Optimizing Pacing Therapy by Using Multi-Programmable Pulse Generators for Cardiac Resynchronization Pacing (CRT-P)
Conditions: Post Market Surveillance Study Following Clinical Routine
Sponsor: Boston Scientific Corporation

Study Reference: Rally-CRT-P 
 
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Optimizing Pacing Therapy by Using Multi-Programmable Pulse 
Generators for Cardiac Resynchronization Pacing (CRT-P) 
RALLY-CRT-P 
 
CLINICAL INVESTIGATION PLAN 
 
Study Reference: Rally-CRT-P-02-2015 
Version and Date: Version AB, 17th November 2015 
Sponsored By 
Boston Scientific, CRM 
4100 Hamline Avenue North 
St. Paul, MN 55112 
 
and 
 
Guidant Europe SA / NV 
a Boston Scientific Company 
CRM Clinical 
Green Square 
Lambroekstraat 5D  
1831 Diegem  
Belgium 
 
 
 
 
 
 
This Clinical Investigation Plan contains confidential information for use by the 
Investigators and their designated representatives participating in this clinical 
investigation. It should be held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
 
 
 

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Revision History 
Revision Number 
Release Date 
Section 
Change 
Reason for Change 
AA 
16-Mar-2015 
NA 
Initial release 
NA 
AB 
17-Nov-2015 
Table 11-1 
- Documentation 
of clinical 
assessment at 1 
month follow-up 
as described in 
section 11.7 
- Wording 
clarification POST 
Function/daily 
measurements 
Correction of editorial 
mistake and 
clarification 
Section 11.4 
Documentation of 
chronic atrial 
fibrillation, 
asthma, COPD 
and LVEF 
Clarification 
Section 10.4, 
11.5, 11.6 and 
11.7 
Abbreviation/ 
wording 
clarification/typo 
Correction of editorial 
mistake 
Table 11-7 
- Age ranges 
- Programmed 
value for 
AMPHR*80% 
Clarification 
Section 11.8 
Wording 
clarification POST 
Function/daily 
measurements 
Clarification 
Section 11.9 
Patients reaching 
16 months follow-
up 
Clarification 
Table 11-8 
1 month follow-up 
source 
documentation 
requirements 
Correction of editorial 
mistake 
Section 13.1 
Data collection -
Echographic 
imaging 
Correction of editorial 
mistake 
 

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Contact Information 
Role 
Contact  
Clinical Contact 
Dr. Torsten Kayser 
Senior Fellow Clinical, Rhythm Management 
Guidant Europe SA / NV, a Boston Scientific Company 
Green Square; Lambroekstraat 5D  
1831 Diegem, Belgium 
Reception +32 2 41 (67216) 
Torsten.kayser@bsci.com 
 
Technical Service Contact Information 
Intltechservice@bsci.com 
+3224167222 
 
 
Clinical Investigation Plan (CIP) development and review: 
• Torsten Kayser, Dr.; Sen Fellow (Boston Scientific; 
Diegem, Belgium) 
• Caroline Beaudoint, Clinical Trial Manager (Boston 
Scientific; Diegem, Belgium) 
• Janet Ramp-Green, Director Medical Writing (ICON; 
Allschwil, Switzerland) 
• Carole Schuhler; Senior Statistician (ICON; Allschwil, 
Switzerland) 
• Marion Neusser, Project Manager (ICON; Vienna, 
Austria)  
• Colleen Delaney, Senior Statistician CRM; Boston 
Scientific; St Paul, MN, USA) 
• Arjun D. Sharma, MD,FACC,FRCPC; VP Medical 
Safety (Boston Scientific CRM; St. Paul, MN, USA)  
 
Coordinating 
Principal 
Investigator 
Sami Pakarinen, MD, PhD 
Helsinki University Central Hospital 
HUCH Heart and Lung Center, Haartmaninkatu 4,  
PO Box 340, FI-00029 Hus, Finland 
Sami.Pakarinen@hus.fi 
Coordinating 
Co-Principal 
Investigator 
Dr. med. Corinna Lenz  
Unfallkrankenhaus Berlin, Klinik für Innere Medizin 
Warener Str. 7 
12683 Berlin; Germany 
Corinna.Lenz@ukb.de  
Investigational Sites 
A list of investigational sites will be maintained and is available 
upon request.  
 

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2. Clinical Investigation Plan Synopsis 
Rally-CRT-P 
Study Objective 
The objective of this Post Market Clinical Follow-up (PMCF) is to collect data 
on the performance of the Ingenio 2 CRT-P devices and to document that 
device-related events, device malfunctions or device deficiencies (DDs) do not 
increase safety risks in Ingenio 2 CRT-P devices (CRT-Ps), both in general and 
specific to the new features and hardware of the devices. 
Device 
 
Indications for 
Use  
Boston Scientific (BSC) Ingenio 2 CRT-Ps (VISIONIST, VISIONIST X4,) are 
clinically indicated for subjects who have symptomatic congestive heart failure 
(CHF) including left ventricular (LV) dysfunction and wide QRS; and/or one or 
more of the following conditions: 
• 
symptomatic paroxysmal or permanent second- or third-degree 
atrioventricular (AV) block 
• 
symptomatic bilateral bundle branch block 
• 
symptomatic paroxysmal or transient sinus node dysfunction with or 
without associated AV conduction disorders (i.e., sinus bradycardia, 
sinus arrest, sinoatrial [SA] block) 
• 
bradycardia-tachycardia syndrome, to prevent symptomatic bradycardia 
or some forms of symptomatic tachyarrhythmias 
• 
neurovascular (vaso-vagal) syndromes or hypersensitive carotid sinus 
syndromes. 
Atrial tracking modes are also indicated for subjects who may benefit from 
maintenance of AV synchrony. Dual-chamber modes are specifically indicated 
for treatment of the following: 
• 
conduction disorders that require restoration of AV synchrony, 
including varying degrees of AV block 
• 
VVI (ventricular single chamber mode) intolerance (i.e., pacemaker 
syndrome) in the presence of persistent sinus rhythm 
• 
low cardiac output or CHF secondary to bradycardia. 
Adaptive-rate pacing is indicated for subjects exhibiting chronotropic 
incompetence and who would benefit from increased pacing rates concurrent 
with increases in minute ventilation (MV) and/or physical activity. 

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Rally-CRT-P 
Device 
Description 
The three Ingenio 2 CRT-P models to be used in this study have similar 
architectural platforms, closely related device features and a very similar 
clinical use association compared to the previously approved and marketed 
BSC implantable devices, Ingenio. Some enhancements have been 
incorporated into Ingenio 2 models, primarily at a component and engineering 
level rather than at a clinical level. No changes from the previous devices have 
been made to clinical indications, intended use or target subject population.  
Component 
Model Number 
Connector Type 
VISIONIST 
U225 
IS1 
VISIONIST 
U226 
IS1/ LV1 
VISIONIST X4 
U228 
IS1/ IS4 
Device 
Specifications 
• External case which functions as an electrode and consists of two 
0.012-inch thick hermetically sealed, perimeter-welded, Grade 1 
titanium case halves, backfilled with dry nitrogen / helium 
• Internal electronic circuitry and SL or EL battery (encapsulated in the 
external case) 
• Overmolded header, consisting of urethane plastic skeletal core 
structure 
• Titanium weld ring 
New Hardware 
Components 
• 
Filtered feedthru 
• 
IS1 coil spring design 
• 
Front liner 
• 
Lead port identifiers 
Study Design 
Study  
Prospective, non-randomized, multi-center, single group, post market clinical 
study 
Number of Study 
Subjects  
62 eligible subjects 
Planned Number 
of Centers / 
Countries 
10-15 investigational centers, including but not limited to: Belgium, Denmark, 
Finland, Germany, Netherlands, Spain. If a site does not enroll a subject within 
a 3-month time period, the site may be replaced at the discretion of the sponsor.  

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Rally-CRT-P 
Endpoints and Objectives 
Primary Safety 
Endpoint 
• 
Evaluate and document device-related complications by assessing the 
device-related complication free rate (DRCFR), for study subjects, at 
the 3 months post-implant 
Primary 
Effectiveness 
Endpoint 
• 
LV pacing threshold measurements performed at 0.5 ms pulse width at 
3 months post-implant. The pacing configuration that the physician 
selects for permanent programming will be compared to prospectively 
determined limits. 
Secondary Safety 
Objectives 
• 
Assessment of proper function of the PaceSafe-left ventricular 
automatic threshold (LVAT) feature with special attention to:  
o inappropriate loss of capture due to LVAT (not related to lead 
dislodgement, connection issue, etc.) and  
o devices which show retry into LVAT followed by Latitude alert  
• 
Assessment of reported events in relation to the use of the Medical 
Implant Communication Service (MICS) during all visits 
• 
Assessment of all reported events in relation to the Quad Lead and 
Header 
Secondary 
Effectiveness 
Objectives 
• 
Collection of user experience with the programmer (PRM) interface 
through the Product Experience Reporting at implant and during follow-
up 
• 
Assessment of LV pacing at implant and follow up (pacing threshold 
per vector, impedance per vector, % pacing) 
• 
Assessment of battery voltage at Latitude based Close-out  
• 
Assessment of Post-Operative System Test (POST): number of out of 
range impedance alerts not related to mitigating factor (header 
connection issue, lead failure, lead dislodgement, etc.) 
• 
Assess the correlation between 6 minute walking test distance at 
1 month and 3 months post-implant and for subjects with heart rate 
score (HRS) < 50 and ≥ 50 
• 
The HRS changes between 1 month follow-up and 3 month follow-up 
will be analyzed for all subjects, for subjects with HRS < 50 and ≥ 50, 
and for subjects in a non-rate adaptive mode and with rate adaptive 
pacing: 
 
All event data may be combined with data from Ingenio 2 devices enrolled into 
the Gentle study. 
Methodologies 
Method of 
Assigning 
Subjects to 
Treatment 
The devices are fully commercially available and all subjects are planned to 
receive a CRT-P implant as part of their standard of care (SOC). The 
assignment of the specific Ingenio 2 device is physician’s choice and will 
consider leads currently in place from previous devices and planned new leads 
(e.g., Acuity X4 and/or other LV leads).   

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Rally-CRT-P 
Enrollment and 
Follow-up 
Schedule 
Clinic visits will occur at: 
• 
Enrollment and Consenting Clinic Visit (≤ 30 days prior to implant 
procedure) (required) 
• 
Implant Procedure (Day 0; all future follow ups based on this date) 
(required) 
• 
Pre-Discharge Clinic Visit (after pocket closure and wound coverage 
0-5 days post-implant procedure) (required) 
• 
1 month post-implant Clinic Visit (30 ± 15 days) (required) 
• 
3 month post-implant Clinic Visit (91 ± 21 days) (required) 
• 
Latitude-based Close-out (91 - 120 days months post last enrollment) 
(reporting only required) 
• 
Unscheduled clinic follow-up (any clinic visit between pre-discharge 
and 3 month follow up which is in addition to the 1 month follow up; 
per center SOC or subject needs; event reporting only) 
• 
Re-implant/Revision (as needed)  
• 
During the trial unanticipated serious adverse device effects (USADEs), 
serious adverse device effects (SADEs), adverse device effects (ADEs), 
DDs, all serious adverse events (SAEs), deaths, and changes in the 
device system must be reported (enrollment to Closeout). 
Study Duration 
Enrollment is expected to take 12 months. The study will be considered 
complete (primary endpoint completion) after all subjects have completed the 
Latitude based close-out 3-4 months after the last study enrollment. All study 
required visits will be completed as part of regularly scheduled clinic visits. 
Study completion is anticipated in 2016. 
Required 
Medication 
Therapy 
Subjects will receive all medication per SOC according to the center.  
Inclusion Criteria 
1. 
18 years or above, or above legal age to give informed consent specific 
to state and national law 
2. 
Willing and capable of providing informed consent  
3. 
Planned to be implanted or replaced with a VISIONIST Ingenio 2 
CRT-P device  
4. 
Planned to be implanted with a 3-lead CRT-P system 
5. 
Planned to be connected to the remote data collection through the 
Latitude® system 
6. 
Able to do a 6 minute walk test 
7. 
Maximum sensor rate of age predicted maximal heart rate (APMHR) 
80% should be clinically acceptable 
8. 
Willing and capable of participating in all visits associated with this 
study at an approved clinical study center and at the intervals defined 

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Rally-CRT-P 
by this CIP   
Exclusion Criteria 
1. 
Documented life expectancy of less than 12 months  
2. 
Currently on the active heart transplant list 
3. 
Enrolled in any other concurrent study without prior written approval 
from BSC, with the exception of local mandatory governmental 
registries and observational studies/registries that are not in conflict 
and do not affect the following:  
o Schedule of procedures for the Rally CRT-P Study (i.e., should 
not cause additional or missed visits) 
o Rally CRT-P Study outcomes (i.e., involve medications that 
could affect the heart rate of the subject) 
o Conduct of the Rally CRT-P Study per Good Clinical Practice 
(GCP)/ International Standard Organization (ISO) 14155:2011/ 
local regulations as applicable  
4. 
In chronic atrial fibrillation 
5. 
APMHR needs to be programmed < 80%. 
6. 
Not planned to receive a functional atrial lead 
7. 
Per the implanting physician’s discretion, subject is not a suitable 
candidate to receive the study device as determined during the implant 
procedure  
8. 
Women of childbearing potential who are or might be pregnant at the 
time of study enrollment  
9. 
Unwilling or unable to participate in all scheduled study follow up 
visits at an approved study center 
10. Does not anticipate being a resident of the area for the scheduled 
duration of the trial. 
Multiple 
Interventions 
During Index 
Procedure 
Subjects are allowed to receive any intervention during the index procedure 
according to the SOC of the center. Any additional interventions will be 
documented.   
Statistical Methods  
Primary Statistical 
Hypothesis 
DRCFR from implant through 3 months post-implant is greater than the pre-
specified performance goal of 87.5% 
Ho: πDRCFR ≤ 87.5% 
HA: πDRCFR > 87.5% 
Mean LV pacing threshold at 3 months post-implant is less than the pre-
specified performance goal of 2.5V 
Ho: mean LV pacing threshold ≥ 2.5V 
HA: mean LV pacing threshold < 2.5V 

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Rally-CRT-P 
Statistical Test 
Method 
Sample Size Methodology: 
• 
Sample size for the primary safety endpoint was calculated using exact 
binomial methods for comparison of a single proportion to a 
performance goal. 
• 
Sample size for the primary effectiveness endpoint was calculated using 
one-sample t-test methodology for comparison of a single mean to a 
performance goal. 
 
Analysis Methods: 
• 
The DRCFR from implant will be calculated as the proportion of 
actively enrolled subjects without a device-related complication through 
3 months after implant. The null hypothesis will be rejected and the 
endpoint considered met if the lower one-sided 95% confidence bound 
for the proportion of subjects with no device-related complication is 
greater than 87.5%. 
• 
Regarding mean LV pacing threshold at 3 months post-implant, the null 
hypothesis will be rejected and this endpoint considered met if the 
upper one-sided 95% confidence bound for the mean LV pacing 
threshold at 3-months is less than 2.5V. 
 
Further details on analytical methods can be found in Section 12.0 of the CIP. 
Sample Size 
Parameters 
DRCFR through 3 months post-implant: 62 subjects. Sample size was 
calculated assuming a 97.5% DRCFR, a performance goal of 87.5%, one-sided 
alpha level of 0.05, 80% power, and 20% attrition. 
Mean LV pacing threshold at 3 months post-implant: 45 subjects. Sample size 
was calculated assuming a mean (± standard deviation [SD]) LV pacing 
threshold of 1.9 ± 1.2V, a performance goal of 2.5V, one-sided alpha level of 
0.05, 90% power, and 20% attrition. 
Based on the above sample size calculations, the minimum required sample size 
to statistically power the primary endpoints is 62 subjects. 

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3. Table of Contents 
1. 
TITLE PAGE  ............................................................................................................ 1 
2. 
CLINICAL INVESTIGATION PLAN SYNOPSIS ........................................................... 4 
3. 
TABLE OF CONTENTS ............................................................................................ 10 
3.1. Table of Figures .......................................................................................... 13 
3.2. Table of Tables ........................................................................................... 14 
4. 
INTRODUCTION ..................................................................................................... 15 
5. 
DEVICE DESCRIPTION ........................................................................................... 18 
5.1. Ingenio 2 Cardiac Resynchronization Therapy Pacemakers ................. 18 
5.1.1. 
PaceSafe ......................................................................................... 21 
5.1.2. 
Post-Operative System Test ........................................................... 21 
5.1.3. 
Atrial Arrhythmia Reports ............................................................. 22 
5.1.4. 
ECG/EGM Snapshots .................................................................... 22 
5.1.5. 
Leads .............................................................................................. 22 
5.1.6. 
ZIP Telemetry ................................................................................ 22 
5.1.7. 
Programming System..................................................................... 22 
5.2. Ingenio 2 CRT-P Indications for Use ....................................................... 23 
5.3. Ingenio 2 CRT-P Contraindications ......................................................... 24 
6. 
STUDY OBJECTIVE ................................................................................................ 24 
7. 
ENDPOINTS ............................................................................................................ 24 
7.1. Primary Safety Endpoint ........................................................................... 24 
7.2. Primary Effectiveness Endpoint ............................................................... 24 
7.3. Secondary Safety Objectives ..................................................................... 25 
7.4. Secondary Effectiveness Objectives ......................................................... 25 
8. 
DESIGN .................................................................................................................. 25 
8.1. Scale and Duration ..................................................................................... 25 
8.2. Treatment Assignment............................................................................... 26 
8.3. Justification for the Study Design ............................................................. 26 
9. 
SUBJECT SELECTION ............................................................................................. 26 
9.1. Study Population and Eligibility ............................................................... 26 

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9.2. Inclusion Criteria ....................................................................................... 27 
9.3. Exclusion Criteria ...................................................................................... 27 
10. SUBJECT ACCOUNTABILITY .................................................................................. 28 
10.1. Point of Enrollment .................................................................................... 28 
10.2. Withdrawal ................................................................................................. 28 
10.3. Subject Status and Classification .............................................................. 29 
10.4. Enrollment Controls .................................................................................. 29 
11. STUDY METHODS .................................................................................................. 30 
11.1. Data Collection ........................................................................................... 30 
11.2. Study Candidate Screening ....................................................................... 33 
11.3. Informed Consent ...................................................................................... 33 
11.4. Enrollment Visit (≤ 30 days prior to implant procedure; required) ..... 33 
11.5. Implant Procedure (Day 0; required); Re-implant/Revision Procedures 
(as needed) .................................................................................................. 34 
11.6. Pre-discharge Clinic Visit (0-5 days post-implant procedure; required)37 
11.7. 1 Month Clinic Visit (30 ± 15 days post-implant procedure; required) 41 
11.8. 3 Month Clinic Visit (91 ± 21 days post-implant procedure; required) 44 
11.9. Latitude based Close-out (91-121 days after the study is closed for 
enrollment; required)................................................................................. 45 
11.10. 
Unscheduled or Interim Visits outside of Study Visit Windows46 
11.11. 
Source Documents ....................................................................... 46 
12. STATISTICAL CONSIDERATIONS ........................................................................... 47 
12.1. Primary Safety and Effectiveness Endpoints .......................................... 47 
12.1.1. Primary Safety Endpoint ................................................................ 47 
12.1.2. Primary Effectiveness Endpoint .................................................... 48 
12.2. Secondary Safety and Effectiveness Objectives ...................................... 49 
12.3. Sample Size ................................................................................................. 50 
12.4. General Statistical Methods ...................................................................... 51 
12.4.1. Analysis Sets .................................................................................. 51 
12.4.2. Descriptive Statistical Methods ..................................................... 51 
12.4.3. Number of Subjects per Investigative Site .................................... 51 
12.5. Data Analyses ............................................................................................. 51 
12.5.1. Interim Analyses ............................................................................ 51 

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12.5.2. Subgroup Analyses ........................................................................ 51 
12.5.3. Other Analyses ............................................................................... 51 
12.5.4. Changes to Planned Analyses ........................................................ 52 
13. DATA MANAGEMENT ............................................................................................ 52 
13.1. Data Collection, Processing, and Review ................................................. 52 
13.2. Data Retention ............................................................................................ 52 
13.3. Core Laboratories ...................................................................................... 53 
14. AMENDMENTS ....................................................................................................... 53 
15. DEVIATIONS .......................................................................................................... 53 
16. COMPLIANCE ......................................................................................................... 53 
16.1. Statement of Compliance ........................................................................... 53 
16.2. Investigator Responsibilities ..................................................................... 54 
16.2.1. Delegation of Responsibility ......................................................... 55 
16.3. Ethics Committee ....................................................................................... 55 
16.4. Sponsor Responsibilities ............................................................................ 56 
16.4.1. Role of Boston Scientific Representatives .................................... 56 
16.5. Insurance ..................................................................................................... 57 
17. MONITORING ......................................................................................................... 57 
18. POTENTIAL RISKS AND BENEFITS ........................................................................ 58 
18.1. Potential Lead Implantation Adverse Events .......................................... 58 
18.2. Risks Associated with the Study Devices ................................................. 60 
18.3. Risks associated with Participation in the Clinical Study ...................... 60 
18.4. Possible Interactions with Concomitant Medical Treatments ............... 60 
18.5. Risk Minimization Actions ........................................................................ 60 
18.6. Anticipated Benefits ................................................................................... 61 
18.7. Risk to Benefit Rationale ........................................................................... 61 
19. SAFETY REPORTING .............................................................................................. 62 
19.1. Definitions and Classification ................................................................... 62 
19.2. Safety Trigger ............................................................................................. 65 
19.3. Relationship to Study Devices ................................................................... 65 
19.4. Investigator Reporting Requirements ...................................................... 66 

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19.5. Boston Scientific Device Deficiencies ........................................................ 66 
19.6. Reporting to Regulatory Authorities / ECs / Investigators .................... 67 
19.7. Subject Death Reporting ........................................................................... 67 
20. INFORMED CONSENT............................................................................................. 68 
21. COMMITTEES ........................................................................................................ 69 
21.1. Safety Monitoring Process ......................................................................... 69 
21.2. Technical Review Committee .................................................................... 70 
22. SUSPENSION OR TERMINATION ............................................................................ 70 
23.1 Premature Termination of the Study ....................................................... 70 
23.1.1 
Criteria for Premature Termination of the Study ........................... 71 
23.2 Termination of Study Participation by the Investigator or Withdrawal 
of EC Approval ........................................................................................... 71 
23.3 Requirements for Documentation and Subject Follow-up ..................... 71 
23.4 Criteria for Suspending/Terminating a Study Center ............................ 71 
23. PUBLICATION POLICY ........................................................................................... 72 
24. BIBLIOGRAPHY ...................................................................................................... 72 
25. ABBREVIATIONS AND DEFINITIONS ...................................................................... 73 
25.1. Abbreviations ............................................................................................. 73 
25.2. Definitions ................................................................................................... 75 
26. APPENDICES .......................................................................................................... 80 
 
 
3.1. Table of Figures 
Figure 4-1: Impact of Rate Responsive Pacemakers on Heart Rate Score ................... 16 
Figure 4-2: Changes in Heart Rate Score (DDD vs. DDD  DDDR: LAT Analysis) 17 
Figure 5-1: VISIONIST X4 CRT-Pacemaker .............................................................. 19 
Figure 5-2: Lead Connections and Setscrew Locations ............................................... 19 
Figure 11-1: Pre-Discharge Programming Screen ........................................................ 38 
Figure 11-2: One Month Follow up Programming Screen ........................................... 42 

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3.2. Table of Tables 
Table 5-1: Ingenio 2 Cardiac Resynchronization Therapy Pacemakers ..................... 18 
Table 5-2: Device Components .................................................................................... 20 
Table 9-2: Exclusion Criteria ........................................................................................ 28 
Table 11-1: Data Collection Requirements ................................................................... 31 
Table 11-2: Implant Procedure Assessments ................................................................ 36 
Table 11-3: Post-pocket Closure Sensing Assessments................................................ 36 
Table 11-4: Pre-discharge Device Assessments ........................................................... 40 
Table 11-5: Pre-discharge Sensing Assessments .......................................................... 41 
Table 11-6: Sensing Configuration ............................................................................... 41 
Table 11-7: Age Predicted Heart Rates (100%, 80%, 70%) ......................................... 43 
Table 11-8: Source Documentation Requirements ....................................................... 47 
Table 12-1: Endpoint Sample Size Estimates ............................................................... 50 
Table 18-1: Potential Adverse Events and Potential Adverse Device Effects for CRT-
Ps................................................................................................................ 59 
Table 19-1: Adverse Event Definitions ........................................................................ 62 
Table 19-2: Criteria for Assessing Relationship of Study Device to Adverse Event ... 65 
Table 19-3: Investigator Reporting Requirements ........................................................ 66 
Table 25-1: Abbreviations ............................................................................................ 73 
Table 25-2: Definitions ................................................................................................. 75 
 

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4. Introduction 
The lifetime risk of developing heart failure (HF) is one in five for a person living to 
age 40 in the developed countries1,2. HF affects 1–2% of the population and causes 
about 5% of all medical admissions amongst adults3. In the US, HF affects almost 5 
million patients with 500,000 new cases documented annually4. The one-year 
mortality rate for symptomatic HR has been reported at nearly 45%5. Quality of life is 
reduced more by HF than by any other chronic illness and it is an enormous burden on 
health and social services, accounting for approximately 2% of all health-care 
spending.6  
 
About half of all HF cases are caused by left ventricular (LV) systolic dysfunction, 
which is commonly due to ischemic heart disease or dilated cardiomyopathy. 
Interestingly, in the early stages of heart failure, patients are more likely to die of 
sudden cardiac death than of pump failure7. Logically therefore, therapy strategies for 
these patients should focus on reducing the risk of sudden death as well as improving 
symptoms and quality of life and in addition, preventing progression of the disease. 
 
The hypothesis behind cardiac resynchronization therapy (CRT) is that prevention of 
the electromechanical delay that creates ventricular dyssynchrony can reduce the 
detrimental effects caused by the dyssynchrony such as decreased stroke volume, 
mitral regurgitation, increased wall stress, and delayed relaxation8, 9, 10. Initial, acute 
studies demonstrated that CRT could reduce mitral regurgitation and wall stress11. 
Larger randomized trials showed that HF patients improved in exercise tolerance, 
symptoms of heart failure and quality of life. In addition there was evidence of reverse 
remodeling of the heart as well as a reduction in HF mortality and morbidity12, 13, 14, 15.  
 
Cardiac resynchronization therapy pacemakers (CRT-Ps) are designed to treat both 
cardiac ventricles in heart failure (HF) patients who may have symptoms despite 
receiving the best available pharmaceutical therapy. The Ingenio 2 family includes 
CRT-P devices that are multi-programmable pulse generators (PGs), offering various 
levels of therapeutic and diagnostic functionality. 
 
The benefits of rate responsive pacemakers (RRP) for chronotropically incompetent 
patients are well established, as measured using objective quantitation of exercise 
performance16 and subjective symptom scores.17 Optimal objective and subjective 
benefit, however, requires accurate programming of rate response parameters.18 A 
heart rate score (HRS) can be significantly reduced with RRP (Figure 4-1). A blended 
minute ventilation (MV)+XL RRP approach is more effective than XL alone at 
decreasing the HRS. An HRS <70% has been associated with reduced mortality in 
implanted cardioverter defibrillator (ICD) and cardiac resynchronization 
therapy-defibrillator (CRTD) patients. These data suggest the need for prospective 
evaluation of HRS, and its reduction with combined XL+MV DDDR, in both 
pacemaker (PM) and ICD patients. One study19 showed that patients with a baseline 
HRS of >70 showed statistically significant improvement in HRS when converting 
from DDD to DDDR pacing, as opposed to maintaining DDD pacing20 (Figure 4-2). 

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These patients decreased their HRS by 3% when staying at DDD and decreased their 
HRS by 11% by changed from DDD pacing to DDDR (with XL) pacing. Although 
these patients will not be analyzed separately in this study due to the non-randomized 
study design, the study will allow a better understanding of the clinical impact of 
optimized rate adaptive pacing driven by MV sensor in HF patients and about sensor 
optimization in HF patients in general, following a 6 minute walking test. 
 
Figure 4-1: 
Impact of Rate Responsive Pacemakers on Heart Rate Score 
 
 
Source: Sulke N, Dritsas A, Chamber J, et al. Is accurate rate response programming necessary? 
PACE 1990; 13:1031–1044. 
HR=heart rate, HRS=heart rate score, RRP=rate response pacemaker, MV=minute ventilation, 
XL=accelerometer, XL+MV=blended sensor (accelerometer+ minute ventilation) 
 
 

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Figure 4-2: 
Changes in Heart Rate Score (DDD vs. DDD  DDDR: LAT 
Analysis) 
 
Source: Richards, M., et al. The Addition of Minute Ventilation to DDDR Pacing Improves the Heart 
Rate Score, A Marker for Chronotropic Incompetence and Increased Mortality. Heart Rhythm, Vol. 11, 
No. 5, May Supplement 2014: p 3-33. 
DDD=dual chamber pacing; DDDR=dual chamber pacing, with sensing (recording) ability  
 
 
The Ingenio 2 CRT-Ps have similar architectural platforms, closely related device 
features and a very similar clinical use association compared to the previously 
approved and marketed BSC implantable devices, Ingenio CRT-P PGs. This approach 
offers several significant advantages, the key one being the well-established clinical 
field experience with this platform. However, some enhancements incorporated into 
Ingenio 2 models are primarily at a component and engineering level rather than at a 
clinical level (Section 5.1). 
 
Another study, GENTLE, is currently ongoing to collect clinical data on BSC’s 
ImageReady MR Conditional Pacing Systems involving the INGEVITY MRI lead 
based on observations / events. The GENTLE study will be leveraged to support the 
Ingenio 2 CRT-Ps as the new features and hardware are consistent between all Ingenio 
2 devices (pacemakers and CRT-Ps).  
 
However, no data are available specifically to support the Ingenio 2 CRT-Ps. 
Therefore, this present PMCF study intends to collect data specific to the Ingenio 2 
CRT-Ps focused on documenting freedom from unanticipated adverse device effects 
(UADEs) and unusual occurrences of new device deficiencies (DD), in order to bridge 
and complement the information from other studies on safety and functionality of the 
Ingenio 2 platform devices. 

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5. Device Description 
5.1. Ingenio 2 Cardiac Resynchronization Therapy Pacemakers 
Ingenio 2 CRT-Ps provide device feature enhancements to commercially available 
Ingenio CRT-Ps manufactured by BSC. However, no changes are anticipated 
regarding the clinical indications, intended use, or target population for the new 
CRT-Ps compared to the previously marketed Ingenio devices.  
 
There are three Ingenio 2 CRT-Ps available, 2 models of VISIONIST and the 
VISIONIST X4. The main device features of the 2 Ingenio 2 CRT-Ps are shown in 
Table 5-1. Photographs of the devices are shown in Figure 5-1; a photograph of the 
lead connections and setscrew locations are shown in Figure 5-2. The basic 
components for each device are noted in Table 5-2. 
 
Basic device specifications include: 
 
• External case which functions as an electrode and consists of two 0.012-inch 
thick hermetically sealed, perimeter-welded, Grade 1 titanium case halves, 
backfilled with dry nitrogen / helium 
• Internal electronic circuitry and SL or EL battery (encapsulated in the external 
case) 
• Overmolded header, consisting of urethane plastic skeletal core structure 
• Titanium weld ring 
 
 
 
Table 5-1: 
Ingenio 2 Cardiac Resynchronization Therapy Pacemakers 
Product Name 
Model 
Number 
Connector 
Type 
Device Feature Overview 
VISIONIST  
U225 
ISI 
CRT-P basic functionality plus: AP 
Scan, Atrial Pacing Preference / 
ProACT, Positive LV Offset, LV-Only 
Pacing, Right Rate™ MV, Pace Safe LV 
in IS-1 and LV-1 models 
VISIONIST 
U226 
ISI/LV1 
VISIONIST X4 
U228 
ISI/IS4 
 
 

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Figure 5-1: 
VISIONIST X4 CRT-Pacemaker 
 
 
 
 
 
 
 
Figure 5-2: 
Lead Connections and Setscrew Locations 
 
 
 
 

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Table 5-2: Device Components 
Component 
Model  
Connector 
Type 
Battery 
Mass 
(g) 
Vol 
(cc) 
Dimensions (cm) 
(H x W x D) 
VISIONIST 
U225 
IS1 
EL 
30.6 
16.2 
6.13 x 4.45 x 
0.75 
VISIONIST 
U226 
IS1/ LV1 
31.1 
16.7 
6.13 x 4.45 x 
0.75 
VISIONIST X4 
U228 
IS1/ IS4 
33.0 
17.6 
6.17 x 4.45 x 
0.75 
 
 
The key new features in the Ingenio 2 CRT-Ps include:  
1. EasyView header with port identifiers. Increased header transparency provides 
enhanced visibility of the lead ports and ease of individual port identification. 
2. LV quadripolar devices, providing 17 pacing configurations and 8 sensing 
configurations for devices compatible with IS4 LV leads 
3. PaceSafeTM Left Ventricular Automatic Threshold (LVAT), which performs 
LV threshold testing every 21 hours and sets an output safety margin; 
maximum amplitude and safety margin are programmable (Section 5.1.1) 
4. enhanced hardware including new battery chemistry, filtered feedthru, IS1 coil 
spring design, and front liner 
5. enhanced diagnostic functions including Post-Operative System Test (POST), 
which provides an automatic device / lead check at a pre-determined time post-
implant to help document proper system functionality without requiring 
manual system testing (Section 5.1.2) 
6. Atrial Arrhythmia Reports (Section 5.1.3) 
7. ECG/EGM (electrogram from device) Snapshot function (Section 5.1.4) 
8. Medical Implant Communication Service (MICS) telemetry band used for 
radio frequency (RF) telemetry communication with the programmer (PRM) 
(Section 5.1.6). 
9. programmable lead impedance limits for daily measurements: high impedance 
limit programmable between 2000 and 3000 Ω; low impedance limit 
programmable between 200 and 500Ω. 
 
Upgrades from the Ingenio devices include: 
• mechanical changes 
1. overmolded header, incorporating the quadripolar LV port, MICS RF 
antenna, and IS1 coil springs 
2. filtered feedthru, adding 2 more feedthru wires for quadripolar LV 
3. silicone rubber front liner, instead of plastic, which includes integrated 
desiccant. 
 

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• electrical changes 
1. analog integrated circuit (IC), with additional quadripolar LV capabilities 
and RF/MICS interface 
2. digital IC, with increased memory 
3. MICS RF module 
4. RC array 
5. capacitor array 
6. filtered feedthru 
7. battery upgrade to 70 mW RF power. 
 
All X4 models used in this study allow the connection of LV quadripolar leads. Leads 
are commercially available (Section 5.1.5) and the ZOOM LATITUDE Programming 
System remains unchanged (Section 5.1.7). 
5.1.1. PaceSafe 
PaceSafe LVAT is designed to dynamically adjust the LV pacing output to ensure 
capture of the left ventricle using a programmable Safety Margin. LVAT will measure 
pacing thresholds from 0.2 V up to the programmable maximum amplitude (7.5 V 
maximum). The output will be at a minimum amplitude of 1.0 V up to the 
programmable maximum amplitude of 7.5 V (with a programmable pulse width). 
 
PaceSafe LVAT automatically performs LV threshold testing every 21 hours and sets 
the pacing pulses amplitude while maintaining output safety margin. Additionally, 
maximum amplitude and safety margin are programmable. 
 
PaceSafe is available in the VISIONIST devices only. 
5.1.2. Post-Operative System Test 
The POST feature provides an automatic device/lead check at a pre-determined time 
post-implant. This helps document proper system functionality without requiring 
manual system testing, which helps facilitate same-day discharge. The clinician can 
select the amount of time after lead attachment when automatic lead test results are 
desired. Any adjustments to the nominal test results time must be programmed prior to 
lead attachment. 
 
If enabled, automatic intrinsic amplitude, impedance, and pace threshold testing will 
be attempted one hour prior to the desired test results time. Left ventricular automatic 
threshold (LVAT) function is available for bipolar electrodes only; thresholds for X4 
leads will need to be tested manually. 
 
Upon interrogation, status of the testing (scheduled to run; in-progress; complete) will 
be provided on the Summary dialog and Summary screen for the first 48 hours 
following lead attachment. Test results can be printed on Quick Notes and Follow-Up 
Reports. 

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5.1.3. Atrial Arrhythmia Reports 
The following Reports are provided: 
• AT / AF percent 
• total time in AT / AF counters 
• AT / AF burden 
• right ventricular (RV) rate during AT / AF 
• pacing percent 
• heart rate 
• activity level 
• respiratory rate trends 
• longest AT / AF 
• fastest right ventricular sensed event (RVS) rate in AT / AF 
• most recent episode information. 
 
A timeline history of interrogations, programming, and counter resets for 1 year are 
also collected.  
5.1.4. ECG/EGM Snapshots 
Up to 6 unique traces of the ECG / EGM display can be stored at any time by pressing 
the Snapshot button. The traces are 10 seconds pre-activation and 2 seconds 
post-activation. A 10 second trace will automatically be stored at the end of Pace 
Threshold tests, which counts as one of the 6 snapshots. 
5.1.5. Leads 
All commercially available BSC leads can be used and are strongly recommended. 
Leads of other manufacturers may be used, if commercially available. In the atrial 
channel only bipolar leads are acceptable. 
5.1.6. ZIP Telemetry 
All investigational devices used in this study will incorporate the capability of 
interrogating the device via ZIP telemetry operating on a RF telemetry band utilizing 
MICS frequency, in addition to telemetry by wand telemetry.  
 
The PRM communicates with the pulse generator using telemetry wand. For study 
devices the PRM can also use wand-less ZIP telemetry which allows two way RF 
communication as an additional option. ZIP telemetry operates with a transmit 
frequency of 402 to 405MHz (MICS) and RF communication is enabled by Zoom 
Wireless Transmitter.  
 
When Zip telemetry is ready for use a message will display on the PRM screen 
indicating that the wand can be removed. 
5.1.7. Programming System 
Programming and interrogation of the investigational devices used in this study is 
accomplished using the approved and commercially available BSC / Guidant Model 

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3120 ZOOM Latitude Programming System and approved Model 2869 Application 
Software. 
5.2. Ingenio 2 CRT-P Indications for Use 
The Ingenio 2 CRT-Ps are indicated for patients who have symptomatic congestive 
heart failure (CHF) including LV dysfunction and wide QRS, and/or one or more of 
the following conditions: 
• symptomatic paroxysmal or permanent second- or third-degree atrioventricular 
(AV) block 
• symptomatic bilateral bundle branch block 
• symptomatic paroxysmal or transient sinus node dysfunction with or without 
associated AV conduction disorders (i.e., sinus bradycardia, sinus arrest, 
sinoatrial [SA] block) 
• bradycardia-tachycardia syndrome, to prevent symptomatic bradycardia or some 
forms of symptomatic tachyarrhythmias 
• neurovascular (vaso-vagal) syndromes or hypersensitive carotid sinus 
syndromes. 
 
Atrial tracking modes are also indicated for patients who may benefit from 
maintenance of AV synchrony. Dual-chamber modes are specifically indicated for 
treatment of the following: 
• conduction disorders that require restoration of AV synchrony, including 
varying degrees of AV block 
• VVI (ventricular single chamber mode) intolerance (i.e., pacemaker syndrome) in 
the presence of persistent sinus rhythm 
• low cardiac output or CHF secondary to bradycardia. 
 
Adaptive-rate pacing is indicated for patients exhibiting chronotropic incompetence 
and who would benefit from increased pacing rates concurrent with increases in MV 
and/or physical activity. 
 
Please refer to the Instructions for Use (IFU) for the most complete labeling 
instructions.   

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5.3. Ingenio 2 CRT-P Contraindications 
BSC Ingenio 2 CRT-P devices have the following contraindications: 
• in patients who have a separate ICD with transvenous leads 
• unipolar pacing or use of the MV/Respiratory Sensor with a subcutaneous ICD 
(S-ICD) is contraindicated because it may cause inappropriate therapy or 
inhibition of appropriate S-ICD therapy. 
• MV is contraindicated in patients with both unipolar atrial and ventricular leads 
• single-chamber atrial pacing is contraindicated in patients with impaired AV 
nodal conduction 
• atrial tracking modes are contraindicated in patients with chronic refractory 
atrial tachyarrhythmias (atrial fibrillation or flutter), which might trigger 
ventricular pacing. 
• asynchronous pacing is contraindicated in the presence (or likelihood) of 
competition between paced and intrinsic rhythms. 
 
Please refer to the IFU for the most complete labeling instructions. 
6. Study Objective 
The objective of this post market clinical follow-up (PMCF) is to collect data on the 
performance of the Ingenio 2 CRT-P devices and to document that device-related 
events, device malfunctions or DDs do not increase safety risks in Ingenio 2 CRT-Ps, 
both in general and specific to the new features and hardware of the devices. 
7. Endpoints 
7.1. Primary Safety Endpoint 
The primary safety endpoint of this study is to: 
• evaluate and document the device-related complications by assessing the 
device-related complication free rate (DRCFR) at the 3 months post-implant. 
Device-related complication is defined as complication (an AE that resulted in death, 
serious injury, a correction using invasive intervention, or permanent loss of device 
functions) assessed as related to the device. 
7.2. Primary Effectiveness Endpoint 
The primary effectiveness endpoint for this study is: 
• 
LV pacing threshold measurements performed at 0.5 ms pulse width at 3 months 
post-implant 
The pacing configuration selected for permanent programming will be compared to 
prospectively determined limits. 

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7.3. Secondary Safety Objectives 
The secondary safety objectives for this study are: 
• Assessment of proper function of the PaceSafe-LVAT feature with special 
attention to:  
o inappropriate loss of capture due to LVAT (not related to lead 
dislodgement, connection issue, etc.) and  
o devices which show retry into LVAT followed by Latitude alert  
• Assessment of reported events in relation to the use of MICS during all visits 
• Assessment of all reported events in relation to the Quad Lead and Header. 
7.4. Secondary Effectiveness Objectives 
The secondary effectiveness objectives for this study include: 
• Collection of user experience with the PRM interface through the Product 
Experience Reporting at implant and during follow-up 
• Assessment of LV pacing at implant and follow up (pacing threshold per vector, 
Impedance per vector, % pacing) 
• Assessment of battery voltage at Latitude based Close-out visit, for all devices. 
A battery voltage of ≤ 75% of expected power level (based on the theoretical 
power consumption calculation in respect to the programmed parameters) will 
be investigated further. 
• Assessment of POST: number of out of range impedance alerts not related to 
mitigating factor (header connection issue, lead failure, lead dislodgement, etc.) 
• Assessment of the correlation between 6 minute walking test distance at 1 
month and 3 months post-implant and for subjects with an HRS < 50 and ≥ 50 
• The HRS changes between 1 month follow-up and 3 month follow-up will be 
analyzed for all subjects, for subjects with HRS < 50 and ≥ 50, and for subjects 
in a non-rate adaptive mode and with rate adaptive pacing. 
All event data may be combined with data from Ingenio 2 devices enrolled into the 
Gentle study. 
8. Design 
This study is prospective, non-randomized, multi-center, single-group PMCF study.  
8.1. Scale and Duration 
Sixty-two eligible subjects planned for implant with an Ingenio 2 CRT-P will be 
enrolled in this study from 10-15 investigational centers, including but not limited to: 
Belgium, Denmark, Finland, Germany, Netherlands, and Spain. If a site does not 
enroll a subject within a 3-month time period, the site may be replaced by the 
discretion of the sponsor.  
 

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Enrollment is expected to take approximately 12 months. Subjects will be followed for 
3 to 16 months after implant with a median follow-up time of 1 year. All study 
required visits will be completed as part of a regularly scheduled clinic visit. 
 
The study will be considered complete (primary endpoint completion) after all subjects 
have completed the Latitude based Close-out 3 to 4 months (91 – 120 days) after last 
study enrollment. The analysis is planned for 2016. Study completion is anticipated in 
2016. 
8.2. Treatment Assignment 
This study is a non-randomized non-blinded post-market study intended to evaluate 
the Ingenio 2 CRT-P (VISIONIST) device in a clinical setting. All enrolled subjects 
will receive an Ingenio 2 CRT-P and the treatment assignment will be based on an 
“all-comers” consecutive basis. The study devices are fully commercially available 
and all subjects are planned to receive a CRT-P implant. The assignment of the 
specific Ingenio 2 device will be determined by the physician; all leads currently in 
place from previously implanted devices and planned new leads (e.g., Acuity X4 
and/or other LV leads) are to be allowed. 
8.3. Justification for the Study Design 
The primary objective of this study is to gather data to establish the chronic safety, 
performance and effectiveness of Ingenio 2 CRT-P and to obtain “standard” clinical 
data on the device use in the clinical setting. In order to obtain a “real world” picture 
of the CRT-P, the study Inclusion/Exclusion Criteria and follow-up schedule has been 
written generally enough to allow for study center specific standard of practice that 
should accurately capture the device use in a “standard” clinical setting. Additionally, 
by requiring study centers to follow their specific standard of practice, risk to the 
subject is minimized because the treatment received by the subject will be similar to 
the treatment the subject would receive if not participating in the study. For this same 
reason, device implantation is not randomized as it will be determined by the study 
doctor, based on implanted leads already in place and other medical factors. 
 
Determination of sample size is provided in Section 12.3. 
9. Subject Selection  
9.1. Study Population and Eligibility  
Inclusion and Exclusion criteria are listed in Sections 9.2 and 9.3 below.  
 
Subjects who are enrolled but later determined to not fulfill all inclusion and exclusion 
criteria after an attempted 3-lead device system implant will be considered to have 
incurred a Clinical Investigation Plan (CIP) deviation. These subjects will not be 
included in the planned data analysis but will be followed until the end of the study. 
Subjects who were intended to be implanted with a Visionist device, or who did not 
receive a Visionist device after an attempted implant should be withdrawn 30 days 
after the unsuccessful attempt if all pending events are closed. Once it has been 

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determined that a subject did not fulfill any inclusion/exclusion criteria, only 
observational data will be collected for that subject at any visit attended. 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (Table 9-1) may be given consideration 
for inclusion in this clinical investigation, provided no exclusion criterion (Table 9-2) 
is met. 
 
Table 9-1: Inclusion Criteria 
1. 18 years or above, or above legal age to give informed consent specific to state and 
national law 
2. Willing and capable of providing informed consent  
3. Planned to be implanted or replaced with a VISIONIST Ingenio 2 CRT-P device  
4. Planned to be implanted with a 3-lead CRT-P system 
5. Planned to be connected to the remote data collection through the Latitude® system 
6. Able to do a 6 minute walk test 
7. Maximum sensor rate of APMHR 80% should be clinically acceptable 
8. Willing and capable of participating in all visits associated with this study at an 
approved clinical study center and at the intervals defined by this CIP. 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9-2) will be excluded from 
this clinical study. 
 

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Table 9-2: Exclusion Criteria 
1. Documented life expectancy of less than 12 months  
2. Currently on the active heart transplant list 
3. Enrolled in any other concurrent study without prior written approval from BSC, 
with the exception of local mandatory governmental registries and observational 
studies/registries that are not in conflict and do not affect the following:  
o Schedule of procedures for the Rally CRT-P Study (i.e., should not cause 
additional or missed visits) 
o Rally CRT-P Study outcomes (i.e., involve medications that could affect 
the heart rate of the subject) 
o Conduct of the Rally CRT-P Study per Good Clinical Practice (GCP)/ 
International Standard Organization (ISO) 14155:2011/ local regulations as 
applicable  
4. In chronic atrial fibrillation 
5. Age predicted maximal heart rate (APMHR) needs to be programmed < 80% for 
clinical reasons at time of enrollment. 
6. Not planned to receive a functional atrial lead 
7. Per the implanting physician’s discretion, subject is not a suitable candidate to 
receive the study device as determined during the implant procedure  
8. Women of childbearing potential who are or might be pregnant at the time of 
study enrollment  
9. Unwilling or unable to participate in all scheduled study follow up visits at an 
approved study center 
10. Does not anticipate being a resident of the area for the scheduled duration of the 
trial. 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects will only be enrolled in this study if they meet all eligibility criteria and 
provide written informed consent. If a subject doesn’t meet all eligibility criteria prior 
to the implant procedure (e.g., no attempt of Rally CRT-P implant is planned) the 
subject will be withdrawn from the study; any points of ineligibility must be clearly 
documented in the enrollment/screening log. These subjects will be considered consent 
ineligible as discussed in Section 10.3, and will not count towards the enrollment 
ceiling. Any subject that signs consent and meets all Inclusion Criteria and does not 
meet any Exclusion Criteria will be enrolled followed in the study. If a subject signs 
consent and meets all eligibility criteria but does not receive the Rally CRT-P implant 
(for example: anesthesia complications, Visionist CRT-P device was finally not 
implanted, etc.), the subject will be followed for 30 days for safety reasons and will 
then be withdrawn from the study (Section 9.1).  
10.2. Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical 
study or lost to follow-up) shall be accounted for and documented. If a subject 
withdraws from the clinical investigation, the reason(s) shall be reported. If such 

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withdrawal is due to problems related to investigational device safety or performance, 
the Investigator shall ask for the subject’s permission to follow his/her status/condition 
outside of the clinical study.   
 
Reasons for withdrawal include physician discretion, subject choice to withdraw 
consent, loss to follow-up, or death. While study withdrawal is discouraged, subjects 
may withdraw from the study at any time, with or without reason, and without 
prejudice to future treatment. All applicable case report forms should be completed up 
to the point of subject withdrawal. Subjects who are “lost-to-follow-up” should have 3 
documented failed phone call attempts to contact the subject as well as a certified letter 
sent to the subject without a response prior to study withdrawal or termination. Sites 
should also contact their municipal registries (as available in the geography) to 
determine if the subject may have expired. A death note will need to be provided 
together with the Serious Adverse Event (SAE) event discription on the Adverse Event 
(AE) form. Additional data may no longer be collected after the point at which a 
subject has been withdrawn from the study or withdraws his/her consent, for whatever 
reason. All open AEs should be closed or documented as chronic or continuing at the 
end of the study. Data collected up to the point of subject withdrawal may be used. A 
Study Withdrawal Case Report Form (CRF) should be completed at this time. A 
retrospective cancelling of subject data collection should be expressed explicitly by the 
subject so that all data can be removed from the database. 
 
Subjects who do not receive an LV lead or an atrial lead will be followed until the 
Latitude based Close-out. 
10.3. Subject Status and Classification 
Consent ineligible subject 
A study subject who has signed informed consent but is found to not meet eligibility 
criteria will be considered a consent ineligible subject and will not count towards the 
enrollment ceiling. There are no follow-up or AE reporting requirements for consent 
ineligible subjects. The original signed Informed Consent must be maintained in the 
center’s administrative file. 
 
Active enrolled subject 
A study subject who meets the eligibility criteria as per Section 9.2 and Section 9.3 
and has signed and dated the Subject ICF is considered actively enrolled in the study. 
These subjects are followed in accordance with the CIP follow-up schedule and 
included in the foreseen study analysis. The original signed Subject ICF and any 
applicable documentation must be maintained in the center’s subject file. All 
applicable eCRFs per the CIP must be completed. 
10.4. Enrollment Controls 
The study is planned to enroll a maximum of 30 device replacements, and a maximum 
of 10 subjects with a known indication for rate adaptive pacing which doesn’t allow 
non-rate adaptive pacing between pre-discharge and one month follow up. 
 

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Each center may enroll up to a maximum of 20 Rally CRT-P study subjects in order to 
mitigate any bias from a single center in the final study analysis.  
 
If a center wishes to exceed these limits, the center must obtain prior approval from 
the sponsor or sponsor’s delegated representative.  
 
Once 62 subjects have been enrolled and registered in the trial database, all centers 
will be informed that enrollment has closed. After closure of enrollment has been 
communicated, centers must obtain approval from the sponsor or the sponsor’s 
delegated representative for all remaining subjects who are consented but not 
implanted or enrolled into the study database. 
11. Study Methods 
11.1. Data Collection 
Details for data collection are shown in Table 11-1. Data collection will take place at 
the following time points: 
• Required visits 
o Enrollment and Consenting Clinic Visit (≤ 30 days prior to implant 
procedure; required)  
o Implant Procedure (Day 0; all future follow ups based on this date; 
required)  
o Pre-Discharge Clinic Visit (after pocket closure 0-5 days post-implant 
procedure; required) 
o 1 month visit (30 days ± 15 days post-implant procedure; required) 
o 3 month Clinic Visit (91 ± 21 days post-implant procedure; required) 
o Latitude-based Close-out (91 – 120 days post last enrollment; reporting 
only required) 
• Optional visits  
o Re-implant/Revision (as needed) 
o Any unscheduled visits or additional interim visits 
In clinic visits that occur outside the specified visit window will be classified as 
“Unscheduled Visits”. CIP visits that occur outside the specified visit window will be 
documented as a CIP deviation. 
All data collected according to the Data Collection Requirements (Table 11-1) and 
specified in Sections 11.2 to 11.10 is to be appropriately noted in the eCRF.

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Table 11-1: Data Collection Requirements 
Procedure/Assessment 
Enrollment 
and 
Consenting 
Clinic Visit 
(required) 
(≤ 30 days prior to 
implant procedure) 
Implant 
Procedure 
(required) 
(Day 0) 
Re-implant/ 
Revision  
(as needed) 
Follow- Up Visits 
Pre-
discharge 
Visit 
(required) 
(0-5 days post-
implant 
procedure) 
1 Month 
Visit 
(required) 
(30 ± 15 days 
post-implant 
procedure) 
3 Month 
Visit 
(required) 
(91 ± 21 days 
post-implant 
procedure) 
Unscheduled 
Visit 
(optional) 
(according to 
Center SOC or 
subject needs) 
Latitude-
based Close-
out1 
(required) 
(91-120 days 
post last 
enrollment) 
Informed Consent Form, including 
informed consent signature and 
date 
X 
-- 
-- 
 
-- 
-- 
-- 
Subject information, 
medical/device history 
X 
-- 
-- 
 
-- 
-- 
-- 
Clinical assessment 
X 
 
 
O 
O 
-- 
 
 -- 
Implant of CRT-P and implant 
measurements 
 
X 
 
 
 
 
 
12 lead ECG recording 
SOC 
 
 
 
SOC 
 
 
12 lead ECG recording upload 
X 
-- 
 
 
X 
-- 
-- 
ECG 10s device based 
 
 
X 
 
X 
 
 
LV pacing threshold for all 
available vectors 
 
 
X 
 
X 
-- 
 
LVAT function (programming and 
documenting) 
 
X 
X 
 
X 
-- 
 
LVAT data report 
 
 
X 
 
X 
-- 
 
Device assessment/interrogation  
 
Leads (impulse, threshold, 
sensing amplitude) 
 
MICS 
 
Header 
 
X 
X 
X 
X 
-- 
 
Manual confirmation ofPOST 
function/daily measurements  
 
X 
X 
-- 
X 
-- 
 
Device programming 
 
 
X 
X 
X 
 
 

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Procedure/Assessment 
Enrollment 
and 
Consenting 
Clinic Visit 
(required) 
(≤ 30 days prior to 
implant procedure) 
Implant 
Procedure 
(required) 
(Day 0) 
Re-implant/ 
Revision  
(as needed) 
Follow- Up Visits 
Pre-
discharge 
Visit 
(required) 
(0-5 days post-
implant 
procedure) 
1 Month 
Visit 
(required) 
(30 ± 15 days 
post-implant 
procedure) 
3 Month 
Visit 
(required) 
(91 ± 21 days 
post-implant 
procedure) 
Unscheduled 
Visit 
(optional) 
(according to 
Center SOC or 
subject needs) 
Latitude-
based Close-
out1 
(required) 
(91-120 days 
post last 
enrollment) 
6 minute walking test 
 
 
 
X 
X 
 
 
Device data collection 
(electronically) and electronic 
upload 
 
 
X 
X 
X 
 
 
Manual threshold and device 
testing 
 
X 
X 
X 
X 
-- 
 
Current/concomitant medications2 
X 
 
X 
X 
X 
 
 
Adverse device events3 and SAEs 
-- 
X 
X 
X 
X 
X 
X 
Latitude report on device data 
collection; battery status/diagnostic 
report 
 
 
X 
X 
X 
X 
X 
ECG=electrocardiogram; HF=heart failure; O=optional; POST=Post-Operative System Test; SAE=serious adverse event; SOC=standard of care; X=required; --=not required 
1. 
 A 12 month post-implant data collection will be done, but will be done remotely and does not require a site visit 
2. 
Only heart failure medication classes (Beta blockers, ACE inhibitors, diuretics, etc.); currently being administered or changes to administration of. 
3. 
To include collection of all USADEs, SADEs, ADEs, DDs; collection of all SAEs 

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11.2. Study Candidate Screening 
After approval by the Investigator’s Ethics Committee (EC) and the sponsor or delegated 
representative, the Investigator will follow standard of care (SOC) practices to screen 
subjects for inclusion in the study. Subjects are considered enrolled after they have met all 
inclusion criteria, none of the exclusion criteria, and provided written informed consent in 
accordance with applicable regulatory agency and EC requirements. 
11.3. Informed Consent 
During the Enrollment and Consenting Visit (Section 11.4) a qualified center representative 
will review the consent with a potential subject. The subject will be encouraged to ask any 
questions about the study. All questions from the subject should be addressed prior to the 
subject signing the informed consent. If the subject signs the informed consent, a signed copy 
should be provided to the subject and the original should be filed in the medical records. 
Documentation of the consent process by the person obtaining consent should be filed in the 
subject study file. Study personnel should explain to the subject that even if the subject 
agrees to participate in the study and signs the study Informed Consent Form (ICF), the 
implant procedure may demonstrate that the subject is not a suitable candidate for the study. 
No study-specific data collection of any procedure should be conducted prior to consent.  
11.4. Enrollment Visit (≤ 30 days prior to implant procedure; required) 
Prior to initiating any study procedures, the Investigator must ensure that appropriate 
informed consent has been documented (Section 11.3). 
 
The data collection at enrollment includes: subject information and medical history; subject 
status and clinical assessment per SOC; and details on previously/currently implanted 
devices. 
 
Baseline data that are not caught in the hospital records must be queried and documented 
with a Note to File. 
 
Subject information and medical history 
• Demographic data: age at time of consent; gender. 
• Additional rhythm disease: information will be collected on additional relevant 
rhythm diseases: atrio-ventricular block; sinus node dysfunction; paroxysmal/chronic 
atrial fibrillation; chronotropic incompetence. 
• Subject etiology: ischemic cardiomyopathy; idiopathic cardiomyopathy; valvular; 
cardiomyopathy; hypertrophic cardiomyopathy; congenital heart disease; infiltrative 
disease; neuromuscular disease (including myotonic dystrophy and Kearns-Sayre 
syndrome).  
• Associated diseases/risk factors: hypertension, diabetes, renal disease, chronic 
pulmonary disease, peripheral artery disease, COPD, asthma, other known 
malignancies (tumor, lymphoma or leukemia), other chronic diseases.  

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• Other subject history: previous stroke; previous myocardial infarction; previous 
hospitalization for heart failure; previous ablation (AV node, atrial fibrillation or 
atrial flutter). 
• Current/concomitant medication: documentation of current/concomitant 
medication classes being administered for treatment of heart failure  
History of implanted devices 
• Pacemaker, ICD, etc. data: Implant date, number of years implanted, model and 
manufacturer 
• Pacing lead data: cardiac chamber (atrial and ventricular), number of years implanted 
and lead-model and manufacturer 
Baseline subject status and clinical assessment 
• Clinical assessment data: weight, height, blood pressure, New York Heart Association 
(NYHA) class, Left Ventricular Ejection Fraction (<1 year old). 
• Electrocardiogram (data collection and document upload in e.g. pdf format): date 
(maximum 1 month before enrollment); rhythm (normal sinus rhythm, junctional rhythm, 
atrial fibrillation, paced); resting heart rate; intrinsic QRS width; intrinsic PR interval, 
intrinsic QT interval; QRS morphology (normal, right bundle branch block (RBBB), left 
bundle branch block (LBBB), other conduction disorders). The Investigator should 
classify the nature of the subjects intrinsic intra-ventricular conduction delay (e.g. LBBB, 
RBBB, or non-specific) per the World Health Organization Guidelines. These guidelines 
can be found in Appendix B: Ventricular Conduction Delay Definitions.   
11.5. Implant Procedure (Day 0; required); Re-implant/Revision Procedures (as 
needed) 
Subjects that meet all of the entry criteria and consent to the procedure are eligible. All 
subjects will be implanted, per center SOC procedure, with one of 3 Rally CRT-P models; 
selection of subject appropriate device will be at the discretion of the Investigator based on 
appropriate medical considerations. All future follow-ups will be based on this date. 
 
Subjects that need re-implant or revision procedures, as determined by the Investigator, will 
undergo the same procedures as described for Day 0. The reason for re-implant/revision is to 
be documented in the eCRF. 
 
While the Investigator should follow the center’s SOC procedures and the IFU, it is 
important to ensure that the pulse generator has good contact with the surrounding tissue of 
the implantation pocket, and then suture it in place to minimize device migration (Figure 
5-2).  
 

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In addition, two strategies are recommended for device configuration and programming: 
1) Non-apical, non-septal-pacing vector, AV optimization, Echocardiographic 
optimization, QLV optimization any acceptable pacing threshold and no PNS 
2) Non apical pacing vector, no further optimization, good pacing threshold and no 
PNS. 
 
All standard lead/device components are to be assessed during and/or after implant. 
 
The following data elements will be captured DURING the index procedure: 
• Procedure time skin to skin, number of LV lead repositioning attempts 
• Model and serial number of all implanted and active devices  
• Final LV pacing configuration: impedance and threshold  
• Final sensing configuration LV-R-wave 
• Artifacts during sensing post-implant (ADE reporting)  
• Confirmation /assessment of MICS, lead insertion, header 
(all lead insertion difficulties or ball seal problems (including but not limited to: 
missing springs, dislodged springs, etc.) must be reported as an event. The subject 
impact should be documented in the event description. 
• Bipolar sensing amplitude for right atrial (RA) and right ventricle (RV) electrodes 
should be measured and recorded 
• Occurrence of any device-related event (unanticipated serious adverse device effect 
[USADE], ADE, DD) or SAEs unrelated to the device  
 
The implant procedure will be noted in the eCRF as intended, attempted or successful.  
 
MICS should be used for any device interrogation. Any DDs (including but not limited to: 
drop-outs during use of MICS, threshold test taking too long, loss of STAT Pace, etc.) are to 
be reported. The subject impact should be documented in the event description. 
 
Details on the occurrence of any USADE, SADE, ADE, DD, SAE or device-related 
malfunction are to be recorded. 
 
Implant data shall be documented as indicated in Table 11-2 and Table 11-3. 
 
 

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Table 11-2: Implant Procedure Assessments 
Pacing 
configuration 
Pacing Threshold 
at 0.5 ms* 
Impedance 
In Ω 
Sensing Amplitude 
E1 – unipolar (PSA) 
 
 
 
E2 – unipolar (PSA) 
 
 
 
E3 – unipolar (PSA) 
 
 
 
E4 – unipolar (PSA) 
 
 
 
Final minimum measurements after pocket closure 
Final RA lead 
measurements 
 
 
 
Final RV lead 
measurements 
 
 
 
Final LV – lead 
configuration 
E… to ….. 
 
 
 
* 0.4 can be used as a standard setting, per Investigator discretion; to be documented in the eCRF 
eCRF=electronic Case Report Form, LV=left ventricle, PSA=Pacing System Analyzer, RA=right atrium 
 
 
 
Table 11-3: Post-pocket Closure Sensing Assessments 
Sensing Configuration V – V During 
Smart Delay with Pacing Configuration 
V-V timing in ms 
E1  
 
E2  
 
E3  
 
E4 
 
 
 

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The POST function is to be switched on POST-IMPLANT for device interrogation. 
Confirmation of all measurements via POST will be noted in the eCRF, with follow-up 
manual confirmation of: 
• pacing threshold for all 3 electrodes 
• pacing threshold of at least 3 of the possible 17 LV vectors per configuration on 
unipolar, bi-polar and extended bipolar  
• impedance for all 3 electrodes 
• intrinsic signal (p-wave, r-wave) 
• all vectors of LV lead.  
 
A DD report is to be submitted for any parameter that does not function appropriately.  
 
11.6. Pre-discharge Clinic Visit (0-5 days post-implant procedure; required) 
A device assessment will be performed in order to document the proper device function and 
any adverse device events or SAEs that may have occurred since the implant procedure. 
Current medication classes prescribed shall be documented, and device interrogation 
performed according to SOC practices.  
 
At this visit, a BiV-paced post-implant 10s programmer ECG recording is required to be 
uploaded to the study database for core lab review (should be manually measured as SOC). 
Channels to be used include: 
• RA (RAS/RAP) 
• RV (RVS/RVP) 
• LV (left ventricular sensed event [LVS]/left ventricular pressure [LVP]) 
• surface ECG. 
 
In general, device based measurements at this visit are to include the PR interval over 
multiple intervals; RVS to LVS timing for each LV electrode; thresholds; and impedances 
and amplitude measurement.  
 
In addition to all automatic POST measurements, manual testing should be done of all leads 
(impulse, threshold, sensing amplitude) and output programming. All out of range alerts from 
POST should be documented on the event page regardless of the direct subject impact. Any 
subject impact is also to be documented in the event description.  
 
Output programming should be tested via LVAT and manually, the functionality of MICS 
confirmed and the PRM interface rating is to be documented. Pre-discharge device 
assessments as noted in Table 11-4, Table 11-5 and Table 11-6 are to be documented.  
 
Device programming (Figure 11-1) should include selection of final LV pacing/sensing 
vectors; Smart delay should be used to determine paced and sensed AV delays and 

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confirmation of LV-RV offset. All subjects are to be programmed to a non-rate adaptive 
pacing mode from the time of discharge until the 1 month follow-up visit (e.g., DDD). 
Accelerometer and/ or MV Sensor might be programmed ON for subjects with previous 
device implants (e.g., pacemaker) with a known need for rate adaptive pacing. If a rate 
adaptive pacing mode is programmed, reasons must be documented in the eCRF. Pacing Rate 
and AV delay should be programmed at the physician’s discretion so that subjects receive a 
maximum of ventricular pacing rate to assure optimal CRT therapy.  
 
To obtain an accurate MV baseline, the MV sensor will be calibrated automatically or can be 
calibrated manually. A new, manual calibration should be performed if the pulse generator is 
removed from the pocket following implant, such as during a lead repositioning procedure, 
or in cases where the MV baseline may have been affected by factors such as lead 
maturation, air entrapment in the pocket, pulse generator motion due to inadequate suturing, 
external defibrillation or cardioversion, or other patient complications (e.g., pneumothorax). 
 
Figure 11-1: Pre-Discharge Programming Screen  
 
 
 
 
 
The LATITUDE data collection system will be set up at discharge (± 5 days). A weekly 
interrogation frequency should be programmed until 3 month follow up. After 3 month 
follow up the interrogation might be less frequent but not less than monthly. Inability to set 
up or program the data collection system will be considered a CIP deviation. 
 

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After the final programming (DDD pacing mode) and setting rate adaptive pacing (MV 
sensor) to “passive”, the final data interrogation must be saved as data file and stored in the 
subject binder. The file should be uploaded as a ZIP file into the study database. 
 
Additional details to be documented in the eCRF: 
• final LV pacing vector 
• SMART delay optimization used (YES/NO) 
• programmed AV delay 
• how accelerometer was programmed at the end of pre-discharge (ON/Passiv ) 
• how MV sensor was programmed at the end of pre-discharge (ON/Passiv ) 
• programmed pacing mode 
 
All information is to be saved to a disc at the end of the visit.  
 
XL and MV sensors should be in the passive mode. 
 
Chronotropic incompetent subjects (e.g. rate trend shows all time < 100 bpm) may receive 
benefit from the use of available rate response functions. 
 
All current/concomitant heart failure medication classes (Beta blockers, 
angiotensin-converting-enzyme [ACE] inhibitors, diuretics, etc.) at baseline and at time of 
discharge are to be noted in the eCRF; any changes made to these medications during 
hospitalization are also to be noted in the eCRF.  
 
Details on the occurrence of any USADE, SADE, ADE, DD, SAE or device-related 
malfunction which have occurred since the implant procedure are to be recorded. 
 

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Table 11-4: Pre-discharge Device Assessments   
Pacing configuration 
Pacing Threshold at  
0.5 ms 
Impedance in Ω 
E1 – unipolar (Can) (device based) 
 
 
E2 – unipolar (Can) (device based) 
 
 
E3 – unipolar (Can) (device based) 
 
 
E4 – unipolar (Can) (device based) 
 
 
E1 – Ext Bipolar (device based) 
 
 
E2 – Ext Bipolar (device based) 
 
 
E3 – Ext Bipolar (device based) 
 
 
E4 – Ext Bipolar (device based) 
 
 
Bipolar E1 E2 (device based) 
 
 
Bipolar E1 E3 (device based) 
 
 
Bipolar E1 E4 (device based) 
 
 
Bipolar E2 E3 (device based) 
 
 
Bipolar E2 E4 (device based) 
 
 
Bipolar E3 E2 (device based) 
 
 
Bipolar E3 E4 (device based) 
 
 
Bipolar E4 E2 (device based) 
 
 
Bipolar E4 E3 (device based) 
 
 
RV Threshold (bipolar) 
 
 
RV Threshold Unipolar (optional) 
 
 
RA Threshold (bipolar) 
 
 
RA Threshold Unipolar (optional) 
 
 
 

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Table 11-5: Pre-discharge Sensing Assessments 
Sensing Configuration V – V during 
Smart Delay with Pacing Configuration 
V-V timing in ms 
E1  
 
E2  
 
E3  
 
E4 
 
 
 
 
Table 11-6: Sensing Configuration 
LV Sensing Configuration 
R-Wave in mV 
LV - E1 
 
LV - E2 
 
RV Sensing 
 
RA Sensing 
 
 
 
11.7. 1 Month Clinic Visit (30 ± 15 days post-implant procedure; required) 
Clinical assessments may be done at this visit, if the assessment is part of the center’s SOC 
procedures. All subjects are to be programmed to a non-rate adaptive pacing mode until this 
visit. 
 
Prior to the initial device interrogation, subjects will do a 6 minute brisk walk, in a non-rate 
adaptive pacing mode. Data to be collected in association with the walk include: 
• age predicted maximal heart rate 
• heart rate prior to and at the conclusion of the walk 
• maximum heart rate 
• distance walked (in meters) 
• any symptoms experienced. 
 
All subjects shall be “interrogated” after the 6 minute walk test and the data must be saved 
prior to any re-programming. 
 
Chronotropic incompetent subjects (e.g., rate trend in the device for the previous 24 hours 
[including the 6 minute walk test] shows all time < 100 bpm) may receive benefit from the 
use of MV sensor.  
 

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If, after the walking test, the maximum heart rate is < 100 bpm or < 80% of the age predicted 
heart rate ([220-age]*80%), the MV sensor should be programmed on (e.g., DDDR); the 
maximum sensor rate should be at 80% of the age predicted maximal heart rate (APMHR).  
 
The accelerometer should be programmed to “Passiv” during the course of the study until the 
Latitude close out follow up. In case the accelerometer needs to be turned on for clinical 
reasons an event and corrective action need to be documented in the study database. 
 
Rate adaptive pacing during this study should be triggered by the MV Sensor only. 
 
Subjects with a maximum heart rate < 80% of their respective age predicted maximum 
([220-age]*80%) after the 6 minute walk will receive sensor optimization, per the 
Optimization Guidelines: 
• The maximum sensor rate should be programmed to: APMHR * 80% (Table 11-7) 
• The maximum sensor rate should not be programed below 110 bpm 
• The programming of the MV “Response Factor” should be programmed (based on the 
result of the sensor modulation after 6 minute walk; starting at nominal 8). 
• The resulting HR frequency in the sensor response modulation (especially in the 2nd 
part of the 6 minute walk) should result in a minimum of 70% of APMHR so that an 
appropriate HR can be achieved during future exercises. 
 
A screen shot for the pacing configuration is shown in Figure 11-2. 
 
Figure 11-2: One Month Follow up Programming Screen  
 

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Table 11-7 provides an overview of the age dependent values as guidance for hall walk 
sensor adjustments to achieve optimal pacing rates, if clinically acceptable. 
 
Table 11-7: Age Predicted Heart Rates (100%, 80%, 70%) 
 
Age 
APMHR 
APMHR*80% 
Programmed 
Value for 
APMHR*80% 
APMHR*70% 
55 
to 
59 
165 
132 
130 
116 
60 
to 
64 
160 
128 
130 
112 
65 
to 
69 
155 
124 
125 
108 
70 
to 
74 
150 
120 
120 
105 
75 
to 
79 
145 
116 
115 
101 
80 
to 
84 
140 
112 
110 
98 
85 
to 
89 
135 
108 
110 
95 
 
APHR=age predicted heart rate, APMHR=age predicted maximal heart rate 
 
 
MICS should be used for device interrogation. Events including (but not limited to) drop-outs 
during use of MICS, threshold test taking too long, loss of STAT Pace, etc. are required to be 
reported. The subject impact should be documented in the event description. 
 
After final programming and sensor optimization, counters must be cleared and the 
final data interrogation can be saved for the clinical records as data file; the data does not 
need to be submitted as part of this study. 
 
All current/concomitant heart failure medication classes, including changes to medications, 
are to be noted in the eCRF. 
 
Details on the occurrence of any USADE, SADE, ADE, DD, SAE or device-related 
malfunction which have occurred since the previous visit are to be recorded.  
 
Subjects will have their device performance, nominal alerts and diagnostic data downloaded 
remotely via the Latitude system by the BSC Latitude team during this visit timeframe. The 
subject device memory file will be collected. The following will be collected from the 
Latitude report by the core lab: 
• Identify the atrial histogram. Report the “10 bpm bin” with most paced beats by 
number and report the %AP.  
• Identify the atrial histogram. Report the “10 bpm bin” with most sensed beats by 
number and report %AS. 

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• HRS calculated from %AP and %AS. 
 
11.8. 3 Month Clinic Visit (91 ± 21 days post-implant procedure; required) 
Clinical assessments may be done at this visit, if the assessment is part of the center’s SOC 
procedures. 
 
The subject should have a vigorous 6 minute walk, to be done in the mode programmed at 
the 1 month follow up visit (e.g., DDDR for chronotropic incompetent patients and DDD for 
patients  who clinically don’t need rate adaptive pacing). Data to be collected in association 
with the walk include: 
• age predicted heart rate 
• heart rate prior to and at the conclusion of the walk 
• maximum heart rate 
• distance walked (in meters) 
• any symptoms experienced. 
MICS should be used for device interrogation. In case of but not limited to: e.g. drop-outs 
during use of MICS, or threshold test taking too long, loss of STAT Pace, etc. it is required to 
report all those events. The subject impact should be documented in the event description. 
 
All subjects will be “interrogated” after the 6 minute walk test and the data must be saved 
prior to any re-programming.  
 
The initial data interrogation the data file must be saved and stored in the subject binder. The 
file must be uploaded as a ZIP file into the study database. 
 
If the HRS is still > 70 the response factor may be increased by 1. 
 
A BiV-paced post-implant 10s programmer ECG recording is required to be uploaded to the 
study database for core lab review. 
 
Subjects will have their device performance, nominal alerts and diagnostic data downloaded 
remotely via the Latitude system by the BSC Latitude team during this visit timeframe.  
 
The final programming will be collected via the Latitude database and does not need to be 
uploaded.  
 
The following will be collected from the Latitude report by the core lab: 
• Identify the atrial histogram. Report the “10 bpm bin” with most paced beats by 
number and report the %AP. 
• Identify the atrial histogram. Report the “10 bpm bin” with most sensed beats by 
number and report %AS. 

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• HRS calculated from %AP and %AS. 
 
This visit is intended to evaluate the confidence interval (CI) using the HRS; confirm device 
diagnostics; and document subject symptoms. In particular all “trending” information should 
be noted. The BiV testing routine should document the PR interval over multiple intervals; 
RVS to LVS timing for each LV electrode; selection of final LV pacing/sensing vectors; use 
of Smart Delay to determine paced and sensed AV delays; and confirmation of LV-RV 
offset. 
 
Output programming should be tested via LVAT and manually, the functionality of MICS 
confirmed and the PRM interface rating is to be documented. All daily measurement 
assessments should be confirmed manually. 
 
All current/concomitant heart failure medication classes, including changes to those 
medications, are to be noted in the eCRF. 
 
Details on the occurrence of any USADE, SADE, ADE, DD, SAE or device-related 
malfunction which have occurred since the previous visit are to be recorded.  
11.9. Latitude based Close-out (91 - 120 days after the study is closed for enrollment; 
required) 
Each subject will be followed up for 3 to 16 months (the maximum time in the study for any 
subject) following the implant procedure. Each subject should have a remote Latitude based 
Close-out (Latitude Report) collected within 3 to 4 months (91 - 120 days) after the date the 
study is closed to enrollment. All centers will be notified of this date. For subjects reaching 
16 months, the Latitude based Close-out will be performed before reaching 16 months in the 
study, since 16 months is the maximum time in the study for any subject. 
 
Subjects will not need to come to the study facility for any study procedures, but any clinical 
assessments done as part of center SOC should be documented on the eCRF. 
 
During the remote Close-out, RV and LV pacing configuration and pacing threshold and 
battery voltage should be documented in the eCRF. Battery longevity will be monitored and 
documented. All device alerts will be reviewed and should correspond to the facility event 
reporting (e.g. SADE, ADE, SAE; DD for confirmed alert; or DD for false positive alert). 
 
Subjects will have their device performance, nominal alerts and diagnostic data downloaded 
remotely from the Latitude BSC team during this visit timeframe. 
 
Once the subject completes the Latitude based Close-out, participation in this study has been 
completed. In case of premature termination of the study, data collection will stop 
accordingly.  
 

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If a device-related event (USADE, SADE, ADE) is ongoing at the time of study completion, 
the subject may be asked to remain enrolled in the study and provide additional information 
regarding the event until the event is resolved. The physician will provide treatment for any 
ongoing events according to SOC regardless of whether the subject agrees to continue 
participating in the study.  
 
11.10. Unscheduled or Interim Visits outside of Study Visit Windows 
Should the subject be hospitalized or have an unscheduled or additional interim 
ambulatory/in clinic visit (e.g., related to center SOC, HF, resynchronization therapy, or 
antiarrhythmic therapy, or a visit with study personnel for any reason), the Investigator is 
responsible for notifying the sponsor. For Unscheduled Visits (outside of study visit schedule 
for any reason) an Unscheduled Follow-up eCRF should be completed in order to document 
this visit. The visit should be documented. If the visit was necessary due to an event which 
was serious or related to the device the Event-report eCRF must be completed. The 
occurrence of any event (USADE, SADE, SAE, ADE or DD, including but not limited to: 
drop-outs during use of MICS, threshold test taking too long, loss of STAT Pace, etc.) must 
be reported. The subject impact should be documented in the event description. 
11.11. Source Documents 
Table 11-8 summarises all source data requirements for this CIP. Most source documents 
will be filed in the subject’s hospital chart since all procedures will follow SOC.  
 
Some device measurements (e.g. 17 pacing vectors, 6 minute walk test, etc.) need to be 
documented on Worksheets which should be filed in the patient binder. Some source 
documents (e.g., 10s programmer ECG strips, device data memory file) will also be kept in 
the patient binder after the upload into the study database. Where copies of the original 
source document and printouts of original electronic source documents are retained, these 
shall be signed and dated by a member of the investigation study team (Research Coordinator 
or Investigator who is authorized per the delegation log). Other copies and measurements 
outside SOC as well as the patient consent form should be kept in the subject binder. 
 
All personal information should be removed from all documents prior uploading into the 
study database and replaced by the study ID. In case this is not possible the database 
administrator will anonymize data as required. 
 

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Table 11-8: Source Documentation Requirements 
Requirement 
Disposition 
Subject Consent Form 
1-Retain subject file, 2-study binder, 3-Subject 
copy 
Enrollment and Baseline Data 
Retain in subject hospital file 
Implant Measurement Worksheet 
Subject binder 
Implant Procedure Medical Records 
Retain in subject hospital file  
Pre-discharge Clinic Visit Data 
Retain in subject hospital file and Subject binder 
1 and 3 month Clinic Visit Data 
Retain in subject hospital file and Subject binder 
Interim and Unscheduled Visit Data 
Retain in subject hospital file 
Latitude report Close-out Data 
Latitude database and pdf - Report in Study 
Database 
Device Event Data 
Retain in subject hospital file and  
report into the study database 
Protocol (CIP) Deviation  
Report in Study Database 
Study Withdrawal Worksheet 
Subject binder 
12-lead ECG e-Recording  
Retain in subject hospital file and copy upload to 
study database 
10s Programmer ECG Recording 
Subject binder, upload to study database 
Device Interrogation and Print-outs 
Retain in subject hospital file  
6 minute walk test results documented on the 
worksheet 
Retain in subject hospital file or in the subject binder 
Latitude device and alert data 
Latitude database and copy upload into study 
database 
 
12. Statistical Considerations 
12.1. Primary Safety and Effectiveness Endpoints  
12.1.1. Primary Safety Endpoint  
The primary safety endpoint for this study is to: 
• evaluate and document the device-related complications by assessing the DRCFR at 
3 months post-implant. 
 
Safety will be evaluated by the DRCFR from implant through 3-months post-implant, based 
on complications that are related to the Ingenio 2 CRT-P device. A device-related 
complication is an AE that resulted in death, serious injury, a correction using invasive 
intervention or permanent loss of device functions, and that was assessed as related to the 
device. Device-related complications that may count against the primary safety endpoint are 
outlined in Section 18.1 and Section 18.2 of this CIP. 

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12.1.1.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The DRCFR from 0-3 months≤ 87.5% 
HA: The DRCFR from 0-3 months > 87.5% 
 
The null hypothesis (H0) will be rejected if the lower one-sided 95% confidence bound for 
the DRCFR is greater than the performance goal of 87.5%. 
12.1.1.2. Statistical Methods 
When the final study subject reaches the 3 Month required follow-up visit, the primary safety 
analysis will be performed based on exact binomial methods for the estimation of the 
DRCFR, including the exact lower one-sided 95% confidence bound. Subjects that 
die/withdraw or are lost-to-follow-up prior to the 3-month endpoint evaluation 
(≤ 91 + 21 days post-implant or post-implant attempt) and have not experienced 
device-related complications will be excluded from the analysis. The sample size was 
adjusted to account for up to 20% attrition to ensure there would be a sufficient number of 
evaluable subjects through 3-months. 
 
The primary safety endpoint will evaluate the DRCFR through 3-months post-implant (or 
implant attempt), calculated using exact binomial methods. The null hypothesis will be 
rejected and the endpoint considered met if the lower one-sided 95% confidence bound for 
the DRCFR at 3-months is greater than 87.5%. 
12.1.2. Primary Effectiveness Endpoint  
The primary effectiveness endpoint of this study is: 
• 
LV pacing threshold measurements performed at 0.5 ms pulse width at 3 months 
post-implant 
 
The pacing configuration that the physician selects for permanent programming will be 
compared to prospectively determined limits. 
12.1.2.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The mean LV pacing threshold at 3 months ≥ 2.5V 
HA: The mean LV pacing threshold at 3 months < 2.5V 
The null hypothesis (H0) will be rejected if the upper one-sided 95% confidence bound for 
the mean LV pacing threshold is less than the performance goal of 2.5V. 
12.1.2.2. Statistical Methods 
When the final study subject reaches the 3 Month required follow-up visit, the primary 
effectiveness analysis will be performed based on one-sample t-test methodology for the 

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comparison of the mean LV pacing threshold, including the upper one-sided 95% confidence 
bound. Implanted subjects with available LV pacing threshold at the 3-month endpoint 
evaluation (91 days ± 21 days post-implant) will be included in the analysis. The sample size 
was adjusted to account for up to 20% attrition to ensure there would be a sufficient number 
of evaluable subjects at 3-months. 
The primary effectiveness endpoint will evaluate the mean LV pacing threshold at 3-months 
post-implant, and comparison will be performed using one-sample t-test methodology. The 
null hypothesis will be rejected and the endpoint considered met if the upper one-sided 95% 
confidence bound for the mean LV pacing threshold at 3-months is less than 2.5V. 
12.2. Secondary Safety and Effectiveness Objectives 
To further characterize the safety, performance, and effectiveness of the Ingenio 2 CRT-P 
device, the following outcomes will also be summarized for all implanted and attempted 
subjects. 
12.2.1.1. Secondary Safety Objectives 
• Assessment of proper function of the PaceSafe-LVAT feature with special attention to:  
o inappropriate loss of capture due to LVAT (not related to lead dislodgement, 
connection issue, etc.) and  
o devices which show retry into LVAT followed by Latitude alert  
• Assessment of reported events in relation to the use of MICS during all visits 
• Assessment of all reported events in relation to the Quad Lead and Header 
12.2.1.2. Secondary Effectiveness Objectives  
• Collection of user experience with the PRM interface through the Product Experience 
Reporting at implant and during follow-up 
• Assessment of LV pacing at implant and follow up (pacing threshold per vector, 
impedance per vector, % pacing) 
• Assessment of battery voltage at the Latitude based Close-out visit, for all devices. A 
battery voltage ≤ 75% of expected power level (based on the theoretical power 
consumption calculation in respect to the programmed parameters) will be investigated 
further. 
• Assessment of POST: number of out of range impedance alerts not related to 
mitigating factor (header connection issue, lead failure, lead dislodgement, etc.) 
• Assessment of the correlation between 6 minute walking test distance at 1 month and 
3 months post-implant and for subjects with HRS < 50 and ≥ 50. 
• The HRS changes between 1 month follow-up and 3 month follow-up will be analyzed 
for all subjects, for subjects with HRS < 50 and ≥ 50, and for subjects in a non-rate 
adaptive mode and with rate adaptive pacing. 

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All event data may be combined with data from Ingenio 2 devices enrolled into the Gentle 
study. 
12.3. Sample Size 
The minimum required sample size to evaluate the primary endpoints and account for up to 
20% attrition is 62 (Table 12-1).  
 
 
Table 12-1: Endpoint Sample Size Estimates 
Endpoint 
Measurement 
Hypotheses1 
Expected 
Performance Power 
Number of Subjects  
needed for 
analysis 
to be 
enrolled for 
≤ 20% 
attrition 
Primary 
Safety 
Endpoint 
DRCFR from 
0 to 3 months 
H0:  DRCFR ≤ 87.5% 
HA:  DRCFR > 87.5% 
97.5% 
80% 
49 
62 
Primary 
Effectiveness 
Endpoint 
LV pacing 
threshold at 
3 months 
H0:  mean ≥ 2.5V 
HA:  mean < 2.5V 
1.9 ± 1.2V 
90% 
36 
45 
1 Hypothesis test based on a one-sided alpha level of 0.05. 
LV=left ventricular; DRCFR=device-related complication free rate 
 
Sample sizes were calculated employing exact binomial methods (primary safety endpoint) 
and one-sample t-test methodology (primary effectiveness endpoint) in nQuery 6.0.  
 
The following assumptions were used for the calculation of sample sizes: 
 
• Primary Safety Endpoint 
o Expected DRCFR = 97.5% (determined from prior comparable BSC devices) 
o Performance goal = 87.5% (clinically accepted delta of 10%, subtracted from 
expected DRCFR) 
o Test significance level (α) = 0.05 (one-sided) 
o Power = 80% 
• Primary Effectiveness Endpoint 
o Expected mean (± standard deviation [SD]) LV pacing threshold = 1.9 ± 1.2V 
(based on prior BSC LV lead performance) 
o Performance goal = 2.5V (used in prior BSC led approval studies) 
o Test significance level (α) = 0.05 (one-sided) 
o Power = 90% 
 

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12.4. General Statistical Methods 
12.4.1. Analysis Sets 
All subjects where implant with the Ingenio 2 CRT-P device was successful will be included 
in the primary endpoints analyses. For the DRCFR primary endpoint, subjects where the 
Ingenio 2 CRT-P device was attempted but not successfully implanted will also be included. 
Nevertheless, for the DRCFR primary endpoint, subjects that die/withdraw or are lost-to-
follow-up prior to the 3-month endpoint evaluation (91 days post-implant or post-implant 
attempt) and have not experienced device-related complication will be excluded from the 
analysis. 
12.4.2. Descriptive Statistical Methods 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary endpoints. Unless otherwise stated, all 
statistical testing will be one-sided and will be performed using a significance (alpha) level of 
0.05. 
Continuous variables as a minimum will be described by number of non-missing 
observations (n), arithmetic mean (Mean), SD, minimum (Minimum), median (Median), and 
maximum (Maximum). One additional decimal point for mean and median and 2 additional 
decimal points for SD will be used.  
Categorical variables will be presented using the number of non-missing observations (n) or 
the number of subjects in the population (N) as applicable and percentages (%). Percentages 
will be rounded to one decimal place. Unless otherwise stated, two-sided 90% CIs will be 
provided when relevant. The two-sided 90% CI will be presented as it provides: 
• the one-sided 95% lower limit when the upper bound is ignored to assess superiority. 
• the one-sided 95% upper limit when the lower bound is ignored to assess superiority. 
12.4.3. Number of Subjects per Investigative Site 
Approximately 10 investigational centers will enroll 62 subjects. If a center does not enroll a 
subject within a 3-month time period, the site may be replaced at the discretion of the 
sponsor. 
12.5. Data Analyses 
12.5.1. Interim Analyses 
No interim analyses are planned. 
12.5.2. Subgroup Analyses 
No subgroup analyses are planned due to the small number of subjects included in this 
evaluation. 
12.5.3. Other Analyses 
Descriptive statistics of subject demographic and baseline characteristics will be presented. 

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12.5.4. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the primary 
endpoints analyses will be documented in an amended Statistical Analysis Plan approved 
prior to performing the analyses of primary endpoints. Changes from the planned statistical 
methods after performing the analyses of primary endpoints will be documented in the 
clinical study report along with a reason for the deviation. 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system. The time periods for recording study data (enrollment, implant data, etc.) is specified 
in the site guidelines. 
 
The clinical database will reside on a production server hosted by AptivAdvantage. All 
changes made to the clinical data will be captured in an electronic audit trail and available for 
review by BSC or its representative. The associated database has been designed to meet 
regulatory compliance for deployment as part of a validated system compliant with laws and 
regulations applicable to the conduct of clinical studies pertaining to the use of electronic 
records and signatures. Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic Case 
Report Forms (eCRFs) in compliance with local regulations. A written signature on printouts 
of the eCRFs must also be provided if required by local regulation. Changes to data 
previously submitted to the sponsor require a new electronic signature by the Investigator 
acknowledging and approving the changes. 
 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and will 
be issued to the site for appropriate response. Site staff will be responsible for resolving all 
queries in the database. 
 
All ECG readings should be uploaded to the study database for core lab review. Refer to the 
Core Lab Manual of Operations for more details.  
13.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative site, in original 
format all essential study documents and source documentation that support the data 
collected on the study subjects in compliance with International Conference on 
Harmonization (ICH)/GCP guidelines. Documents must be retained for at least 2 years after 
the formal discontinuation of the clinical investigation of the product. These documents will 
be retained for a longer period of time by agreement with BSC or in compliance with other 
local regulations. It is BSC’s responsibility to inform the Investigator when these documents 
no longer need to be maintained. The Investigator will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 

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Investigator withdraws responsibility for maintaining these essential documents, custody 
must be transferred to an individual who will assume responsibility and BSC must receive 
written notification of this custodial change.  
13.3. Core Laboratories 
All ECG readings should be uploaded to the study database for core lab review. Refer to the 
Core Lab Manual of Operations for more details.  
14. Amendments  
If a CIP revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., EC) of 
the revised CIP must be obtained prior to implementation. 
15. Deviations 
An Investigator must not make any changes or deviate from this CIP, except to protect the 
life and physical well-being of a subject in an emergency. An Investigator shall notify the 
sponsor and the reviewing EC of any deviation from the investigational plan to protect the 
life or physical well-being of a subject in an emergency, and those deviations which affect 
the scientific integrity of the clinical investigation. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days. 
  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using on the EDC eCRF and a 
CIP Deviation Worksheet should also be completed and filed in the subject file. Sites may 
also be required to report deviations to the EC, per local guidelines and government 
regulations.  
 
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, center re-training, or 
discontinuation) will be put into place by the sponsor. 
16. Compliance 
16.1. Statement of Compliance 
This study will be conducted in accordance with ISO 14155 (Clinical Investigation of 
Medical Devices for Human Subjects - Good Clinical Practice), the relevant parts of the ICH 
Guidelines for Good Clinical Practices, ethical principles that have their origins in the 
Declaration of Helsinki, and pertinent individual country laws and regulations. The study 
shall not begin until the required approval/favorable opinion from the EC and/or regulatory 
authority has been obtained, if appropriate. Any additional requirements imposed by the EC 
or regulatory authority shall be followed, if appropriate. 

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16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the CIP/protocol, 
ISO 14155, ethical principles that have their origins in the Declaration of Helsinki, any 
conditions of approval imposed by the reviewing EC, and prevailing local and/or country 
laws and/or regulations, whichever affords the greater protection to the subject. 
 
The Principal Investigator’s responsibilities include, but are not limited to, the following:  
• prior to beginning the study, sign the Investigator Agreement and CIP Signature page 
documenting his/her agreement to conduct the study in accordance with the CIP. 
• provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the center team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• make no changes in or deviate from this CIP, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved CIP that occurred during the course of the clinical investigation. 
• create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all 
clinical-investigation-related records are retained per requirements. 
• ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the eCRFs and in all required reports. 
• record, report, and assess (seriousness and relationship to the device/procedure) every 
observed DD. 
• report to BSC, per the CIP requirements, all USADEs, SADEs, ADEs, DDs; all SAEs; 
documentation of freedom from UADEs and device-related malfunctions. 
• report to the EC and regulatory authorities any SAEs and DDs that could have led to a 
SADE, if required by the national regulations or this CIP or by the EC, and supply 
BSC with any additional requested information related to the safety reporting of a 
particular event. 
• allow the sponsor to perform monitoring and auditing activities, and be accessible to 
the monitor and respond to questions during monitoring visits. 
• allow and support regulatory authorities and the EC when performing auditing 
activities. 
• ensure that informed consent is obtained in accordance with this CIP and local EC 
requirements. 
• provide adequate medical care to a subject during and after a subject’s participation in 
a clinical study in the case of a device event, as described in the ICF. 

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• inform the subject of the nature and possible cause of any device events experienced. 
• inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment. 
• ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together 
with identification and compliance information for concomitant treatment measures 
(contact address and telephone numbers shall be provided). 
• inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical 
investigation. 
• make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation. 
• ensure that maintenance and calibration of the equipment relevant for the assessment 
of the clinical investigation is appropriately performed and documented, where 
applicable. 
16.2.1. Delegation of Responsibility 
When specific tasks are delegated by an Investigator, including but not limited to conducting 
the informed consent process, the Investigator is responsible for providing appropriate 
training and adequate supervision of those to whom tasks are delegated. The Investigator is 
accountable for regulatory violations resulting from failure to adequately supervise the 
conduct of the clinical study.  
16.3. Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to the 
sponsor documentation verifying that their EC is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
 
A copy of the written EC and/or competent authority approval of the CIP (or permission to 
conduct the study) and ICF, must be received by the sponsor before recruitment of subjects 
into the study. Prior approval must also be obtained for other materials related to subject 
recruitment or which will be provided to the subject. 
 

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Annual EC approval and renewals will be obtained throughout the duration of the study as 
required by local/country or EC requirements. Copies of the Investigator’s reports and the EC 
continuance of approval must be provided to the sponsor.  
16.4. Sponsor Responsibilities 
Boston Scientific will serve as the sponsor of this clinical investigation. A sponsor is defined 
as individual or organization taking responsibility and liability for the initiation or 
implementation of a clinical investigation. It is the responsibility of BSC as the sponsor to 
ensure proper monitoring of the investigation and to see that all clinical requirements are 
met. In addition, BSC representatives may participate in the conduct of the trial to the extent 
described in the following section that describes the role of the BSC representatives. BSC 
personnel may or may not be blinded to the study results. Participation in the study’s conduct 
will be limited to BSC personnel who are appropriately qualified and trained such as those 
personnel with an engineering, technical or nursing degree or equivalent training, or who 
have significant experience in cardiology, electrophysiology or the implantable 
cardiovascular device industry. All personnel will be aware of general clinical study 
regulations and guidelines for medical device trials.  
 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC. Only authorized BSC personnel or a BSC 
representative including Contract Research Organization (CRO) will have access to these 
confidential records. Authorized regulatory personnel have the right to inspect and copy all 
records pertinent to this study. Study data collected during this study may be used by BSC 
for the purposes of this study, publication, and to support future research and/or other 
business purposes. All data used in the analysis and reporting of this study will be without 
identifiable reference to specific subject name. 
 
BSC will keep subjects’ health information confidential in accordance with all applicable 
laws and regulations. BSC may use subjects’ health information to conduct this research, as 
well as for additional purposes, such as overseeing and improving the performance of its 
device, new medical research and proposals for developing new medical products or 
procedures, and other business purposes. Information received during the study will not be 
used to market to subjects; subject names will not be placed on any mailing lists or sold to 
anyone for marketing purposes.  
16.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel may provide technical support to the Investigator and other 
health care personnel (collectively HCP) as needed during implant, testing required as part of 
hospital SOC, and follow-ups. Support may include HCP training, addressing HCP 
questions, or providing clarifications to HCPs concerning the operation of BSC 
equipment/devices (including PRMs, analyzers, and other support equipment). 
 
At the request of the Investigator and while under Investigator supervision, BSC personnel 
may operate equipment during implant or follow-up, and assist with the conduct of testing.  
 

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Typical tasks may include the following: 
• interrogating the device or programming device parameters to 
Investigator-requested settings as well as operating investigational equipment 
• performing lead diagnostic testing using a Pacing System Analyzer (PSA) or PRM 
to obtain pacing and sensing thresholds and impedance measurements. 
• clarifying device behavior, operation or diagnostic output as requested by the 
Investigator or other health care personnel 
• assisting with the collection of study data from PSAs, PRMs, and other equipment. 
 
In addition, BSC personnel may perform certain activities to ensure study quality. These 
activities may include the following: 
• observing testing or medical procedures to provide information relevant to CIP 
compliance 
• reviewing collected data and study documentation for completeness and accuracy. 
Boston Scientific personnel will not do the following: 
• practice medicine 
• provide medical diagnosis or treatment to subjects 
• discuss a subject’s condition or treatment with a subject without the approval and 
presence of the HCP 
• independently collect critical study data (defined as primary or secondary endpoint 
data) 
• enter data in electronic data capture systems. 
16.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
17. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the CIP 
and applicable regulations. In addition, the monitor verifies that study records are adequately 
maintained, that data are reported in a satisfactory manner with respect to timeliness, 
adequacy, and accuracy, and that the Investigator continues to have sufficient staff and 
facilities to conduct the study safely and effectively. The Investigator/institution guarantees 
direct access to original source documents by BSC personnel, their designees, and 
appropriate regulatory authorities. 
 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and 

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relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
18. Potential Risks and Benefits 
18.1. Potential Lead Implantation Adverse Events 
This study is following the Visionist Instructions for Use as well as the hospital standard of 
care and will therefore not increase the risks for the subject. All subjects are planned to 
receive a CRT-P implant as part of the SOC treatment, therefore there are no additional 
procedural risks at implant or regular follow-up to the subject for being included in this 
study.  
 
The Ingenio 2 CRT-P Visionist device is fully commercially available and subjects that will 
be enrolled in the Ingenio 2 CRT-P PMCF Study are following a standard implant in the 
hospital. During the study, procedures and follow up visits will be scheduled following the 
Visionist Instructions for Use and the hospital standard of care.  
 
Device data at predefined time points will be collected from the central Latitude database. 
Given the well-established clinical field experience with this pacing platform no additional 
risks are expected if compared to implantation and follow up procedures associated to any 
commercially available CRT-P device. Residual risks are mitigated by appropriate subject 
selection according to the criteria of the present CIP and by using SOC procedure and 
management deserved to subjects indicated for CRT-P. 
 
Based on the literature and on previous experience with pacemakers, Table 18-1 includes an 
alphabetical list of device-related events associated with implantation of a PG and/or lead 
system. As the devices in this study are all approved devices no additional device-related 
events are anticipated.  
 

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Table 18-1: Potential Adverse Events and Potential Adverse Device Effects for CRT-Ps 
• 
Air embolism 
• 
Lead fracture 
• 
Allergic reaction 
• 
Lead insulation breakage or abrasion 
• 
Bleeding 
• 
Lead perforation 
• 
Bradycardia 
• 
Lead tip deformation and/or breakage 
• 
Cardiac tamponade 
• 
Local tissue reaction 
• 
Chronic nerve damage 
• 
Loss of capture 
• 
Component failure 
• 
Myocardial infarction (MI) 
• 
Conductor coil fracture 
• 
Myocardial necrosis 
• 
Death 
• 
Myocardial trauma (e.g., tissue damage, 
valve damage) 
• 
Electrolyte imbalance/dehydration 
• 
Myopotential sensing 
• 
Elevated thresholds 
• 
Oversensing/undersensing 
• 
Erosion 
• 
Pacemaker-mediated tachycardia (PMT)  
• 
Excessive fibrotic tissue growth 
• 
Pericardial rub, effusion 
• 
Extracardiac stimulation (muscle/nerve 
stimulation) 
• 
Pneumothorax 
• 
Fluid accumulation 
• 
Pulse generator migration 
• 
Foreign body rejection phenomena 
• 
Shunting current during defibrillation with 
internal or external paddles 
• 
Formation of hematomas or seromas 
• 
Syncope 
• 
Heart block 
• 
Tachyarrhythmias, which include 
acceleration of arrhythmias and early, 
recurrent atrial fibrillation 
• 
Inability to pace 
• 
Thrombosis/thromboemboli 
• 
Inappropriate pacing 
• 
Valve damage 
• 
Incisional pain 
• 
Vasovagal response 
• 
Incomplete lead connection with pulse 
generator 
• 
Venous occlusion 
• 
Infection including endocarditis 
• 
Venous trauma (e.g., perforation, 
dissection, erosion) 
• 
Lead dislodgment 
• 
Worsening heart failure 
 

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Subjects may develop psychological intolerance to a pacemaker or CRT-P and may 
experience the following: 
• dependency 
• depression 
• fear of premature battery depletion 
• fear of device malfunction. 
 
Additionally, potential AEs associated with the implantation of a coronary venous lead 
system include: 
• allergic reaction to contrast media 
• breakage/failure of implant instruments 
• prolonged exposure to fluoroscopic radiation 
• renal failure from contrast media used to visualize coronary veins. 
 
18.2. Risks Associated with the Study Devices  
There are no known incremental risks that are associated with the study device beyond those 
mentioned in Section 18.1 related to study participation.  
 
Atrial arrhythmia reporting, POST, and snapshot ECG / EGM display were evaluated and no 
new risks were identified.  
18.3. Risks associated with Participation in the Clinical Study 
During the first month of study participation, subjects who did not require rate response 
programming at pre-discharge due to known clinical reasons will not have the benefits of rate 
adaptive pacing. However, if the study doctor feels this programming causes significant 
limitations for the subject, sensor optimization may be done 15 days after implant or earlier. 
 
There are no other known specific additional risks to the subject over and above the risks 
mentioned in the Section 18.1.  
18.4. Possible Interactions with Concomitant Medical Treatments 
The implanted leads contain steroid for the purpose of helping to reduce tissue inflammation 
response at the distal electrode. There are no data that show there are any drug interactions 
with this local steroid, or with any other portion of the implanted system. 
18.5. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this CIP, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 

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procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this CIP. 
18.6. Anticipated Benefits 
Subjects will be implanted with the Ingenio 2 CRT-P, which incorporates the following new 
features:  
1) MICS telemetry band used for Radio Frequency (RF) telemetry communication 
(wireless at any time) with the PRM which may support faster implant and follow 
up procedures. 
2) LV Quadripolar devices, providing 17 pacing/sensing configurations for devices 
compatible with IS-4 LV leads to optimize CRT and avoid invasive procedures 
due to phrenic nerve stimulation or inability to deliver CRT 
3) PaceSafeTM LVAT for bipolar leads, allowing automatic LV threshold testing for 
optimized energy consumption and effective CRT. 
4) enhanced hardware including new battery chemistry, filtered feedthru, IS1 coil 
spring design, front liner, and lead port identifiers for optimized longevity and 
handling 
5) enhanced diagnostic functions including POST, which provides an automatic 
device / lead check at a pre-determined time post-implant to help document 
proper system functionality without requiring manual system testing, Atrial 
Arrhythmia Reports, and Snapshot, which provides the ability to store traces of 
the ECG / EGM display for optimized therapy and procedures 
6) All study subjects will receive a Visionist device which has an MV sensor which 
allows rate adaptive pacing based on MV.  
7) The sensor optimization (required by the CIP) may lead to better therapy outcome 
or reduced mortality (HRS 2014). 
8) All subjects in the study are planned to receive a Latitude system for remote 
subject follow up associated to a complex alert system which may lead to 
optimized subject care and was shown to be associated to reduced mortality 
(Altitude data) 
 
In addition, the study specifies a detailed evaluation of chronothropic incompetence of the 
subject, to be followed by sensor optimization. This sensor optimization in HF subjects could 
be associated with better HF treatment outcome. 
18.7. Risk to Benefit Rationale 
Subjects enrolled in the Rally CRT-P study will not be exposed to any additional testing, 
visits or risks as compared to subjects who are routinely implanted with any clinically 
approved PG system and not enrolled in this study. Standard device interrogation and testing 
that will be performed in the present study are part of SOC procedures specified in the 
Visionist Instructions for Use and the hospital SOC that occurs for each subject implanted 
with a PG who are followed-up under standard clinical practice.  
 
The 6 minute walking test will be used to identify chronotropic incompetent subjects as well 
as optimization of the MV sensor, and is routinely used for HF patients as well as for sensor 

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optimization. The study requires connecting all devices with the remote monitoring system 
Latitude which allows closer follow up by the Investigator due to automatic alerts, diagnostic 
data collected by the device and system performance. The sensor optimization and use of the 
Latitude system specified in this CIP are widely underutilized although often associated with 
clinical patient benefits. 
 
Even if electronic devices such as PG are subject to random component failures that cannot 
be predicted, those risks are not affected by this CIP and would be equally applicable to all 
subjects implanted with a market released PG system. Risks can be minimized through 
adherence to the guidelines for subject selection, close monitoring of the subject's 
physiologic status during visits and by promptly supplying BSC with all pertinent 
information required by this CIP. 
19. Safety Reporting 
19.1. Definitions and Classification 
Definitions are provided in Table 19-1. Administrative edits were made to combine 
definitions from ISO 14155-2011 and medical device guidance (MEDDEV) 2.7/3 12/2010. 
 
The only events that are to be reported as part of this study are any device associated events 
(ADEs, SADEs, USADEs, and DDs; ISO-14155) and SAEs (MEDDEV). Events such as 
flue, nose infection, etc. will not be reported; “AEs” as defined in Table 19-1 will not be 
reported.  
 
 
Table 19-1: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the investigational 
medical device.  
NOTE 1: This includes events related to the investigational medical device 
or comparator. 
NOTE 2: This definition includes events related to the procedures involved 
(any procedure in the CIP). 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 
insufficient or inadequate instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 

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Table 19-1: Adverse Event Definitions 
Term 
Definition 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event that: 
• Led to death, 
• Led to serious deterioration in the health of the subject, that either 
resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function 
• Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in health, is not 
considered an SAE.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: ASADE=Anticipated Serious Adverse Device Effect; CIP=Clinical Investigation Plan; 
EC=Ethics Committee; SAE=Serious Adverse Event; SADE=Serious Adverse Device Effect; 
USADE=Unanticipated Serious Adverse Device Effect,  
 
*Per 21 Code of Federal Regulations 803.3(bb): 
1) Serious injury means an injury or illness that: 
i) Is life-threatening; 
ii) Results in permanent impairment of a body function or permanent damage to 
body structure; or 

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iii) Necessitates medical or surgical intervention to preclude permanent impairment 
of a body function or permanent damage to a body structure. 
2) Permanent means, for purposes of this subpart, irreversible impairment or damage to a 
body structure or function, excluding trivial impairment or damage. 
**Invasive interventions are those in which treatment necessary to correct the AE is 
delivered by cutting or piercing of the skin or placing an instrument in a body cavity to 
provide therapy. Examples of invasive interventions (complication) include: 
• Surgical revision of a lead 
• Electrophysiology study in which an ablation is performed 
• Angiogram in which angioplasty or stent placement is performed 
• Intravenous medications 
• Blood transfusions 
• Intubation to provide respiratory support 
• Chemical (pharmacologic) cardioversion with IV sedation (considered a complication 
due to the IV antiarrhythmic medication used for the cardioversion) 
***Permanent loss of device function is where a malfunction occurs in a manner which 
results in compromised therapy:   
• Malfunction: failure of a device to meet its performance specifications, to perform its 
essential function, or otherwise perform as intended. “Performance specifications” 
include claims made in the labeling of the device. (i.e., device is not functioning 
within labeling) 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should be recorded as an SAE, and 
should include a detailed description of circumstances and expected cause.  
 
Any event (USADE, SADE, SAE, ADE, DD) experienced by the study subject after 
informed consent, whether during or subsequent to the procedure, must be recorded in the 
eCRF. 
 
Refer to the BSC Physician’s Lead Manual for the known risks associated with the study 
devices. 
 
All device-related adverse events will be evaluated at least monthly during the trial and might 
be extracted from the Rally CRT-P database in order to pool those data with other available 
data sets (e.g. trials). Pooling of those datasets on product performance on a broader sample 
size will be done especially to support safety aspects of all medical devices in this trial. 
 

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19.2. Safety Trigger 
Device malfunctions or unintended device behavior, that are either unanticipated or occurring 
in a higher rate than anticipated, and have or could result in serious injury, will be considered 
towards the trial safety review. 
 
For rate calculations the small size of this trial precludes this being the sole source of events. 
The event rate will be determined from the denominator of the entire sold (implanted) device 
base with a numerator of all similar events in the entire post market experience reported. 
 
As a comparison for all calculated event rates in the trial the calculated event rate from 
regular vigilance reporting will be used. This constantly updated event rate is provided to the 
notifying body or authorities, and can be used as reference. 
 
19.3. Relationship to Study Devices 
The Investigator must assess the relationship of the AE to the study device as related or 
unrelated (Table 19-2). 
 
Table 19-2: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or 
effect of another device/drug and is not related to the study device. 
Related 
• The adverse event is determined to be potentially related to the study 
device, and an alternative etiology is equally or less likely compared 
to the potential relationship to study device, or 
• There is a strong relationship to the study device, or recurs on re-
challenge, and another etiology is unlikely, or 
• There is no other reasonable medical explanation for the event. 

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19.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 19-3. 
 
Table 19-3: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Serious Adverse Event 
including:  
• 
Unexpected Serious Adverse 
Device Effects 
• 
Serious Adverse Device 
Effects 
• 
Adverse Device Effects 
• 
Device Deficiencies 
(including but not limited to 
failures, malfunctions, and 
product nonconformities) 
 
Note: Any Investigational 
Device Deficiency that might 
have led to a serious adverse 
event if: 
a) suitable action had not 
been taken or  
b) intervention had not been 
made or  
c) if circumstances had been 
less fortunate is considered a 
reportable event. 
 
Complete Event Reporting eCRF 
page with all available new and 
updated information. 
Provide all relevant source 
documentation (unidentified) for 
reported event. 
Within 2 business days of first 
becoming aware of the event or as 
per local/regional regulations. 
Reporting required through the end of 
the study when documentation is 
available 
Abbreviations: eCRF=electronic Case Report Form  
19.5. Boston Scientific Device Deficiencies 
All DDs (including but not limited to failures, malfunctions, use errors, product 
nonconformities, and labeling errors) will be documented and reported to BSC. If possible, 
the devices should be returned to BSC for analysis. Instructions for returning the 
investigational devices will be provided. If it is not possible to return the device, the 
Investigator should document why the device was not returned and the final disposition of 
the device. Device failures and malfunctions should also be documented on the Device 
Malfunction eCRF and in the subject’s medical record. 
 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are to be reported in the eCRF but are not to be classified as AEs. However, 
an AE that results from a device failure or malfunction would be recorded on the appropriate 
AE eCRF page. 
 

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Any Investigational DD that might have led to a SAE if a) suitable action had not been taken 
or b) intervention had not been made or c) if circumstances had been less fortunate is 
considered a reportable event. 
 
Device deficiencies are to be reported from the study center to BSC or the study database 
within 24 hours of Investigator awareness. Device deficiencies will be evaluated at least 
monthly during the trial and might be extracted from the Rally CRT-P database in order to 
pool those data with other available data sets (e.g. trials). Pooling of datasets on product 
performance on a broader sample size will be done especially to support safety aspects of all 
medical devices in this trial. 
19.6. Reporting to Regulatory Authorities / ECs / Investigators 
BSC is responsible for reporting AE information to all participating Investigators and 
regulatory authorities, as applicable.  
 
The Principal Investigator is responsible for informing the EC and regulatory authorities of 
any USADE, SADE and SAE as required by local/regional regulations. 
19.7. Subject Death Reporting 
A subject death during the study should be reported to BSC within 1 business day of center 
notification. Data entry into EDC shall suffice to fulfill notification requirement. The center’s 
EC must be notified of any deaths in accordance with that center’s EC policies and 
procedures. 
 
Other required information for death events include a detailed narrative (death letter) that 
provides information describing the circumstances surrounding the death, signed by the 
principal Investigator or authorized co-Investigator. A death narrative in the local language is 
acceptable.  
 
The death narrative must include all of the following, if available: 
• date and time of death 
• place death occurred 
• immediate cause of death 
• rhythm at the time of death, if known (include any available documentation) 
• whether the death was related to the pacemaker, lead/catheter, clinical 
investigation, procedure, or subject condition 
• whether or not the death was witnessed 
• device status and/or activity at the time of death  
• whether the subject had worsening heart failure 
• any other circumstances surrounding the death 
• approximate time interval from the initiating event to death (temporal course) 
• Investigator or co-Investigator signature and date. 
 

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Any information listed above that is unavailable or unknown must be specified as 
unavailable or unknown, as applicable, in the narrative. Also submit the following 
documentation: 
 
• If the subject expired in the hospital: 
o a copy of the medical records for that admission (e.g., report of medical history 
and physical examination, consults, test results, operative reports, and/or progress 
notes from the hospital chart) 
o death certificate (if available) 
o autopsy report (if applicable). 
 
• if the subject expired outside of the hospital (e.g., home): 
o a copy of the most recent clinic visit (if not already submitted to BSC) 
o death certificate (if available). 
 
Death narratives and supporting documents should be submitted to the BSC Safety 
department. 
20. Informed Consent 
Subject participation in this clinical study is voluntary. Informed Consent is required from all 
subjects or their legally authorized representative. The Investigator is responsible for 
ensuring that informed consent is obtained prior to any data collection.  
 
The obtaining and documentation of informed consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local EC and/or Regulatory authority body, as applicable. The ICF must be approved by the 
center’s EC. 
 
BSC will provide a study-specific template of the ICF to Investigators participating in this 
study. The ICF template may be modified to meet the requirements of the investigative 
center’s EC. Any modification requires approval from BSC prior to use of the form. The ICF 
must be in a language understandable to the subject and if needed, BSC or its delegates will 
assist the center in obtaining a written consent translation. Translated consent forms must 
also have EC approval prior to their use. Privacy language shall be included in the body of 
the form or as a separate form as applicable.   
 
The process of obtaining Informed Consent shall: 
• be conducted by the Principal Investigator or designee authorized to conduct the 
process  
• include a description of all aspects of the clinical study that are relevant to the 
subject’s decision to participate throughout the clinical study 
• avoid any coercion of or undue influence of subjects to participate 
• not waive or appear to waive subject’s legal rights 

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• use native language that is non-technical and understandable to the subject or his/her 
legal representative 
• provide ample time for the subject to consider participation and ask questions if 
necessary 
• ensure important new information is provided to new and existing subjects 
throughout the clinical study. 
 
The ICF shall always be signed and personally dated by the subject or legal representative 
and by the Investigator or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the center and a copy of the signed and dated document and 
any other written information must be given to the person signing the form.  
 
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements. Any violations of the informed consent process must be 
reported as deviations to the sponsor and local regulatory authorities (e.g. EC), as 
appropriate. 
 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the CIP, a change in Principal Investigator, administrative changes, or following annual 
review by the EC. The new version of the ICF must be approved by the EC. BSC approval is 
required if changes to the revised ICF are requested by the center’s EC. The EC will 
determine the subject population to be re-consented. 
 
Study personnel should explain that even if a subject agrees to participate in the study and 
signs an Informed Consent form, the Index Procedure may demonstrate that the subject is not 
a suitable candidate for the study. The ICF will note that the transmission of confidential 
subject data, such as copies of source documents, will be required and that by signing the 
consent, the subject gives permission for his/her confidential subject data to be transmitted to 
the sponsor. 
21. Committees 
21.1. Safety Monitoring Process 
To promote early detection of safety issues, and consistent coding across projects an internal 
BSC Event Review Team (Technical Services, Clinical CRM, Medical Safety, and assigned 
persons from ICON plc.) will provide at least monthly review and an overview of all events 
reported in the study database. 
 

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 Specific tasks will include: 
• Safety Event Reconciliation (event coding) by BSC. 
• In addition to the event review and coding by the study team, every event reported in 
the EDC system will generate an automated e-mail to the following departments 
within BSC:  
o Event Analysis, Medical Safety, Technical Services and Regulatory personnel 
 
• These immediate notifications are sent for Vigilance reporting purposes for trial 
independent follow up. Every review will be entered into the BSC Systems for Event 
Analysis and Technical services. 
• Technical Services will have access to all subjects in the Rally CRT-P database to 
obtain immediate additional information after e-mail notification. 
 
Procedures for Event Coding 
• Event Coding will be handled by the Boston Coding Team represented by Clinical 
Safety, BSC-Project Management, ICON-Project Management and Technical 
Services. 
• During Event review a four digit classification code will be used to classify each 
reported event. 
• The classification codes will be entered into the EDC module for AE coding for each 
event. The role of ‘Boston Coding Investigator’ has been created within the Coding 
Team. The Coding Investigator will enter the Classification Code Number and Team 
AE review date for all reported events. Team members assigned to this role will have 
“read only” access to the rest of the eCRF. 
 
Review and coding will be done to support device hazard analysis and monitoring of event 
rates. This process requires dynamic collection (as soon as the event is reported) of 
unmonitored data.  
 
During scheduled monitoring visits, clinical research monitors and locally responsible FCS 
will support the dynamic reporting process through their review of source document 
information.  
21.2. Technical Review Committee 
Technical Review will be performed by BSC’s Technical Service department to evaluate any 
technical issues (device-related AEs and DDs) with the device experienced during the trial. 
All device-related reporting will be reviewed independently from event analysis. 
22. Suspension or Termination 
22.1. Premature Termination of the Study 
BSC reserves the right to terminate the study at any stage but intends to exercise this right 
only for valid scientific or administrative reasons and reasons related to protection of 

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subjects. Investigators, associated ECs, and regulatory authorities, as applicable, will be 
notified in writing in the event of study termination. 
22.2. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• the occurrence of USADEs or unusual trends of SAE or SADEs that present a 
significant or unreasonable risk to subjects enrolled in the study 
• an enrollment rate far below expectation that prejudices the conclusion of the study 
• a decision on the part of BSC to suspend or discontinue development of the device. 
22.3. Termination of Study Participation by the Investigator or Withdrawal of EC 
Approval 
Any Investigator or EC in the Rally-CRT-P Study may discontinue participation in the study 
or withdrawal approval of the study, respectively, with suitable written notice to BSC. 
Investigators, associated ECs, and regulatory authorities, as applicable, will be notified in 
writing in the event of these occurrences. 
22.4. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by BSC. The EC and 
regulatory authorities, as applicable, will be notified. Detailed information on how enrolled 
subjects will be managed thereafter will be provided.  
 
In the event an EC terminates participation in the study, participating Investigators, 
associated ECs, and regulatory authorities, as applicable, will be notified in writing. Detailed 
information on how enrolled subjects will be managed thereafter will be provided by BSC. 
In the event an Investigator terminates participation in the study, study responsibility will be 
transferred to a Co-Investigator, if possible. In the event there are no opportunities to transfer 
Investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by BSC. 
 
The Investigator must return all documents to BSC, unless this action would jeopardize the 
rights, safety, or welfare of the subjects. 
22.5. Criteria for Suspending/Terminating a Study Center 
BSC reserves the right to stop the inclusion of subjects at a study center at any time after the 
study initiation visit if no subjects have been enrolled for a period beyond 3 months after 
center initiation, or if the center has multiple or severe CIP violations/noncompliance without 
justification and/or fails to follow remedial actions. 
 
In the event of termination of Investigator participation, all study devices and testing 
equipment, as applicable, will be returned to BSC unless this action would jeopardize the 
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should be notified. All subjects enrolled in the study at the center will continue to be 
followed according to standard clinical practice of the center. The Principal Investigator at 
the center must make provision for these follow-up visits unless BSC notifies the 
investigational center otherwise. 
23. Publication Policy 
In accordance with the Corporate Policy on the Conduct of Human Subject Research, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication 
or presentation relating to a BSC study or its results. In accordance with the Corporate Policy 
for the Conduct of Human Subject Research, BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. BSC 
adheres to the Contributorship Criteria set forth in the Uniform Requirements of the 
International Committee of Medical Journal Editors (ICMJE; http://www.icmje.org). In order 
to ensure the public disclosure of study results in a timely manner, while maintaining an 
unbiased presentation of study outcomes, BSC personnel may assist authors and Investigators 
in publication preparation provided the following guidelines are followed: 
• all authorship and Contributorship requirements as described above must be followed 
• BSC involvement in the publication preparation and the BSC Publication Policy 
should be discussed with the Coordinating/ Principal Investigators and/or Scientific 
Committee at the onset of the project 
• the First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
24. Bibliography 
1. Heart & Lung: The Journal of Acute and Critical Care November-December 2004. 
Volume 33, Issue 6: p. 362-371. 
2. Neumann, T., et al. Heart Failure: the Commonest Reason for Hospital Admission in 
Germany Medical and Economic Perspectives. Dtsch Arztebl Int. 2009 April; 106(16): 
p. 269–275. 
3. Claes, N., et al. Impact of heart failure on hospital activity and healthcare costs in 
Belgium. March 2008, Vol. 11, No. 1: p. 71-79. 
4. Stewart, S., et al. The current cost of heart failure to the National Health Service in the 
UK. Eur J Heart Fail. 2002 Jun; 4(3): p. 361-71. 
5. Medicare patients. American Heart Association, www.americanheart.org. 
6. Mebazaa, A., et al. Acute Heart Failure. 2008 Editor Springer London: p. 5-6. 
7. Uretsky, B. and R. Sheahan, Primary prevention of sudden cardiac death in heart failure: 
will the solution be shocking? Journal of College of Cardiology, 1997. 30: p. 1589-1597. 
8. Auricchio, A. and W. Abraham, Cardiac resynchronization therapy: Current state of the 
art: Cost versus benefit. Circulation, 2004. 109: p. 300-307. 
9. Leclercq, C. and J. Hare, Ventricular resynchronization: Current state of the art. 
Circulation, 2004. 109: p. 296-299. 

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10. Strickberger, S., J. et al., Patient selection for cardiac resynchronization therapy. 
Circulation, 2005. 111: p. 2146-2150. 
11. Auricchio, A., et al., Effect of resynchronization therapy on ventricular remodeling. 
Journal of Cardiology and Failure, 2002. 8: p. S549-555. 
12. Abraham, W., et al., Cardiac resynchronization in chronic heart failure. New England 
Journal of Medicine, 2002. 346: p. 1845-1853. 
13. Linde, C., et al., Long-term benefits of biventricular pacing in congestive heart failure: 
results from the MUltisite Stimulation In Cardiomyopathy (MUSTIC) study. Journal of 
the American College of Cardiology, 2002. 40: p. 111-118. 
14. Higgins, S., J. et al., Cardiac resynchronization therapy for treatment of heart failure in 
patients with interventricular conduction delay and malignant ventricular 
tachyarrhythmias. Journal of the American College of Cardiology, 2003. 39: p. 2026-
2033. 
15. Cleland, J., et al., The effect of cardiac resynchronization on mortality and morbidity in 
heart failure. New England Journal of Medicine, 2005. 352: p. 1539-1549. 
16. Nordlander R, Hedman A, Pehrsson SK. Rate responsive pacing and exercise capacity—
a comment. PACE 1989; 12:749–751. 
17. Lau C, Antoniou A, Ward DE, et al. Initial clinical experience with a minute ventilation 
sensing rate modulated pacemaker: Improvements in exercise capacity and 
symptomatology. PACE 1988; 11(Pt. II):1815–1822. 
18. Sulke N, Dritsas A, Chamber J, et al. Is accurate rate response programming necessary? 
PACE 1990; 13:1031–1044. 
19. Richards, M., et al. The Addition of Minute Ventilation to DDDR Pacing Improves the 
Heart Rate Score, A Marker for Chronotropic Incompetence and Increased Mortality. 
Heart Rhythm, Vol. 11, No. 5, May Supplement 2014: p 3-33. 
20. Richards, M., et al. Heart Rate Score, an Easy and Intuitive Measure of Chronotropic 
Incompetence in Device Patients.  35th Annual Scientific Sessions of the Heart Rhythm 
Society. 2014. Session 29: Abstract 29-05. 
25. Abbreviations and Definitions  
25.1. Abbreviations 
Abbreviations are shown in Table 25-1.   
Table 25-1: Abbreviations 
Acronym/Abbreviation 
Term 
ADE 
Adverse Device Effect 
AE  
Adverse Event 
APMHR 
Age Predicted Maximal Heart Rate 
ASADE 
Anticipated serious adverse device effect 
AV 
Atrioventricular 
BSC 
Boston Scientific 
CHF 
Congestive Heart Failure 
CI 
Confidence interval 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 

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Acronym/Abbreviation 
Term 
CRT 
Cardiac Resynchronization Therapy 
CRT-D 
CRT Defibrillator 
CRT-P 
CRT Pacemaker 
CRO 
Contract Research Organization 
CRM 
Cardiac Rhythm Management (a business division of Boston Scientific) 
DD 
Device deficiency 
DRC(FR) 
Device-related complication (free rate) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGM 
Electrogram (from device) 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HCP 
Health Care Professional 
HRS 
Hearth Rhythm Society 
ICD 
Implantable Cardioverter-Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
ISO 
International Standard Organization 
LBBB 
Left bundle branch block 
LV 
Left ventricle/ ventricular 
LVAT 
Left ventricular automatic threshold 
LVS 
Left ventricular sensed event 
MEDDEV 
Medical Device Guidance 
MICS 
Medical Implant Communication Service 
MV 
Minute ventilation 
PG 
Pulse generator 
PMCF 
Post Market Clinical Follow-up 
PRM 
Programmer  
PSA 
Pacing System Analyzer 
RA 
Right atrial/atrium 
RALLY CRT-P 
Optimizing pacing therapy by using multi-programmable pulse generators for 
cardiac resynchronization pacing (CRT-P)  
RBBB 
Right bundle branch block 
RF 
Radio Frequency 
RRP 
Rate Response Pacemaker 
RV 
Right ventricle/ ventricular 
RVS 
Right ventricular sensed event 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
S-ICD 
Subcutaneous Implantable Cardioverter-Defibrillator 
SOC 
Standard of Care 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
XL 
Accelerometer 
 

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25.2. Definitions 
Terms are defined in there are no direct benefits to subjects with participation to this PMCF 
study.  
Table 25-2: Definitions 
Term 
Definition 
Attempt 
Refers to a subject who 1) has been enrolled in the CRT-P Study, 2) has 
had anesthesia administered in preparation for the surgical implant 
procedure, 3) has had the Visionist CRT-P device introduced, but 4) is not 
successfully implanted with the Visionist CRT-P.   
Attempt subjects must be followed 30 ± 7 days post-attempted implant to 
assure there are no associated adverse events, or to assure the resolution of 
any adverse events associated with the attempted implant. 
Cardiac Perforation 
Penetration of the lead tip through the myocardium to the pericardium or 
beyond (including micro-perforation), either clinically suspected by chest 
x-ray, fluoroscopy or, intra-cardiac electrogram and/or confirmed by 
echocardiogram, CT or visually at operation.  
Cardiac Tamponade 
 
Also known as pericardial tamponade is an acute type of pericardial 
effusion in which hemodynamic compromise results and urgent 
intervention is required. This will be considered a serious adverse device 
event (SADE).  
Complication 
An adverse event that resulted in: death, serious injury, a correction using 
invasive intervention, or permanent loss of device functions. 
Conductor 
Fracture/Lead Fracture 
A mechanical break/ disruption within the lead conductor (includes 
connectors, coils and/or electrodes) observed visually, electrically or 
radiographically. 
Device-related 
Complication 
A complication (an AE that resulted in death, serious injury, a correction 
using invasive intervention, or permanent loss of device functions) 
assessed as related to the device. 
Elevated Pacing 
Thresholds 
At implant, pacing thresholds for the permanently programmed electrode 
that are greater than 3.0 volts and at follow-up pacing thresholds for the 
permanently programmed electrode that are either: (1) An observed 
increase of 2-fold over the first chronic threshold; or (2) An observed 
threshold greater than 3.5 volts. Please note that these elevations in pacing 
threshold values may be physiologic, pathologic or device-related. 
Extracardiac 
Stimulation (e.g., 
phrenic, diaphragm) 
Clinical observation of inadvertent muscle/nerve stimulation other than 
cardiac muscle. 
Hematoma 
If a hematoma requires invasive intervention to evacuate the hematoma, it 
will be considered a serious adverse event. 
High Pacing 
Impedance 
Pacing impedance is considered abnormal based on lead model and 
measurement range of the device. 

St u d y Refere nce : R all y-C R T - P 
 
C o nfi de nti al  
B ost o n Scie ntific  
Rall y C R T -P St u d y CI P, Versi o n A B , 1 7 t h N o ve m ber  2 0 1 5  
P a ge 7 6  of 8 6  
 
T a ble 2 5 -2 : Defi niti o ns 
Ter m  
Defi niti o n  
Hi g h S h oc k I m pe da nce 
S h oc k i m pe da nce is c o nsi dere d a b n or mal base d o n lea d m o del a n d 
meas ure me nt ra n ge of t he de vice.  
Hi g h S h oc k I m pe da nce 
w he n atte m pti n g t o 
deli ver a s h oc k  
Hi g h s h oc k i m pe da nce is c o nsi dere d  a b n or mal base d o n lea d m o del a n d 
meas ure me nt ra n ge of t he de vice w he n atte m pti n g t o deli ver a s h oc k.  
I na p pr o priate s h oc k 
d ue t o o ver -se nsi n g 
S h oc k deli vere d d ue t o o ver-se nsi n g res ulti n g fr o m eit her p h ysi ol o gic or 
n o n- p h ysi ol o gic ca uses.  
I na p pr o priate sh oc k 
S h oc k deli vere d b y t he de vice w hic h is n ot a p pr o priate t hera p y/treat me nt 
per t he de vice pr o gra m mi n g.  
I nfecti o n 
If oral a nti bi otics are prescri be d f or treat me nt of a n i nfecti o n, it will be 
c o nsi dere d as a n a d verse e ve nt. If i ntra ve n o us (I V) a nti bi otics are re q uire d 
f or treat me nt of t he i nfecti o n, t he n it will be c o nsi dere d a seri o us a d verse 
e ve nt.  
A n y c o nfir me d p oc ket se psis or lea d e n d ocar ditis re q uiri n g de vice s yste m 
( ge nerat or a n d lea d) e xtracti o n will be c o nsi dere d a seri o us a d verse e ve nt. 
I nte nt 
Refers t o a s u bj ect w h o has bee n e nr olle d, b ut d oes n ot u n der g o a n i m pla nt 
pr oce d ure of a Visi o nist C R T -P de vice . T he ori gi nal I C F a n d scree ni n g 
d oc u me ntati o n f or i nte nt s u bj ects s h o ul d be mai ntai ne d i n t he ce nter’s 
files. T here are n o f oll o w-u p visit re q uire me nts f or i nte nt s u bjects. 
I nter mitte nt Se nsi n g 
I nter mitte nt l oss of se nsi n g or fail ure t o detect i nte n de d i ntri nsic car diac 
si g nals (atrial or ve ntric ular) d uri n g n o n-refract or y peri o ds at pr o gra m me d 
se nsiti vit y setti n gs. 
Lea d A brasi o n  
U p o n ret ur ne d pr o d uct a nal ysis, lea ds are a nal yze d f or a brasi o n. K n o w n 
e xa m ples of lea d a brasi o n occ ur 1) pr o xi mal a brasi o ns ass ociate d wit h 
lea d- o n-lea d or lea d- o n-P G c o ntact i n t he p oc ket; 2) mi d -lea d i ns ulati o n 
da ma ge ca use d b y cla vicle fle x -fati g ue or cr us h, s ut ure or s ut ure slee ve, 
i ns ulati o n wear i n t he area of vei n i nserti o n a n d 3) distal re gi o n wear d ue 
t o lea d- o n-lea d (i ntracar diac), lea d- o n-heart val ve or lea d - o n-a n ot her 
a nat o m y c o ntact. 
Lea d I ns ulati o n Breac h  A disr u pti o n or brea k i n lea d i ns ulati o n o bser ve d vis uall y, electricall y or 
ra di o gra p hicall y. 
Lea d 
Mi grati o n/ Disl o d g me nt 
Ra di o gra p hic a n d electrical e vi de nce of electr o de dis place me nt fr o m t he 
ori gi nal i m pla nt site or electr o de dis place me nt t hat a d versel y affects 
paci n g a n d/ or lea d perf or ma nce. 
 Micr o
- disl o d ge me nt is n ot i ncl u de d. 
Lea d Re visi o n / 
Re p ositi o n 
 
A n i n vasi ve pr oce d ure t hat i n v ol ves ma ni p ulati o n of t he lea d(s) t o m o dif y 
t he a nat o mical i m pla nte d l ocati o n of t he i ntra-t h oracic p orti o n of t he lea d.  
L oss - of- Ca pt ure 
I nter mitte nt or c o m plete fail ure t o sti m ulate car diac sti m ulati o n (atrial or 
ve ntric ular) at pr o gra m me d o ut p ut deli vere d o utsi de of t he car diac 
refract or y peri o d. 

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Table 25-2: Definitions 
Term 
Definition 
Low Pacing Impedance Pacing impedance is considered abnormal based on lead model and 
measurement range of the device. 
Low Shock Impedance 
Shock impedance is considered abnormal based on lead model and 
measurement range of the device. 
Low shock impedance 
when attempting to 
deliver a shock 
Low shock impedance is considered abnormal based on lead model and 
measurement range of the device) when attempting to deliver a shock. 
Normal Battery 
Depletion 
For pulse generators , the condition when a) a device is returned with no 
associated complaint and the device has reached its elective replacement 
indicator(s) with implant time that meets or exceeds the nominal (50 
percentile) predicted longevity at default (labeled) settings, or b) the 
device is returned and the device has reached it elective replacement 
indicator(s) with implant time exceeding 75% of the expected longevity 
using the longevity calculation tool available at the time of product 
introduction, calculated using the device’s actual use conditions and 
settings. 
Other, Lead related 
Specific proprietary attributes of a lead, such as sensors which affect a 
leads ability to perform as designed and remain in service. 
Other, Pulse 
Generator/Header 
related 
Specific proprietary attributes of a pulse generator/header, which affect a 
device’s ability to perform as designed and remain in service. 
Oversensing 
The occurrence of cardiac or non-cardiac events being misinterpreted as 
cardiac depolarization, (e.g., T waves, multiple counting, skeletal muscle 
potentials and extra-cardiac electromagnetic interference (EMI)). 
Pacing Impedance 
Changes 
Pacing impedance changes are considered clinically significant if the value 
changes by more than a 2:1 ratio from the previous value. 
Pain 
A pain requiring oral medication is not considered serious. Pain requiring 
IV analgesics or results in prolonged hospitalization will be considered a 
complication. 
Pneumothorax 
Is a collection of air in the pleural space, causing the lung to collapse. It 
will be considered a serious adverse event if invasive intervention is 
needed for treatment. 
Pocket Revision 
Assuming that the subject continues to participate in the study, a pocket 
revision is an invasive procedure that involves modification in some 
manner to the extra-thoracic device pocket and/or lead(s) therein. There is 
no repositioning of the lead(s) tip in the heart. 

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Table 25-2: Definitions 
Term 
Definition 
Possible Malfunction 
May be considered if neither of the two listed below occurred. 
a) Malfunction with compromised therapy, PG – The condition 
when a device is found to have “malfunctioned” in a manner that 
compromised pacing or defibrillation therapy (including complete 
loss or partial degradation) while implanted and in service. 
Therapy is considered to have been compromised if no therapy is 
available or critical subject protective pacing or defibrillation 
therapy is not available 
b) Malfunction without compromised therapy, PG - The 
condition when a device is found to have “malfunctioned” in a 
manner that did not compromise pacing or defibrillation therapy 
while implanted and in service. Therapy is not compromised as 
long as critical patient protective pacing or defibrillation therapies 
are available. Changes in device setting that occur as intended by 
design (i.e. Power-on-reset (POR)) that do not result in loss of 
critical patient protective therapies but are reported as reasons for 
explant shall be classified as malfunctions without compromised 
therapy. 
Shock Impedance 
Changes 
Shock impedance changes are considered clinically significant if the value 
changes by more than a 2:1 ratio from the previous value. 
Significant r-wave 
amplitude decrease 
over 2 weeks or less 
A decrease in r-wave value is considered clinically significant if the value 
changes by more than a 2:1 ratio over the course of two (2) weeks or less. 
Source Data 
All information in original records of clinical findings, observations, or 
other activities in a clinical investigation, necessary for the reconstruction 
and evaluation of the clinical study (original records or certified copies). 
Source Document 
Printed, optical or electronic document containing source data. Examples: 
Hospital records, laboratory notes, device accountability records, 
radiographs, records kept at the investigation site, and at the laboratories 
involved in the clinical study. 
Suspected Lead 
Fracture 
May be manifested by abnormal device measurements (i.e. RV lead 
impedance, thresholds, inappropriate shocks) which may be caused as a 
result of conductor/lead fracture. Investigators are requested to complete a 
through lead assessment; confirm through visual, radiographic and 
electrical analysis, and are strongly recommended to return the lead to for 
analysis. 
Suspected Lead 
Abrasion 
May be manifested by abnormal device measurements (i.e. RV lead 
impedance, thresholds) which may be as a result of unknown lead abrasion 
type (which are not already defined above). Investigators are requested to 
complete a through lead assessment; and strongly recommended to return 
the lead to for analysis. 

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Table 25-2: Definitions 
Term 
Definition 
Twiddler’s Syndrome 
A complication of pacemaker treatment, in which repeated torsional 
pocket forces applied to the generator cause rotation and, by a ratchet 
mechanism, lead retraction. This may potentially result in lead 
displacement and loss of device function. 
Undersensing 
Complete or intermittent loss of sensing or failure to detect the intended 
intrinsic cardiac signals (atrial or ventricular) during non-refractory 
periods at programmed sensitivity. 
 
 
 
 
 
 
 
 

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26. Appendices 
APPENDIX A: DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 

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8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable and 
need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, other potential conflicts of interest, incentives for subjects and 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements for post-study 
access by study subjects to interventions identified as beneficial in the study or access to 
other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any 
serious adverse events. No change to the protocol may be made without consideration and 
approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. The responsibility for the protection of research subjects must 

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always rest with the physician or other health care professional and never the research 
subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this population 
or community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimise the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 

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sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorised representative. These individuals must not be included in 
a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead be 
performed with competent persons, and the research entails only minimal risk and minimal 
burden.  
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research should be obtained as soon as possible from the 
subject or a legally authorised representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their 
reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 

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placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extrem 
care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the patient 
or a legally authorised representative, may use an unproven intervention if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where 
possible, this intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, where appropriate, 
made publicly available. 
 
 
 

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Appendix B. Six-Minute Walk Test 
The six-minute walk test is a self-paced sub-maximal exercise test that has proven useful as 
an outcome measure for patients with congestive heart failure (CHF). Previous studies have 
shown that this test is well tolerated by individuals and is more closely related to the patient’s 
daily activities than maximal exercise testing.   
The walking test should be conducted in an enclosed corridor on a course approximately 100 
feet (30.5 meters) long. The length should be marked in either feet or meters to allow easy 
measurement of the distance walked. The corridor should not be heavily transited and should 
be free of obstacles and distractions. Chairs should be placed at either end of the course so 
that patients may rest when needed.  
Instructions 
The patient is to take nothing by mouth except for clear liquids for at least two hours prior to 
the test. Prescribed medications should be taken as usual. Patients should be advised not to 
smoke for at least two hours prior to exercise. Patients should also be advised to wear 
suitable footwear. 
Patients are instructed to walk the marked course from end to end at their own pace, covering 
as much distance as possible in six minutes. Patients may slow down or stop to rest if 
necessary, but should be instructed to resume walking when they feel they are able to do so. 
The aim is that at the end of the test, the patient believes that they could not have walked any 
further in the six minutes.   
The following instructions are to be read verbatim to the patient: 
“The purpose of this test is to determine how far you can walk in six minutes. You will 
start here and go to the chair at the end of the hall, turn around, and walk back. After 
arriving back at the starting point, you will go back and forth again. Go back and forth 
as many times as you can in the six-minute period. If necessary, stop and rest and stay 
there until you can start again. However, the most important thing about the test is that 
you cover as much distance as possible during the six-minute period.”   
“I will let you know when each minute has passed. When I say ‘STOP’ after 6 minutes, 
please stand right where you are.”   

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“Do you have any questions about the test?” 
“Please explain to me what you are going to do.” 
“Are you ready?” 
“Start when I say ‘GO’.” 
 
Walking Protocol 
The walk test should be performed after completing the physical assessment of the patient. 
Patient safety is the highest priority, and the walk test should not be initiated if the physician, 
coordinator or patient have concerns regarding the patient’s ability to perform the test. If the 
patient begins the walk test, and concerns arise regarding their ability to continue, stop the 
test. 
1. Stand the patient at the beginning of the course.   
2. Record the patient’s heart rate. 
3. Simultaneously say “GO” and start a stop watch. Observe the patient for the six minute 
period while recording the successful completion of each length of the course. In order to 
standardize the test, encouragement is not offered during the walk. Do not otherwise 
speak to the patient except to answer questions he or she poses. Stop the test if the patient 
reports severe shortness of breath, muscular pain, dizziness, or anginal symptoms.   
4. At the end of the six minute interval, tell the patient to “STOP” and immediately measure 
the patient’s standing pulse rate.   
5. Record the distance traveled to the nearest foot or meter. If the patient ceases 
participation prior to the end of the six minute interval, record the distance covered (to 
the nearest foot or meter) and the patient’s heart rate at the time he or she stops walking.