterioration in the health of the subject, that either resulted in 
1. A life-threatening illness or injury, or 
2. A permanent impairment of a body structure or a body function, or 
3. In-patient or prolonged hospitalization, or 
4. Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, or requires an invasive strategy to 
remedy 
5. Chronic disease 
          c. Led to fetal distress, fetal death or a congenital abnormality or birth defect including physical or  
mental impairment. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
 
Sponsor understands that the following items meet the definition of serious adverse event if they 
require hospitalization or prolong hospitalization, even though an invasive approach may not be 
necessary to resolve: AV fistula, pseudoaneurysm, blood transfusions, tricuspid valve damage, 
pericardial effusion, pulmonary embolus, device dislodgement, right ventricular or right atrial 
perforation, thrombus formation on the device, ventricular arrhythmias even if not associated 
with an invasive strategy to remedy. 
 
Non-invasive means such as device re-programming do not meet the criteria for medical or 
surgical intervention. 
 
Successful Implant: A subject who leaves an attempted de novo implant procedure with functioning 
atrial and ventricular LPs implanted, including established i2i communication 
 
Successful Upgrade: A subject with a pre-existing Aveir ventricular LP who was successfully 
implanted with an Aveir atrial LP, and the Aveir VR LP can be programmed to a dual-chamber mode 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 80 of 96 
 
Time to discharge:  Defined as the time from introducer sheath removal to discharge. 
 
Unanticipated (serious) adverse device effect (UADE/USADE):  Any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the 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)]  
 
Unavoidable adverse event:  An unavoidable AE is defined as an adverse event related to the 
implant procedure that is expected to occur for a projected duration in all subjects. 
 
Undersensing:  The failure of the pulse generator to sense R-waves, causing delivery of 
inappropriately timed, asynchronous or competitive output pulses.  Undersensing can sometimes 
be corrected by programming the device to a more sensitive setting, i.e., decreasing the millivolt 
value. 
 
Unsuccessful Implant: A subject who leaves an attempted de novo implant procedure without a 
functioning atrial or ventricular LP implanted, or where i2i communication was not established. 
 
Unsuccessful Upgrade: A subject with a pre-existing Aveir ventricular LP who leaves an attempted 
upgrade procedure without an Aveir atrial LP or where the Aveir VR LP cannot be programmed into 
dual-chamber mode. 
 
Upgrade success rate:  Defined as the number subjects with pre-existing Aveir ventricular LPs 
leaving the upgrade procedure with an Aveir atrial LP and can be programmed in a dual-chamber 
mode, divided by the number of subjects in whom an upgrade is attempted. 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 81 of 96 
 
APPENDIX III: SITE CONTACT INFORMATION 
Contact information for each participating clinical site is available under separate cover by contacting 
the Sponsor at: 
 
Clinical Studies Department 
Abbott Medical  
15900 Valley View Court 
Sylmar, CA  91342 
TEL: +1 (818) 493-3297 
FAX: +1 (800) 254-6411 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 82 of 96 
 
APPENDIX IV: FORESEEABLE ADVERSE EVENTS AND  
ANTICIPATED ADVERSE DEVICE EFFECTS 
Access site bleeding event* 
Interruption of desired LP function due to 
electrical interference, either electromyogenic 
or electromagnetic  
Air embolism 
Ischemic Stroke 
Ateriovenous fistula  
Loss of normal device function due to 
component malfunction  
Cardiac arrhythmias 
Nausea 
Cardiac perforation  
Oversensing  
Cardiac tamponade  
Pacemaker syndrome 
Death  
Palpitations 
Device dislodgement  
Pericardial effusion or rub 
Dizziness  
Pericarditis 
Dyspnea  
Peripheral nerve damage 
Embolization of foreign material 
Phrenic nerve/diaphragmatic/extra-cardiac 
stimulation 
Embolism 
Pneumothorax/Hemothorax 
Endocarditis  
Premature battery depletion 
Excessive bleeding  
Premature deployment with LP migration 
Exit block  
Premature deployment without LP migration 
Failure to capture/loss of capture  
Programmer/software anomaly  
General surgery risks and 
complications from comorbidities 
such as hypotension, 
hypertension, groin pain, 
respiratory failure, pneumonia, 
cardiac failure, reaction to 
sedation, renal failure/kidney 
injury, anemia, and death 
Pseudoaneurysm formation  
Heart Failure 
Pulmonary embolism 
Helix Distortion 
Reaction/Toxic Effect due to contrast media 
Hematoma formation, including 
retroperitoneal 
hematoma/hemorrhage  
RV pacing induced cardiomyopathy 
High impedance 
Syncope  
Hypersensitivity reaction to 
device materials or substances 
Threshold elevation 
Inability to disengage snare from 
docking button  
Thromboembolism 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 83 of 96 
 
Inability to interrogate or 
program due to programmer or 
LP malfunction  
Thrombosis 
Inadequate Fixation during 
implant with LP migration 
Transient ischemic attack  
Inadequate Fixation during 
implant without LP migration 
Tricuspid valve damage and/or regurgitation 
Inappropriate rate sensor 
response 
Undersensing 
Infection, local at access site, or 
systemic 
Vascular dissection  
Intermittent capture 
Vascular perforation 
Intermittent or loss of i2i 
communication 
Vascular puncture 
Intermittent or loss of sensing 
Venous occlusion 
                *Access site bleeding event is defined in section 6.5.1 
 
A right atriogram and ventriculogram carries risk, most notably, allergic reaction to contrast 
media. 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 84 of 96 
 
APPENDIX V: SIX-MINUTE WALK AND GRADED EXERCISE TEST (CAEP PROTOCOL) 
The Aveir atrial LP senses right-atrial blood temperature to provide an increase in pacing rate with 
increased metabolic demand. The Aveir atrial LP employs algorithms with rate response parameters 
customized for each patient.   
 
The sensor gain can also be programmed to different settings to adjust the responsiveness of the rate 
response algorithm and can be optimized for each patient.  The programmer has an optimization tool 
and provides a graphic view of the effects of revised sensor parameter settings on the device’s rate 
response to the patient’s exercise during a programming session. 
 
The temperature-based rate response feature in the Aveir atiral LP will be assessed in Aveir DR i2i 
Study to support the secondary effectiveness endpoint by evaluating whether an appropriate and 
proportional rate response of the atrial LP in de novo subjects can be achieved during a graded 
exercise test. 
 
It is estimated that a minimum sample size of 8 subjects would be sufficient to evaluate this feature. To 
ensure that a robust cross-section of subjects is evaluated, however, up to 30 subjects are targeted to 
undergo this assessment. 
  
Rate Response Protocols 
 
Six Minute Walk Test (6MWT) 
 
All capable subjects at participating centers will be asked to perform a six-minute walk test (6MWT) 
simulating daily walking activity to identify the appropriate sensor parameters for each subject prior to 
conducting the graded exercise protocol. The rate response feature should be programmed in AAIR ON 
or passive mode. Subjects who have an intolerance of high-sensor driven rates are contraindicated for 
rate-responsive pacing and should not be selected in this assessment. After completion of the 6MWT, 
the appropriate sensor parameters are to be programmed into the Aveir device and used for the 
subsequent exercise protocol. The 6MWT may be performed any time after the beginning of the 1-
month visit window through the end of the 3-month visit window.   
 
Chronotropic Assessment Exercise Protocol (CAEP)  
 
All capable subjects who completed the 6MWT will be asked to perform the following maximal effort 
chronotropic assessment exercise protocol (CAEP) to demonstrate an appropriate and proportional 
response of sensor-indicated rate in graded exercise tests. Subjects who have an intolerance of high-
sensor driven rates are contraindicated for rate-responsive pacing and should not be selected for this 
assessment. The CAEP is designed specifically for chronotropic assessment and is structured to collect 
heart rate data at submaximal and peak exercise intensities. This protocol has been applied to support 
mathematical models to describe the normal cardiac chronotropic response to exercise.i  
 
The CAEP protocol must be performed after completion of the 6MWT protocol and at any time after the 
beginning of the 3-month visit window through the end of the 6-month visit window.  If the 6MWT 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
Template: 86357 Rev. J 
Page 85 of 96
protocol is conducted the same day as the CAEP protocol, subjects are to wait at least 1 hour after the 
6MWT protocol has been completed before starting the CAEP protocol.  
The CAEP protocol must be administered on a treadmill that could be programmed to the speed and 
grade/incline settings for each stage of the protocol shown below. 
Prior to administration, the Aveir LP rate response settings should be programmed with the same 
optimized sensor gain that was derived from the 6MWT. However, the physician has discretion to alter 
these parameters if medically appropriate.  The CAEP protocol should be administered the with rate-
response feature in AAIR ON mode. After a short period of rest, subjects will begin exercise on the 
treadmill at stage 0 and only progress to the next stage after 2 minutes of exercise. Subjects should be 
instructed to exercise as long as possible until maximal effort is achieved. Subjects should be instructed 
to stop if they feel dizzy, chest pain, shortness of breath, fatigue, etc. or any other symptoms. 
Additionally, at least 5 minutes of rest should be recorded after the patient has ended exercise.  
The Chronotropic Assessment Exercise Protocol (CAEP) 
Stage 
Speed 
(MPH) 
Speed 
(KPH) 
Grade 
(%) 
Time 
(min) 
Cumulative time 
METs 
0 
1.0 
1.6 
0 
2 
2 
1.5 
1 
1.0 
1.6 
2 
2 
4 
2.0 
2 
1.5 
2.4 
3 
2 
6 
2.8 
3 
2.0 
3.2 
4 
2 
8 
3.6 
4 
2.5 
4.0 
5 
2 
10 
4.6 
5 
3.0 
4.8 
6 
2 
12 
5.8 
6 
3.5 
5.6 
8 
2 
14 
7.5 
7 
4.0 
6.4 
10 
2 
16 
9.6 
8 
5.0 
8.0 
10 
2 
18 
12.1 
9 
6.0 
9.7 
10 
2 
20 
14.3 
10 
7.0 
11.3 
10 
2 
22 
16.5 
11 
7.0 
11.3 
15 
2 
24 
19.0 
i Wilkoff, B. L., Corey J., "A Mathematical Model of the Cardiac Chronotropic Response to Exercise", 
Journal of Electrophysiology, 3(3) June 1989, pages 176-180 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 86 of 96 
 
APPENDIX VI: LABELS 
Sponsor will provide all implants and accessories with labels stating, “CAUTION—Exclusively for 
Clinical Investigation.”  Sponsor will also provide implants and accessories for use in other countries 
with appropriate country-specific labeling. 
 
Sponsor will provide all implants and catheters as sterile units, and the packaging lists the method of 
sterilization, manufacturing date, manufacturer name and address, use before date, that devices are 
single use only, model number, and lot or serial number. 
 
The programmer and accessories’ labels contain the company name, location and phone number, 
model number, and lot or serial number.   
 
Software versions are displayed on the programmer screen and in printed or saved reports. Validated 
changes to implant and programmer software are allowed during the study, when necessary, to correct 
an observed nonconformance with intended device operation. 
 
Leadless implants, catheters and programmers will be stored in a clean, dry, secure location at room 
temperature prior to shipment to the clinical site. 
 
Copies of all current labeling and Instructions for Use documents for investigational devices listed in 
Section 2.2.3 will be provided under separate cover to FDA as part of the IDE submission and to clinical 
sites included with other study documentation/information or as part of the Investigator Brochure. 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 87 of 96 
 
APPENDIX VII: CASE REPORT FORMS 
Final draft case report forms (CRFs) will be provided to FDA under Separate Cover as part of the IDE 
Submission. 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 88 of 96 
 
APPENDIX VIII: INFORMED CONSENT FORM 
 
A template informed consent form will be provided under a separate cover. 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 89 of 96 
 
APPENDIX IX: MONITORING PLAN 
A copy of the Monitoring Plan can be obtained upon request from the Sponsor Clinical Project Manager 
for the clinical investigation. 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 92 of 96 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 93 of 96 
 
APPENDIX XI: CIP SUMMARY 
Clinical 
Investigation 
Name and 
Number 
Aveir DR i2i Study 
 
Title 
Aveir Dual-Chamber Leadless i2i IDE Study 
Objective(s) 
The purpose of this clinical investigation is to evaluate the clinical safety and 
effectiveness of the Aveir DR LP system in a patient population indicated for 
DDD(R) pacing to support regulatory pre-market submissions for both DDD(R) 
and AAI(R) pacing indications in various geographies.   
Device Under 
Investigation 
Aveir DR Leadless Pacemaker system 
Number of 
Subjects Required 
for Inclusion in 
Clinical 
Investigation 
Up to 550 subjects from up to 85 sites worldwide (United States, Canada, 
Europe, Asia-Pacific) 
Clinical 
Investigation 
Design 
This is a prospective, multi-center, international, single-arm, pivotal 
investigational study    
Primary 
Endpoint(s) 
Primary Safety Endpoint: 
The primary safety endpoint evaluates the 3-month Aveir DR LP system 
Complication Free Rate (CFR) in de novo subjects based on CEC adjudication 
of adverse events. 
 
Primary Effectiveness Endpoint#1: 
The primary effectiveness endpoint #1 evaluates the 3-month composite 
success rate of acceptable atrial pacing thresholds and P-wave amplitudes in 
de novo subjects.   
 
Primary Effectiveness Endpoint#2: 
The primary effectiveness endpoint #2 evaluates the 3-month AV-synchrony 
success rate at rest while seated in de novo subjects.   
Major (Powered) 
Secondary 
Endpoints  
Secondary Safety Endpoint: 
The secondary safety endpoint evaluates the Aveir Atrial LP complication free 
rate (CFR) at 3-months post-implant in de novo subjects based on CEC 
adjudication of adverse events. 
 
Subject Follow-up 
• 
Baseline, Implant, Pre-discharge, 1-month, 3-month, 6-month, 12-month, and 
every 6 months thereafter 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 94 of 96 
 
Inclusion Criteria 
1.  Subject must have at least one of the clinical indications before device 
implant in adherence with ACC/AHA/HRS/ESC dual chamber pacing 
guidelines 
2.  Subject is ≥ 18 years of age or age of legal consent, whichever age is 
greater 
3.  Subject has a life expectancy of at least 1 year 
4.  Subject is willing to comply with clinical investigation procedures and agrees 
to return to clinic for all required follow-up visits, tests, and exams 
5.  Subject has been informed of the nature of the clinical investigation, agrees 
to its provisions and has provided a signed written informed consent, 
approved by the IRB/EC 
Exclusion Criteria 
1. Subject is currently participating in another clinical investigation that may 
confound the results of this study as determined by the Sponsor 
2. Subject is pregnant or nursing and those who plan pregnancy during the 
clinical investigation follow-up period 
3. Subject has presence of anatomic or comorbid conditions, or other medical, 
social, or psychological conditions that, in the investigator’s opinion, could 
confound the assessment of the investigational device and/or implant 
procedure limit the subject’s ability to participate in the clinical investigation 
or to comply with follow-up requirements of the clinical investigation results 
4. Subject is a known allergy or hypersensitivity to < 1 mg of dexamethasone 
sodium phosphate or any blood or tissue contacting material listed in the IFU 
5. Subject has an implanted vena cava filter or mechanical tricuspid valve 
prosthesis 
6. Subject has  pre-existing, permanent endocardial pacing or defibrillation 
leads (does not include lead fragments) 
7. Subject has current implantation of either conventional or subcutaneous 
implantable   cardioverter defibrillator (ICD) or cardiac resynchronization 
therapy (CRT) device 
8. Subject has an implanted leadless cardiac pacemaker (except for an Aveir 
ventricular LP) 
9. Subject is implanted with an electrically-active implantable medical device 
with stimulation capabilities (such as neurological or cardiac stimulators) * 
10. Subject is unable to read or write 
 
**NOTE: Does not apply to a medical device with no known impact to the Aveir 
Leadless Pacemaker System, including the Aveir Link Module. Patient evaluation and 
the decision to implant the LP should take into account the presence of other active 
implantable devices and should include consultation with the Sponsor and/or 
manufacturer of the co-existing device.  
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 95 of 96 
 
17.0 REFERENCES 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

 
Study Name: Aveir DR i2i Study 
Clinical Investigation Plan 
 
 
 
 
Template: 86357 Rev. J 
 
Page 96 of 96